RCSIsmj 2024

Inside: A shot of renewal: the potential of stem cells in transforming the arthritis landscape

RCSI

Tides of change

Royal College of Surgeons in Ireland

Student

Medical Journal smj

Acknowledgements

Thank you to the RCSI alumni for their continued support of current RCSI students – providing career advice, acting as mentors, facilitating clinical electives, and supporting the publication of the RCSIsmj since its inception in 2008. As today’s generation of students and tomorrow’s generation of alumni, we are very grateful for your ongoing support.

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

We would also like to thank the Deputy Vice Chancellor for Academic Affairs, Prof. Hannah McGee, for her sponsorship, and Margaret McCarthy in the DVCAA office for her unwavering endorsement and assistance.

A sincere thank you to the team at Think Media for seamlessly publishing the RCSIsmj to such a high standard year after year. We are also thankful this year for our new website – www.rcsismj.com – designed by Think Media with the same consistent care and consideration that they have shown us since our inception.

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

Cover art: We are honoured to feature Michelene Huggard’s Between Two Lands on our cover this year, which was shortlisted in the Royal College of Physicians Ireland’s Art Competition on Climate and Health. In her own words: “Between Two Lands seeks to portray the reality of life for arriving migrants; the endless queues for healthcare and shelter, the unsettling skies. Homeless and far from home, they are neither there nor here; in every sense, Between Two Lands”. Between Two Lands perfectly represents this edition’s theme of ‘Tides of change’. Amid Ireland’s existing housing and healthcare crisis, the rapid influx of migrants has amplified the urgent need for effective solutions. Michelene is a visual artist living and working in Dublin. For more on the RCPI Art Competition, go to: https://www.rcpi.ie/View-the-winning-entries-and-shortlisted-artwork-in-RCPIs-Art-Competition-Climate-and-Health

This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for non-commercial purposes only, and only so long as attribution is given to the creator.

CC BY-NC 4.0

RCSIsmj. Dublin: RCSI University of Medicine and Health Sciences. Vol 17, 2023-24. © RCSI University of Medicine and Health Sciences

RCSIsmj contents

Royal College of Surgeons in Ireland

Student Medical Journal

Executive Committee

Director Charlotte Fager

Editor-in-Chief Stephen Clare

Senior Editor Victoria Srbely

Peer Review Director Saro Aprikian

Assistant Peer

Review Director Jawad Al-Kassmy

Executive Secretary Nicholas Clausen

Assistant Secretary Zahra Rashid

Webmaster Cillian Scott

Director of Education Ruby Sannoufi

Education Officer Zahra Rashid

Education Officer Sara Ladak

Director of Public Relations

Delfina Mancebo Guinea Arquez

PR Officer Waheebah Ahmed

Peer Reviewers

Katelyn Gallo Saumeh Saeedi

Jaifar Alomairi Harpriya Khela

Lauren Li Orla Keenan

Anjali Murally Armaan Nazir

Asma Maqsood Caoimhe Healy

Mohammad Alabdulrahman

Farah Elnakoury Grant Schutte

Kurdo Araz Lok Man Li

Nariko Kuwahara Michael Palayew

Renitha Reddi Bathuni Samantha Bloom

Sarah Chitnis Rama Alkhaldi

Stefan Radevic

Peer Reviewer of the Year Fatimah Rajabally

Senior Staff Writer

Leon Gilligan-Steinberg

Staff Writers

Jennifer Engler Sadie Badrie

Sidonie Chard Claire Reimer

India Dhillon Noshin Shermili

Dhruv Jivan Arianna Gholami

an innovative xenograft model for inoculation of myeloma cell

Describing miRNA-target networks of miR22-3p and miR145-5p involved in neuroinflammation

Impact of nutritional deficiencies following bariatric surgery on maternal and neonatal outcomes

Pathophysiological link of Alzheimer’s disease and type 2 diabetes mellitus: novel therapeutic applications of anti-diabetic drugs

Hashimoto’s encephalopathy: a review of cases

Horse tranquiliser: the cure for depression?

A shot of renewal: the potential of stem cells in transforming the arthritis landscape

Exogenous hormone therapy for adults who are transgender: considerations for the cardiovascular system

Home on the range: approaches to rural medicine exposure in medical education

Too hot to handle? An investigation of the efficacy of heat mitigation strategies in vulnerable populations

Application of artificial intelligence for early detection of breast cancer

Striding toward change: addressing the burden of clubfoot in lowand middle-income countries

This is your brain on computers: a glimpse into the exciting world of brain–machine interfaces

Creatine and cognition – enhancing the brain through creatine supplementation

Advances in targeted therapies and immunotherapy for glioblastoma: a glimpse into precise treatment strategies

Telemental health: an effective solution for increasing access to rural mental healthcare

Acute ischaemic stroke management with thrombolysis in paediatric patients: a comprehensive review of the literature

The Malthouse, 537 NCR, Dublin 1. T: 01-856 1166 F: 01-856 1169 www.thinkmedia.ie

Design: Rebecca Bohan, Tony Byrne, and Meliosa Fitzgibbon

Editorial: Ann-Marie Hardiman, Paul O’Grady and Colm Quinn

RCSIsmj editorial and director’s welcome

Tides of change

Over the past year, medicine and society have been faced with impending change, both wonderful and dreadful in scope. There is a palpable energy of hope and promise in the air as technologies such as artificial intelligence advance quickly and seem poised to transform healthcare and humanity.

At the same time, fear exists about the ramifications of such advancements. Behind the veil of any such progress lie questions of access: Who? When? Where?

Many global populations are faced with worsening systemic inequalities. Unequal service provision in a rapidly changing landscape may only serve to worsen these divides. As we advance medical science into previously theoretical spaces, we are increasingly faced with very real threats: global warming, mass migration, poverty, and war. We find ourselves looking toward these ever taller waves of change, hopeful that they may provide solutions to entrenched problems, and guarded about the ramifications for those who may be swept away. This edition of the RCSIsmj is about these tides of change. Among the articles published this year you will find incredible descriptions of new technologies being used in radical ways: from the application of artificial intelligence in treating breast cancer, to brain–machine interfaces and wild advancements in neuroscience, immunotherapy, and stem cell research. We also feature an interview with Clare Harney, Director of Digital Development at HCI, about the burgeoning role of digital technology and artificial intelligence in healthcare.

Director’s welcome

Greetings to all of our readers across the globe, and welcome to the 17th edition of the ever-evolving RCSIsmj! Since its inception 16 years ago, the RCSIsmj has prided itself on both tradition and growth with each passing of the torch. Staff are encouraged to stay involved year to year to build on their skills and take on new responsibilities, which generates a collective wisdom that allows the RCSIsmj to evolve. This year’s talented staff of student writers, peer reviewers, editors, and administrative staff were bursting with creative ideas from the start, which resulted in an especially collaborative and interdisciplinary year. We collaborated with the Cardiology Society for journal club, and held a powerful narrative medicine workshop with the Gold Humanism Honor Society.

One of our staff writers, Sadie Badrie, re-launched the RCSIsmj blog. This year’s cover is a piece by Michelene Huggard that was featured in the Climate and Health Exhibition at the Royal College of Physicians Ireland.

Many previous discoveries have been repurposed in innovative ways, such as telemedicine for mental health provision, ketamine as a promising treatment for depression, or creatine as a cognitive supplement.

Alongside these articles you will read pieces centred on the growing problems of our increasingly globalised world – the retention of general practitioners in rural settings, the effect of increasingly brutal heatwaves on our most vulnerable populations, the safety and efficacy of hormone therapy for adults who are transgender, and the accessibility of surgical intervention in low- and middle-income countries. As our world is buffeted onward by waves of promise, many people worldwide remain isolated due to geographical or socioeconomic factors. The devastating effects of the war in Ukraine continue to be felt by its citizens, and we include a touching reflective piece by one of the many RCSI students who are personally affected by this ongoing humanitarian crisis.

Stephen Clare Editor-in-Chief, RCSIsmj 2023-2024

Much as a ship requires ballast, I hope that the balanced and varied perspectives in this edition help you find stability in our changing world. It has been my privilege to compile work by such talented writers and researchers, and I hope you enjoy reading them as much as I did.

Our wonderful team of publishers at Think Media worked with us throughout the year to create a stunning new website that reflects the calibre of work that we publish, and increases accessibility to the journal across the student body. A massive thank you to our biggest advocates in the DVCAA office – Deputy Vice Chancellor of Academic Affairs Prof. Hannah McGee, and Margaret McCarthy – as well as the incredible faculty at RCSI that assist us throughout the year, especially Prof. David Smith and his Health Care Ethics team. And most of all, a sincere thank you to every student who contributed to this publication and the collective wisdom of the RCSIsmj – your dedication and enthusiasm are the pillars that uphold our high standards.

Charlotte Fager Director, RCSIsmj 2023-2024

RCSIsmj prize

The ethics of social media use in healthcare Ethics Challenge 2024/2025

Alan is three years old and suffers from a terminal congenital condition called juvenile Tay-Sachs disease, an autosomal recessive neurodegenerative disease caused by a mutation in gene HexA. He has had numerous hospital admissions for seizures that started at six months of age, and he is developmentally delayed. There is no known treatment for Tay-Sachs disease other than supportive care, including pain relief and seizure management. The medical team explains to his parents John and Mary that life expectancy is short, and that usually a child will die before five years of age. However, the medical team says that they can keep him comfortable and pain free as long as he lives. His parents have been researching on social media sites and have contacted Dr Murphy and his team in UChan Medical School in Massachusetts, who claim to have identified an experimental genetic therapy, which they believe may extend Alan’s life. Clinical trials are ongoing.

This is the 16th instalment of the RCSIsmj Ethics Challenge. The editorial staff would like to congratulate Riya Sharma on her winning essay in the 2023/2024 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 2025 print edition of the RCSIsmj. Please note that the deadline for submission of essays will be available on our website – www.rcsismj.com – and will be separate from the general submission deadline for the 2025 edition of the RCSIsmj

John and Mary are Alan’s guardians and decision-makers for his medical treatment. They want to take him out of the care of the hospital and bring him to Dr Murphy in Boston. They are prepared to fund the costs involved with the transfer and any additional treatments.

Questions to address:

1. Which principles or concepts of medical ethics are relevant in this case? Explain.

2. What legal aspects are relevant to this case?

3. The Minister for Health and the Irish Medical Council have tasked you with devising a strategy to counteract the threat of easily accessible medical misinformation on social media sites – what ethical and legal components will be important to consider?

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 of the RCSIsmj.

RCSIsmj ethics challenge

ETHICS CHALLENGE WINNER 2023/2024

To opt in or opt out: that is the question

“Under no circumstance I will use his body to advance my knowledge or my fame, unless in his last moment, he or his widow give me his corpse, so that his death may help me understand how to soothe another’s pain.”

The Hippocratic Oath1

Every day, 17 patients die awaiting an organ transplant in the United States.2 As the demand for organ transplants increases globally, opt-out or presumed consent donation policies have been adopted or considered in many countries that are seeking to expand their organ supply. In such systems, the State presumes that lack of explicit refusal constitutes consent for the transplant of organs and tissues post mortem. Meanwhile, the opt-in organ donation system aims to respect individual autonomy by requiring explicit consent prior to donation.3 Some countries, including the United Kingdom, Spain, Austria, Uruguay, and Chile, have already adopted opt-out organ

donation policies, while other nations such as Switzerland, Australia, the United States, Romania and Germany are currently considering transitioning to this type of system.4

An opt-out donation system was widely regarded as a magic bullet for the organ donation issue.5 However, is opt-out truly a panacea or does it risk overstepping the bodily autonomy of the deceased and their families? Conversely, does the opt-in model go far enough in addressing the shortage of life-saving organs or does it lead to needless deaths? This analysis will examine the complex ethical tensions between individual choice, physician duties, and public health through the lens of medical ethics principles.

Is presumed consent ethical?

Organ donation is an altruistic act: the voluntary giving of one’s organs to aid unknown others without expectation of reward. When an individual consents to donate their organs post mortem, their

Riya Sharma RCSI medical student

RCSIsmj ethics challenge

decision is driven by empathy and concern for those suffering from organ failure. The donor usually derives no material benefit.6

Fundamentally, it can be posited that an opt-out system constitutes a victory for utilitarianism. Utilitarianism holds that the morally right action is that which produces the greatest good for the greatest number of individuals. Opt-out policies aim to maximise the availability of organs, resulting in a greater good for organ recipients and the broader community due to health needs being met.7

However, this may override patient autonomy, as it is usually unclear that presumed consent is equivalent to an informed decision on the part of the donor. Consider a scenario: in a country with an opt-out framework, an X number of individuals are inherently opposed to donating their organs posthumously but, owing to lack of public education, have their organs procured. How large does X have to be in order for a moral wrong to have occurred? Accounting for n patient fatalities during surgery, does the survival of patients (X – n) make it a moral right?

When an individual consents to donate their organs post mortem, their decision is driven by empathy and concern for those suffering from organ failure.

I argue that it would not. Individuals vary greatly as to whether they will allow intrusion, with reasons ranging from the social, cultural, and religious, to the economic or personal.8 Everyone has a right to protection from bodily violation after death and this requires explicit consent.9 McEwen even argues that non-consensual organ procurement would detract from the altruistic nature of organ donation and undermine the dignity of the dead.10 Truly informed consent requires proactive outreach about the rights and procedures involved in organ donation, not just passive opt-out forms. Otherwise, opt-out systems may inadvertently affect disadvantaged or vulnerable groups that have no next of kin or are unable to properly opt out.11

While thoughtfully crafted opt-out organ donation policies could strive to uphold autonomy through straightforward and widely disseminated opt-out procedures, achieving truly informed consent would still prove an arduous and long-term endeavour. Without it, opt-out policies would never truly be ethical. The scope of such policies, such as to which organs and tissues they apply,12 and whether family members are still consulted and asked for consent before organ procurement proceeds, are also crucial considerations. For example, Austria and Singapore have ‘hard’ opt-out policies, in which there is no allowance for family veto of donation if the

deceased did not formally opt out while alive.13 An often overlooked implication of such presumed consent policies is the potential to psychologically harm grieving families who feel donation wrongly occurred without proper consent. Finally, broader mistrust of healthcare institutions caused by an opt-out framework could discourage people from seeking care and undermine public health.8

Applying medical ethics principles to opt-out systems

While respecting autonomy is central when evaluating opt-out organ donation policies, employing a comprehensive ethical framework requires examining such systems through medical ethics pillars such as beneficence, nonmaleficence, and justice.

The principle of beneficence means that healthcare providers have a duty to act in the best interests of their patients and promote their welfare. Opt-out policies intend to increase overall beneficence by providing more lifesaving organs to those in need. Moreover, opt-out countries have higher rates of organ donation compared to opt-in countries.14 However, the reasons behind such statistics are multifactorial. For example, Spain has the highest rates of organ donation in the world. The Director of the National Transplant Organization in Spain does not attribute such statistics to opt-out policies, but rather to improved organ transplant infrastructure due to the placement of transplant co-ordinators in each hospital, as well as a high regard for the wishes of the family.15 Moreover, some studies have shown that there is limited evidence that an opt-out framework is responsible for increased donation rates.16-18 Therefore, it may be prudent to instead promote the development of complementary policies such as increasing awareness and transplant infrastructure, or alternative approaches such as bioprinted organs, to fulfil both the necessity and ethics criteria.19

The Hippocratic Oath’s injunction to “first, do no harm” speaks to the physician’s duty of nonmaleficence, which is to avoid directly inflicting harm or injury on patients. In this context, increasing the supply of organs is critical to avoid needless deaths. However, changing guidelines for the declaration of death for donors20 and living organ donation still present complex ethical situations. For example, with living organ donation, although the donor voluntarily undergoes an operation to remove an organ for transplantation, the surgery still carries a risk of medical harm to the patient that must be ethically weighed. There is a 5-10% risk for surgical complications and a 0.5-1% risk of death, with nearly all donors experiencing varying degrees of pain and disability.21 This raises the question of whether encouraging living organ donation adheres to the principle of nonmaleficence, given the potential for avoidable harm to a healthy donor. Moreover, there have also been concerns that opt-out policies

RCSIsmj ethics challenge

could incentivise physicians to withdraw care prematurely to hasten organ procurement. This risks causing harm by taking life-sustaining measures away from patients prematurely.22

The Hippocratic Oath’s injunction to “first, do no harm” speaks to the physician’s duty of nonmaleficence, which is to avoid directly inflicting harm or injury on patients.

Lastly, justice in organ donation often focuses on fairness in allocation and equality of access. Some scholars contend that presumed consent policies are ethically viable because they aim to increase the overall supply of donated organs available for transplantation. This would reduce the need for physicians to make difficult decisions about which specific patients on long organ transplant waiting lists receive the scarce donated organs, thus reducing potential discrimination.23 However, opt-out policies may exacerbate injustice for certain groups. For example, Black, Asian, and Minority Ethnic (BAME) communities in the UK are more likely to opt out for cultural or religious reasons, with 74.3% of opt-outs in the UK being from BAME groups.24 Yet these groups are also more likely to experience barriers in accessing opt-out systems and primary care in general, given factors like language, lower socioeconomic status, and rural isolation.25 Due to such health inequities, incomplete consent may be obtained from BAME demographics, which could result in their donation preferences being violated despite higher reluctance. Moreover, since ethnicity is critical for organ matching, opt-out alone may not increase donations usable by minority communities.26 Thus, rather than promoting justice, presumed consent may maintain disparities.

The role of medical professionals

Physicians have a life-long commitment to public health and service. Due to their understanding of the arduous wait times for transplants and the suffering of patients, medical professionals could be strong proponents of organ donation. Trusted physicians advocating for donation could dispel harmful myths and increase public willingness to donate.

Encouraging organ donors aligns with the duties of a doctor; however, their unique position does not necessitate a moral obligation. Beyond the nonmaleficence concerns, I trust there is an ethical distinction between physicians encouraging organ donation to a known recipient versus to an anonymous stranger, alongside whether or not they were the initiator. For example, living organ donation to a loved one is often driven by personal bonds and emotions. Thus, it may offer psychological benefits for the donor,

making risks more ethically justifiable and gentle encouragement to be considered in a different light. On the other hand, competent and informed adults have the autonomous right to take on reasonable personal risks, including donating a kidney to a stranger of their own volition. If, after adequate disclosure, an individual independently decides to donate to a stranger, it would be unethical for a physician to obstruct this choice. However, it is problematic for a physician to actively initiate donation, or push someone to donate to a stranger, as opposed to simply providing neutral information when asked and perhaps gently reiterating the extraordinary altruism in the act of organ donation. Therefore, while physicians may provide information, the decision may be best left to patients’ own moral values. Ultimately, the debate over physicians ethically encouraging organ donation to strangers raises broader questions about the appropriate societal limits on promoting bodily donation to benefit others and whether we, as citizens of a society, are ethically obliged to increase the number of available organs for transplants. It has been argued that since one is commended for going above and beyond in the act of organ donation, it is not a moral obligation but rather a demonstration of extraordinary moral good.27 Similarly, for physicians surrounded by a complex interplay of ethical dilemmas every day, encouraging organ donation should not be regarded as a moral obligation, but rather as beneficial voluntary advocacy that aligns with their duty to save lives.

Justice in organ donation often focuses on fairness in allocation and equality of access.

The

way forward

Considering a purely moral standpoint, this paper finds it very likely that present-day opt-out systems are unethical. As a future medical professional, however, I am sympathetic towards opt-out policies. Expanding the pool of donated organs is a widely shared goal; the salient question is how to ethically and effectively achieve higher donation rates. In a pluralistic society, respecting the array of perspectives on organ donation requires policies based on voluntary informed choice, not presumed agreement. The key is overcoming defaults that nudge passive agreement through proactive, transparent community engagement. Diligent, thorough, and responsible opt-out design, paired with respect for persons during registration and retrieval, could potentially uphold ethical standards. However, any presumed consent model demands extreme care to avoid slipping into coercion and erosion of autonomy, regardless of intent. The bar for ethical opt-out is high; whether it can be reached through meticulous safeguards remains debated.

ethics challenge

References

1. Hippocrates’ Oath. Available from: https://www.bu.edu/arion/files/2010/03/Arenas_05Feb2010_Layout-3. pdf.

2. Organ Procurement and Transplantation Network. The Organ Procurement and Transplantation Network Data. [Internet]. [Published online 2023; Accessed January 17, 2024.] Available from: https://optn.transplant.hrsa.gov

3. Etheredge HR. Assessing global organ donation policies: opt-in vs opt-out. Risk Manag Healthc Policy. 2021;14:1985-98.

4. Molina-Pérez A, Rodríguez-Arias D, Delgado J. Opt-out policies capacity to increase organ donors is limited. Transplantation. 2021. [Internet.] Available from: https://www.medrxiv.org/content/10.1101/2021.08.27.21262033v3.f ull

5. Rieu R. The potential impact of an opt-out system for organ donation in the UK. J Med Ethics. 2010;36(9):534-8.

6. Cutler JA. Donation benefit to organ donor families: a current debate. Proc (Bayl Univ Med Cent). 2002;15(2):133-4.

7. Morris J, Holt J. Applying utilitarianism to the presumed consent system for organ donation to consider the moral pros and cons. Br J Nurs. 2021;30(19):1127-31.

8. Miller J, Currie S, O’Carroll RE. ‘If I donate my organs it’s a gift, if you take them it’s theft’: a qualitative study of planned donor decisions under opt-out legislation. BMC Public Health. 2019;19(1):1463.

9. Qurashi GM. Opt-out paradigms for deceased organ donation are ethically incoherent. J Med Ethics. 2023;49(12):854-9.

10. McEwen PM. Valid informed consent: the key to increasing supply of organs for transplantation? Crit Care Resusc. 2005;7(3):246-9.

11. Irish Department of Health. Public Consultation Introduction of an Opt-Out System of Consent for Organ Donation. 2020. [Internet.]

[Accessed January 19, 2023.] Available from: https://www.gov.ie/en/press-release/ada8aa-public-consultation-introd uction-of-an-opt-out-system-of-consent-for/

12. Williams NJ, O’Donovan L, Wilkinson S. Presumed dissent? Opt-out organ donation and the exclusion of organs and tissues. Med Law Rev. 2022;30(2):268-98.

13. Scottish Government. Opt out organ donation: a rapid evidence review. 2018. [Internet.] Available from: https://www.gov.scot/binaries/content/documents/govscot/publication s/research-and-analysis/2018/07/opt-out-organ-donation-rapid-evidenc e-review/documents/00538437-pdf/00538437-pdf/govscot%3Adocum ent/00538437.pdf

14. Bilgel F. The impact of presumed consent laws and institutions on deceased organ donation. Eur J Health Econ. 2012;13(1):29-38.

15. Fabre J, Murphy P, Matesanz R. Presumed consent: a distraction in the quest for increasing rates of organ donation. BMJ. 2010;341:c4973.

16. Matesanz R, Domínguez-Gil B. Opt-out legislations: the mysterious viability of the false. Kidney Int. 2019;95(6):1301-3.

17. Arshad A, Anderson B, Sharif A. Comparison of organ donation and transplantation rates between opt-out and opt-in systems. Kidney Int. 2019;95(6):1453-60.

18. Rodríguez-Arias D, Wright L, Paredes D. Success factors and ethical challenges of the Spanish model of organ donation. Lancet. 2010;376(9746):1109-12.

19. Platt JL, Cascalho M. New and old technologies for organ replacement. Curr Opin Organ Transplant. 2013;18(2):179-85.

20. Doran SE, Vukov JM. Organ donation and declaration of death: combined neurologic and cardiopulmonary standards. Linacre Q. 2019;86(4):285-96.

21. Eghtesad B, Jain AB, Fung JJ. Living donor liver transplantation: ethics and safety. Transplant Proc. 2003;35(1):51-2.

22. Baginski W. Hastening death: dying, dignity and the organ shortage gap. Am J Law Med. 2009;35(4):562-84.

23. Marquardt R. Presumed consent for organ donation: principlism opts out. Bioeth Faith Pract. 2017;3(1):11-22.

24. NHS (UK). Organ Donation and Transplantation Data for Black, Asian and Minority Ethnic (BAME) Communities. 2020. [Internet.] Available from: https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/19753/b ame-report-201920.pdf

25. Ajayi (Sotubo) O. A perspective on health inequalities in BAME communities and how to improve access to primary care. Future Healthc J. 2021;8(1):36-9.

26. Pradeep A, Augustine T, Randhawa G, Ormandy P. Examining the role of the health belief model framework in achieving diversity and equity in organ donation among South Asians in the United Kingdom. Transpl Int. 2023;36:11243.

27. Zimmerman A. Public policy through the lens of necessity. Voices Bioeth. [Internet.] [Published online January 29, 2021]. Available from: https://journals.library.columbia.edu/index.php/bioethics/article/view/ 7859#:~:text=Generally%2C%20to%20use%20the%20defense,would %20come%20from%20the%20act

Leading in digital health

Senior Staff Writer LEON GILLIGAN-STEINBERG spoke to Clare Harney, Director of Digital Development at HCI, about the burgeoning role of digital technology and AI in the field of healthcare.

Thank you so much for speaking with us Ms Harney, we're all very curious about your work. I understand you work as the Director of Digital Development at HCI, and developed RCSI’s ‘Leading Digital Health Transformation’ Professional Diploma. Would you mind explaining your role and what digital health is?

Within RCSI, the Graduate School of Healthcare Management decided to launch a Professional Postgrad Diploma in leading digital health transformation. The goal is to teach healthcare professionals

how to lead on the application of digital health within healthcare and within their own contexts of work. It’s a blend of leadership, digital health technologies, and understanding digital health and where in healthcare technology could be leveraged to help. It’s a nine-month programme aimed to enable people in full-time jobs to continue working. It’s mainly asynchronous learning during which people can access the content at a time that suits them. It’s aimed to be global in reach and the theory behind it is not solely focused on the Irish health system.

RCSIsmj interview

Your biography mentions an emphasis on the elements of regulatory science and quality assurance within digital health. Could you elaborate on the concept of regulatory science within digital health?

A priority for me is that the regulations keep up with the advancement of digital health technology. Regarding my own background, after working in hospitals for a number of years, I moved into the Health Information and Quality Authority, or HIQA, the regulator for healthcare in Ireland. I was responsible for working on health information standards and governance around how we manage health information in our health system.

While a lot of people shy away from the regulations as just rules that we have to follow, my goal with them is always to make them as proactive as possible. For that reason, I’m still involved in the development of standards at the European level now with CEN [the European Committee for Standardization] and ISO [the International Organization for Standardization] standards. My focus is on ensuring that they are actually applicable, that we’re not just developing standards for the sake of having a standard, but rather ensuring that they make sense and avoid impeding innovation.

What is it that got you interested in working in health information?

How we deliver healthcare has largely remained the same for the past hundred years. We’ve advanced in those areas and our treatments have advanced, but how we treat people hasn’t really changed. That is something that can improve with technology, and the rate that we adopt technology in healthcare is particularly slow. There are opportunities to accelerate that. We can learn from the pandemic and how technology took a front seat and was safely adopted. One of my mantras is ‘there’s got to be a better way’. We’re faced with issues in healthcare that we’ve known for a long time. We have an ageing population and fewer young people coming into the workforce to support them. It’s disheartening to see that these problems are only getting worse, such as overpacked emergency departments, and waiting lists getting longer and longer. We can leverage technology to help with a lot of those things and we’re not really doing that effectively yet. Budgets are not appropriately diverted to enable technology, which should increase in value over time as opposed to everything else we purchase in healthcare.

Is there anything on the horizon that you think deserves to be implemented safely soon?

I think in healthcare there’s a lot of administrative functions that must happen. If you take infection prevention and control in healthcare, for

example, during the pandemic the instances of infection within hospitals increased dramatically. The reporting requirements increased alongside that, with [the implementation of] dedicated infection prevention and control personnel in hospitals. An eight-hour shift often turned into 16 hours by the time [the provider] got their paperwork done because they still had to see patients. A simple way to leverage technology around that is to have the paperwork, the administrative side of it, handled by a virtual robot, which is all rules based. If a certain type of infection is acquired in the hospital, all of that information is already in either paper charts or electronic systems. It can then be taken by a virtual robot and reported appropriately by filling out the correct forms and submitting them to the relevant authorities. This is an example of robotic process automation (RPA), and the return on investment is usually measured in days and weeks rather than the longer term, making a strong business case for adoption in many areas.

That’s an example of an administrative function that we can take completely away from the healthcare professional. It’s not what they signed up to do in the first place. I don’t think anyone ever started studying healthcare in any of the clinical practices thinking, ‘I can’t wait to spend half my day filling out forms’. That’s something we can safely take away from our healthcare professionals and free up their time to actually deliver care. That has a knock-on effect on things like patient experience, patient outcomes, and waiting lists.

You mentioned the virtual robot. I assume that it utilises artificial intelligence (AI) and some AI systems?

You can have very simple bots where they’re taking a very manual function like filling out a form, and taking data from one system and putting it in the format of a form, transcribing it and filling it out. There’s not a whole lot of AI involved in that. But we are moving now to a point where bots can assist with decisions. This is not about clinical decision-making. When clinical decision-making is involved it is considered medical device territory rather than just software. Using AI to make administrative decisions around waiting lists, booking of appointments, making appointments available: we can start to do that within a rules-based approach so that it’s safe.

We always keep what we call the human in the loop. Essentially, there is a human who is reviewing or taking any exceptions. The virtual robot won’t carry out a task if all of the rules are not met. That’s a safety mechanism so that if there are any exceptions to the rule, it’s immediately flagged to the human in the loop. This way, you have a human only dealing with perhaps 1% instead of 100% of the admin burden. And then when you want to go further into AI, you can start to deal with larger datasets that we’re now having access to as we

move more electronic in healthcare. The robot itself streamlines a lot of the decisions and flags only the important things that need to be looked at. It is working 24/7. It doesn’t need coffee breaks. And these are what I would call the low-hanging fruit in healthcare in that they’re very safe implementations that are very cost efficient. They’re not taking people’s jobs. What they’re doing is freeing up our clinical professionals to actually do the jobs that they’re trained to do.

This new technology has been spreading for a while, but I think it’s only really entered the public sphere quite recently, in this capacity at least. Our readers might be familiar with ChatGPT and other AI assistive technologies. Could you just give a brief, very simple explanation of these services?

Generative AI would be based on large language models [LLMs], which are models whereby giant datasets are created, sometimes by commercial bodies, sometimes by governments. These LLMs are the data that the AI uses to run its algorithm and come up with an answer to a question. They have huge potential in healthcare but there are also safety risks and ethical risks around that as well. In healthcare, what we have to be really careful about is how these LLMs were developed, and the data that the AI is using to find the answers. For example, if an LLM was created by a right-wing-leaning government, it will be biased with a lot of the sentiments and cultures of that [government]. Similarly, a commercial body that develops an LLM may inadvertently have included some of their thoughts around which products are better than others. It’s really important that you understand the integrity of your data and the provenance of it. Where did it originate? For some purchased data, the provenance cannot be shown and it can be heavily biased and unethical, or unsafe to use in healthcare.

A good example of where that does work quite effectively in healthcare (because it is using generative AI, but it’s also using the human in the loop) is the type of software that you can run across digital images, diagnostic images, and it can carry out the first read on an X-ray or an MRI. It can do that a lot more quickly than a human can. If you think of a PET CT scan for example, it’s thousands and thousands of images overlaid by the machine and the AI algorithm can run across that very quickly, much more quickly than a human can. It learns how to spot a tumour, or how to spot an aorta that’s larger than it should be, or an aneurysm. What it’s doing is reading thousands and thousands of examples of that type of diagnosis so that it can learn when it looks at a new one that it has seen this before and link it to a diagnosis.

However, we still have humans read those, because [the algorithms] are not infallible. Again, bias can leak into it, but what [AI] is

interestingly doing is helping us to catch the human bias on reading of diagnostic images. It will find the obvious thing, but it will also find the things that are not so obvious, and that is already implemented across a number of healthcare systems to help us with reading large volumes of diagnostic images, and it’s helping to clear the backlog. In a lot of cases where a cursory diagnosis has been made, treatment has already been carried out, but it is allowing us to look back over those using an algorithm and an LLM.

Is there anything that you utilise to make it easier to find the provenance of data?

What I’m seeing now is that sometimes in certain cases governments are starting to build their own LLMs that will be tightly locked down and regulated by their own authorities. The UK is a good example. The NHS is building its own LLM. The issue around that is cost up into the billions, with a return on investment that will take decades. Once developed, the NHS can leverage it for healthcare and social care applications as long as it remains in tight control of where the data comes from.

Are there any other mechanisms that are utilised to remove bias from an AI model?

Interestingly, there are AI algorithms that can be run across datasets to detect bias, but again I think when it comes to something like healthcare, that’s not good enough. We must trust the provenance of data. Microsoft has built an LLM that can show huge parts of its provenance. Another good example of data that can add to the value of an LLM is through healthcare registries. They contain tightly controlled and validated data, across decades in some cases, for specific conditions, and are quite often linked across multiple countries as well. We just don’t see them as LLMs yet. We need to get better at meta-tagging and clinical coding, and ensuring that we’re using health information standards across these databases. That way, other data that may not be initially thought of, can be used for AI. There’s opportunity to improve the data that we have in things like clinical registries. And there’s a huge programme planned in Ireland to create what you would call a ‘registry of registries’. Most registries are populated by consent. Currently though, these registries do not communicate. We have no way of knowing that that person exists across multiple registries, such as an individual in a diabetes and a cystic fibrosis registry, and the real value is in understanding the entire person as opposed to their condition alone.

I think cystic fibrosis is a really good example, because people are living thankfully much longer than they could have expected to before with modulators. And we’re seeing a lot of firsts with that

RCSIsmj interview

cohort of people. Recently I was speaking to a lady who is very happy for her data to be shared because she is the first person in the world with cystic fibrosis to go through menopause. We have no understanding on the planet of how a person with cystic fibrosis will react to hormone replacement therapy, for example. She has full understanding that everything that happens to her, and the medications that she takes going forward, have global value in terms of the understanding of how to treat [ageing people with cystic fibrosis], and how to expect people will react to certain types of medication and certain life stages that they go through. Thus, she really wants her data to be shared for those reasons, so that other people can learn. We start to lose the fear around these things. That’s a real example where combining data that exists in siloed databases at the moment is really important, and combining that data in a meaningful way where we can actually de-identify people but still track them across multiple databases is the building of an LLM. We don’t call it that, but that’s what it is. And we could then start to really extrapolate some incredible insights into treating people going forward. We’re a long way away from that though, sure.

Within regulatory sciences, part of your job involves exploring what risks there may be with technologies that get implemented. You have touched on bias, but what are some other main risks that need to be considered as AI assistive technology integrates into medical care?

One of the key aspects is that of trust. We must be aware of bias and take into account data that we don’t know the provenance of. Additionally, we risk an over-trust in the algorithms. The human in the loop will always be hugely important. We will not replace clinical professionals with AI. We will be able to take away some of the mundane tasks and perhaps provide first reads or even directions towards diagnosis. However, AI algorithms are rules based and cannot think outside the box like a person can. A clinician seeing a patient can notice things about that person, like social issues, that can lead to a diagnosis that an algorithm based on data just cannot. Over-reliance on AI could be a risk in the future. We need to learn how much we can benefit from it without over-relying on it and over-trusting it. The machines will not make the decisions on these things. We need to recognise that our clinicians and our nursing staff and all of our allied health professionals will always be the ultimate decision-makers.

We also already talk about the problems with people using ‘Dr Google’, where they start to look up all of their symptoms, and invariably they come back saying ‘I think I have a brain tumour’. And that’s the danger. You can get to almost any diagnosis if you plug

enough bits of information in. It will always take people to be able to turn data into meaningful information. That will always be a people issue, not an AI issue.

Are there any obstacles that you think stand in the way of AI assistive technology being implemented?

I think one of the biggest obstacles is budget, which is beginning to change. It typically starts with private healthcare systems who are looking ahead to ‘return on investment’ and they build business cases for these things. We are starting to see budget diversion into proven technologies. But one of the biggest obstacles that I’m seeing is, first of all, understanding what AI can and cannot do for us.

There is quite a distance between where technologists sit and where clinicians sit, and that gap is starting to close when we have clinicians studying things like digital health and health informatics. We do need to build the understanding of what digital health can do for healthcare. We need to build an understanding of that among technologists who would have very black and white thinking: see a problem, solve that problem, move on. Healthcare doesn’t work like that. I think the answer to that is education without moving people out of the clinical world – education not on how to code and build these technologies, but on how to understand where [these technologies] can fit, and what impacts they could potentially have.

As you know, we’ve a lot of history of technology coming into healthcare where we have to change how we do everything because the computers are in now. We’ve often had to work around the technology, and that’s changing, and it should change. It should be technology working around people.

But also, we need to upskill and educate our clinical teams on how we can leverage technology to genuinely help us in delivering healthcare without taking us away from our jobs. This is quite a big obstacle and I think while there’s lots of postgraduate-level courses available on this now, we need to start really bringing that in at undergraduate-level clinical study as well. And I don’t think that’s happening enough just yet.

Are there any key steps that the medical world has to take to facilitate these positive changes?

Anyone going to study pharmacy, nursing, medicine now, coming out of school, they were born digital. They understand how to use the technology around us, and they have an expectation around the use of technology. They would be very surprised if you told them that in order to transfer money at the bank, you must go into the bank with a book and have a person write into your book that you’re moving €50 from one place to another and then manually process that. I

think we’d all leave that bank fairly quickly. I remember when banking was done that way, but you know, people going in to study medicine now wouldn’t have any memory of that because it hasn’t existed in that way in their lifetime. Technology has enabled us to conduct our banking through our phones. This next generation of healthcare workers were born into a world where we have that expectation around technology that allows us to conduct many of our day-to-day tasks using our phones. The question is starting to be asked: why can’t we do this with healthcare? Why can’t I access my health record on my phone, digitally send my previous health information to my new GP, or see my own clinical images on an app? The thing is, the technology is already there around these things, and it can be done at quite a low cost. What we really need now is that injection of learning at the undergraduate level rather than what we are currently doing, which is ‘untraining’ people who have that digital mindset. We’re training them to not have that mindset in the clinical world, and we need to at best allow them to keep their digital mindset and actually educate around what’s going to be helpful going forward. Because it’s not just clinicians coming into medicine who will be expecting this. It’s also patients, people who’ve been born digital, who are starting to really demand access to their own health records in digital format. Education is the key, but education earlier than we’re doing it right now.

How long do you expect it to be until the technology that we’ve discussed, and a lot of the AI assistive devices, will begin to have a footprint in modern medicine?

I’m almost afraid to answer this question because if you asked me that 20 years ago, I would have told you within five years. Now I know better. It’s not a Big Bang approach and there’s a lot of evidence to suggest we shouldn’t take a Big Bang approach. We have been adopting technology for years in a piecemeal approach. We had a bit of an uplift during the pandemic, using technologies that we are using in other industries already. The pandemic accelerated our need for things such as telehealth, virtual appointments, and more streamlined collection of prescriptions.

It is a stepwise approach. We did see an acceleration during the pandemic, and I hope that that acceleration continues. We’re seeing some application of AI now in healthcare and we’re seeing greater access to large datasets. And if you think about the amount of data available in the ‘omics’ world, so genomics data for example, enabling things like precision medicine and in cancer care. On the flip side, we have many legacy systems in healthcare, particularly in acute care, while in community care there are usually few systems employed. So we have an opportunity in community

care to actually leapfrog and apply more cost-efficient technologies faster that are already proven either in other industries or in other parts of healthcare.

We need a unified approach. We do have a national strategy here in Ireland. We’ve another one coming, but really we need road maps for implementing those strategies that we stick to and that we have to budget for. I would say in the next 10 years, I would expect to see a significantly different landscape in healthcare than we have now, with the caveat that people are usually the obstacles to this technology when it comes to adoption of digital health.

Do you have any advice for healthcare workers, to ease the transition into the world of medicine enhanced by machine learning?

Start to see your clinical practice the same way you see other parts of your life. Ask yourself: why can’t we interact with healthcare professionals in the same way? Why can’t we conduct simple transactions that way? Start thinking about things like: if I want to book a taxi, I use an app. Now I don’t have to stand out on the street and hope that one will pass me. Adopting that mindset makes it easier to see where technology can start to fit. And if you ever have thought ‘there’s got to be a better way’, then usually it’s something to do with technology. Don’t be afraid to look into it, and to speak to people like me. My role is to take those opportunities and bring them forward.

Any resources you’d suggest for someone interested in learning a bit more about this sector of medicine?

So in RCSI in particular, there is the nine-month programme on leading digital health transformation. But also if you have a keen interest in just a specific area, RCSI is launching shorter courses that are just five weeks in length, bite-size chunks, about specific aspects of digital health, for example, the internet of health things, which is the application of devices and remote monitoring to facilitate diagnostics, courses in robotics, and a basic introduction to digital health.

This has been so informative, thank you Ms Harney. Do you have any closing remarks?

Don’t be afraid of technology. It’s not going to solve all of our problems, but it helps to see it as an enabler. If you start seeing it like that, then you’ll start to see those processes where you can begin to ask: “Could I not get the technology to do that so that I can actually see patients?” Changing your mindset I think is really important. Don’t be afraid of it: you don’t need to understand how to build it to be able to use it and benefit from it.

Mohammed Almaawali

RCSI medical student

Izabela Cymer BSc

Siobhan V. Glavey MB

BCh BAO PhD

Ann M. Hopkins BSc PhD HDip

Optimising an innovative xenograft model for inoculation of myeloma cell lines

Abstract

Introduction: Multiple myeloma (MM) is a haematological condition characterised by abnormal proliferation of plasma cells in the bone marrow. The disease progresses from an asymptomatic phase to MM. Testing drugs preclinically is crucial for developing novel therapies, and the chick embryo xenograft chorioallantoic membrane (CAM) model is gaining popularity compared to other models.

Methods: Gelatin was used as a matrix for delivering MM cell lines onto the CAM to mimic tumour growth and facilitate drug testing. Gelatin concentrations of 10%, 8%, and 6% were prepared, and the RPMI 8226 cell line was chosen for experiments. Fertilised hen eggs were prepared for incubation, and on embryonic development day 7 (EDD7), RPMI 8226 MM cells mixed with gelatin were implanted on the CAM. On EDD14, the CAM was excised for histological analysis.

Results: In vitro viability analysis demonstrated that 6% and 8% gelatin concentrations were most favourable for cell retention. On EDD14, angiogenic responses and tumour growth were observed. Histological analysis confirmed the presence of plasma cell growth on the CAM. The 8% gelatin concentration had the highest number of vessels, indicating angiogenesis, and also showed good viability.

Conclusion: The CAM model combined with gelatin as a delivery matrix shows promise for studying MM and testing novel therapies. Future studies may explore other extracellular matrix components.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 15-20.

Introduction

Multiple myeloma (MM) is a haematological condition characterised by the malignant proliferation of plasma cells in the bone marrow. This leads to an abnormal increase in the number of monoclonal immunoglobulins, which, if undetected, could result in specific end organ damage. MM arises from an asymptomatic phase termed monoclonal gammopathy of undetermined significance (MGUS), which is considered to be pre malignant.1 MGUS can then develop into smouldering multiple myeloma (SMM) or MM. A study found that the 10-year

cumulative probability of SMM developing into MM was 10%, with the overall annual risk of progression being approximately 1%.2 MM can be identified by the presence of one or more of the following features: plasma cells occupying >60% of bone marrow; free immunoglobulin light chain ratio of >100mg/L; ≥1 focal lesion of ≥5mm identified on MRI; and, features of end-organ damage – hypercalcaemia, renal failure, anaemia, and lytic bone lesions, also known as the SLiM CRAB criteria.3 In Ireland, the Irish Cancer Society states that annual MM incidence is 380 cases.4

Table 1: Summary of the different inoculation techniques for multiple myeloma cells in the chick embryo xenograft chorioallantoic membrane model.

Model MM cells

Human mesenchyme OPM2 Martowicz et al.7 2015 cells, collagen type-I RPMI 8226

Gelatin sponges, OPM2 Steiner et al.13 2015 human mesenchyme NCI-H929 cells U266 RPMI 8226

Gelatin sponges MM.1S Roccaro et al.14 2006

Multiple myeloma endothelial cells

Human umbilical vein endothelial cells

Gelatin sponges Primary MMEC Mangieri et al.15 2008

primary MGUS

Gelatin sponges, Primary MMEC Scavelli et al.16 2007 phosphate-buffered saline

Although many treatments have been developed for MM, the disease remains incurable. The main aim of treatment is to prolong remission and address complications. In Ireland, treatment is mainly pharmacological, through the use of chemotherapy or steroids, and depends on specific patient parameters.5 Some of these parameters include the cytogenic abnormality of the disease (genetic translocations and deletions) and the levels of lactate dehydrogenase.6

MM arises from an asymptomatic phase termed monoclonal gammopathy of undetermined significance (MGUS), which is considered to be pre malignant.

Testing drugs preclinically is a critical step in the development of novel therapies. Providing in vivo models of MM that resemble disease in humans aids in understanding disease complexity and facilitates drug testing.7 Murine models have long been preferred for studying haematological malignancies, given their similarity to human molecular characteristics and the histopathological microenvironment. The murine models for cancer testing are associated with a number of limitations, including longer observational periods, being relatively expensive, and ethical concerns.8 Alternatively, the chick embryo xenograft chorioallantoic membrane (CAM) model is becoming more favourable due to numerous advantages over murine models.9 The CAM is a highly vascularised extraembryonic membrane that performs biological

functions essential for chick embryo survival.10 The CAM model is used extensively as a research tool for tumour growth and its subsequent analysis. This model aligns with the 3Rs principle (Replacement, Reduction, Refinement) as the chick does not develop pain perception until day 17 of incubation, and thus is exempt from EU scientific animal licensing legislation to date. Additionally, the model is relatively inexpensive and the short gestation period for chick embryos (21 days) accelerates the experimental process. Moreover, the CAM model allows direct visualisation of tumour growth, invasion, and angiogenesis, and exhibits natural immunodeficiency, facilitating transplantations.11 Despite the various advantages of the CAM over other models, some disadvantages exist, such as short embryonic development leading to short observation periods of the growing tumour. Other biological limitations include the inability to test oral drug routes, chick sensitivity to surroundings, and difficulties in differentiating existing from newly formed vessels.12

Cell culturing assays provide a wealth of information but they lack a 3D structural environment. Introducing supportive elements for the cell to grow, such as gelatin, may be beneficial. Gelatin is a hydrocolloid that is receiving increased attention in the cell culturing field, as illustrated by Table 1. There are two types of gelatin, type A and type B: the latter is used in this experiment.17 Type B gelatin is produced by partially hydrolysing collagen from bovine skin by an alkali.18 Although there is literature to support the use of gelatin sponges to measure angiogenesis with patient samples, gelatin may act as an alternative delivery vehicle for MM cell lines as it is inexpensive, accessible, and easy to handle.19 Additionally, gelatin can be reconstituted at various concentrations; therefore, this vehicle is more malleable to the application.

The aim of the project was to optimise the application of MM cell lines onto the chick CAM xenograft using liquid gelatin. The liquid gelatin matrix served as a controlled medium for gradual release of myeloma cells onto the CAM membrane.

Murine models have long been preferred for studying haematological malignancies, given their similarity to human molecular characteristics and the histopathological microenvironment.

Materials and methods

Gelatin preparation

Gelatin from bovine skin was purchased from Sigma-Aldrich (G9391). Gelatin concentrations of 20%, 16%, 12%, and 8% were made using

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8g, 6.4g, 4.8g, and 1.6g, respectively, in 40mL fresh media in small Pyrex bottles. Using sterile magnetic stir bars, the gelatin was dissolved on a magnetic hotplate stirrer set to 40°C and 220RPM for 20 minutes. These concentrations would later be halved to produce final concentrations of 10%, 8%, 6%, and 4% when 50μL of gelatin solution was mixed with 50μL of MM cells resuspended in RPMI 1640 media supplemented with 10% foetal bovine serum (FBS) and 1% penicillin/streptomycin (for the CAM assay). The 4% gelatin was used only in the in vitro experiment. This procedure was carried out under aseptic conditions. Gelatin was stored in the fridge and liquefied using a hotplate set to 40°C. Many cell lines are available to model MM. Based on the experience of the Hopkins-Glavey group with CAM xenograft models, RPMI 8226 was chosen to model this experiment. RPMI 8226 MM cell line viability was tested in each gelatin concentration on a 96-well plate at 1 x 106 and 0.5 x 106 cells/100μL incubated for seven days at 37°C. Viability of the cells was counted on days 0, 2, and 7 using Countess.

an 18G needle, approximately 4ml of albumin was withdrawn by keeping the needle flush with the wall of the shell to avoid piercing the egg yolk. The needle entry site was sealed with tape. A strip of tape was placed on top of the egg to pre-emptively stop the shell from cracking onto the membrane. Using scissors, an oval 1cm x 2cm window was cut and then resealed with a semi-permeable membrane tape to be placed back into the incubator until EDD7.21

Ethical consent was not necessary, as avian embryos are not defined as ‘animals’ prior to trimester three of development under European animal protection legislation (as they do not develop pain receptors before embryonic development day [EDD] 17).

Multiple myeloma cell line seeding

On EDD7, RPMI 8226 cells were counted to a concentration of 1.0 x 106 cells/50μL. The procedure was carried out in the same conditions as before. The window was re-opened to place a sterilised silicon ring (bathed in 70% ethanol for at least 24 hours, washed and stored in double-distilled water [ddH2O] prior to implantation) on a large blood vessel on the CAM, away from the developing embryo.

the CAM membrane.

The aim of the project was to optimise the application of MM cell lines onto the chick CAM xenograft using liquid gelatin. The liquid gelatin matrix served as a controlled medium for gradual release of myeloma cells onto

Egg preparation and incubation

A batch of fertilised hen eggs (n=15) was purchased from Grange Hatchery in Limerick. Ethical consent was not necessary, as avian embryos are not defined as ‘animals’ prior to trimester three of development under European animal protection legislation (as they do not develop pain receptors before embryonic development day [EDD] 17).20 Eggs were placed into an incubator at 37°C with a tray of de-ionised autoclaved water with copper sulphate to maintain humidity and inhibit microbial growth. Eggs were wiped with cotton wool dampened with 70% ethanol, and autoclaved de-ionised water to remove excess ethanol. Eggs were observed for damage (slight cracks were sealed with semi-permeable tape) and then laid horizontally in the incubator for 72 hours.

Chorioallantoic membrane preparation

All instruments used were autoclaved and placed in 70% ethanol. On EDD3, in a laminar flow hood, a window was created to visualise the CAM on eggs. Eggs were placed flat on a petri dish padded with cotton wool under a heat lamp. On one side of the wider end of the egg, using

50μL of 20%, 16%, and 12% gelatin was mixed with 50μL of resuspended RPMI 8226 with a pipette, and then pipetted into the middle of the ring without touching the membrane. The 10%, 8%, and 6% eggs, respectively, were resealed and placed back into the incubator for another seven days.

Technical replicates were made for each concentration (n=5).

Tumour harvesting

On EDD14, embryos were euthanised and the tumour xenografts extracted. Using scissors and tweezers, the tumour and the surrounding margin of the CAM was cut. This was then fixed using 4% natural buffered formalin.

Samples were embedded in paraffin wax, sectioned and stained by Lance Hudson (Department of Surgery, RCSI). Slides were haematoxylin and eosin (H&E) stained to visualise the CAM and tumour, imaged using a Glissando objective imaging scanner, and viewed using an Aperio ImageScope.

All instruments used were autoclaved and placed in 70% ethanol.

FIGURE 1: Viability of RPMI 8226 cells on a 96-well plate measured on day 0, 2, and 7. A: This graph represents the starting point for the concentration of RPMI 8226 cells at 1 x 106 cells/100μL. B: This graph represents the starting point for the concentration of RPMI 8226 cells at 0.5 x 106 cells/100μL.

Results

In vitro analysis of cell count viability

Prior to implantation, a viability test for different gelatin concentrations was conducted for RPMI 8226. Results are demonstrated in Figure 1.

On day 2, gelatin concentration of 8% (Figure 1a) had the best count of viable cells mixed with gelatin (4.6 x 105cells/100μL), while for the higher cell concentration (Figure 1b), 6% concentration of gelatin performed better by retaining 6.9 x 105/100μL viable cells. On day 7, 4% concentration of gelatin had the best retaining cell ability for both cell concentrations.

Figures 1a and 1b demonstrate that the 4% gelatin concentration had the smallest slope (Figure 1a, M=-1.54; Figure 1b, M=-3.68). The slope was used to express the decline in the viable cells (the higher the value, the smaller the drop in viable cells); therefore, the slope values demonstrated the smallest decline in cell viable count when using the 4% gelatin concentration. This decline was due to the fact that the 4% gelatin consistency was too liquid and would have completely dissipated along the CAM surface. Nevertheless, the experiment was carried out using 6%, 8%, and 10% gelatin.

2A-F: Angiogenesis response observed on the chick embryo xenograft chorioallantoic membrane (CAM) model at day 14 in 6%, 8%, and 10% concentrations of gelatin. Yellow arrows indicate the growing tumour. The silicon rings inside which cells were implanted can be seen in (F), indicated by the black arrow. The blue arrows represent the number of vessels growing towards the tumour.

The slope was used to express the decline in the viable cells (the higher the value, the smaller the drop in viable cells); therefore, the slope values demonstrated the smallest decline in cell viable count when using the 4% gelatin concentration.

In vivo analysis of tumour growth

On day 14 of incubation, macroscopic observation was made of the angiogenic response of allantoic vessels growing towards the implant (Figure 2).

Angiogenic responses were observed on the CAM as the vessels grew towards the implanted tumour with an increased density. Counting vessels was carried out by visually identifying the vessels converging to the tumour within the radius of the ring. This was done on two replicates for the 10% gelatin, and three replicates each for the 8% and 6% gelatin. The 8% gelatin rendered the highest average number of vessels on the CAM model, as demonstrated in Table 2 These findings support the results observed in the in vitro assay. MM cells were then visualised microscopically after H&E staining of the excised CAM, as shown by the green arrow on Figures 3a and 3d

FIGURE

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FIGURE 3A-F: Haematoxylin and eosin (H&E) staining of the excised chick embryo xenograft chorioallantoic membrane (CAM) model. The green arrows indicate multiple myeloma (MM) cells. The red arrows indicate blood vessels. The blue arrow indicates a pocket of gelatin. The yellow arrow indicates necrotic/apoptotic cells.

The cells were situated near structures that look very much like gelatin, as indicated by the blue arrow on Figure 3c

Discussion

This project set out to modify a chick embryo CAM model for use in future MM cancer research studies. The CAM model for tumour implantation has demonstrated success in various cancer studies.22 This study evaluated a new method of inoculating MM cells onto the CAM surface. While gelatin sponges and collagen are widely used in the application method of MM cells on the CAM assay, as demonstrated in Table 1 , this study tested gelatin in liquid form at varying concentrations.23 The higher concentrations of gelatin (10%) had the advantage of being stiffer at 37°C, but as shown in the case of RPMI 8226 in Figure 1, this is not necessarily a favourable medium for cell growth. Figure 1 demonstrates that 6% and 8% gelatin were most favourable for the cell retention rate. No additional media were supplemented to the cells in vitro experiment, which may explain the drop in cell count. In contrast, cells growing on the CAM were supplemented by angiogenesis.

There were a number of observations made in this experiment. It was noted that the CAM texture was different when compared with previous experiments, in that it was thicker on excision, which might

indicate that the gelatin has spread along the surface of the CAM. Five eggs were used per replicate; however, there was a 20% loss in viable embryos for both 8% and 10% gelatin (Table 2). This might be related to the cells being suffocated (lack of oxygen and space for cells to grow) in higher concentrations of gelatin.

Gelatin supported in vivo implantation of cell lines, since visible tumours could be observed (Figure 2c) on the CAM surface (8% gelatin) on EDD14. This is likely promoted by strong angiogenic growth towards the implanted cells. In vitro, however, there was a decline in viability with the same concentration of gelatin (Figures 1a and 1b), which is likely linked to insufficient media. Additional media were not supplemented to the cells in the in vitro analysis to avoid diluting the gelatin.

Overall, the 8% concentration of gelatin in the in vivo CAM model demonstrated the best observed outcomes; there was recording of the highest number of vessels indicating angiogenesis, and it demonstrated a good viability of plasma cells on H&E stained slides.

This project set out to modify a chick embryo CAM model for use in future MM cancer research studies.

MM cells are notoriously difficult to culture; therefore, finding a suitable medium in which the cells can hold their composition within the matrix is of integral importance. Although gelatin showed relatively satisfactory results for growing the MM cells, investigation of other extracellular matrix (ECM) components for inoculation of cancer cells is crucial.

One of the other options is collagen, which has been used in the same field of research with promising results.7 Additionally, as the bone marrow microenvironment is comprised of many different components that support MM cell growth, it is advantageous to supplement MM cell lines with mesenchymal stem cells.24

Incorporating additional methods in future studies should be considered. For example, enhanced green fluorescent protein (eGFP) tagging of MM cell lines and then using GFP ELISA to measure the GFP content will allow tracking of the MM cell lines’ migration on the CAM surface and within the chick.7 Additionally, staining the cells with specific MM markers like CD130 would be important to confirm the presence of MM cells.

There were some limitations faced during this experiment. The short observational time for tumour growth (14 days) makes this model unsuitable for tumours requiring longer periods for macroscopic development. In addition, there was limited availability of an efficient counting mechanism of the viable cells.

Table 2: Angiogenesis response in different gelatin concentrations (6%, 8%, and 10%).

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In conclusion, the CAM model along with the gelatin matrix is a good candidate for the study of haematological malignancies. However, improvements and further investigations are required.

References

1. Albagoush SA, Shumway C, Azevedo AM. Multiple myeloma. In: StatPearls [Internet.] Treasure Island (FL): StatPearls Publishing; January 30, 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534764/

2. Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. Br J Haematol. 2007 Dec;139(5):730-43.

3. International Myeloma Working Group (IMWG). Criteria for the Diagnosis of Multiple Myeloma. [Internet.] [Accessed May 7, 2023.] Available from: https://www.myeloma.org/international-myeloma-working-group-imwg-cri teria-diagnosis-multiple-myeloma

4. Irish Cancer Society. Multiple myeloma. [Internet.] [Accessed May 10, 2023.] Available from: https://www.cancer.ie/cancer-information-and-support/cancer-types/multi ple-myeloma

5. Russell SJ, Rajkumar SV. Multiple myeloma and the road to personalised medicine. Lancet Oncol. 2011;12(7);617-9.

6. Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. 2020;10(9):94.

7. Martowicz A, Kern J, Gunsilius E, Untergasser G. Establishment of a human multiple myeloma xenograft model in the chicken to study tumor growth, invasion and angiogenesis. J Vis Exp. 2015;(99):e52665.

8. de Jong M, Maina T. Of mice and humans: are they the same? –Implications in cancer translational research. J Nucl Med. 2010;51(4):501-4.

9. Kersten K, de Visser KE, van Miltenburg MH, Jonkers J. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol Med. 2017;9(2):137-53.

10. Nowak-Sliwinska P, Segura T, Iruela-Arispe ML. The chicken chorioallantoic membrane model in biology, medicine and bioengineering. Angiogenesis. 2014 Oct;17(4):779-804.

11. Ribatti D. The chick embryo chorioallantoic membrane as a model for tumor biology. Exp Cell Res. 2014;328(2):314-24.

12. Chu PY, Koh AP, Antony J, Huang RY. Applications of the chick chorioallantoic membrane as an alternative model for cancer studies. Cells Tissues Organs. 2022;211(2):222-37.

13. Steiner N, Ribatti D, Willenbacher W, Jöhrer K, Kern J, Marinaccio C et al Marine compounds inhibit growth of multiple myeloma in vitro and in

The work of I. Cymer was supported by the Health Research Board and Breakthrough Cancer Research under the Health Research Charities Ireland 2022 scheme (grant HRCI-HRB-2022-020).

vivo. Oncotarget. 2015;6(10):8200-9.

14. Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H et al Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res. 2006;66(1):184-91.

15. Mangieri D, Nico B, Benagiano V, De Giorgis M, Vacca A, Ribatti D. Angiogenic activity of multiple myeloma endothelial cells in vivo in the chick embryo chorioallantoic membrane assay is associated with a down-regulation in the expression of endogenous endostatin. J Cell Mol Med. 2008;12(3):1023-8.

16. Scavelli C, Di Pietro G, Cirulli T, Coluccia M, Boccarelli A, Giannini T et al Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma. Mol Cancer Ther. 2007 Dec 1;6(12):3256-62.

17. Raja Mohd Hafidz RN, Yaakob CM, Amin I, Noorfaizan A. Chemical and functional properties of bovine and porcine skin gelatin. International Food Research Journal. 2011;18:813-7.

18. Baydin T, Aarstad OA, Dille MJ, Hattrem MN, Draget KI. Long-term storage stability of type A and type B gelatin gels: the effect of Bloom strength and co-solutes. Food Hydrocoll. 2022;127:107535.

19. Ribatti D. The chick embryo chorioallantoic membrane in the study of tumor angiogenesis. Rom J Morphol Embryol. 2008;49(2):131-5.

20 Elisa G, Godefridus P. Beyond animal models: implementing the 3Rs principles and improving pharmacological studies with new model systems. Expert Opin Drug Metab Toxicol. 2021;17(8):867-8.

21. Ribatti D, Nico B, Vacca A, Presta M. The gelatin sponge-chorioallantoic membrane assay. Nat Protoc. 2006;1(1):85-91.

22. Sharrow AC, Ishihara M, Hu J, Kim IH, Wu L. Using the chicken chorioallantoic membrane in vivo model to study gynecological and urological cancers. J Vis Exp. 2020;(155):e60651.

23. Ribatti D, Gualandris A, Bastaki M, Vacca A, Iurlaro M, Roncali L, Presta M. New model for the study of angiogenesis and antiangiogenesis in the chick embryo chorioallantoic membrane: the gelatin sponge/chorioallantoic membrane assay. J Vasc Res. 1997;34(6):455-63.

24. Papadimitriou K, Kostopoulos IV, Tsopanidou A, Orologas-Stavrou N, Kastritis E, Tsitsilonis O et al. Ex vivo models simulating the bone marrow environment and predicting response to therapy in multiple myeloma. Cancers (Basel). 2020;12(8):2006.

original article

Describing miRNA–target networks of miR22-3p and miR145-5p involved in neuroinflammation

Abstract

Background: MicroRNAs (miRNAs) control biological processes and inflammatory responses of microglia. Their post-transcriptional capabilities play important roles in limiting neuroinflammation in multiple sclerosis (MS).

Purpose: This project aims to investigate miRNA expression – miR-22-3p and miR-145-5p –during microglia activation and targets for these deregulated miRNAs.

Methods: The N9 microglia cell line was classically activated in vitro by lipopolysaccharide (LPS). IL-6 and TNF-α production was determined with ELISA to confirm LPS activation, and miRNA expression was quantified using cDNA and qPCR at six and 24 hours. Validated targets found in silico from miRTarBase were then compared to the Gene Expression Omnibus (GEO) dataset: GSE183038 to analyse gene expression modifications in microglia during neuroinflammation. Results: miR-22-3p was significantly upregulated with LPS activation at six hours with a relative quantification of 0.068 ± 0.004 when compared to the control of 0.052 ± 0.003 (p=0.004) at six hours. Targets of miR-22-3p were significantly upregulated (Ass1, Arpc5, Ywhaz and Max), and downregulated (Cdc25c, Irf8 and Hdac4 (p<0.001)). Ass1 is most dysregulated, with a log fold expression of 0.631 (p = 6.80E-20).

Conclusion: miR-22-3p was significantly upregulated at six hours and validated genes were found to be dysregulated. Regulation of miR-22-3p expression is a promising therapeutic strategy for MS treatment.

Grace Tan RCSI medical student

Introduction

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is a result of an immune-mediated inflammatory process.1,2 MS is characterised by neuroinflammation, demyelination and axonal degeneration.3 Microglia are key drivers of neuroinflammatory responses and play roles in active inflammation and remyelination. Activated microglia are responsible for antigen presentation to T cells, phagocytosis of myelin, and proinflammatory cytokines release.1,4 The aetiology of MS is multifactorial and epigenetic, resulting from

interactions between genetic and environmental factors, e.g., Epstein-Barr virus, smoking and vitamin D deficiency.5,6 Retrobulbar neuritis is often the first manifestation of MS, followed by other constitutional symptoms and neurological deficits that appear with disease progression, e.g., motor weakness and gait disturbance.7 There are three clinical phenotypes: relapsing-remitting MS; secondary progressive MS; and, primary progressive MS.3,7 MS has an early onset in life, usually around 20 to 40 years of age, making it the most common chronic and neurodegenerative disease in young

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 21-26.

adults. Without a definitive curative therapy available, MS is a leading cause of progressive disability, with significant disease burden in younger age groups.2,8

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is a result of an immune-mediated inflammatory process.

Existing treatments are only moderately beneficial; none are able to completely halt disease progression. Therefore, finding new treatments that may target progressive phases of MS or repair damaged lesions have been of great interest.3,5 MicroRNAs (miRNAs) are non-coding single-stranded 21- to 24-nucleotide-long RNA molecules that have been proven to control biological processes. Their regulatory capabilities are impressive, making it likely that they play a central role in MS.3,5,9 A single miRNA has the ability to bind up to 200 messenger RNA target sequences; therefore, inhibition or overexpression of an individual miRNA has a significant effect on cellular functions.3 In the context of MS, miRNAs may regulate inflammatory responses of microglia, and have important roles in remyelination and in limiting neuroinflammation. They also have epigenetic mechanisms identified in MS pathogenesis, as they regulate gene expression at the post-transcriptional level.4,10 Aberrant expression of certain miRNAs such as miR-145-5p and miR-22-3p is seen in MS. MiR-145-5p has been found to mediate anti-inflammatory pathways, support remyelination by activating microglia and, potentially, regulate peripheral monocyte/macrophage differentiation.3,11,12 Therefore, miR-145-5p may be an ideal therapeutic target. MiR-22-3p plays a role in the development of MS, and is highly upregulated in many tissues, T regulatory cells, and plasma, which makes it a useful biomarker.13,14 Few studies, however, have explored the regulation of miR-22-3p expression as an MS treatment strategy.15 An ongoing McCoy Lab study has analysed deregulated miRNAs in organotypic brain slices during demyelination and remyelination, as well as conditioned media from these cultures, and CSF miRNA profiles from MS patients. Results have shown that miR-22-3p and miR-145-5p are candidate miRNAs involved in demyelination and remyelination processes of MS.3 This project investigated the expression of miR-22-3p and miR-145-5p during microglia activation, as well as targets for these deregulated miRNAs. To elucidate the roles of these miRNAs of interest under classical M1 activation, the N9 microglia cell line was activated in vitro by lipopolysaccharide (LPS). Expression of miRNA and production of cytokines interleukin-6 (IL-6) and tumour necrosis

factor alpha (TNF- ) were then quantified. To establish potential networks of miRNA in MS, publicly available datasets of gene expression were used to determine the feasibility of miRNA–gene interaction in microglia.

Methods

Laboratory-based data collection (in vitro)

Cell culture and LPS activation

Murine N9 microglia cells were cultured in two 24-well plates and LPS (100ng/mL) was used for microglial activation. A total of 500 μ L of LPS was added to each well while controls were left inactivated. Supernatants and cells were then collected at zero, six and 24 hours.

RNA isolation, extraction and quantification

RNA was isolated with the TRIzol Reagent (Thermo Fisher Scientific; Waltham, MA, USA) kit. The monolayer of cells was lysed and homogenised in 600L of TRIzol Reagent. RNA extractions were performed according to manufacturer’s instructions, with an additional step of adding 1μL of GlycoBlue Coprecipitant. RNA pellets were solubilised, and total RNA was eluted with nuclease-free water and stored at -18°C for later use. RNA yield was then quantified using the Nanodrop ND-1000 spectrophotometer at 450nm.

IL-6 and TNF-α enzyme-linked immunosorbent assay

Levels of IL-6 and TNF-α in cell-free supernatants were determined to confirm LPS activation using DuoSet enzyme-linked immunosorbent assay (ELISA) kits (Human IL-6 DuoSet ELISA, Human TNF-alpha DuoSet ELISA; R&D Systems, USA) according to the manufacturer’s protocols. After substrate development, sample concentration of cytokines was determined from a standard curve obtained by assaying serial dilutions of recombinant mouse IL-6 and TNF-α standard. IL-6 and TNF-α concentrations obtained (p<0.001) in control groups and the groups treated with LPS at six and 24 hours were compared and examined with an unpaired Student’s t-test and a one-way ANOVA test.

cDNA preparation, miRNA analysis and qPCR

RNA samples were diluted to have an input of 10ng RNA per sample, and thus had concentrations of 5ng/μL each. The Applied Biosystems TaqMan Advanced miRNA cDNA Synthesis kit (Applied Biosystems; Foster City, CA, USA) was used to obtain miRNA cDNA.

Three plates of qPCR were then performed to analyse expression of miRNAs of interest miR-22-3p and miR-145-5p, endogenous normalisers miR-16-5p and miR-24-3p, and a positive exogenous

RCSIsmj original article

control, miR-155. The normalised equation 2-ΔCt, where ΔCt = Ct (miRNA of interest) - Ct (normaliser) was used to obtain relative quantification. Statistical significance was evaluated by one-way ANOVA test for comparisons between all groups. The unpaired Student’s t-test was used for comparisons between a particular control and LPS group.

Computer-based data collection (in

silico)

Validated targets and analysis of gene expression modifications in microglia

To identify potential miRNA–target interaction profiles of miR-22-3p and miR-145-5p, the publicly available database miRTarBase was used.16 Only validated targets of Mus musculus and those validated experimentally by reporter assay, western blot, and microarray were analysed. Search terms ‘microglia’, ‘neuroinflammation’, and ‘LPS’ were used to identify suitable datasets and GEO dataset: GSE183038 was selected and downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) repository.17 This dataset had a similar experimental set-up, where

FIGURE 1a and 1b: IL-6 and TNF-α production induced by LPS in N9 cells measured by ELISA. IL-6 and TNF-α concentration presented as the means ± SD. P<0.001 was obtained for all comparisons: control groups compared to groups treated with LPS at six and 24 hours, as examined with unpaired Student’s t-test and one-way ANOVA test.

FIGURE 2a-2c: qPCR analysis of mi-22-3p, miR-145-5p and miR-155. Ct values of miR-22-3p, miR-145-5p and miR-155 were normalised by endogenous normalisers miR-16-5p and miR-24-3p, and are represented as relative quantification ± SD, respectively. Statistical significance was evaluated by one-way ANOVA test for comparisons between all groups. The unpaired Student’s t-test was used for comparisons between a particular control and LPS group where** = P<0.010, and *P<0.050.

murine N9 microglial cells were treated with LPS (1μg/ml) for six hours. Validated targets found previously were then compared to the GEO database and analysis of gene expression modifications in microglia during neuroinflammation was performed.

Results

Levels of IL-6 and TNF-α were determined by ELISA to check for LPS activation in N9 microglia cells (Figure 1). Unstimulated N9 cells produced negligible amounts of IL-6 and TNF-α. In LPS-stimulated N9 cells, significant increases in secretion of IL-6 and TNF-α, which peaked at 24 hours, were observed (p<0.001). With LPS activation, IL-6 concentration was 485.59 ± 23.623pg/mL at six hours, and 598.59 ± 19.857pg/mL at 24 hours. With LPS activation, TNF-α concentration was 1392.3 ± 36.48pg/mL at six hours and 1,704.2 ± 79.9pg/mL at 24 hours. This confirmed LPS activation.

cDNA was prepared from RNA samples and qPCR was performed to quantify the expression of miR-22-3p and miR-145-5p with LPS activation (Figure 2).

FIGURE 3: Validated targets of miR-22-3p and analysis of GEO dataset for dysregulation of target genes. Differentially up- and downregulated validated target genes of miR-22-3p from miRTarBase and their log fold changes found in GSE183038 dataset, where *** = P<0.001.

For miR-22-3p, the combined analysis of the five sample groups showed no statistically significant difference in expression (p=0.073). However, further analyses of the subgroups showed that miR-22-3p was significantly upregulated with LPS activation at six hours. At six hours, the relative quantification was 0.052 ± 0.003 for the control group, and 0.068 ± 0.004 for the LPS group, a statistically significant difference (p=0.004). MiR-22-3p had a slight upregulation trend in the LPS group at 24 hours, although comparison with the control group was not statistically significant (p=0.136). The relative quantification at 24 hours was 0.070 ± 0.041 for the control group, and 0.116 ± 0.029 for the LPS group. Other subgroup comparisons showed no statistically significant differences or trends (p>0.05 for comparison between the control at zero hours, and the LPS group at six hours and 24 hours).

For miR-145-5p, the combined analysis of the five sample groups showed no statistically significant difference in expression (p=0.090). Analysis of the subgroups at six hours and at 24 hours also showed no statistically significant differences (p>0.05). There was a singular outlier in the control group at zero hours, with a relative quantification of 0.352, which skewed the mean to the right. For miR-155, the combined analysis of the five sample groups showed statistically significant difference of expression (p=0.009). There was significant upregulation at six hours (p=0.047) and 24 hours (p=0.003). Therefore, the exogenous positive internal control validated that the experimental conditions were optimal and that the qPCR worked.

As upregulation was seen in vitro for miR-22-3p, correlation analysis of miRNAs and mRNA expression in the in silico datasets was performed

only for miR-22-3p. The validated targets found in miRTarBase included Ass1, Mecom, Erbb3, Cdc25c, Arpc5, Ywhaz, Irf8, Hdac4, SIRT1, Max, Mecp2., and Sirt1 (Figure 3). Further in silico analysis of possible interactions between miR-22-3p, its targets, and their log fold expression in the GEO dataset was done. This revealed that miR-22-3p brought about a significant upregulation of Ass1, Arpc5, Ywhaz and Max, and downregulation in Cdc25c, Irf8 and Hdac4 (p<0.001). Ass1 is most dysregulated, with a log fold expression of 0.631 (p=6.80E-20).

Discussion

LPS activation of N9 microglia was confirmed with ELISA, as both IL-6 and TNF-α were elevated. MiR-22-3p was significantly upregulated at six hours with qPCR. Recent literature has supported these findings and implicated the expression and dysregulatory effects of miRNAs in neurodegenerative diseases, including MS.18 Manna et al. (2018) analysed miRNA profiles and found that miR-22-3p was an ideal biomarker of MS and prognostic tool for interferon beta (IFN-β) therapy response monitoring in MS patients, as they found miR-22-3p to be significantly upregulated in treated patients compared to treatment naive patients.13 In a microarray analysis, Siegel et al. (2012) also identified miR-22-3p to be upregulated in individuals with MS, and found that it can serve mainly as a biomarker.14 However, there is a lack of studies that investigate treatment strategies targeting miR-22-3p as a potential therapeutic method for autoimmune diseases. Since miR-22-3p takes part in the development and pathophysiology of MS, regulation of its expression may be a promising therapeutic strategy for MS treatment.19 Lu et al. (2015)

RCSIsmj original article

reported that miRNA inhibition is possible with strategies such as targeting miR-22-3p with a locked nucleic acid, which could possibly reduce inflammaiton.20

LPS activation of N9 microglia was confirmed with ELISA, as both IL-6 and TNF- α were elevated.

Microglia activation is categorised into two opposite types: classical (M1); or, alternative (M2). M1 microglia release inflammatory mediators, while M2 microglia release anti-inflammatory mediators and induce neuroprotection. Hence, while microglia activation is necessary for host defence, excessive microglia activation leads to neuronal death and an increase in proinflammatory cytokines, as is seen in MS.2,4,11,21 M1 activation is observed in this study, while miR-145-5p had no patterns of dysregulation. However, other studies have proven otherwise.12,22,23 This could be due to the fact that miR-145-5p may only be dysregulated with M2 activation. A miRNA profiling study observed that miR-145-5p had been significantly upregulated in IL-4-stimulated primary microglia, and induced neuroprotection and anti-inflammatory processes.11 In silico analysis underpins the relevance of miR-22-3p in neuroinflammation, as is seen in this study with LPS activation in N9 microglia. The upregulated genes, Ass1 and Arcpc5, and the downregulated gene Irf8 seemed most relevant in the context of MS as seen in the computer-based data collection done in this study. Ass1 is the only functional gene involved in argininosuccinate synthase (AS) expression.24 Cellular nitric oxide production, dependent on arginine availability, occurs with microglia activation, and has been implicated in the pathophysiology of many neurodegenerative and inflammatory diseases. Kawahara et al. (2001) had found in LPS and IFN-α-activated murine microglial MG5 cells that the mRNA for AS had increased, as demonstrated by the increase in AS proteins.24 This demonstrates how Ass1, which mediates AS, could be an important contributor to the neuronal damage seen in neurodegenerative diseases like MS. In an MS model of experimental autoimmune encephalomyelitis in mice, Ma et al. (2020) had explored the roles of various miRNAs in vivo, and tested the respective target genes and expression levels, in which they found the upregulation of Arcpc5 Hence, they suggested to further investigate strategies aimed at manipulating miRNA levels in the CNS of MS patients to find innovative therapies that might enhance the endogenous mechanisms of remyelination.25 Irf8 was found to be dysregulated in

a Genome Wide Association Study datasheet.26 A 2009 meta-analysis of genome scans and replication identified Irf8 as a new validated MS susceptibility locus, and determined that the allele near Irf8 is associated with higher mRNA expression of IFN response pathway genes in subjects with MS.26

To further investigate the upregulation expression of miR-22-3p, cDNA preparation for gene analysis and qPCR for deregulated targets with TATA-binding protein (tbp) – a transcription factor as an endogenous normaliser in vitro – could be performed. A comparison of deregulated targets with the MS genomic map in silico would also be an ideal extension of this study.

The outcomes of this study have promising implications for the advancement of therapeutic strategies in the context of MS. The discerned upregulation of miR-22-3p during microglial activation presents a distinct target for precision medicine in MS treatment. Delving into this avenue, there lies the prospect of developing miR-22-3p-centric therapies, potentially synergising with existing modalities, to confer a nuanced and tailored therapeutic approach. Noteworthy among the identified dysregulated genes are Ass1, Arpc5, Ywhaz, Max, Cdc25c, Irf8, and Hdac4. This molecular delineation invites a more granular understanding, providing a foundation for stratifying patients based on their miRNA expression profiles. Such stratification could usher in a predictive paradigm for treatment response, and a new era of personalised therapeutics for neuroinflammatory disorders, particularly in the landscape of MS.

Conclusion

This study has investigated and discussed the substantial roles that miRNAs have in neuroinflammation. LPS activation of the N9 microglia was confirmed with ELISA as IL-6 and TNF-α were elevated. The main finding was that miR-22-3p was significantly upregulated at six hours with qPCR. Validated genes were found to be dysregulated in silico, with Ass1 being significantly upregulated. The results of this study are supported in the literature, which suggests that miR-22-3p is a possible novel regulator of MS. More studies are needed to further establish the precise role of miR-22-3p in the mechanisms of MS, and to determine potential therapeutic strategies targeting miR-22-3p for MS treatment.

More studies are needed to further establish the precise role of miR-22-3p in the mechanisms of MS, and to determine potential therapeutic strategies targeting miR-22-3p for MS treatment.

RCSIsmj original article

References

1. Sand IK. Classification, diagnosis, and differential diagnosis of multiple sclerosis. Curr Opin Neurol. 2015;28(3):193-205.

2. Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol. 2019;26(1):27-40.

3. Duffy CP, McCoy CE. The role of microRNAs in repair processes in multiple sclerosis. Cells. 2020;9(7):1711.

4. Guerrero BL, Sicotte NL. Microglia in multiple sclerosis: friend or foe? Front Immunol. 2020;11:374.

5. Ma X, Zhou J, Zhong Y, Jiang L, Mu P, Li Y et al. Expression, regulation and function of microRNAs in multiple sclerosis. Int J Med Sci. U.S. 2014;11(8):810-8.

6. Belbasis L, Bellou V, Evangelou E, Ioannidis JPA, Tzoulaki I. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol. U.S. 2015; 14(3):263-73.

7. Lubin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in multiple sclerosis. Neurology. 2012;46(4):907-11.

8. Kaufmann M, Puhan MA, Salmen A, Kamm CP, Manjaly Z-M, Calabrese P et al. 60/30: 60% of the morbidity-associated multiple sclerosis disease burden comes from the 30% of persons with higher impairments. Front Neurol. 2020;11:156.

9. Piket E, Zheleznyakova GY, Kular L, Jagodic M. Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: a comprehensive overview. J Autoimmun. 2019;101:17-25.

10. Jamebozorgi K, Rostami D, Pormasoumi H, Taghizadeh E, Barreto GE, Sahebkar A. Epigenetic aspects of multiple sclerosis and future therapeutic options. Int J Neurosci. 2019;131(1):56-64.

11. Freilich RW, Woodbury ME, Ikezu T. Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia. PLoS One. 2013;8(11):e79416.

12. Sharaf-Eldin WE, Kishk NA, Gad YZ, Hassan H, Ali MAM, Zaki MS et al

Extracellular miR-145, miR-223 and miR-326 expression signature allow for differential diagnosis of immune-mediated neuroinflammatory diseases. J Neurol Sci. 2017;383:188-98.

13. Manna I, Iaccino E, Dattilo V, Barone S, Vecchio E, Mimmi S et al Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients. FASEB J. 2018;32(8):4241-6.

14. Siegel SR, Mackenzie J, Chaplin G, Jablonski NG, Griffiths L. Circulating microRNAs involved in multiple sclerosis. Mol Biol Rep. U.S. 2012;39(5):6219-25.

15. Wang B, Yao Q, Xu D, Zhang J-A. MicroRNA-22-3p as a novel regulator and therapeutic target for autoimmune diseases. Int Rev Immunol. U.S. 2017;36(3):176-81.

16. miRTarBase. The experimentally validated microRNA-target interactions database. [Internet.] [Accessed May 26, 2022.] Available from: mirtarbase.cuhk.edu.cn.

17. Home – Geo – NCBI. National Center for Biotechnology Information. Available from: http://www.ncbi.nlm.nih.gov/geo

18. Muñoz-San Martín M, Gomez I, Miguela A, Belchí O, Robles-Cedeño R, Quintana E, Ramió-Torrentà L. Description of a CSF-enriched miRNA panel for the study of neurological diseases. Life (Basel). 2021;11(7):594.

19. McCoy CE. mir-155 dysregulation and therapeutic intervention in multiple sclerosis. Adv Exp Med Biol. 2017;1024:111-31.

20. Lu W, You R, Yuan X, Yang T, Samuel EL, Marcano DC et al. The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote T(H)17 cell-dependent emphysema. Nat Immunol. 2015;16(11):1185-94.

21. Guo S, Wang H, Yin Y. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci. 2022;14:815347.

22. Hemond CC, Healy BC, Tauhid S, Mazzola MA, Quintana FJ, Gandhi R et al. MRI phenotypes in MS: longitudinal changes and miRNA signatures. Neurol Neuroimmunol Neuroinflamm. 2019;6(2):e530.

23. Kornfeld SF, Cummings SE, Fathi S, Bonin SR, Kothary R. MiRNA-145-5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor. J Cell Physiol. 2021;236(2):997-1012.

24. Kawahara K, Gotoh T, Oyadomari S, Kajizono M, Kuniyasu A, Ohsawa K et al. Co-induction of argininosuccinate synthetase, cationic amino acid transporter-2, and nitric oxide synthase in activated murine microglial cells. Brain Res Mol Brain Res. 2001;90(2):165-73.

25. Ma Q, Matsunaga A, Ho B, Oksenberg JR, Didonna A. Oligodendrocyte-specific Argonaute profiling identifies microRNAs associated with experimental autoimmune encephalomyelitis. J Neuroinflammation. 2020;17(1):297.

26. De Jager PL, Jia X, Wang J, de Bakker PIW, Ottoboni L, Aggarwal NT et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet. 2009;41(7):776-82.

RCSI medical students

Impact of nutritional deficiencies following bariatric surgery on maternal and neonatal outcomes

Abstract

Bariatric surgery (BS) is a viable option for the management of severe obesity, as it promotes substantial weight loss and improves general metabolic health. In women of reproductive age, the consequent weight reduction has been shown to lower the risk of gestational diabetes, macrosomia, and neonatal intensive care unit admission. However, due to altered gastrointestinal anatomy, malabsorption, and decreased food intake, this procedure can result in the development of micro- and macronutrient deficiencies. Iron, protein, vitamin D, and calcium are among some of the common nutritional deficiencies that can have detrimental effects on maternal health and foetal development. It is therefore crucial to provide preconception counselling, multidisciplinary care, nutritional monitoring and supplementation, individualised care, and annual lab testing. Healthcare professionals, including obstetricians, bariatric surgeons, and nutritionists, must work closely together to provide the utmost care to this unique cohort.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 27-32.

Rama Alkhaldi

Jamie MacLennan

Fatimah Zahra Rajabally

RCSIsmj review

Introduction

Obesity is a major public health challenge in many parts of the world, such as in the United States, where one in nearly two American women of childbearing age are classified as either overweight or obese.1,2 A pre-conception body mass index (BMI) above 30kg/m2 is universally classified as maternal obesity, which can cause a myriad of severe future health complications for both mother and foetus.3 As the rate of maternal obesity continues to rise, so too does the demand for BS. Between 2013 and 2014, over 6,500 BS procedures were performed in Canada. Approximately 78% of these surgeries were conducted on women, half of whom were in the reproductive age group. This statistic suggests a potential rise in pregnancies following BS.4 Following BS, women have a much lower risk of complications during pregnancy, including gestational diabetes, hypertensive disorders, and neonates that are large for gestational age.4 However, the prevalence of micronutrient deficiencies, predominantly iron deficiency, in these women is high, which negatively impacts both mother and foetus.5 This review aims to examine the impacts of nutritional deficiencies following BS on both mother and foetus, and to identify novel and optimal methods whereby healthcare professionals may ensure proper nutrition and well-being in this cohort.

A

pre-conception body mass index (BMI)

above 30kg/m2 is universally classified as maternal obesity, which can cause a myriad of severe future health complications for both mother and foetus.

The development of nutritional deficiencies following bariatric surgery

The development of nutritional deficiencies post BS is multifactorial. One cause is decreased oral intake and gastrointestinal absorption, which refers to the process by which nutrients from the digested food are taken up into the bloodstream through the epithelial cell layer of the small and large intestines, facilitating their entry into the body, which occurs post surgery.5,6 Furthermore, deficiencies in micronutrients, water, fat-soluble vitamins and trace elements might already be present and persist post surgery.7 Treating these dietary factors is necessary to ensure the efficacy of BS.8

Fat-soluble vitamin deficiencies are particularly rampant after BS due to altered fat digestion.9 This phenomenon explains the development of vitamin A deficiency, compounded by the natural reduction in

vitamin A during pregnancy due to haemodilution.9 The emergence of vitamin D deficiency due to surgery can be attributed to decreased dietary intake after the patient develops dietary intolerance to fortified dairy products in combination with bypassed absorption sites.9 In women who have had BS, the pathogenesis of deficiencies in vitamin B12 and folate (B9) can be partially explained by malabsorption, and decreased production of intrinsic factor and hydrochloric acid.9

The development of nutritional deficiencies post BS is multifactorial.

The types of BS can be subdivided into restrictive and malabsorptive, such as the laparoscopic adjustable gastric band (LAGB), and Roux-en-Y gastric bypass (RYGB), respectively.9 A multi-centre prospective cohort study was performed across five hospitals in Belgium from 2009 to 2011, comparing restrictive versus malabsorptive BS and their relative effects on micronutrient levels in women.9 The results indicated that vitamin deficiencies were overall more common and pronounced in malabsorptive (RYGB) compared to restrictive (LAGB) surgeries.9 This difference is likely attributed to the malabsorptive nature of RYGB, which involves rerouting the digestive tract, leading to reduced absorption of essential vitamins and minerals, whereas restrictive surgeries primarily limit food intake without altering nutrient absorption mechanisms.9 As a follow-up, it was noted that with supplementation, the micronutrient deficiency effects of BS were diminished.10

The types of BS can be subdivided into restrictive and malabsorptive, such as the laparoscopic adjustable gastric band (LAGB), and Roux-en-Y gastric bypass (RYGB), respectively.

Maternal outcomes in pregnant women who have undergone bariatric surgery

In pregnancy, the micronutrient demand increases, particularly during the third trimester. Vitamins such as folate (B9) are required three to six months prior to conception to prevent deficiencies that can lead to neural tube defects.11

Several studies corroborate that micronutrient deficiencies are a prevalent concern in pregnancies post BS. The nutritional parameters can be assessed by blood serum levels in pregnant women across the first, second, and third trimesters.12 The most common micronutrient deficiencies in pregnancy post BS are vitamins A, B1, B9, B12, and D, iron, ferritin, and calcium.9,12 A summary of micronutrient deficiencies

Protein deficiency Hair loss

Calcium deficiency

Bone loss, reduction of calcium secretion in the milk

Iron deficiency

Iron deficiency anaemia, preterm birth

Vitamin A deficiency

Retinal injury

Vitamin D deficiency

Caesarean section, placental inflamation, pre-eclampsia, preterm birth

in patients after surgery and their associated outcomes is illustrated in Figure 1 12

In addition to nutritional deficiencies, BS predisposes women to other complications of pregnancy, including gestational diabetes, hypertension, and pre-eclampsia.13

In pregnancy, the micronutrient demand increases, particularly during the third trimester. Vitamins such as folate (B9) are required three to six months prior to conception to prevent deficiencies that can lead to neural tube defects.

Foetal outcomes

BS on the mother prior to pregnancy has been proven to be associated with a range of effects on the foetus, both beneficial and detrimental. A retrospective cohort study by Getahun et al. (2022)14 investigated perinatal outcomes after BS and identified that the surgery was associated with a reduction in risks for gestational diabetes, foetuses and/or infants that are large for gestational age, and neonatal intensive care unit (NICU) admission. However, there was a significantly increased risk for neonates to be small for gestational age, which was

independent of the time interval between surgery and subsequent pregnancy.14 A study conducted by Gascoin et al. (2017)15 found that the main factor associated with low birth weight in mothers who had undergone BS prior to pregnancy was the decrease in BMI following the surgery. The study then went on to compare the maternal and umbilical cord blood biological characteristics of 56 mothers with prior RYGB with 56 non-obese mothers after normal pregnancy. It was observed that neonates from RYGB mothers had lower birth weight, and lower levels of IGF-1, leptin, calcium, iron, zinc, and vitamin A, compared to controls. Another study conducted by Malik et al. (2020)16 also examined foetal outcomes in mothers who had undergone BS and been followed up with bodyweight measurements at various time points ranging from six months to three years. They observed no growth delay and that none of the children’s weight measurements dropped beneath the third percentile in this time period; bodyweight gain was rapid after birth, providing reassurance that in most cases, there were no long-term repercussions.16 However, a limitation in this study was that follow-up weight measurements of children in the post-surgery group was incomplete; thus no absolute conclusion that all children had no further growth retardation after delivery can be made.

Nutritional deficiencies are common post surgery, especially following RGYB due to its malabsorptive component.12 This creates a concern

FIGURE 1: Maternal micronutrient deficiencies outcomes. Created with BioRender.

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B12, folic acid, and omega-3 deficiency

Neural tube defects and impaired neurological development

Iodine deficiency Cretinism

Zinc deficiency anaemia, anencephaly, low birth weight, neural tube defects

for post-surgical patients, especially during pregnancy, as micronutrient and vitamin requirements are increased.17 Consequently, a range of complications can affect the foetus the long-term consequences of which are unknown. Figure 2 summarises the effects of certain nutritional deficiencies on newborns.12

A study conducted by Gascoin et al. (2017) found that the main factor associated with low birth weight in mothers who had undergone BS prior to pregnancy was the decrease in BMI following the surgery.

Despite careful maternal supplementation and follow-up, detrimental foetal outcomes such as being small for gestational age and nutritional deficiencies still seem to occur in newborns of mothers who have undergone BS. This calls for regular prenatal monitoring, nutritional supplementation, and close management of any complications related to pregnancy to help optimise foetal outcomes for women who have undergone BS.

Future recommendations

There are many ways that healthcare professionals can help to ensure optimal health for both mother and foetus to avoid the nutritional

Vitamin D and calciium deficiency

Poor bone mineralisation and skeletal abnormalities

Iron deficiency

Pre-term birth

Low birth weight baby

deficiencies that can arise post BS. Continuing to provide care before, during, and after BS can help to promote future favourable pregnancy outcomes.

Despite careful maternal supplementation and follow-up, detrimental foetal outcomes such as being small for gestational age and nutritional deficiencies still seem to occur in newborns of mothers who have undergone BS.

Pre-conception counselling

Pre-conception counselling is crucial for women who have undergone BS and wish to conceive. A multidisciplinary group of medical professionals should be included, involving bariatric surgeons, obstetricians, endocrinologists, and dietitians.3 The objective of preconception counselling is to offer in-depth explanations and suggestions on several subjects, including:

n when a woman should become pregnant post surgery, taking into consideration her weight stability, nutritional status, and any potential difficulties;

FIGURE 2: Maternal micronutrient deficiencies – effects on foetus. Created with BioRender.

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n contraceptive methods to prevent unintended pregnancies in the initial postoperative period;18

n how to recognise and treat any nutritional deficiencies, such as those in iron, vitamin B12, and vitamin D;3

n review of comprehensive medical history to identify any pre-existing medical issues or genetic risk factors;19

n assessment of weight loss after surgery, and suggestions for healthy levels of weight gain throughout the pregnancy;20 and,

n benefits and drawbacks of the specific type of BS performed related to pregnancy.20

Continuing to provide care before, during, and after BS can help to promote future favourable pregnancy outcomes.

Multidisciplinary care

A multidisciplinary approach that involves the bariatric surgeon, obstetrician, and a nutritionist is useful in the prevention of complications in pregnancy. A proper food plan should be devised in collaboration with healthcare professionals to guarantee optimal nutritional intake during pregnancy. The patient’s health status must be closely monitored to enable prompt intervention and management of any new problems.20 Regular follow-up consultations should be scheduled to assess the mother’s well-being, dietary needs, weight gain, and foetal development. In the case of women who have undergone surgery, these consultations should be tailored to address specific postoperative considerations, ensuring comprehensive care that accounts for surgical impacts on maternal health, nutritional requirements, and the unique aspects of foetal development following the procedure. This approach allows healthcare providers to monitor and optimise the well-being of both the mother and the developing foetus in the context of surgical interventions.20

A multidisciplinary approach that involves the bariatric surgeon, obstetrician, and a nutritionist is useful in the prevention of complications in pregnancy.

Individualised care and annual lab testing

Preoperative weight loss, the type of BS done, underlying medical conditions, and general health should all be considered when creating individualised care regimens.18 For instance, due to higher food malabsorption, people who have had malabsorptive surgeries like gastric bypass may need more regular monitoring and supplementation.12 Regular adjustments and examinations may be

necessary during the pregnancy to yield the best results.21 According to expert advice, annual laboratory testing for all patients who are more than a year out from surgery may lower the possible hazards of important nutrient deficits on maternal and foetal health.7

Preoperative

weight loss, the type of BS done, underlying medical conditions, and general health should all be considered when creating individualised care regimens.

It is important to remember that these are general concepts, and that standards and procedures may vary based on the specific patient characteristics and preferences of their providers.18 Medical professionals with experience managing post-BS pregnancies can provide individualised nutritional guidance, while considering the patient’s particular surgical background and dietary requirements. Moreover, because excessive or inadequate weight increase can influence the health of both mother and foetus, it is important to carefully monitor the patient’s weight gain during pregnancy to make sure they adhere to advised guidelines.12

Conclusion

In conclusion, the collective findings from various studies emphasise the critical importance of addressing maternal micronutrient deficiencies post BS to ensure favourable pregnancy outcomes. Pregnant and postpartum women with a history of bariatric surgery are particularly susceptible to micronutrient deficiencies, posing risks

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to both maternal and foetal health. To minimise the deleterious outcomes that this unique cohort are subject to, contraceptive advice, pregnancy timing, gestational weight gain recommendations, and pregnancy-specific diets should be further explored. Optimal microand macronutrient monitoring before and during pregnancy is crucial to improve maternal and foetal well-being, preventing potential disorders such as pre-eclampsia and cretinism. Co-operative efforts among researchers, clinicians, and policymakers are necessary to advocate for evidence-based care in these circumstances, which will improve outcomes for both mothers and foetuses.

References

1. Mechanick J, Youdim A, Jones D, Garvey W, Hurley D, McMahon M et al Clinical Practice Guidelines for the Perioperative Nutritional, Metabolic, and Nonsurgical Support of the Bariatric Surgery Patient – 2013 Update: Cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Endocrine Pract. 2013 Mar;19(2):337-72.

2. Vahratian A. Prevalence of overweight and obesity among women of childbearing age: results from the 2002 National Survey of Family Growth. Matern Child Health J. 2008;13(2):268-73.

3. Akhter Z, Heslehurst N, Ceulemans D, Rankin J, Ackroyd R, Devlieger R. Pregnancy after bariatric surgery: a nested case-control study of risk factors for small for gestational age babies in AURORA. Nutrients. 2021;13(5):1699.

4. Carreau AM, Nadeau M, Marceau S, Marceau P, Weisnagel SJ. Pregnancy after bariatric surgery: balancing risks and benefits. Can J Diabetes. 2017;41(4):432-8.

5. O’Kane M, Parretti HM, Pinkney J, Welbourn R, Hughes CA, Mok J et al British Obesity and Metabolic Surgery Society Guidelines on perioperative and postoperative biochemical monitoring and micronutrient replacement for patients undergoing bariatric surgery – 2020 update. Obes Rev. 2020;21(11):e13087.

6. Kiela PR, Ghishan FK. Physiology of intestinal absorption and secretion. Best Pract Res Clin Gastroenterol. 2016;30(2):145-59.

7. Hazart J, Le Guennec D, Accoceberry M, Lemery D, Mulliez A, Farigon N et al. Maternal nutritional deficiencies and small-for-gestational-age neonates at birth of women who have undergone bariatric surgery. J Pregnancy. 2017;2017:4168541.

8. Bettini S. Diet approach before and after bariatric surgery. [Internet.] europepmc.org. 2020. Available from: https://europepmc.org/article/med/32734395.

9. Devlieger R, Guelinckx I, Jans G, Voets W, Vanholsbeke C, Vansant G. Micronutrient levels and supplement intake in pregnancy after bariatric surgery: a prospective cohort study. PLoS One. 2014;9(12):e114192.

10. Coupaye M, Legardeur H, Sami O, Calabrese D, Mandelbrot L, Ledoux S. Impact of Roux-en-Y gastric bypass and sleeve gastrectomy on fetal growth and relationship with maternal nutritional status. Surg Obes Relat Dis. 2018;14(10):1488-94.

11. Mousa A, Naqash A, Lim S. Macronutrient and micronutrient intake during pregnancy: an overview of recent evidence. Nutrients. 2019;11(2):443.

12. Costa MM, Belo S, Souteiro P, Neves JS, Magalhães D, Silva RB et al Pregnancy after bariatric surgery: maternal and fetal outcomes of 39 pregnancies and a literature review. J Obstet Gynaecol Res. 2018;44(4):681-90.

13. Ciangura C, Coupaye M, Deruelle P, Gascoin G, Calabrese D, Cosson E et al. Clinical practice guidelines for childbearing female candidates for bariatric surgery, pregnancy, and post-partum management after bariatric surgery. Obes Surg. 2019;29(11):3722-34.

14. Getahun D. Perinatal outcomes after bariatric surgery. Am J Obstet Gynaecol. 2022;226(1):e1-121.

15. Gascoin G, Gerard M, Sallé A, Becouarn G, Rouleau S, Sentilhes L et al Risk of low birth weight and micronutrient deficiencies in neonates from mothers after gastric bypass: a case control study. Surg Obes Relat Dis. 2017;13(8):1384-91.

16. Malik S et al. Maternal and fetal outcomes of Asian pregnancies after bariatric surgery. Surg Obes Relat Dis. 2020;16(4):529-35.

17. Kumari A, Nigam A. Bariatric surgery in women: a boon needs special care during pregnancy. J Clin Diagn Res. 2015;9(11):QE01-5.

18. Magdaleno R, Pereira BG, Chaim EA, Turato ER. Pregnancy after bariatric surgery: a current view of maternal, obstetrical and perinatal challenges. Arch Gynecol Obstet. 2011;285(3):559-66.

19. Johnson K. Recommendations to Improve Preconception Health and Health Care – United States: A Report of the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care. [Internet.] CDC Recommendations and Reports. 2019. Available from: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5506a1.htm.

20. Faria SL, Faria OP, de Gouvêa HR, Amato AA. Supplementation adherence and outcomes among pregnant women after bariatric surgery. Obes Surg. 2018;29(1):178-82.

21. Mead NC, Sakkatos P, Sakellaropoulos GC, Adonakis GL, Alexandrides TK, Kalfarentzos F. Pregnancy outcomes and nutritional indices after 3 types of bariatric surgery performed at a single institution. Surg Obes Relat Dis. 2014;10(6):1166-73.

Kurdo Araz RCSI medical student

Pathophysiological link between Alzheimer’s disease and type 2 diabetes mellitus: novel therapeutic applications of anti-diabetic drugs

Abstract

This review aims to distinguish type 2 diabetes (T2D) and Alzheimer’s disease (AD) as independent illnesses, while also highlighting the relationship of insulin resistance (IR) between the two conditions. Elucidating a similar mechanism of IR in T2D and AD may uncover the potential for diabetic therapies to treat AD. The cause of AD is unknown, although it is established that T2D is a major risk factor. The focus of this review will be to: 1. examine the mechanistic cross-talk between insulin-mediated signalling pathways in both T2D and AD; 2. highlight the similar cellular structural changes in the brain associated with cognitive impairments in both T2D and AD; and, 3. assess the effectiveness of diabetic therapies to ameliorate AD-related cognitive impairments. AD has been described as a brain-specific diabetes due to the presence of IR within regions of the brain exhibiting high insulin signalling and insulin receptor expression (e.g., the hippocampus). IR is associated with decreased hippocampal glucose metabolism in AD and T2D, leading to cognitive impairments. Future longitudinal studies should be conducted on AD-predisposed populations, or individuals exhibiting early signs of AD, to assess the effectiveness of diabetic therapies on outcomes associated with cognitive impairments before irreversible complications arise.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 33-37.

Introduction

Alzheimer’s disease (AD) is the most common age-related form of dementia, and leads to progressive brain atrophy, decreased cortical activity, and memory impairments.1 AD is characterised by extracellular plaques containing amyloid-beta peptide (A β ) aggregates formed from abnormal amyloid precursor protein (APP) cleavage, and the presence of neurofibrillary tangles (NFTs) as a result of abnormal phosphorylation of the tau protein within the brain.2 AD is associated with chronic inflammation, oxidative stress (OS), mitochondrial dysfunction, DNA damage, loss of cholinergic neurons, and disruption in neural communication within the brain.2 The cause of AD is unknown; however, it is established that ageing and type 2 diabetes (T2D) are major risk factors.3

T2D is caused by systemic insulin resistance (IR) leading to characteristic features such as chronic hyperglycaemia, hyperinsulinaemia, and insulin deficiency.4 Similar to AD, T2D is associated with low-grade chronic inflammation, increased OS, mitochondrial dysfunction, DNA damage, and increased apoptosis of insulin-sensitive cells.5 Risk factors of T2D include ageing, obesity, and sedentary lifestyles.

Recent evidence supports that IR and insulin deficiency within the brain are involved in AD-related neurodegeneration.6 Individuals with T2D have been shown to have an increased risk of dementia or AD, and animal models for T2D have shown increased cognitive impairments when compared to controls.6 IR leads to brain hypoperfusion, which can exacerbate cognitive impairments and cause hyperinsulinaemia, ultimately impairing the blood–brain barrier’s (BBB) ability to transport insulin to the brain in patients with T2D.7 T2D has been associated with atrophy within regions of the brain that are affected in AD, including the hippocampus, which is closely linked with memory and learning.8 The question remains whether or not T2D or pre-diabetes prime an individual to develop AD, although it is likely that T2D and AD are independent of one another, since Aβ plaques and NFTs are not characteristic pathological signs of T2D. AD prevalence is increasing within developed countries that have an ageing population.9 As a consequence, the economic and caregiver burden is expected to increase. Major efforts have been made to push for a cure, but so far there remains a lack of validated therapeutic targets due to the incomplete understanding of the pathogenesis of AD. However, recently it has been discovered that individuals with AD have been shown to exhibit brain IR and insulin deficiency leading to decreased glucose metabolism within the brain.10 The focus of this review will be to: 1. examine the mechanistic cross-talk between insulin-mediated signalling pathways in both T2D and AD; 2. highlight similar cellular structural changes in the brain associated

with cognitive impairments in both T2D and AD; and. 3. assess the effectiveness of diabetic therapies to ameliorate AD-related cognitive impairments. This review aims to distinguish T2D and AD as independent diseases; however, it will draw on the relation of IR between the two to support the theory11 that AD is a diabetic-like illness localised within the brain.

Alzheimer’s disease is the most common age-related form of dementia, and leads to progressive brain atrophy, decreased

cortical activity, and memory impairments.

Mechanistic cross-talk between type 2 diabetes and Alzheimer’s disease as a consequence of insulin resistance

Insulin synthesis has been reported in hippocampal and cerebral neocortex neurons by detecting insulin mRNA transcripts.12 However, research has shown that the DNA in human neuronal brain cells does not actually express insulin, but rather expresses the insulin receptors.13 Insulin is produced in the pancreas and enters the brain by crossing the BBB through a receptor-mediated process, which establishes that neuronal brain cells are insulin sensitive.13 Upon insulin receptor binding, the insulin receptor is activated via auto-phosphorylation, which then activates insulin receptor substrates 1 and 2 (IRS-1/2) simultaneously.13 Activated IRS-1/2 activates phosphatidylinositol-3-kinase (PI3K), which activates protein kinase B (Akt). Activated Akt inhibits glycogen-synthase-3β (GSK-3β) via phosphorylation, resulting in glycogen synthesis.14

Real-time qPCR analysis of post-mortem AD frontal lobe samples have shown lower insulin and insulin receptor mRNA levels compared to healthy controls, suggesting the presence of IR within the brain.14 IR has been shown to downregulate Akt leading to the activation of GSK-3β, which then modulates apoptotic events.2 GSK-3β is known to phosphorylate tau proteins, and GSK-3β over-activation causes increased phosphorylation of tau proteins leading to NFT formation.15 This suggests that GSK-3β may have a role in neuronal cell loss and the disruption of neural communication in neurodegenerative diseases that have characteristic brain IR, such as AD.

Increases in Aβ in the hippocampus have been shown to disrupt insulin receptor signalling by binding to the insulin receptor and activating the c-JUN N-terminal kinase (JNK) pathway, ultimately leading to the inhibitory phosphorylation of IRS-1/2.16 This suggests a potential mechanistic link between Aβ deposition in AD leading to IR

within the brain; however, the exact mechanism by which Aβ activates the JNK pathway remains unclear. Brain IR results in brain hyperinsulinaemia, which leads to the competitive inhibition of Aβ degradation, since both insulin and Aβ are substrates for the insulin-degrading enzyme (IDE) in neurons and glia.17 Insulin regulates IDE, and lack of insulin signalling leads to lower IDE expression, hindering Aβ degradation further.17 Impaired insulin signalling leads to increased OS, which is associated with the abnormal cleavage of APP into Aβ 17 Characteristics of T2D (such as IR) that lead to the lack of insulin signalling and hyperinsulinaemia, act as a cross-talk mechanism with AD pathologies, including tau protein phosphorylation and Aβ aggregation. Such a link suggests that brain IR is a possible mechanism for the pathogenesis of AD.

Structural and functional brain changes related to cognitive impairment in type 2 diabetes and Alzheimer’s disease

Aside from glucose transport and metabolism regulation, the main role of insulin in the brain is homeostatic regulation, synaptic plasticity modulation, and neurotransmission – all of which influence cognitive function.18 Expression of insulin and insulin receptors are highest in regions of the brain such as the hippocampus, which suggests the role of insulin in memory and learning.19 This means that the hippocampus has high metabolic demand, and if IR is present in the hippocampus, it can cause pronounced atrophy, leading to memory deficits. A longitudinal study has estimated that the rate of global brain atrophy is three times faster in patients with T2D compared to healthy subjects, suggesting that systemic IR plays a role in neurodegeneration.20 However, the latter study was not age matched, a confounding variable, as brain atrophy is a consequence of ageing.20 Furthermore, a study conducted by Baker et al. (2011) used fludeoxyglucose-positron emission tracer scans of individuals displaying mild cognitive impairments (MCIs) to detect brain glucose metabolism, since MCIs are a known pre-clinical symptom of AD.21 Reduced glucose metabolism in the hippocampus was reported years before the onset of dementia in individuals who have a high risk of developing AD. However, the study did not determine if it was due to brain hypoperfusion, brain IR or both.21

Post-mortem brain samples of patients with T2D and prediabetes showed no significant increase in Aβ plaques or NFT when compared to normoglycaemic controls; however, they did show significant brain atrophy.22 The lack of AD pathology in the T2D brain suggests that these two diseases are independent from one another, and perhaps brain IR is not characteristic of T2D. However, both T2D and AD exhibit decreased glucose metabolism and atrophy in similar brain

regions such as the hippocampus. The suggested link between common brain structural and functional traits in T2D and AD patients might be due to brain hypoperfusion and a leaky BBB, ultimately decreasing insulin delivery to the brain and resulting in cognitive impairments.23 Both diseases exhibit white matter hyperintensities as a result of increased activation of microglia, leading to increased OS that can cause neuronal cell loss.6 Hippocampal cell loss leads to decreased synapses, causing impairments to memory and learning. Increased OS, neuronal cell loss, and cognitive impairments are all age-related processes. Thus, the brain imaging studies that suggest similarities in T2D and AD structural brain changes are inconclusive, but do suggest an interrelatedness between common key characteristics.

Aside from glucose transport and metabolism regulation, the main role of insulin in the brain is homeostatic regulation, synaptic plasticity modulation, and neurotransmission – all of which influence cognitive function.

Effectiveness of diabetic approaches to reduce cognitive impairments associated with Alzheimer’s disease

Anti-A β drug therapies to treat AD have failed, showing no improvements in cognitive impairments related to AD.24 It has ultimately been determined that Aβ does not accurately predict cognitive impairments.24 Failure of pharmacotherapy development for AD is largely due to the ambiguous pathophysiology of AD. The pathophysiology of AD is difficult to study because cognitive impairments that arise in AD come in later stages and therapies that target Aβ start when brain atrophy is irreversible.24 As a result of research efforts studying brain IR, irregular brain glucose metabolism and influences of brain hyperinsulinaemia in AD, many initiatives have investigated the effectiveness of diabetic therapies to treat AD-related cognitive impairments.25

Brain IR in patients with AD displays brain insulin deficiency, which suggests that increasing brain insulin levels is a viable treatment option. However, typical diabetic insulin injections in AD patients would lead to potentially lethal hypoglycaemia, since they do not exhibit systemic IR.26 Intranasal administration has been shown to transiently increase brain insulin and lower plasma glucose to normal ranges.27 Both acute and chronic intranasal insulin therapy in AD patients improve memory and selective attention in a dose-dependent manner. Intranasal insulin treatment appears to reduce cognitive impairments associated with AD by increasing

insulin signalling, leading to increased activity in the hippocampus, which was previously in an insulin-deficient state.27

In recent clinical trials, insulin-sensitising agents, such as metformin, were used long term in T2D patients, leading to a significantly lower incidence of dementia, and suggesting that metformin has neuroprotective effects.28 It has been demonstrated that metformin reduces phosphorylated tau protein levels in the hippocampus in AD rat models, which led to improved memory.29 It was mentioned that metformin attenuates the passing of Aβ across the BBB, leading to decreased plaque formation; however, this was not proven with any technique. In addition, glucagon-like peptide 1 (GLP-1) agonists increase insulin secretion, leading to neuroprotective effects and improved cognition in AD rat models.30 It is evident that IR treatment in AD brains shows promise in improving cognitive processes due to neuroprotection as a result of increased insulin signalling modulating synaptic plasticity. However, this is inconclusive and requires intensive clinical trials in humans to further assess the benefits of using diabetic treatments to ameliorate cognitive impairments in AD.

Future longitudinal studies should be conducted on AD-predisposed populations or individuals exhibiting early signs of AD, in order to assess the effectiveness of diabetic therapies on outcomes associated with cognitive impairments before irreversible complications arise. This will provide clear evidence that targeting brain IR, and normalising insulin signalling within brain regions such as the hippocampus, can prevent cognitive impairments in populations that have a high risk of developing AD. Such studies should be carried out in AD animal models to track Aβ plaques and NFTs to relate these pathologies to aberrant brain insulin signalling.

Conclusion

T2D is a risk factor for AD; however, AD pathological signs such as Aβ plaques and neurofibrillary tangles are not characteristic of T2D, suggesting that these two conditions are independent from one

another.3 Thus, AD is considered a brain-specific, diabetes-like condition due to the presence of IR within regions of the brain with high insulin and insulin receptor expression (e.g., the hippocampus).19 Aβ deposition exacerbates brain IR, leading to the downregulation of the PI3K/Akt signalling pathway and the over-activation of GSK-3β, which then phosphorylates tau proteins, leading to neurofibrillary tangles.16,17 Decreased insulin signalling within the brain is associated with atrophy within the hippocampus in patients with AD.23 IR is associated with decreased glucose metabolism within the hippocampus of AD and T2D patients, leading to cognitive impairments.22

Clinical trials for diabetic treatments in the early stages of AD are missing from the literature due to delayed diagnoses in patients who have already developed cognitive impairments, or through post-mortem brain analysis to identify key pathologies. The ability to identify the specific neuroprotective mechanisms of diabetic treatments remains to be elucidated, which is crucial in order to develop more targeted AD therapies that ameliorate brain IR. Such future studies can guide researchers in developing novel diabetic therapies that treat cognitive impairments in AD, and to identify specific targets that reverse or attenuate brain IR. Lastly, specific proven targets can be used as markers to assess an individual’s susceptibility and therapeutic prognosis to AD in order to ensure early therapeutic intervention and prevent irreversible AD.

Clinical trials for diabetic treatments in the early stages of AD are missing from the literature due to diagnosis of AD occurring late onset once cognitive impairments arise, or through post-mortem brain analysis to identify key pathologies.

References

1. Zhou M, Chen S, Peng P, Gu Z, Yu J, Zhao G et al. Dulaglutide ameliorates STZ induced AD-like impairment of learning and memory ability by modulating hyperphosphorylation of tau and NFs through GSK3β Biochem Biophys Res Commun. 2019;511(1):154-60.

2. Rahman SO, Panda BP, Parvez S, Kaundal M, Hussain S, Akhtar Mohd et al Neuroprotective role of astaxanthin in hippocampal insulin resistance

induced by Aβ peptides in animal model of AD. Biomed Pharmacother. 2019;110:47-58.

3. Gabbouj S, Natunen T, Koivisto H, Jokivarsi K, Takalo M, Marttinen M et al

Intranasal insulin activates Akt2 signaling pathway in the hippocampus of wild-type but not in APP/PS1 Alzheimer model mice. Neurobiol Aging. 2019;75:98-108.

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4. Sengupta U, Ukil S, Dimitrova N, Agrawal S. Expression-based network biology identifies alteration in key regulatory pathways of T2D and associated risk/complications. PLoS ONE. 2009;4(12):e8100.

5. Cardoso CRL, Leite NC, Carlos FO, Loureiro AA, Viegas BB, Salles GF. Efficacy and safety of diacerein in patients with inadequately controlled T2D: a randomized controlled trial. Diabetes Care. 2017;40(10):1356-63.

6. Verdelho A, Madureira S, Ferro JM, Basile AM, Chabriat H, Erkinjuntti T et al. Differential impact of cerebral white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The LADIS study. J Neurol Neurosurg Psychiatry. 2007;78(12):1325-30.

7. Rodriguez-Rodriguez P, Sandebring-Matton A, Merino-Serrais P, Parrado-Fernandez C, Rabano A, Winblad B et al. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons. Brain. 2017;140(12):3269-85.

8. Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A et al. Brain atrophy in T2D: regional distribution and influence on cognition. Diabetes Care. 2013;36(12):4036-42.

9. Fillit HM, O’Connell AW, Brown WM, Altstiel LD, Anand R, Collins K et al Barriers to drug discovery and development for Alzheimer disease. Alzheimer Dis Assoc Disord. 2002;16(Suppl. 1):S1-8.

10. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in AD and diabetes. J Pathol. 2011;225(1):54-62.

11. de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes –evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101-13.

12. Molnár G, Faragó N, Kocsis AK, Rózsa M, Lovas S, Boldog E et al GABAergic neurogliaform cells represent local sources of insulin in the cerebral cortex. J Neurosci. 2014;34(4):1133-7.

13. Avila J, León-Espinosa G, García E, García-Escudero V, Hernández F, DeFelipe J. Tau phosphorylation by GSK3 in different conditions. Int J Alzheimers Dis. 2012;2012:578373.

14. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of AD: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005;8(3):247-68.

15. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of AD. J Neurochem. 2008;104(6):1433-9.

16. Zhao WQ, Lacor PN, Chen H, Lambert MP, Quon MJ, Krafft GA et al Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric Aβ. J Biol Chem. 2009;284(28):18742-53.

17. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for T2D and AD. Biochimica et Biophysica Acta. 2009;1792(5):482-96.

18. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708-19.

19. Zhao W, Wu X, Xie H, Ke Y, Yung W. Permissive role of insulin in the expression of long-term potentiation in the hippocampus of immature rats. Neurosignals. 2010;18(4):236-45.

20. Kooistra M, Geerlings MI, Mali WPTM, Vincken KL, van der Graaf Y, Biessels GJ. Diabetes mellitus and progression of vascular brain lesions and brain atrophy in patients with symptomatic atherosclerotic disease. The SMART-MR study. J Neurol Sci. 2013;332(1-2):69-74.

21. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early T2D. Arch Neurol. 2011;68(1):51-7.

22. Willette AA, Johnson SC, Birdsill AC, Sager MA, Christian B, Baker LD et al. Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement. 2015;11(5):504-510.e1.

23. Arab L, Sadeghi R, Walker DG, Lue L-F, Sabbagh MN. Consequences of aberrant insulin regulation in the brain: can treating diabetes be effective for AD. Curr Neuropharmacol. 2011;9(4):693-705.

24. Anderson RM, Hadjichrysanthou C, Evans S, Wong MM. Why do so many clinical trials of therapies for AD fail? Lancet. 2017;390(10110):2327-9.

25. Muñoz-Jiménez M, Zaarkti A, García-Arnés JA, García-Casares N. Antidiabetic drugs in AD and mild cognitive impairment: a systematic review. Dement Geriatr Cogn Disord. 2020;49(5):423-34.

26. Dhuria SV, Hanson LR, Frey WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654-73.

27. Benedict C, Hallschmid M, Schultes B, Born J, Kern W. Intranasal insulin to improve memory function in humans. Neuroendocrinology. 2007;86(2):136-42.

28. Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L et al. Effects of the insulin sensitizer metformin in Alzheimer disease: pilot data from a randomised placebo-controlled crossover study. Alzheimer Dis Assoc Disord. 2017;31(2):107-13.

29. Chen JL, Luo C, Pu D, Zhang GQ, Zhao YX, Sun Y et al. Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance. Exp Neurol. 2019;311:44-56.

30. Tai J, Liu W, Li Y, Li L, Hölscher C. Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of AD. Brain Res. 2018;1678:64-74.

Sophia

RCSI medical students

Hashimoto’s encephalopathy: a review of cases

Abstract

Hashimoto’s encephalopathy (HE) is a rare autoimmune encephalitis characterised by anti-thyroglobulin and/or anti-thyroperoxidase antibodies in combination with a heterogenous array of neuropsychiatric symptoms. Often, clinical diagnosis is challenging and reliant upon diagnostic suspicion, as it is an uncommon disease with highly variable clinical presentations. This paper reviewed case reports published on PubMed, Embase, and Web of Science over the last six years, totalling 182 cases. The mean age of presentation was 43.2 years with a female predominance. The most common clinical presentations were psychiatric pathology, neurological deficit, and altered mental status; 62% of patients experienced multiple distinct symptoms. Most patients presented with raised anti-thyroperoxidase autoantibodies, with fewer exhibiting anti-thyroglobulin antibodies. Laboratory and imaging investigation findings were as disparate as patient presentations. The most common treatment was IV methylprednisolone followed by secondary immunotherapies if unresponsive. In total, 149 patients demonstrated clinical improvement, 92 made a full recovery, and 29 relapsed. Thus, the compiled data supports HE as a highly heterogenous disease, with no specific clinical presentation or diagnostic clues, so it should be suspected when neuropsychiatric symptoms fail to respond to standard treatments.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 38-44.

Rachel Frankle

Downey

RCSIsmj review

Publications identified from:

PubMed (n=283)

Embase (n=234)

Web of Science (n=155)

Total (n=672)

Publications screened (n=497)

Publications assessed for eligibility

Publications removed before screening: Duplicate records removed (n=152)

Total publications excluded (n=337)

Publications excluded: Alternative diagnosis, i.e., not HE (n=238) Not in English (n=18)

Not available via institutional access (n=38) Not case report (n=43)

Cases included in review (n=182)

Publications (n=160)

Introduction

Hashimoto’s encephalopathy (HE) or encephalitis was first described in 1966 by Lord Brain as a neurological manifestation of Hashimoto’s thyroiditis.1 However, with the emergence of more cases, it became evident that HE did not only result from Hashimoto’s thyroiditis, and biomarkers for thyroiditis were no longer sufficient for diagnosis. Proposed diagnostic criteria now rely on the detection of autoantibodies against thyroglobulin and/or thyroperoxidase, in combination with neurologic/psychiatric symptoms and response to immunosuppressive therapy.2,3 Although the specific pathophysiology of HE is currently unknown, it has been theorised that it may represent a vasculitis, an immune complex disease, or a demyelinating process; the anti-thyroperoxidase and anti-thyroglobulin characteristics of the disease may not in fact contribute to the pathologic mechanism.1,4-8

The presentation of HE is highly variable, and can include a broad range of neuropsychiatric signs and symptoms. Diagnosis is therefore frequently delayed, by exclusion only, or missed entirely. Differential diagnoses often include viral encephalitis, schizophrenia, depression, epilepsy, paraneoplastic syndromes (e.g., anti-NMDA-R, anti-Hu), and Creutzfeldt-Jakob disease. Findings supportive of a diagnosis of HE include elevated white cells and protein in the cerebrospinal fluid, altered thyroid function, and nonspecific magnetic resonance imaging (MRI) and electroencephalogram (EEG) abnormalities; however, none of these are unique to HE, and can only lend support to the diagnosis.2-11

FIGURE 1: Publication screening methods. PubMed, Web of Science, and Embase were searched for cases of HE with the terms ‘Hashimoto encephalopathy’ or ‘Hashimoto’s encephalopathy’ or ‘Hashimoto encephalitis’ or ‘Hashimoto’s encephalitis’ or ‘steroid-responsive encephalopathy associated with autoimmune thyroiditis’ or ‘SREAT’, yielding 672 results. Records present in multiple databases were counted as one publication, so 152 publications were duplicates. A total of 497 were then screened, of which 160 papers yielded 182 cases. Exclusion criteria included: alternative diagnosis to Hashimoto’s encephalopathy; publications not in the English language; not available via institutional access at the Royal College of Surgeons in Ireland; or, publications that were not case reports.

As HE is known to be autoimmune in origin, the standard treatment is intravenous corticosteroids with an oral taper, yet other immunosuppressive treatments are often used, with variable clinical response.3-7,11 Long-term prognoses and complications remain largely unreported and are therefore relatively unknown. This literature review aims to detail the epidemiology and relative prevalence of the various clinical presentations of HE, as well as laboratory findings, treatment, and therapeutic responses of this little studied disease.

Methods

We searched for the terms ‘Hashimoto encephalopathy’ or ‘Hashimoto encephalitis’ or ‘steroid-responsive encephalopathy associated with autoimmune thyroiditis’ or ‘SREAT’. Searches were conducted on September 2, 2023. To find raw case data, we restricted publications to the last six years, thus spanning the period 2017-2023. In PubMed and Embase, we were able to restrict results to case reports, and in Web of Science we restricted results to articles and letters. Preliminary results included 283 papers from PubMed, 155 from Web of Science, and 234 from Embase. Any paper that did not describe a case of HE was excluded. Studies for which full access was unavailable, and those not available in English, were also excluded. Multiple cases within the same publication were extracted as separate cases. Thus, data included 99 cases from PubMed, 21 from Web of Science, and 62 from Embase, providing a total of 182 cases (Figure 1).

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Table 1: Clinical presentations.

Similar to other autoimmune encephalopathies, HE has a diverse range of clinical presentations, which were broadly classified into the above categories. Additionally, patients with signs and symptoms applicable to multiple categories were counted in each one relevant, as well as in the category of multiple presenting symptoms.

We extracted data from each case regarding the patients’ sex, age, signs and symptoms, thyroid function tests (TFTs), anti-thyroglobulin (anti-TPO) and anti-thyroperoxidase (anti-TG) antibodies, protein and white blood cells (WBCs) in the cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) or electroencephalogram (EEG) findings, and any demonstrated treatment(s), response to treatment, and any available relapse information. In certain publications, information for all categories of data were not given – in the absence of quantitative data, the available description was coded qualitatively. Data was then analysed in R12 and jamovi.13

History and diagnostic criteria:

Hashimoto’s encephalopathy

The first reported case of HE occurred in a patient with Hashimoto’s thyroiditis; hence, the disease was first termed ‘Hashimoto’s encephalopathy’. However, further cases revealed patients with hyperthyroidism or even normal thyroid function, calling into question HE as an apt description. A new name – steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) – was proposed because many patients with HE did not have concurrent Hashimoto’s thyroiditis. Moreover, the anti-thyroid antibodies considered characteristic of HE do not appear to contribute to the underlying pathology. Of interest, one large-scale study demonstrated anti-TPO and anti-TG in 11.3% and 10.4%, respectively, of the general population, and the antibodies were more prevalent in women and with increasing age (sample size of 17,353 demographically representing the United States).14 This indicates that antibodies may be detected in those without HE, but the combination of suggestive symptoms and positive antibodies is still highly indicative of HE. Although the autoimmune nature of HE is well established, the pathogenic mechanism is still highly debated. Suggested

FIGURE 2: Thyroperoxidase (anti-TPO Ab) and thyroglobulin (anti-TG Ab) antibody values. Quantitative values of anti-thyroglobulin or anti-thyroperoxidase autoantibodies are visualised. A value for each case is plotted when available, and a box and whisker plot demonstrates the spread and distribution of values.

pathophysiologic mechanisms include vasculitis, immune complex deposition, and demyelination, but none have been definitely proven.1,4-8 Most physicians accept the diagnostic criteria of HE, which require neuropsychiatric abnormality, the presence of elevated thyroid peroxidase antibodies and/or thyroglobulin autoantibodies, and response to immunosuppressive therapy. HE is a diagnosis of exclusion in many cases – infectious, psychiatric, toxic, metabolic, paraneoplastic, and other autoimmune encephalopathies must be excluded.

Presentation of Hashimoto’s encephalopathy

The most common presenting complaints in the reviewed studies included specific psychiatric disorders, general altered mental status (AMS), seizure, status epilepticus (SE), neurological deficit, ataxia/cerebellar dysfunction, and stroke-like episodes (Table 1). Some 62% of patients presented with signs and symptoms of multiple types, e.g., psychosis in combination with neurological deficits. Upon further laboratory investigation, anti-TPO antibodies were present in 155 patients with a mean value of 1050.33IU/mL, and anti-TG antibodies were present in 82 patients with a mean value of 556.74IU/mL (Figure 2a/b). However, anti-TPO antibodies were far more commonly measured and reported than anti-TG.

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FIGURE 3: Thyroid function tests. TSH and free T4 values are plotted in the box and whisker plots, with each point representing an individual case. Thyroid status is presented in Table 2. Some 49% of patients were euthyroid, a statistic easily visualised in the above figure, as the interquartile range falls within the normal ranges of TSH and T4. Outliers were calculated using the interquartile range rule (Q1 – 1.5IQR, Q3 + 1.5IQR) and are not displayed on the graph.

Some 49% of patients presented as euthyroid at time of diagnosis, while 23% were hypothyroid and 14% hyperthyroid (normal TSH 0.5-5mIU/L, FT4 0.7-1.9ng/dL). This differentiation was based where possible on reported TSH and T4 values combined with the normal range provided in the Oxford Handbook of Clinical Medicine, 15 and where exact values were not reported the description in the study of thyroid status was accepted. The distribution of TFT values is represented in Figure 3, and descriptive thyroid status is presented in Table 2

CSF abnormalities were also observed, with 60 cases of elevated protein (normal 15-40mg/dL) and 24 cases of pleocytosis (WBCs >5).15 The mean CSF protein value was found to be 92.77mg/dL (range: 1-600, n=53). The mean WBC count in the CSF was found to be 27.45 (range: 0-388, n=44). The majority of patients with CSF protein and WBC tested had elevated values, but few patients had these tests performed and thus definitive conclusions cannot be made.

Moreover, MRI yielded abnormalities in 58% of patients, and EEG found abnormalities in 74% of patients, which highlights the utility of these investigations in aiding diagnosis (Table 2). Although findings

Laboratory and imaging investigations with the corresponding results are categorised here. Thyroid function tests were classified in comparison to the normal range of TSH 0.5-5mIU/L and FT4 0.7-1.9ng/dL, and quantitative data are presented in Figure 4. Of the patients that underwent MRI and/or EEG, the abnormalities were grouped by common features with or without multiple categories of features, or normal results.

on EEG and MRI are frequently abnormal, the specific findings are as heterogenous as the presentation. Findings do, however, typically correspond to the patient’s clinical signs.

Normal results on tests including bloodwork, CSF analysis, imaging, and EEG do not exclude HE as a cause; moreover, there are no specific findings characteristic of HE. Considered together, clinical presentation, laboratory investigations, and imaging can be used to elucidate a diagnosis in many cases.

Our review highlights the diversity in neurological and psychiatric presentations occurring in HE, often resulting in missed or delayed diagnosis. Of note, the majority of patients presented with multiple

symptoms, of which the most common are psychiatric disorders, altered mental status, specific neurologic deficits, and a combination thereof. Overall, two patterns of HE have been described: a relapsing-remitting course with prominent focal neurological deficits; and, a progressive course with cognitive or psychiatric manifestations.10,16,17 Interestingly, our findings vary from those reported in the most recent literature reviews.16,17 Moreover, investigations also demonstrate a large scope of abnormal findings, once again reflecting the heterogeneity often seen in an autoimmune encephalopathy. Although no distinct trends or relationships emerged to aid in the diagnosis of HE, recognition of an autoimmune encephalitis remains the key step in the management of patients with HE in order to facilitate timely treatment.

Normal results on tests including bloodwork, CSF analysis, imaging, and EEG do not exclude HE as a cause; moreover, there are no specific findings characteristic of HE.

Epidemiology of Hashimoto’s encephalopathy

Based on our research, HE affects predominantly females with a ratio of 2.3:1 (126:55). It has a mean age of onset of 43.2 years (range: 6-89). This female predominance reflects trends observed in other autoimmune conditions, namely a predilection for women of reproductive age. Interestingly, 19.8% of the cases (n=36) occurred in children less than 18 years of age, with a weaker female predominance (21:15). The age distribution is displayed in Figure 4

The management of HE varied widely, but most cases received steroids with secondary immunosuppressive therapies as needed. However, many also received other classes of medications during the disease course, whether necessary for seizure or psychosis, or resulting from an initial misdiagnosis.

Although our reported epidemiology is in keeping with these reviews, the clinical presentations and investigations differ in the prevalence of abnormal findings. This further highlights the diversity of HE cases, the lack of distinctive clinical features, and the need to revisit the utility of current diagnostic criteria.

Treatment and prognosis

First-line therapy and the most used treatment in this review was 1g IV methylprednisolone once daily for five days, with an oral prednisolone taper starting at 60mg. Second-line therapies included IV immunoglobulin (IVIG), plasmapheresis, or other immunosuppressive medication (e.g., rituximab, azathioprine). Frequently, multiple forms of immunosuppressive therapy were required to suppress disease activity, as is commonplace in the management of autoimmune conditions.18 A summary of treatments is presented in Table 3. To manage their symptoms, and in part because of a delay in diagnosis, many patients also received antipsychotics/antidepressants, antimicrobials, and/or antiepileptics. Antivirals and antibiotics were frequently given empirically with the assumption of viral/bacterial encephalitis, sepsis, etc., and stopped when laboratory investigations eliminated an infectious cause. Antiepileptics and antipsychotics are necessary in the treatment course to stop seizure activity or psychosis, and their use is therefore appropriate. The success rate for treatment is quite high, with 149 of 157 patients demonstrating clinical improvement. Unfortunately, only 92 patients made a full recovery, while the other 65 had remaining symptoms. Twenty-nine patients who experienced any degree of clinical improvement experienced later relapse. The relapse and recovery rates in this study are similar to figures reported in the

FIGURE 4: Age distribution at first onset of symptoms.

Table 3: Treatments for Hashimoto’s encephalopathy.

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literature.4,6,7,16,17 Overall, the prognosis is mixed, with high rates of residual deficits and relapse. However, given that case reports do not usually include information regarding follow-up beyond the initial episode, our ability to fully evaluate the prognosis was limited.

Although no distinct trends or relationships emerged to aid in the diagnosis of HE, recognition of an autoimmune encephalitis remains the key step in the management of patients with HE in order to facilitate timely treatment.

Fortunately, with increasing awareness of autoimmune encephalopathies, HE is more likely to be considered in any patient presenting with unexplained neurological symptoms. For the individual clinician and patient, however, the specific diagnosis of HE is less important than the overall diagnosis of autoimmune encephalitis. This generalised diagnosis allows for effective treatment, and it should prompt the necessary investigations into encephalitis sub-classification and treatment of any underlying thyroid pathology if found.3 Our results describing treatments that are currently in use reflect current guidance for the treatment of autoimmune encephalitis, which suggests the use of IV and/or oral steroids, with

the use of secondary immunotherapies if the patient is unresponsive to initial glucocorticoids.3,5 Moreover, this treatment strategy is supported by recent literature reviews.16,17

Fortunately, with increasing awareness of autoimmune encephalopathies, HE is more likely to be considered in any patient presenting with unexplained neurological symptoms.

Limitations

This review of cases has several limitations. Primarily, HE is a very rare and hence relatively unstudied and under-recognised disease, with few reported cases and little research. Misdiagnosis may prevent a certain percentage of patients from ever receiving the correct diagnosis. Furthermore, our review is constrained in scope due to access and language limitations. We did not do an extensive systematic search of large-scale databases such as Google Scholar or Scopus. Publications not listed in PubMed, Web of Science, and Embase were therefore missed. Despite the currently limited information presented here, future additional reported cases will enable better statistical analysis and identification of trends to better describe the natural history of HE.

RCSIsmj review

Despite the currently limited information presented here, future additional reported cases will enable better statistical analysis and identification of trends to better describe the natural history of HE.

Conclusion

Based on our review of case studies on HE published in the past six years, few trends are readily apparent. No significant associations between patient characteristics, imaging, diagnostics, and presentation can be gleaned from the currently available data. However, analysis of the above dataset allows a good understanding of the high variability in presentation and disease course of HE. In a

References

1. Brain, Jellinek EH, Ball K. Hashimoto’s disease and encephalopathy. Lancet. 1966;288(7462):512-14.

2. Graus F, Titulaer MJ, Balu R et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.

3. Pollak TA, Lennox BR, Müller S et al. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020;7(1):93-108.

4. Laurent C, Capron J, Quillerou B et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): characteristics, treatment and outcome in 251 cases from the literature. Autoimmun Rev. 2016;15(12):1129-33.

5. Rubin DI. Hashimoto encephalopathy. UpToDate. [Internet.] [updated February 16, 2021; cited July 5, 2021.] Available from: https://www.uptodate.com/contents/hashimoto-encephalopathy

6. Pinedo-Torres I, Paz-Ibarra JL. Current knowledge on Hashimoto’s encephalopathy: a literature review. Medwave. 2018;18(6):e7298.

7. Chong JY, Rowland LP, Utiger RD. Hashimoto encephalopathy: syndrome or myth? Arch Neurol. 2003;60(2):164-71.

8. Mahad DJ, Staugaitis S, Ruggieri P et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis and primary CNS demyelination. J Neurol Sci. 2005;228(1):3-5.

9. Boelen R, de Vries T. Clinical characteristics of paediatric Hashimoto’s encephalopathy. European J Paediatr Neurol. 2021;32:122-7.

patient presenting with unusual neurological signs and symptoms, autoimmune encephalitis should be considered and autoantibodies examined to facilitate prompt diagnosis and initiation of immunosuppressive therapy. This review can thus aid the clinician in the diagnosis and management of HE, including relapsing or recurrent HE. As increasing numbers of cases emerge, more robust data will be available for statistical analysis and the natural history of HE further clarified.

This review can thus aid the clinician in the diagnosis and management of HE, including relapsing or recurrent HE.

10. Menon V, Subramanian K, Thamizh JS. Psychiatric presentations heralding Hashimoto’s encephalopathy: a systematic review and analysis of cases reported in literature. J Neurosci Rural Pract. 2017;8(2):261-7.

11. Kothbauer-Margreiter I, Sturzenegger M, Komor J et al. Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment. J Neurol. 1996;243(8):585-93.

12. R Foundation for Statistical Computing. R: A Language and environment for statistical computing. [program.] 4.1.0 version. Vienna, Austria. 2021.

13. The jamovi project. jamovi. [program.] Sydney, Australia. 2021.

14. Hollowell JG, Staehling NW, Flanders WD et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-99.

15. Wilkinson IB, Raine T, Wiles K, Goodhart A, Hall C, O’Neill H. Oxford Handbook of Clinical Medicine (10th ed.). Oxford University Press Inc. 2017.

16. Chaudhuri J, Mukherjee A, Chakravarty A. Hashimoto’s encephalopathy: case series and literature review. Curr Neurol Neurosci Rep. 2023;23(4):167-75.

17. Waliszewska-Prosół M, Ejma M. Hashimoto encephalopathy – still more questions than answers. Cells. 2022;11(18):2873.

18. Baan RA, Stewart BW, Straif S (eds.). Tumour Site Concordance and Mechanisms of Carcinogenesis. Lyon, France: International Agency for Research on Cancer 2019.

Gabrielle Diebold RCSI medical student

Horse tranquiliser: the cure for depression?

Abstract

Ketamine, a structural analogue of phencyclidine, has for years been used as a sedative for procedures and surgery. Treatment-resistant depression (TRD) is depression that has failed to respond to at least two different antidepressants. Recent studies have shown that intravenous ketamine infusions are safe and effective in the short-term treatment of TRD, prompting consideration of its use as an adjunct or alternative to more traditional forms of depression treatment. A nasal spray formulation of ketamine has been approved for use in both the United States and Ireland. Off-label use of ketamine in the United States has expanded to include treatment of anxiety, post-traumatic stress disorder and chronic pain. Long-term efficacy and side effects of maintenance ketamine treatment remain to be studied.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 45-50.

Introduction

Depression afflicts 350 million people worldwide, with a lifetime incidence of 28%.1 Standard treatment for depression consists of psychotherapy and selective serotonin reuptake inhibitor (SSRI) antidepressants. Serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors can also be used, but these usually have more significant side effect profiles compared to SSRIs.2

Treatment-resistant depression (TRD) is defined as failure to respond to at least two different antidepressants, and occurs in one-third of all patients with depression.1 Treatment for TRD includes adding additional antidepressants, as well as the use of nonpharmacologic modalities such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).3 Recently, the treatment of TRD with intravenous ketamine infusions has been studied. This review will examine the efficacy results of some of those studies, as well as the safety profile of ketamine, its comparison to other treatment modalities, and its current clinical use in the treatment of TRD in the United States and Ireland.

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The history of ketamine

Ketamine hydrochloride was first synthesised in 1962. As a shorter-acting structural analogue of phencyclidine (PCP), it retains similar anaesthetic potential but with less emergence delirium. While first used as a veterinary anaesthetic and commonly known as a horse tranquiliser, it quickly found its use in humans and was administered to soldiers in the Vietnam War as a field anaesthetic.4 Ketamine continues to be used worldwide for general anaesthesia, analgesia, and procedural sedation.

Ketamine is known to be a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, and for that reason, it started to be tested for the treatment of depression after NMDA antagonists were found to have antidepressant effects in animal models. However, its exact mechanism of action in the treatment of depression remains unknown, and is likely complex. It has been suggested that ketamine has an antidepressant effect by modulating cortical gamma-aminobutyric acid (GABA) levels.5 Ketamine may also treat depression by suppressing pro-inflammatory cytokines,6 affecting ion channels,7 and/or affecting the concentration of plasma brain-derived neurotrophic factor, which are all processes implicated in depression.8 A 2010 experiment in rats revealed that ketamine rapidly activates the brain’s rapamycin (mTOR) signalling pathway, which controls protein synthesis required for new synaptic connections between neurons. Specifically, ketamine’s actions on this pathway restored connections between the rats’ prefrontal cortex neurons that had been damaged by chronic stress.9

Ketamine hydrochloride was first synthesised in 1962. As a shorter-acting structural analogue of phencyclidine (PCP), it retains similar anaesthetic potential but with less emergence delirium.

The evidence in favour of ketamine for treatment-resistant depression

While ketamine has not yet been approved to manage TRD, early studies have shown promising results. The first study examining the use of ketamine for the treatment of TRD was a randomised, placebo-controlled, double-blind study in 2006, which showed the rapid antidepressant effects of two infusions given a week apart.3 Further studies have been done throughout the years, some of which will be examined in this review. All included studies administered ketamine at a dose of 0.5mg/kg over 40 minutes via intravenous infusion.7 For reference, a dissociative intravenous (IV) dose given for

sedation or general anaesthesia is 1mg/kg over 30 seconds.8 The studies used either the Hamilton or the Montgomery-Aspberg depression rating scale (HDRS or MADRS) as the primary measurement to assess for alleviation of depressive symptoms with treatment. Both scales take into account a patient’s rating of their depressed mood, anxiety, physical symptoms, and suicidality. Of the eight studies, three were not placebo controlled, three used saline as a non-active placebo, and two used midazolam as an active placebo. Ketamine was given either as a single infusion, as two infusions, or as six infusions over two weeks.

While ketamine has not yet been approved to manage TRD, early studies have shown promising results.

Single-infusion studies of ketamine showed promising results. One study reported a mean seven-point reduction in the HDRS scores of participants.10 Another study showed that ketamine infusions were more effective than midazolam infusions in rapid depression relief, with patients’ MADRS scores decreasing by 7.95 points more with ketamine than with midazolam.11 In that study, there was also a higher percentage of patients who responded to ketamine (64%) compared to patients who responded to midazolam (28%). Studies that administered two infusions of ketamine showed a similar significant improvement in depression relief and reduction in depression rating scales when compared to saline placebo.3,12 In these studies, the effects were rapid, with one study showing the beneficial effects within just 110 minutes of infusion.3 In a similar study, 70.8% of patients responded to treatment with a mean 18.9-point reduction in MADRS scores within two hours post infusion.13 The rapid effect of ketamine may be beneficial when used as a bridge to help patients until more traditional forms of treatment have a chance to kick in and start working.

Repeat infusions were also effective in treating depression and may be more effective than single infusions.14 A systematic review of 21 studies found that the effect of ketamine treatment was significantly greater with repeat infusions than with a single infusion.15 In one study, participants experienced an 85% reduction in their MADRS score after six infusions over two weeks.16 The frequency of infusions did not cause any significant difference in effect, with another study showing an 18.4-point reduction in the MADRS scores of patients who received twice-weekly infusions and a similar 17.7-point reduction in patients receiving thrice-weekly infusions.17 Repeat infusions may therefore have a more sustained effect than a single infusion.

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Real-world use of ketamine

Alnefeesi et al. (2022) reviewed studies of the use of ketamine for treatment of depression in practice.18 These studies, which did not limit participation by excluding patients with suicidality, comorbidities (specifically psychotic disorders, such as schizophrenia), concurrent antidepressant use, or current substance use or abuse, showed that the mean antidepressant effect of ketamine is still substantial in ‘real-world’ patients, with 43% of participants responding to treatment and 30% experiencing remission of their depression.18

Ketamine has also been found to be beneficial in the treatment of other mental health disorders such as post-traumatic stress disorder (PTSD), anxiety, obsessive-compulsive disorder, bipolar depression, and suicidal ideation, where the anti-suicidal effect is almost immediate and can last a week, during which time the patient can receive further traditional treatment.19-28 In bipolar patients, ketamine has also been shown to improve depression symptoms without an increase in manic symptoms.20 Ketamine may also be helpful in the treatment of depression related to Parkinson’s disease and Alzheimer’s disease.29,30

Ketamine has also been found to be beneficial in the treatment of other mental health disorders such as post-traumatic stress disorder (PTSD), anxiety, obsessive-compulsive disorder, bipolar depression, and suicidal ideation.

Risk of relapse

Despite the success in the immediate relief of depression symptoms, studies show that these results may not be long lasting. In one study, eight out of nine patients relapsed into depression within an average of 19 days after their last ketamine treatment.16 In a similar trial, 13 out of 17 patients relapsed within an average of 18 days post treatment.13 Other studies showed that the effectiveness of ketamine treatment is not substantial even just one week after the last infusion, with only 35% of patients maintaining their initial response by day seven in one study,31 and a meagre 13% in another.10

A systematic review by Coyle et al. (2015)15 and a meta-analysis by Kryst et al. (2020)32 reinforced the idea that ketamine infusions are not substantial treatments in the long term, as its antidepressant effects were not seen after 12-14 days post infusion and after seven days post infusion, respectively. This suggests that while ketamine has a rapid effect in TRD, the effect is short term and patients are likely to

experience a relapse soon after the last infusion. For this reason, many clinics offer maintenance sessions. Weekly maintenance infusions have been found to be beneficial, and long-term maintenance therapy with esketamine, the S enantiomer of ketamine, when given weekly or every two weeks as a nasal spray, has also been shown to be beneficial in preventing relapse.2,13,33,34

Despite the success in the immediate relief of depression symptoms, studies show that these results may not be long lasting.

The

safety of ketamine

Multiple studies have also shown that ketamine infusion treatment for depression is relatively safe. The most common adverse effects experienced by participants receiving a ketamine infusion are dissociation, perceptual disturbances, blurred vision, confusion, elevations in blood pressure and heart rate, nausea or vomiting, euphoria, dizziness, and headache, all of which resolved within four hours after the start of the infusion.3,10,11,13,14,16,17

Ketamine vs other treatments for treatment-resistant depression

In comparison to other treatment modalities for TRD, ketamine has been found to be noninferior to ECT.35 A 2023 study showed that after three weeks, 55% of participants who received twice-weekly ketamine infusions reported at least a 50% improvement in their depression symptoms compared to 41% of participants who received ECT. During a six-month follow-up period, only 34% of participants treated with ketamine relapsed versus 56% of those treated with ECT.35 Another study found that ketamine is effective in patients who did not respond to ECT, with an even larger effect in patients who were never exposed to ECT.36 Ketamine may also have the added benefit of not causing either anterograde or retrograde amnesia, which can be seen with ECT.

TMS is another recognised treatment for TRD. In a trial on 28 patients combining TMS with ketamine infusions, it was found that due to ketamine’s analgesic effect, participants could endure a higher intensity of output power from the magnetic head coil, resulting in fewer and shorter sessions needed when compared to using TMS alone. Long-term remission of depressive symptoms was seen in these subjects for two years following treatment.37

Use of ketamine in the USA

Clinical use of ketamine in the treatment of TRD has already begun. Ketamine is a mixture of two mirror-image molecules, R-ketamine

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(arketamine) and S-ketamine (esketamine). Esketamine is a more potent NMDA glutamate receptor antagonist than its mirror image arketamine and is available as a nasal spray under the brand name Spravato. Spravato received FDA approval in March 2019 for the treatment of TRD in a medically supervised setting, such as a hospital or clinic.

While esketamine has been approved for the treatment of TRD, ketamine itself, a Schedule III controlled substance in the United States, is approved by the Food and Drugs Administration (FDA) only for the induction and maintenance of general anaesthesia. Its other common and ubiquitous uses, such as procedural sedation, pain management, and treatment for psychiatric disorders, are all considered ‘off-label’ use and are not FDA approved. Nonetheless, ketamine infusion centres have recently been established in the United States for the off-label treatment of depression, anxiety, PTSD and chronic pain.38 Not typically covered by health insurance, the cost of treatment averages $500 USD per administration, usually with a six-dose treatment plan recommended (given either weekly for six weeks or twice a week for three weeks).39 These sites offer in-office intravenous and intranasal administration. Doses are sub-anaesthetic and sub-dissociative, but may still have transient side effects during administration. It should be noted that the cost of ketamine itself is trivial, about $25 USD for a 500mg vial.

Ketamine infusion centres have recently been established in the United States for the off-label treatment of depression, anxiety, PTSD and chronic pain.

Use of ketamine in Ireland

A trial on the use of ketamine as adjunctive therapy in Ireland was conducted by researchers at Trinity College Dublin in 2021. Trial participants were patients admitted to St Patrick’s Mental Health Services for the treatment of a depressive episode. Results of the trial showed that there was no major difference in HRSD-24 scores between those who received intravenous ketamine versus those who received intravenous midazolam.40 Ketamine infusions were generally felt to be safe and well tolerated. The study concluded that a definitive trial in the use of adjunctive ketamine is feasible.40 That trial, however, did not start without controversy, as evidenced by an opinion article in The Irish Times wherein the author recounted ketamine’s use as a recreational street drug, and expressed concern about patients developing dependence, as well as the abuse potential

of ketamine nasal spray in particular.41 A similar article published in the Irish Medical Journal cited concerns about potential long-term side effects, and cautioned that more research into ketamine’s safety profile and mechanism of action were needed before it could be authorised for depression treatment.42

A trial on the use of ketamine as adjunctive therapy in Ireland was conducted by researchers at Trinity College Dublin in 2021.

In March 2022, Spravato was approved for reimbursement in Ireland for adults with TRD when used in combination with an SSRI or SNRI. Prescribed by a psychiatrist, it is self-administered under the direct supervision of a healthcare professional.43

In March 2022, Spravato was approved for reimbursement in Ireland.

Conclusion

Ketamine has been shown to be rapidly effective in the treatment of TRD. Unfortunately, the effects do not appear to be sustained. Future endeavours looking into maintenance therapy with oral daily dosing, daily or weekly nasal spray, or long-acting parenteral preparations are warranted. Possible long-term side effects, including dependence or misuse, as well as long-term efficacy, would need to be monitored. Removal of use restrictions in people

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who are susceptible to psychotic episodes, and those who drink alcohol or use psychoactive substances, warrants further investigation as well. Finally, the role of ketamine as a sole agent versus as an adjunct to more conventional antidepressants and therapies remains to be determined.

References

1. Corriger A, Pickering G. Ketamine and depression: a narrative review. Drug Des Devel Ther. 2019;13:3051-67.

2. Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173(8):816-26.

3. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64.

4. Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosc. 2016;10:612.

5. Perrine SA, Ghoddoussi F, Michaels MS, Sheikh IS, McKelvey G, Galloway MP. Ketamine reverses stress-induced depression-like behavior and increased GABA levels in the anterior cingulate: An 11.7 T 1H-MRS study in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:9-15.

6. Chen MH, Li CT, Lin WC, Hong CJ, Tu PC, Bai YM et al. Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: a randomized, double-blind control study. Psychiatry Res. 2018;269:207-11.

7. Frenkel C, Urban BW. Molecular actions of racemic ketamine on human CNS sodium channels. Br J Anaesth. 1992;69(3):292-7.

8. Zheng W, Zhou Y, Wang C, Lan X, Zhang B, Zhou S et al. Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression. PeerJ. 2021;9:e10989.

9. Hampton T. Ketamine’s success. JAMA. 2010;304(13):1432.

10. Thase M, Connolly R. Unipolar depression in adults: choosing treatment for resistant depression. [Internet.] UpToDate. [cited October 25, 2023.]

Available from: https://www.uptodate.com/contents/unipolar-depression-in-adults-choosin g-treatment-for-resistant-depression.

11. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-6.

Ketamine has been shown to be rapidly effective in the treatment of TRD. Unfortunately, the effects do not appear to be sustained.

12. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4.

13. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A et al Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176(5):401-9.

14. Rush J. Patient education: depression treatment options for adults (Beyond the Basics). [Internet.] UpToDate. Available from: https://www.uptodate.com/contents/depression-treatment-options-for-adu lts-beyond-the-basics#H446121025

15. Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015;30(3):152-63.

16. aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67(2):139-45.

17. Sleigh J, Harvey M, Voss L, Denny B. Ketamine – more mechanisms of action than just NMDA blockade. Trends in Anaesthesia and Critical Care. 2014;4(2-3):76-81.

18. Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F et al Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res. 2022;151:693-709.

19. Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S et al Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder. JAMA Psychiatry. 2014;71(6):681-8.

20. Joseph B, Parsaik AK, Ahmed AT, Erwin PJ, Singh B. A systematic review on the efficacy of intravenous racemic ketamine for bipolar depression. J Clin Psychopharmacol. 2021;41(1):71-5.

21. Banov MD, Young JR, Dunn T, Szabo ST. Efficacy and safety of ketamine in the management of anxiety and anxiety spectrum disorders: a review of the literature. CNS Spectr. 2020;25(3):331-42.

22. Whittaker E, Dadabayev AR, Joshi SA, Glue P. Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment

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of refractory anxiety spectrum disorders. Ther Adv Psychopharmacol. 2021;11:204512532110567.

23. Martinotti G, Chiappini S, Pettorruso M, Mosca A, Miuli A, Di Carlo F et al

Therapeutic potentials of ketamine and esketamine in obsessive-compulsive disorder (OCD), substance use disorders (SUD) and eating disorders (ED): a review of the current literature. Brain Sci. 2021;11(7):856.

24. Fancy F, Haikazian S, Johnson DE, Chen‐Li DCJ, Levinta A, Husain MI et al

Ketamine for bipolar depression: an updated systematic review. Ther Adv Psychopharmacol. 2023;13:20451253231202723.

25. Faria-Guimarães D, Vieira F, Breno Souza-Marques, Silva SS, Bandeira ID, Souza LS et al. Letter to the Editor: Antidepressant and antisuicidal effects of esketamine in adolescents with major depressive disorder and suicidal ideation: a case series. J Child Adolesc Psychopharmacol. 2022;32(6):366-7.

26. Alario AA, Niciu MJ. (Es)Ketamine for suicidal ideation and behavior: clinical efficacy. Chronic Stress (Thousand Oaks). 2022;6:247054702211280.

27. DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71(12):1605-11.

28. Andrade C. Ketamine for depression, 6: effects on suicidal ideation and possible use as crisis intervention in patients at suicide risk. J Clin Psychiatry. 2018;79(2):18f12242.

29. Bartlett MJ, Flores AJ, Ye T, Smidt SI, Dollish HK, Stancati JA et al. Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia. Exp Neurol. 2020;333:113413.

30. Mohammad Shehata I, Masood W, Nemr N, Anderson A, Bhusal K, Edinoff AN et al. The possible application of ketamine in the treatment of depression in Alzheimer’s disease. Neurol Int. 2022;14(2):310-21.

31. Dold M, Bartova L, Kasper S. Treatment response of add-on esketamine nasal spray in resistant major depression in relation to add-on second-generation antipsychotic treatment. Int J Neuropsychopharmacol. 2020;23(7):440-5.

32. Kryst J, Kawalec P, Mitoraj AM, Pilc A, Lasoń W, Brzostek T. Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials. Pharmacol Rep. 2020;72(3):543-62.

33. Vande Voort JL, Morgan RJ, Kung S, Rasmussen KG, Rico J, Palmer BA et al Continuation phase intravenous ketamine in adults with treatment-resistant depression. J Affect Disord. 2016;206:300-4.

34. Andrade C. Ketamine for depression, 1: clinical summary of issues related to efficacy, adverse effects, and mechanism of action. J Clin Psychiatry. 2017;78(04):e415-9.

35. Anand A, Mathew SJ, Sanacora G, Murrough JW, Goes FS, Murat Altinay et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023;388(25):2315-25.

36. Best SRD, Pavel DG, Haustrup N. Combination therapy with transcranial magnetic stimulation and ketamine for treatment-resistant depression: a long-term retrospective review of clinical use. Heliyon. 2019;5(8):e02187.

37. Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG et al. Rapid decrease in depressive symptoms with an N-methyl-D-aspartate antagonist in ECT-resistant major depression. Prog Neuroosychopharmacol Biol Psychiatry. 2011;35(4):1155-9.

38. Yahr N, Huynh K. New businesses emerge with a novel answer for depressed Madisonians: ketamine. [Internet.] The Cap Times. 2023. [cited January 19, 2024.] Available from: https://captimes.com/news/business/new-businesses-emerge-with-a-novelanswer-for-depressed-madisonians-ketamine/article_c9750b11-3ae2-5d8f8f68-27a0eef8b0a1.html

39. Yahr N, Huynh K. Ketamine is promising but pricey for Madisonians. [Internet.] The Cap Times. 2023. [cited January 19, 2024.] Available from: https://captimes.com/news/business/ketamine-is-promising-but-pricey-formadisonians/article_426bf678-59e5-595d-a1a8-56a0037350ba.html

40. Gallagher B, Foley M, Slattery CM, Gusciute G, Shanahan E, McLoughlin DM. Ketamine as an adjunctive therapy for major depression – a randomised controlled pragmatic pilot trial (Karma-Dep Trial). HRB Open Res. 2022;3:90.

41. Houston M. Is use of ketamine for treating depression a step too far? [Internet.] The Irish Times. 2019 [cited October 26, 2023.]. Available from: https://www.irishtimes.com/life-and-style/health-family/is-use-of-ketamine-f or-treating-depression-a-step-too-far-1.3914378

42. Frere M, Tepper J. Ketamine: future treatment for unresponsive depression? [Internet.] Irish Medical Journal. Available from: https://imj.ie/ketamine-future-treatment-for-unresponsive-depression/.

43. Norton D. SPRAVATO (esketamine) nasal spray approved for reimbursement in Ireland for adults with treatment-resistant major depressive disorder. [Internet.] Hospital Professional News. 2022 [cited October 28, 2023.] Available from: https://hospitalprofessionalnews.ie/2022/03/03/spravato-%E2%96%BC-es ketamine-nasal-spray-approved-for-reimbursement-in-ireland-for-adults-wit h-treatment-resistant-major-depressive-disorder/

A shot of renewal: the potential of stem cells in transforming the arthritis landscape

Abstract

Osteoarthritis (OA) is the most common joint disorder, with increasing socioeconomic impacts due to the ageing population and rising obesity rates. As global life expectancy remains high, with concurrent rises in obesity trends, the number of patients who will be affected by OA is likely to significantly increase in the coming years. The current management of OA follows standardised guidelines developed by multiple academic and professional societies. Intra-articular joint injections have proven to be quite effective for managing OA; they tend to be more effective than simple analgesia and there are numerous substances that can be delivered directly into the joint, which serve as the basis for this review. In particular, mesenchymal stem cells (MSCs) have demonstrated great promise in regenerative medicine because of their exceptional capacity to develop into a wide variety of cell types. Preliminary research supports the safety and effectiveness of autologous and allogeneic stem cell transplantation – patients report significant pain alleviation, improved mobility, and cartilage regeneration. However, widespread therapeutic use presents logistical and financial challenges, which are explored in this review. Understanding these implications may lead to a revolutionary change in the treatment of OA.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 51-56.

Marc Bouchard

Mark Polemidiotis

RCSI medical students

Introduction

Osteoarthritis (OA) is the most common joint disorder, with increasing socioeconomic impacts due to the ageing population and rising obesity rates.1 This degenerative and progressive disease is characterised by the loss of articular hyaline cartilage and remodelling of underlying bone (Figure 1), mediated by chondrocytes in the articular cartilage and inflammatory cells in surrounding tissues.1,2 It commonly affects large, diarthrodial, weight-bearing joints such as the hips, knees, and spine, with radiographic evidence in >80% of individuals over the age of 75.3 OA is one of the leading causes of pain and disability worldwide with a multifactorial aetiology.2 Primary OA is the most common cause of arthritis and arises without a specific cause.1 Increasing age, obesity, and female gender have been shown to contribute to the risk of developing this disease.1 Secondary OA results from trauma, infection, or other infiltrative/connective tissue diseases.2 Because the articular surface plays a pivotal role in load transmission across a joint, there is good evidence suggesting that certain conditions and jobs (e.g., manual labourers) that increase load transfer and load distribution can accelerate the initiation and progression of OA.3 Since OA is a complex inflammatory condition affecting multiple components of the joint, the symptoms are often associated with significant functional impairment, which has important social and economic implications for society.2,3 As global life expectancy remains high, with concurrent rises in obesity trends,

the number of patients who will be affected by OA is likely to increase significantly in the coming years.1,2 It is therefore clear that adequate management and definitive treatment options for OA can have significant implications for public health systems across the world. The current management of OA follows standardised guidelines developed by multiple academic and professional societies.3,4 There are conservative management strategies, pharmacological, and surgical options to treat OA, which are often employed in a stepwise fashion (Figure 2). The strategy employed is dependent on the severity of disease and level of functional impairment. Conservative strategies include patient education, joint support (i.e., offloading braces), and physiotherapy to strengthen the muscles surrounding the joint. Weight loss is also advised in overweight or obese patients.3,4 These conservative strategies are often combined with pharmacological treatments, which are mostly related to symptom relief rather than disease modification.1 Simple analgesics and topical non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of medical management of OA alongside other conservative measures.3,4 Should this fail or patients require more long-term symptomatic relief, intra-articular joint injections (Figure 3) have proven to be effective for managing OA.2,5 They tend to be more effective than simple analgesia2 and numerous substances can be delivered directly into the joint, which serves as the basis for this review. Most of these injections

FIGURE 1: Pathogenesis of osteoarthritis.

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First-line treatment

First- + secondline treatment

First- + second+ third-line treatment

Surgery

Pharmacological pain relief aids and passive treatments given by a therapist

Education, exercise and weight control

Few

Some All

can be given in an outpatient setting and newer options currently being trialled aim to reverse the disease process and have shown potential for cartilage regeneration.6 If conservative and medical therapies fail, or if quality of life becomes substantially impacted, surgical intervention is often considered. Arthroplasty, the surgical procedure to restore joint function, is currently the only definitive or curative option for OA.2,5 This review will serve to highlight the effectiveness and plausibility of these newer intra-articular joint injection options, notably mesenchymal stem cell (MSC) injections, which may ultimately guide future clinical decision-making and treatment guidelines for OA.

Corticosteroid injections

Corticosteroids are potent anti-inflammatory agents that exert their effects by interrupting the inflammatory and immune cascade at

several levels.2,5 Early studies reported that corticosteroid injections may have suppressed proteoglycan synthesis in articular cartilage.7 However, newer in vivo studies have since demonstrated that low-dose intra-articular corticosteroid injections actually normalised cartilage proteoglycan synthesis, and significantly reduced osteophyte formation as well as the incidence of cartilage erosion.5 Different corticosteroid formulations have been used over the years with similar efficacy, the main ones being triamcinolone acetonide, mycophenolic acid (MPA), prednisolone acetate, and dexamethasone.5 Because of the perceived efficacy, low cost, and lack of major toxicity, intra-articular corticosteroids remain one of the mainstay options for the long-term management of OA.2,5 They can be delivered safely into the same joint up to four times per year and are often given at three-month intervals.

FIGURE 2: Management of osteoarthritis –stages of progression.

FIGURE 3: Intra-articular joint injection of the knee.

E. Roos

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Viscosupplementation with hyaluronic acid

Hyaluronic acid (HA) is a natural glycosaminoglycan produced by chondrocytes, type B synovial cells, and fibroblasts, which is then secreted into synovial fluid. It is a novel, safe and effective form of local treatment for OA.2,5 Because the arthritic joint has a decreased concentration and molecular weight of HA, viscosupplementation (injection of HA directly into the joint) with artificial HA aims to return the elasticity and viscosity of the synovial fluid back to normal.2,5 Anti-inflammatory and anti-oxidant properties have also been described with the use of viscosupplementation.2,5,8 While the majority of studies show clinical benefit compared to their control groups, the evidence of its true effects on the progression of human OA remains controversial.5,9 These injections are more expensive than corticosteroid intra-articular injections, although they provide longer-term relief and are typically given at six-month intervals.2,5 The results of the previous studies suggest that this treatment may be more effective in younger patients with higher levels of knee pain, with considerable evidence supporting the positive joint cellular and immunological functions.2,9

Regenerative medicine

Newer intra-articular injections have been developed and tested with the aim of halting OA progression.2 Among these formulations are autologous conditioned serum (ACS), platelet-rich plasma (PRP), and

MSCs.2,8 PRP injections are the most commonly used and tested of these formulations. Numerous studies and systematic reviews have found statistical superiority with PRP injections compared to intra-articular injections of a control.10 Because it requires a few vials of a patient’s blood as well as centrifugation to separate the platelets, these injections are quite expensive in comparison to the other aforementioned options. While these methods appear promising, it is still an evolving field that requires more research to define and standardise the optimal preparation of these products.2 Here, we introduce the topic of MSCs and review the evidence for their use in OA, which has been tested in several clinical trials throughout the years.

Newer technologies: mesenchymal stem cells

Stem cells repair the body by replenishing and regenerating tissues as needed during development and adulthood. Their remarkable ability to differentiate and self-renew makes them a valuable research topic in the medical field.11,12 Across various branches of medicine, stem cells have promising applications, from treating illnesses to regenerating damaged organs. While research is ongoing, their possibilities for future medical treatments are vast and ground-breaking.13

More specifically, the ability of MSCs to differentiate into bone, cartilage, muscle, tendon, and ligament tissues (Figure 4) makes them a viable candidate for the treatment of degenerative and post-traumatic conditions like OA.13 Multiple stem cell studies,

FIGURE 4: Stem cell injection therapy.

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including autologous transplants, where stem cells are taken from and given back to the same patient, and allogeneic stem cells from a donor,12 have shown promising results with few side effects.13-16 This progress has led to many in vitro, animal, and in vivo trials that have endorsed the safety and potential of MSCs in human orthopaedic applications.11 Despite these successes and unlimited potential, MSCs are famous for budding many social debates. The efficacy of stem cells as a treatment for OA, plus their logistical and financial considerations, are discussed in this review.

Despite these successes and unlimited potential, MSCs are famous for budding many social debates.

Research findings

Early studies in the field highlighted a successful intra-articular MSC injection technique that resulted in no adverse effects and statistical improvements in radiological, arthroscopic, and histological measures.6 This method in particular focused on intra-articular injections as a more suitable treatment option for OA than previous surgical implementation strategies.6 Patients generally demonstrated impressive pain reduction, with increased mobility and decreased articular cartilage defects, through cellular regrowth of cartilage that was previously degrading. Similar findings with regard to functional improvements have since been repeated in sequential studies with no notable adverse side effects at the six-month follow-up mark.14,15

Early studies in the field highlighted a successful intra-articular MSC injection technique that resulted in no adverse effects and statistical improvements in radiological, arthroscopic, and histological measures.

In 2015, the first study to demonstrate the safety and feasibility of allogeneic MSCs while providing a solid indication of their efficacy in OA was published.12 This study compared allogeneic stem cell treatment in 15 patients to 15 control patients injected with HA. Allogeneic stem cells have the advantage of being more financially obtainable and easily applicable for widespread use due to high quantity reproduction and quality control. The short-term side effects were minimal and mainly related to predictable procedure recovery. This study proposes that allogeneic generic MSCs should be considered as a treatment for OA.11 Since then, multiple studies have

reproduced the findings of positive outcomes with minimal adverse effects with varying sources of the MSCs.11,13-17 The reported adverse effects from the more recent studies are readily explained due to predictable disease progression during extended follow-up periods. Although no clinical evidence of increased neoplasm risk was found in any of the MSC sources, consistent follow-up is needed to confirm the long-term safety.

In 2015, the first study to demonstrate the safety and feasibility of allogeneic MSCs while providing a solid indication of their efficacy in OA was published.

Logistical considerations

While the MSC treatments show widespread promise, the logistical complications are a significant challenge with scaling any stem cell treatment. Clinically, cell harvesting involves multiple procedural steps, potentially delayed by a one- to two-week laboratory culture expansion. This complexity and other procedural difficulties can escalate the duration and cost of stem cell treatments.13 Advancements in stem cell research require addressing these existing challenges, with recent studies pinpointing low-dose single-cell-type treatments that offer sustained benefits from six months,14,15 one year,11 and up to four years,16 with as little as one injection. Ongoing phase III studies are working to further research these minimally invasive single-cell treatments.17 Additionally, as evident in contemporary research, the large-scale cultivation and pre-administration quality control of allogeneic treatments underscore their potential to mitigate procedural and logistical challenges. Although there is a promising outlook for the feasibility of MSCs, the transition from autologous stem cell therapy to allogeneic stem cell treatment should be approached with caution due to the unknown long-term effects and small sample size of current studies.12

While the MSC treatments show widespread promise, the logistical complications are a significant challenge with scaling any stem cell treatment.

Conclusion

Over the past few decades, MSCs have emerged as a promising therapeutic approach for OA. These treatments consistently present a low adverse effect profile compared to disease progression and other treatments. Several studies highlight the positive outcomes and safety

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of using MSCs in orthopaedic applications, with some emphasising the potential use of allogeneic MSCs due to their cost-effectiveness and ease of application. The transition from autologous to allogeneic treatments and stem cell therapy requires careful consideration due to potential long-term effects, limited sample sizes, and relatively short follow-up times in current research. Although stem cell therapies are not FDA approved for OA, the exciting findings in primary and review articles inspire the medical community to push for further rigorous clinical trials. The potential of MSCs in treating OA is evident, and with continued research and understanding, we may soon witness a revolutionary shift in OA management.

The transition from autologous to allogeneic treatments and stem cell therapy requires careful consideration due to potential long-term effects, limited sample sizes, and relatively short follow-up times in current research.

References

1. Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2(1):1-18.

2. Mora JC, Przkora R, Cruz-Almeida Y. Knee osteoarthritis: pathophysiology and current treatment modalities. J Pain Res. 2018;11:2189-96.

3. Goldring SR, Goldring MB. Clinical aspects, pathology and pathophysiology of osteoarthritis. J Musculoskelet Neuronal Interact. 2006;6(4):376-78.

4. Hunter DJ, Neogi T, Hochberg MC. Quality of osteoarthritis management and the need for reform in the US. Arthritis Care Res (Hoboken). 2011;63(1):31-8.

5. Uthman I, Raynauld JP, Haraoui B. Intra-articular therapy in osteoarthritis. Postgrad Med J. 2003;79(934):449-53.

6. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32(5):1254-66.

7. Pelletier JP, Haraoui B, Martel-Pelletier J. Modulation of cartilage degradation in arthritic diseases by therapeutic agents. Inflammatory Disease and Therapy. 1993;12:503.

8. Ayhan E, Kesmezacar H, Akgun I. Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. World J Orthop. 2014;5(3):351-61.

9. Dougados M. Sodium hyaluronate therapy in osteoarthritis: arguments for a potential beneficial structural effect. Semin Arthritis Rheum 2000;30(2 Suppl. 1):19-25.

10. Aiyer R, Noori S, Schirripa F, Schirripa M, Aboud T, Jain S et al. Treatment of knee osteoarthritic pain with platelet-rich plasma: a systematic review of clinical studies. Pain Manag. 2021;11(4):419-31.

11. Freitag J, Bates D, Wickham J, Shah K, Huguenin L, Tenen A et al

Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med. 2019;14(3):213-30.

12. Zhu C, Wu W, Qu X. Mesenchymal stem cells in osteoarthritis therapy: a review. Am J Transl Res. 2021;13(2):448-61.

13. Centeno CJ, Al-Sayegh H, Freeman MD, Smith J, Murrell WD, Bubnov R. A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. Int Orthop. 2016;40(8):1755-65.

14. Lee WS, Kim HJ, Kim KI, Kim GB, Jin W. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. Stem Cells Transl Med. 2019;8(6):504-11.

15. Pers YM, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F et al. Adipose mesenchymal stromal cell-cased therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5(7):847-56.

16. Lamo-Espinosa JM, Prósper F, Blanco JF, Sánchez-Guijo F, Alberca M, García V et al. Long-term efficacy of autologous bone marrow mesenchymal stromal cells for treatment of knee osteoarthritis. J Trans Med. 2021;19(1):506.

17. ClinicalTrials.gov. Multicenter Clinical Trial Comparing Treatment With Allogeneic Mesenchymal Cells Versus Autologous Mesenchymal Cells and Versus Active Control With Hyaluronic Acid in Patients With Knee Osteoarthritis (ARTROCELL). [Internet.] [Accessed October 26, 2023.]

Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05086939

Mitchell Neuert RCSI medical student

Exogenous hormone therapy for adults who are transgender: considerations for the cardiovascular system

Abstract

The transgender population is a steadily increasing, heterogeneous group of individuals whose gender identity and expression differ from their birth-assigned sex. Gender-affirming hormone therapy (GAHT) is the most sought-after component of transgender care; however, the effect of exogenous sex hormones on cardiovascular health remains incompletely understood. This article reviews large cohort-based studies of transgender individuals receiving GAHT, and studies of sex hormone supplementation in cisgender populations, to identify the potential implications for cardiovascular risk factors and outcomes. Existing epidemiological evidence suggests that masculinising GAHT may have negative influences on lipid profiles in transgender men, and that transgender women undergoing feminising GAHT have an increased risk of venous thromboembolism. The effects of GAHT on blood pressure, myocardial infarction, and cerebrovascular accidents is not clear, and current observational studies are limited by diverse treatment regimes, short-term follow-up, and the inclusion of data on modifiable cardiovascular risk factors (physical activity, diet, etc.) of the cohorts.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 57-64.

Table 1: Glossary of relevant terms and their definitions.

Terms Definitions16,50

Sex

Gender

Cisgender

Transgender

Man who is transgender (TGM)

Woman who is transgender (TGW)

Gender dysphoria

Gender-affirming hormone therapy (GAHT)

A set of biological attributes related to reproductive capacity assigned at birth (e.g., sex hormones, sex chromosomes, genitalia)

The socially constructed roles, behaviours, and identities that comprise an individual’s sense of being a girl/woman, a boy/man, a combination of both or neither

When an individual’s gender identity corresponds with their birth-assigned sex

When an individual’s gender identity differs from their birth-assigned sex

An individual whose birth-assigned sex is female, but gender identity is male

An individual whose birth-assigned sex is male, but gender identity is female

Clinically significant distress caused by the difference between an individual’s birth-assigned sex and their gender identity

The use of exogenous hormone supplementation to match physical characteristics with an individual’s gender identity

Introduction: background and rationale Transgender is a term used to refer to a heterogeneous group of individuals whose gender identity differs from the sex they were assigned at birth (Table 1).1 In North America, it is estimated that approximately 1.2-1.5 million individuals identify as transgender, comprising roughly 0.4-0.6% of the total population.2,3 Despite recent increases in public and political advocacy, improvements in gender-affirming care access, and the medical community’s calls to action, the transgender population remains marginalised and underserved, and they experience disproportionately worse cardiovascular health.4-6 The transgender population exhibits elevated behavioural risk factors such as increased levels of tobacco use, drug and alcohol use, sedentary behaviour, and poor sleep quality.7-10 In addition, transgender individuals present with elevated psychosocial risk factors such as chronic stress, depression, anxiety, stigmatisation, and discrimination,11-13 all of which are associated with worsening clinical risk profiles and increased risk of cardiovascular disease (CVD).14,15

In North America, it is estimated that approximately 1.2-1.5 million individuals identify as transgender, comprising roughly 0.4-0.6% of the total population.

Many, but not all transgender individuals experience gender dysphoria. Gender dysphoria is a condition characterised by clinically significant distress and impairment caused by the discrepancy between an individual’s birth-assigned sex and their gender identity.16 To alleviate this, many afflicted transgender individuals opt for

gender-affirming procedures such as hormone therapy and/or surgical interventions.16 Gender-affirming hormone therapy (GAHT) involves the use of exogenous sex hormone supplements, administered to stimulate and/or suppress physical and secondary sex characteristics, so that their physical features align more closely with those of their identified gender.16 There is robust evidence that GAHT is an effective treatment option to improve gender dysphoria.17 It is also associated with improved quality of life and improvements in several behavioural and psychosocial risk factors.18,19 However, sex hormones have broad effects on cardiovascular physiology. There exists suspicion, and preliminary evidence, that GAHT may modulate blood pressure and lipid profiles among transgender individuals, potentially exacerbating the risk of CVD among an already susceptible population. As such, a detailed investigation of the interaction between GAHT and the cardiovascular system is necessary to guide cardiovascular risk management of transgender individuals seeking GAHT and improve quality of care. The following review will: 1. summarise the current use of GAHT and its potential implications on cardiovascular health; 2. outline pertinent literature that examines the association between GAHT and cardiovascular risk factors and outcomes; and, 3. offer suggestions for future research.

A detailed investigation of the interaction between GAHT and the cardiovascular system is necessary to guide cardiovascular risk management of transgender individuals seeking GAHT and improve quality of care.

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Table 2: Common gender-affirming hormone therapy (GAHT) treatment regimens.

Feminising GAHT Route

Oestrogen Transdermal

Intramuscular

Oestradiol patch

0.025-0.2mg/day

Oestradiol gel Varies with preparation

Oestradiol valerate 2-30mg/1-2 wks

Oestradiol cypionate 2-30mg/1-2 wks Oral or sublingual Oestradiol 2-6mg/day

Anti-androgen

Masculinising GAHT Route

Testosterone

Intramuscular Testosterone enanthate 50-200mg/1-2 wks

Treatment regimens adapted from T’Sojoen et al. (2020) and Coleman et al. (2022).51,52

An overview of gender-affirming hormone therapy

Currently, GAHT is the most sought-after gender-affirming medical intervention for gender dysphoria. 20 GAHT can be further subdivided into either masculinising or feminising therapies based upon the patient-centred goals and the specific hormone regimen used. Masculinising hormone therapy involves the use of parenteral testosterone supplementation, with the objective to develop male secondary sex characteristics and suppress female characteristics, whereas feminising hormone therapy typically comprises an oestrogen formulation combined with an anti-androgen agent. Oestrogen is primarily responsible for the development of female secondary sex characteristics and the anti-androgen agent is largely involved in suppressing masculine characteristics. Commonly used drug formulations, routes of administration, and dosages are listed in Table 2

GAHT can be further subdivided into either masculinising or feminising therapies based upon the patient-centred goals and the specific hormone regimen used.

As per current clinical treatment guidelines, GAHT is initiated for individuals with a clinician-confirmed diagnosis of persistent gender dysphoria, who have provided informed consent.16,20 Alterations in physical characteristics usually occur within three to six months, with the most pronounced effects observed following two to four years.16 Importantly, each transgender individual has unique treatment goals. Some individuals target maximum feminisation or masculinisation,

Testosterone undecanoate 750-1000mg/10-12 wks

involving full suppression of natal sex characteristics and full expression of those of the desired gender, whereas others seek only some phenotypic changes and express the desire to retain certain characteristics of their birth-assigned sex. For example, a patient may desire to develop feminine breasts yet retain erectile function for reproductive purposes. As a result, dosage regimes are not standardised, and are carefully titrated to achieve the patient-directed phenotypic endpoints.16,20 The variability in dosage and treatment regimens noted in the literature can also be explained by the lack of randomised controlled trials comparing the efficacy and safety of different GAHT regimes.

As per current clinical treatment guidelines, GAHT is initiated for individuals with a clinician-confirmed diagnosis of persistent gender dysphoria, who have provided informed consent.

Effects

of gender-affirming hormone therapy on

blood pressure

Sex hormones have an important role in the regulation of blood pressure (BP).21 Oestrogen receptors (ERs; both and subtypes) are present on vascular endothelial and smooth muscle cells (VSMCs), and ER activation has been implicated in downstream modulations of vascular tone.22 In vivo and in vitro research suggests that exogenous oestrogen induces vasodilation, mediated in part by increasing endothelial nitric oxide synthase activity, and by inhibiting Ca2+ influx

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in VSMCs.23,24 Sex hormones also exert indirect effects on the renin-angiotensin-aldosterone system (RAAS). Exogenous oestrogen supplementation in postmenopausal women has been shown to upregulate angiotensinogen, increase angiotensin I concentrations and, in some instances, reduce BP.25,26 In contrast, long-term testosterone supplementation in spontaneously hypertensive rats has been shown to have deleterious effects on components of the RAAS, such as elevations in BP and hypertension exacerbation.27,28 Along this simplistic line of thinking, it appears reasonable to hypothesise that feminising GAHT (oestrogens and anti-androgens) may reduce BP, whereas masculinising GAHT (testosterone) may increase BP. Despite this rationale, the influence of GAHT on BP in transgender medicine is much more convoluted, and highlights the gap in the literature regarding the complex interactions between the hormonal milieu, and differences in the sex chromosome complement (XX vs XY) in the regulation of BP. Larger observational cohort studies of transgender individuals with pre- and post-GAHT measurements of BP have demonstrated mixed results, with reports of increases, decreases, and no clinically significant changes.29-31 Conclusive evidence on the influence of GAHT on BP is lacking, and comparability between studies has been limited by widely varying treatment regimes, short follow-up periods, lack of cisgender control groups, and unclear inclusion criteria (e.g., whether it is known if individuals underwent sex reassignment surgeries during follow-up, and if this potentially confounds GAHT’s effect on BP). Indeed, a recent 2020 systematic review noted that there is insufficient evidence to definitively state if GAHT influences BP, or if any observed differences are clinically meaningful and associated with worse CVD outcomes.32 In summary, the influence of GAHT on BP remains a contentious topic and a definitive conclusion cannot be discerned without further research that addresses these gaps.

The influence of GAHT on BP in transgender medicine is much more convoluted, and highlights the gap in the literature regarding the complex interactions between the hormonal milieu, and differences in the sex chromosome complement (XX vs XY) in the regulation of BP.

Effects of gender-affirming hormone therapy on lipid profiles

There are several lines of evidence that suggest that testosterone supplementation may unfavourably modify lipid profiles in

transgender men (TGM). Maraka et al . (2017) conducted a meta-analysis of 29 studies, comprising 1,500 TGM undergoing GAHT with varying formulations, dosages, and follow-up periods (ranges from three months to 41 years).33 The findings suggest that testosterone therapy for longer than 24 months was associated with increases in triglycerides (TGs) (21.4mg/dL [95% CI: 0.14 to 42.6]) and low-density lipoprotein cholesterol (LDL-C) (17.8mg/dL [95% CI: 3.5 to 32.1]), a reduction in high-density lipoprotein cholesterol (HDL-C) (-8.5mg/dL [95% CI: -13 to -3.9]), and no changes in total cholesterol.33 Notably, lipid profiles appeared to worsen (larger increase in TG, LDL-C and larger decrease in HDL-C) with longer durations of testosterone therapy, raising concerns about the cumulative lifelong effect on CVD risk.33 However, as neither a control group nor data on lifestyle factors were included, it is unclear if this is a causal relationship with the duration of testosterone treatment, or if these can be explained by normal ageing-related increases in lipid levels known to occur in middle age.34

Further recent studies exhibit agreeable results. Allen et al. (2021) tracked changes in lipid profiles in 91 TGM using testosterone supplements (dosage/formulation not stated) over five years via retrospective chart review and observed significant increases in LDL-C and decreases in HDL-C. About 30% of TGM in this study had a previous history of GAHT prior to baseline assessments.35 This may have confounded the observed changes in lipid levels in this proportion of TGM, as it remains unknown if lipid levels return to baseline physiologic levels when testosterone use is discontinued. In addition, Emi et al. (2008) found that in comparison to TGM who did

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not opt for GAHT, TGM using intramuscular testosterone had higher levels of LDL-C and reduced levels of HDL-C.36 In summary, evidence from observational studies would suggest that masculinising GAHT results in a net reduction in HDL-C and increases in LDL-C and TG. These alterations may potentially be exacerbated with increasing duration of treatment.

Among transgender women (TGW), the influence of feminising GAHT regimes on changes in lipid profiles is unclear. Maraka et al.’s (2017) lipid profile meta-analysis also pooled data on 3,231 TGW using differing combinations and dosages of oral, transdermal, or intramuscular oestrogens, with some regimens including spironolactone, GnRH agonists, and/or cyproterone acetate. The results showed no significant changes of HDL-C, LDL-C, or total cholesterol from baseline following either shorter (three to 24 months) or longer (greater than 24 months) durations of treatment.33

A significant increase in TG (31.9mg/dL [95% CI: 3.9 to 59.9]) was observed when GAHT duration exceeded 24 months; however, this was limited to the subgroup using oral oestrogen formulations.33 Likewise, a retrospective chart review conducted by Allen et al. (2021) noted inconsistent, variable and nonsignificant changes in LDL-C, HDL-C and TG over the course of five years among 126 TGW using oral or injected oestradiol.35

This differs from the findings of the prospective study by the European Network for the Investigation of Gender Incongruence, which noted alterations in the lipid profile among 242 TGW following 12 months’ use of oral or transdermal oestrogen with cyproterone acetate.30 Compared to pre-treatment levels, HDL-C (-0.13mmol/L [95% CI: -0.10 to -0.16]), LDL-C (-0.16mmol/L [95% CI: -0.09 to -0.22]), and TG (-0.09mmol/L [95% CI: -0.05 to -0.13]) all decreased.30 In contrast, a prospective observational study of 13 TGW using oral oestradiol and spironolactone noted a trend increase in HDL-C (58.5mg/dL IQR (16) to 66.5mg/dL IQR (25.5)) six months following GAHT initiation.37 The contrasting effects on HDL-C levels may be explained by the co-administration of oestrogen with either spironolactone (observed increase in HDL-C) or cyproterone acetate (observed decrease in HDL-C). Fung et al. (2016) conducted a retrospective chart analysis to compare the influence of oestrogen plus spironolactone (n=82 TGW) or cyproterone acetate (n=31 TGW) on serum HDL-C levels. TGW receiving cyproterone acetate exhibited a reduction in HDL-C (-0.07mmol/L SD (0.21)), whereas the spironolactone group’s increased (0.10mmol/L SD (0.24)) at 12 months post GAHT initiation.38 This highlights a potential difference in how these two anti-androgen agents interact with and modulate circulating HDL-C levels in TGW. This suggests a worsening of the lipid profile with cyproterone acetate and modest improvement with

spironolactone; however, it remains unknown if this differential effect leads to differences in long-term cardiovascular outcomes. In summary, the influence of feminising GAHT on changes in the lipid profile is equivocal, with the majority of studies demonstrating no significant effect on LDL-C, TG or total cholesterol. Differences in HDL-C levels may be explained by the specific anti-androgen agent prescribed.

Effect of gender-affirming hormone therapy on cardiovascular outcomes

Oddly, the apparent worsening of the cardiometabolic risk profile in TGM following GAHT is not conclusively linked with poorer cardiovascular outcome when compared to age-matched cisgender men or women.33 Several observational cohort studies with varying treatment regimens and follow-up periods have observed no difference in risk of myocardial infarction (MI), cerebrovascular accident (CVA), or venous thromboembolism (VTE) among TGM undergoing GAHT when compared to cisgender men.39-41 However, a single study noted a higher risk of MI when compared with cisgender women (standard incidence ratio (SIR) of 3.69 [95% CI: 1.94 to 6.42].39

In contrast, in TGW using oestrogen in combination with spironolactone, the favourable changes in lipid profile (increased HDL-C) observed do not translate to a reduced risk of cardiovascular disease.33 In fact, the opposite may occur. Two United States-based retrospective studies demonstrated increased risk of VTE among TGW receiving GAHT (n=2,517 and n=2,842), and noted an SIR of 5.52 [95% CI: 4.36 to 6.90] and 5.5 [95% CI: 4.3 to 7.0], respectively,

when compared to the general cisgender female population.39,42 Notably, both studies had mean follow-up durations ranging from 4.0 to 9.3 years and are limited in their analysis (could not compare differences in GAHT regimes) by a low total number of adverse events.39,42 In these studies, GAHT is initiated at a relatively young age (approximately 30 years), where relative cardiovascular risk is low, and the shorter duration of follow-up may not have been sufficient to capture cardiovascular events. Two large (n=966; n=816; both Netherlands) prospective cohorts corroborated the increase in VTE risk following GAHT, and observed a 20- and 40-fold increase in the risk of VTE compared to the general cisgender male population in the Netherlands.43,44 In addition, the authors noted that transdermal oestrogen may lower the risk of VTE when compared to oral oestrogen use.40,43 Mechanistically, the increase in VTE incidence may be explained by alterations in the coagulation pathway (not covered in the scope of this review), with TGW receiving oestrogen and cyproterone acetate exhibiting increases in platelet activation factors, systemic and endothelial inflammation markers, and a reduction in anticoagulant proteins after 12 months of GAHT.45,46 Data on the influence of feminising GAHT on MI and CVA is not as conclusive, with several studies reporting nonsignificant or protective effects on MI and CVA incidence,40,43 whereas others report increases.41,42

Oddly, the apparent worsening of the cardiometabolic risk profile in TGM following GAHT is not conclusively linked with poorer cardiovascular outcome when compared to age-matched cisgender men or women.

Knowledge gaps and future directions

While this review has discussed several of the potential direct effects of GAHT on blood pressure and serum lipid profiles, there are several indirect effects of GAHT on cardiovascular health.30 Many studies have noted favourable changes in behavioural and psychosocial cardiovascular risk factors following GAHT, such as increases in

References

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Conclusion

The area of GAHT and cardiovascular health is a relatively new and emerging field that has important implications for the care and management of transgender individuals across the world. To date, current research on the influence of feminising and masculinising GAHT on blood pressure, lipid profiles and cardiovascular outcomes is inconsistent. However, there is evidence suggesting that masculinising GAHT has negative influences on the lipid profiles of TGM, and that TGW undergoing feminising GAHT have an increased risk of VTE.

The area of GAHT and cardiovascular health is a relatively new and emerging field that has important implications for the care and management of transgender individuals across the world.

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41. Wierckx K, Elaut E, Declerq E et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol. 2013;169(4):471-8.

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45. Schutte MH, Kleemann R, Nota NM et al. The effect of transdermal gender-affirming hormone therapy on markers of inflammation and hemostasis. PLoSOne. 2022;17(3):e0261312.

46. Scheres LJJ, Selier NLD, Nota NM, van Diemen JJK, Cannegieter SC, den Heijer M. Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen. J Thromb Haemost. 2021;19(4):1029-37.

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Jennifer Engler RCSI medical student

Home on the range: approaches to rural medicine exposure in medical education

Abstract

The imperative of providing equitable healthcare access to geographically dispersed populations is particularly pronounced in Canada, Australia, and Ireland, with their significant rural landscapes. This review illustrates the three different approaches of these countries to rural healthcare training, focusing on medical student exposure to rural practice as a key determinant in retaining physicians in rural areas. In Canada, socially accountable medical schools, exemplified by the Northern Ontario School of Medicine, have demonstrated success by cultivating a commitment to rural service among graduates. Australia’s Bonded Medical Program, though effective in attracting physicians to underserved regions, faces criticisms related to flexibility and long-term retention. Ireland, uniquely positioned with a surplus of medical graduates but a shortage of rural physicians, grapples with the departure of international students post graduation. A continuous evaluation and refinement of strategies is required to ensure the long-term retention of physicians in rural communities, beginning early in medical education.

Introduction

Access to quality healthcare is a fundamental right for all individuals regardless of geographic location. Rural areas are particularly challenged in attracting and retaining healthcare professionals, as physicians often choose to stay in larger centres where they were trained, or where access to resources such as tertiary care centres is more readily available.1

Countries with vast rural landscapes are tasked with the responsibility of providing equitable, accessible healthcare to their rural populations. Countries such as Canada, Australia, and Ireland have continuously reported ongoing shortages of physicians to care for their rural populations.2,3 This is significant considering that the World Bank reported in 2022 that 36% of Irish, 18.3% of

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 65-70.

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Recruitment

factors

Pathways to integration and adaptation

Markers of integration and adaptation

1. Rural familiarity and/or rural interest

n Existing social bonds

n Enjoyment of lifestyle and environment

Rural experiences

2. Social connection and place integration

n Opportunities to make friends

n Enjoyment of lifestyle Upbringing

3. Community participation and satisfaction

n Sense of belonging

n Attachment to place

n ‘At-home -ness’ 4. Fulfilment of life aspiration

n Personal and professional needs are met

n Identity in place

Reasons to leave

n Life stage (early adulthood)

n Workplace/role dissatifaction

n Personal/life events

n Lack of professional career opportunities

n Lack of social connection/loneliness

Turnover (leave)

Canadians, and 14% of Australians reside in rural areas.4 Despite the common challenge of rural physician shortages, these countries have varied their approaches to medical student exposure and incentives to practise in rural areas in order to address these shortages.

Factors such as distance to tertiary care supports and financial constraints have been identified as major barriers to rural practice, with more recent focus on physician background and experiences as key elements to retention.5 A scoping review completed in Australia identified rural familiarity, social connection, community participation, and life aspiration fulfilment as four factors integral to the retention of physicians in rural areas (Figure 1).5

Similar reviews of both the Irish and Canadian rural physician recruitment schemes have identified social themes of rural background and community integration as key to retention.3,6 The challenge lies in the fact that the current rural physician recruitment programmes in Canada, Australia, and Ireland focus heavily on social and financial incentives, without yet prioritising the importance of building rural connections early to foster development of rural determinants throughout medical training.

Students trained in rural environments are more likely to evolve into physicians who practise in rural environments.1,2 This review will explore

1: Conceptual framework on the social determinants of rural physician retention.5

Reasons to stay

n Social connection/belonging

n Work/role fulfilment

n Professional/career satisfaction

Retention (stay)

Canadian, Australian, and Irish medical school initiatives to integrate students into rural practice before or during their medical training. The three healthcare systems will be examined for their evolving approaches to recruiting and integrating medical students into rural practice, highlighting both the successes and challenges of such initiatives.

Factors such as distance to tertiary care supports and financial constraints have been identified as major barriers to rural practice, with more recent focus on physician background and experiences as key elements to retention.

Canada: the socially accountable medical school

The Canadian healthcare system is publicly funded and provides universal access to healthcare services.6 Rural physician retention initiatives revolve around collaborative practice and various incentives for qualified doctors to either be retained in or to relocate to rural practices.6 Collaborative practice encompasses healthcare professionals of a variety of disciplines comprehensively supporting

FIGURE

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patient care, and in rural settings may include general practitioners (GPs), pharmacists, nurse practitioners, consult specialty services, and beyond. The Government of Canada provides loan forgiveness, tuition reimbursements, and grants to encourage medical students and practising physicians to work in underserved areas.7 Despite these financially driven efforts, Canada still faces challenges in rural physician retention driven by factors such as limited access to specialised resources and social isolation.6 It has been reported that only 14% of Canadian GPs and 2% of specialists work in rural areas to serve the 18.3% of Canadians living rurally.4,8 A unique solution to this challenge has been the establishment of the “socially accountable medical school”.

The Canadian healthcare system is publicly funded and provides universal access to healthcare services.

Socially accountable medical schools are institutions that prioritise education on the needs of underserved and marginalised populations, including those in rural areas.9 By focusing on training students who have signalled early interest in serving in rural communities, these schools play an essential role in mitigating the rural physician shortage. One example of a socially accountable medical school in Canada is the Northern Ontario School of Medicine. Established in 2005 as a joint venture between Laurentian University in Sudbury and Lakehead University in Thunder Bay, this medical school was specifically designed around the World Health Organization definition of social accountability to “direct their education, research and service activities towards addressing the priority health concerns of the community, region and the nation that they have a mandate to serve”.9,10 The school’s mission is to train and support physicians who are willing to practise in underserved regions, with an emphasis on cultural competence and community engagement.10 The unique curriculum of the Northern Ontario School of Medicine incorporates community-based learning and immersive experiences in rural and remote settings. Through these experiences, medical students gain a deeper understanding of the healthcare challenges faced by rural populations, fostering a commitment to address these needs in their future practice. Research has shown that graduates are significantly more likely to practise in rural areas compared to graduates of other medical schools in Canada, with 23% of graduates choosing to practise in rural areas since 2011.9,11

The establishment of a socially accountable medical school has proven to be a promising strategy in addressing rural physician shortages in Canada. Institutions focused on attracting medical

students who are interested in serving rural communities will contribute to the improvement of both healthcare access and quality in rural areas by retaining rural-minded medical students as working rural physicians.

Socially accountable medical schools are institutions that prioritise education on the needs of underserved and marginalised populations, including those in rural areas.

Australia: The Bonded Medical Program

Australia’s healthcare system has both public and private care, with rural areas often experiencing a shortage of healthcare professionals. Compared to populations in major cities, those living in rural areas, as defined by the Australian Statistical Geography Standard, are 20% more likely to report barriers to GP care, and 58% more likely to report barriers to specialist care due to geographical availability.12 To enhance rural physician retention, Australia has implemented a variety of strategies, including the Bonded Medical Program.13

Australia’s healthcare system has both public and private care, with rural areas often experiencing a shortage of healthcare professionals.

The Bonded Medical Program is a government initiative implemented to address the rural physician shortage in Australia. This programme offers subsidised education to medical students in exchange for their commitment to work in underserved areas, including rural and remote communities, for a specified period after graduation.13 There is a direct exchange, upon acceptance of admission, for at least three years of service obligation in an eligible rural and remote area.13 This programme has shown promising results as it has increased the number of physicians willing to serve in rural areas.13 By offering incentives and support, such as relocation stipends and alumni networks, it successfully attracts medical graduates to rural practice, enhancing healthcare access and reducing health disparities in these remote regions.13 In this programme, acceptance of a seat in medical school is bonded directly to a rural return of service contract, and the two are linked directly from application. Additionally, the bonding aspect of the programme ensures that graduates fulfil their obligation to work in rural communities, leading to higher retention rates and a more stable rural healthcare workforce. However, the Bonded Medical Program has faced criticism, with concerns over potential urban bias

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in medical education, short-term solutions to rural shortages, and the potential impact on the quality of care in rural communities.14 A weakness of the current model is that the bonded return of service agreement to a pre-approved rural area may be completed at any time over an 18-year period, does not need to be continuous, and the physician may travel in and out of the rural area as required.13 While these conditions allow the programme to remain flexible to the needs of the recruited students, it does little to address the lasting determinants of rural physician retention, such as social connection and community participation. In some cases, physicians may choose to ‘fly-in, fly-out’ in exchange for a place in medical school, rather than invest socially in the rural community they commit to serve.15 A 2017 audit of the programme reported that of the 9,976 rurally bonded medical students to date, 5% had withdrawn, and fewer than 1% had completed their rural return of service obligation.16

Ensuring the long-term success of the Bonded Medical Program requires a comprehensive approach that addresses its loopholes while continuing to support and incentivise physicians to serve in rural and remote regions. A criticism of the Australian programme is that it reduces medical students’ ability to prioritise their own personal preference for the location they would like to train and practise in, and does not account for any changes to that preference that may occur during medical school. Despite criticisms of its effectiveness, the Bonded Medical Program continues to admit students and may achieve sustainable improvements in rural healthcare access and physician retention with stronger regulation on service agreements.

Ensuring the long-term success of the Bonded Medical Program requires a comprehensive approach that addresses its loopholes while continuing to support and incentivise physicians to serve in rural and remote regions.

Ireland: 2023 HSE and ICGP GP Trainee Recruitment Programme, and the medical student paradox Ireland’s healthcare system is a combination of public and private healthcare. Rural areas often struggle to attract and retain physicians due to urbanisation and uneven distribution of healthcare resources. It is predicted that by 2025 Ireland will be short 493 to 1,380 GPs, with only 15% of GPs working in rural areas at present.17,18 To address these challenges, Ireland has adopted various approaches to improve rural physician retention, with the most recent being the 2023 Health Service Executive (HSE) and Irish College of General Practitioners

(ICGP) programme.19 The programme aims to address the rural physician shortage in Ireland through targeted efforts to attract both Irish-trained and international medical graduates to general practice and commit them to practise in underserved areas. Examples of these efforts include trainee specialist funding supports, examination reimbursements, and the non-EU rural GP programme, which aims to integrate internationally trained GPs into the rural workforce.19

Compared with Canada and Australia, where there are rural medical education programmes targeted at prospective doctors, Ireland provides exposure to rural practice following selection of training institution and acceptance to programme of study. Programmes such as rural electives and rural placements offer medical students the opportunity to work in rural healthcare settings, giving them first-hand experience of the unique rewards and challenges of practising in underserved areas.20,21 Valuable as these experiences are, they are not as wide in scope as the approaches used in the Canadian socially accountable medical schools, nor as binding as the Australian Bonded Medical Program.

Ireland’s healthcare system is a combination of public and private, and rural areas often struggle to attract and retain physicians due to urbanisation and uneven distribution of healthcare resources.

Despite the exposure to rural medicine throughout medical school, Ireland faces a unique paradox when compared to Canada and Australia that must be examined in order to understand rural physician shortages. Ireland has the highest number of graduating medical students among the 20 member countries of the Organization for Economic Co-operation and Development (OECD), yet still experiences significant shortages of rural physicians.22 Approximately half of all medical students in Ireland were international students between 2017 and 2018, including an astounding 78% of the student body at the Royal College of Surgeons in Ireland.22 Upon completion of medical school in Ireland, international students, along with Irish or European Union (EU) nationals, are eligible to apply for a 12-month internship under a numerus clasus system. In this system, these graduates are considered for internship and training schemes separately from European students.22 However, the majority of international students tend to leave Ireland upon completion of their medical training, as in 2016 only 2% of the applications to the Irish intern placements were from non-Irish/EU students who had completed their medical degree in

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Ireland.23 In recent years, there has also been a downward trend within the Irish internship programme itself, with a fall in filled posts from 854 in 2021 to 821 in 2022, a loss of 3.9%.24 There are also significant numbers of physicians who leave Ireland once they complete their intern year. In 2022, 442 of the 725 Irish physicians who had graduated in 2021 and completed an intern year were issued work visas for Australia.24,25 This drain on qualified doctors educated in Ireland is felt most acutely in rural areas, and only approximately 15% of Irish GPs work in a rural practice.26 In response to this trend, the ICGP issued a statement, urging that “we cannot train our way out of this GP workforce crisis”.18

Despite the exposure to rural medicine throughout medical school, Ireland faces a unique paradox when compared to Canada and Australia that must be examined in understanding rural physician shortages.

The Irish rural GP shortage is complex and multifaceted. It is not clear whether elements of the Canadian socially accountable medical schools or the Australian Bonded Medical Program would be feasible or effective in addressing this crisis, although they provide interesting demonstrations of how other nations with significant rural populations target and train rurally minded practitioners. Elements of these programmes may integrate young Irish future physicians into the long-term solution for these shortages, rather than continuing with the short-term model of attracting foreign-trained graduates.

Conclusion

Addressing the rural physician shortage is complex and multifaceted, requiring comprehensive strategies tailored to the unique

References

1. Curran V, Rourke J. The role of medical education in the recruitment and retention of rural physicians. Med Teach. 2004;26(3):265-72.

2. Viscomi M, Larkins S, Gupta TS. Recruitment and retention of general practitioners in rural Canada and Australia: a review of the literature. Can J Rural Med. 2013;18(1):13-23.

3. Stanley F, Homeniuk R, O’Callaghan M, Casey M, Collins C, Glynn L. GPs at the edge: a quantitative description of Irish rural general practice. Rural

environment and circumstances of each country. Canada, Australia, and Ireland have each employed different approaches to retain physicians in rural areas, driven primarily by the nature of their healthcare systems, cultural factors, and geographical landscapes. The concept of socially accountable medical schools, as seen in Canada, and the Bonded Medical Program in Australia, show a spectrum of success in addressing rural physician shortages at the medical undergraduate level.10,16 Ireland faces a unique paradox with increasing numbers of medical students, including substantial amounts of international students graduating each year, while still experiencing a significant shortage of rural physicians.22

The Irish rural GP shortage is complex and multifaceted.

To achieve long-term success in retaining physicians in rural areas, Canada, Australia, and Ireland must continue to evaluate and refine their strategies, address potential challenges, and work towards creating an environment that fosters the long-term retention of physicians in rural communities. By doing so, these nations can continue to work towards providing equitable healthcare access for all citizens, regardless of geographical location.

To achieve long-term success in retaining physicians in rural areas, Canada, Australia, and Ireland must continue to evaluate and refine their strategies, address potential challenges, and work towards creating an environment that fosters the long-term retention of physicians in rural communities.

Remote Health. 2023;23(1):8134.

4. World Bank. Rural population (% of total population) – Canada, Australia, Ireland. [Internet.] [Accessed July 30, 2023.] Available from: https://data.worldbank.org/indicator/SP.RUR.TOTL.ZS?locations=CA-AU-IE

5. Cosgrave C, Malatzky C, Gillespie J. Social determinants of rural health workforce retention: a scoping review. Int J Environ Res Public Health. 2019;16(3):314.

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6. Canadian Institute for Health Information (CIHI). Supply, Distribution and Migration of Canadian Physicians. [Internet.] [Accessed July 30, 2023.] Available from: https://www.cihi.ca/en/access-data-reports/results?f%5B0%5D=field_geogr aphies%3A2023&f%5B1%5D=field_primary_theme%3A2050

7. Canadian Collaborative Center for Physical Resources. Canadian physician resources – 2019 basic facts. 2019. [Internet.] Available from: https://www.cma.ca/quick-facts-canadas-physicians.

8. Canadian Collaborative Center for Physician Resources. Canadian physician resources – 2012 basic facts. 2012. [Internet.] Available from: http://www.cma.ca/multimedia/CMA/Content_Images/Policy_Advocacy/P olicy_Research/19-PhysFacts2012-E.pdf

9. Boelen C, Heck JE. Defining and measuring the social accountability of medical schools. World Health Organization; 1995. Report No.: WHO/HRH/95.7. Available from: https://www.who.int/publications/i/item/defining-and-measuring-the-socia l-accountability-of-medical-schools.

10. Wenghofer EF, Hogenbirk JC, Timony PE. Impact of the rural pipeline in medical education: practice locations of recently graduated family physicians in Ontario. Hum Resour Health. 2017;15(1):16.

11. Northern Ontario School of Medicine. Where are NOSM University grads working? 2022. [Internet.] Available from: https://www.nosm.ca/our-community/nosm-physician-workforce-strategy/ northern-ontario-physician-workforce-data/

12. Australian Institute of Health and Welfare. Survey of Health Care: selected findings for rural and remote Australians. Cat. no. PHE 220. Canberra. 2016. [Internet.] Available from: https://www.aihw.gov.au/reports/rural-remote-australians/survey-health-car e-selected-findings-rural-remote/contents/summary

13. Australian Government Department of Health and Aged Care. Bonded Medical Program. [Internet.] [Accessed July 30, 2023.] Available from: https://www.health.gov.au/our-work/bonded-medical-program

14. Buykx P, Humphreys J, Wakerman J, Pashen D. Improving primary health care workforce retention in small rural and remote communities: how important is ongoing education and training? Australian Journal of Rural Health. 2010;18(4):166-74.

15. Margolis SA. Is fly in/fly out (FIFO) a viable interim solution to address remote medical workforce shortages? Rural Remote Health. 2012;12:2261.

16. Department of Health. Review of the Rural Health Workforce Support Activity: Department of Health final Report. 2020. [Internet.] Available from: https://www.health.gov.au/sites/default/files/documents/2021/03/review-o f-the-rural-health-workforce-support-activity-program.pdf

17. McGovern E, Morris R. Medical workforce planning: future demand for general practitioners 2015-2025. Dublin: Health Service Executive. 2015. [Internet.] Available from: https://www.hse.ie/eng/staff/leadership-education-development/met/plan/ gp-medical-workforce-planning-report-sept-2015.pdf

18. Irish College of General Practitioners. Shaping the Future. A discussion paper on the workforce and workload crisis in general practice in Ireland. October 2022. [Internet.] Available from: https://www.icgp.ie/speck/properties/asset/asset.cfm?type=LibraryAsset&id =9D6A8295%2D73F2%2D4623%2D816F366DC386B2A1&property=asse t&revision=tip&disposition=inline&app=icgp&filename=Shaping%5Fthe% 5FFuture%5F%2D%5FICGP%5FDiscussion%5FPaper%5FWorkforce%5FWo rkload%5FCrisis%5Fin%5FGeneral%5FPractice%5FOctober%5F2022%2Ep df

19. Irish College of General Practitioners. ICGP Trainee Recruitment. [Internet.] [Accessed July 30, 2023.] Available from: https://www.icgp.ie/go/become_a_gp/gp_trainee_recruitment.

20. Kilgannon D, Power J, Foley T et al. Experience of undergraduate medical students in rural communities of Ireland. Rural Remote Health. 2017;17(2):4055.

21. Howe A, Ives G. Does community-based experience alter career preference? New evidence from a prospective longitudinal cohort study of undergraduate medical students. Med Teach. 2001;23(4):483-9.

22. Smith L, Barry S. The Irish paradox: doctor shortages despite high numbers of domestic and foreign medical graduates. Human Resources for Health. 2017;15(1):62.

23. Health Service Executive. National Doctors Training and Planning: Annual report 2016. 2017. [Internet.] Available from: https://www.hse.ie/eng/staff/leadership-education-development/met/publi cations/ndtp-annual-report-2016.pdf

24. Hynes T, O’Connor P. An Analysis of Medical Workforce Supply. Research Services & Policy Unit, Department of Health, Irish Government Economic and Evaluation Service. March 2023.

25. Australian Department of Home Affairs. Temporary Work (skilled) visas granted pivot table report at 2023-06-30. 2013. [Internet.] [Retrieved September 16, 2023.] Available from: https://data.gov.au/dataset/ds-dga-2515b21d-0dba-4810-afd4-ac8dd92e 873e/distribution/dist-dga-13e0c12d-f17a-40f6-ba9f-fedcdfaf5b8c/details ?q=

26. Bruff G, Gunning K, Lavelle M et al. Rural and urban comparison of GP trainees on international recruitment schemes. Ir Med J. 2018;111(3):724.

staff review

Too hot to handle? An investigation of the efficacy of heat mitigation strategies in vulnerable populations

Abstract

Claire Reimer RCSI medical student

The effect of extreme heat on human health is an increasingly important target for public health intervention in a warming world, and the efficacy of these measures with regard to heat-vulnerable groups is of particular interest. Heat action plans, educational awareness and air conditioning were identified as common heat mitigation strategies studied in the literature. However the multifactorial and diverse nature of these interventions make it difficult to measure their efficacy. Additionally, few studies focus on the impact of interventions on heat-related mortality and morbidity in vulnerable groups outside of older adults. Further research is needed to determine the efficacy of heat mitigation strategies at preventing mortality and morbidity among people belonging to vulnerable demographics.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 71-75.

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Introduction

July 2023 was the hottest month ever recorded on average globally, as previous temperature records were surpassed in many places around the world.1 From a record temperature of 52.2°C in Algeria to a temperature high of 45.3°C in Xinjiang China, countries around the world faced extreme heat and adverse weather conditions.1 These extreme temperatures represent a significant threat to human health, and are a direct consequence of human-caused climate change and global warming.1,2

The definition of extreme heat depends on geographical location and is related to both temperature and humidity. For example, Environment Canada issues heat warnings when temperatures are above 30°C with a humidity index of 40 or more, or if temperatures are above 40°C.3 This is in contrast to parts of the UK, where a heatwave can be declared when the average daily temperature is above 25°C over three consecutive days.4 Heatwaves, as defined by the World Health Organization (WHO), are periods of hot weather that can last for several days.5 Heatwaves have been associated with increased morbidity, mortality, and premature death by up to a year.6-10 Many countries have previously reported excess mortality related to heat; France reported over 15,000 deaths during a heatwave in 20039 and Argentina reported a heat wave during 2013-2014 that resulted in a relative risk of death of 1.23 (95% CI 1.20-1.28), meaning that for every 100 non-heat-related deaths there were 123 heat-related ones.10 More recent reports estimated over 61,672 heat-related deaths in Europe during the summer of 2022.6 However, not all individuals are equally affected by exposure to extreme heat. Fouillet et al.’s (2006) analysis of the 2003 heatwave in France demonstrated that the number of excess deaths (deaths in excess of what would be expected during a given time period) increased with age, with 1,157 excess deaths occurring in people aged 35-74, and 8,226 excess deaths occurring in those aged 75 years or older.9 The majority of these deaths occurred due to conditions directly related to heat exposure (dehydration, heatstroke, hyperthermia), resulting in mortality ratios of observed-to-expected deaths of 19.6, and excess deaths of 2,852. Notably, there were also increases in deaths due to circulatory, respiratory, and nervous system diseases, as well as ill-defined conditions, mental disorders, and endocrine conditions. This suggests that the presence of comorbidities may increase the risk of adverse effects due to heat exposure.9 Furthermore, a meta-analysis by Bouchama et al. (2007) found that comorbidities such as pulmonary, cardiovascular, and/or mental illness, as well as being unable to care for oneself, not leaving the home and being confined to bed, were risk factors for all-cause mortality during heatwaves.11 This is in contrast to reported protective

factors against heatwave-related mortality, which included increased social contact, working home air conditioning, and visiting other air-conditioned places.11 The results from Bouchama et al. (2007) suggested that many risk factors were indicators of social precariousness and poor overall health, and that reducing the exposure of vulnerable populations to excess heat is key to effectively preventing excess death.11

Finally, a systematic review from Son et al. (2019) found strong evidence that older age and female sex were associated with increased temperature mortality, while there was limited evidence that race, socioeconomic status, and chronic conditions acted as modifiers of heated-associated mortality, indicating that these factors may play a role in heat-related mortality.12 Additionally, while proxies of disability such as chronic conditions, mental illness, and being unable to care for oneself or leave the home have been identified as risk factors for increased susceptibility to heat, it is unclear if disability as a risk factor has been investigated in previous research.10-12

While many factors increase the risk of poor heat-related health outcomes, it is unclear how effective heat mitigation strategies are at reducing heat-related morbidity and mortality within vulnerable populations. This article will explore whether three heat mitigation strategies (heat action plans, educational initiatives, air conditioning) are effective at preventing negative outcomes due to extreme heat, such as hospitalisation, morbidity, and mortality, in elderly people and those with disabilities. In an increasingly hot world, policies and programmes that reduce the risk of heat-related death will become essential. Therefore, it is important to understand what interventions effectively mitigate the risk of adverse heat-related events for vulnerable groups, and how they can be implemented in the future.

Heat action plans

Heat action plans are policy frameworks meant to prevent and manage heat-related threats to human health.13 Components of heat action plans include accurate and timely alert systems, reductions in indoor heat exposure, a focus on care for vulnerable populations, heat-related information systems, development of health and social services, urban planning, and real-time surveillance and evaluation.14,15 The WHO has published a guidance document for the implementation of heat action plans, which outlines how multiple sectors of society, including healthcare, local government, social services, retirement homes, schools, and transportation should be involved in protecting against excess heat.16 According to the WHO, heat action plans should be made up of national and regional components that address the needs unique to different areas of a

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country.16 While heat action plans are increasingly popular, there remains significant difficulty in quantifying their effects.17,18

Vu et al.’s (2019) systematic review of heat-related health prevention measures and adaptation in older adults concluded that health action plans are heterogeneous, fairly novel, and lack established methods of formal evaluation.17 They found that some of the included studies demonstrated a reduction in mortality rates associated with high temperatures. For example, one included study from Liotta et al. (2018) found the mortality rate was reduced by 13%, while Benmarhnia et al. (2016) found that heat action plans lead to a reduction of 2.52 deaths per day.17,19-22 Another systematic review by Hasan et al . (2021) examined the application of community-based interventions for the prevention of heat-related illness.23 One of the included studies, Hess et al. (2018), found that the implementation of a health action plan led to the avoidance of 2,380 deaths during hot weather.23 Moreover, Schifano et al (2012)21 reported a decrease in elderly mortality from +36.7% to +13.3%, with increases in temperature between 9°C and 12°C above the study’s set reference temperature defined as the 25th percentile of the maximum apparent temperature.23

A further review of the literature on heat action plans from Dwyer et al . (2022) found that only two of the 11 included studies demonstrated a clear improvement in health outcomes.13 Dywer et al. (2022) aimed to identify potential solutions to the challenges of effectively measuring the effects of heat action plans. These challenges included: controlling for other factors (e.g., improved healthcare, better housing); differentiating the effects of individual aspects of heat action plans; establishing control groups/comparison groups; accounting for mortality displacement; the lack of morbidity outcomes; and, the difficulty with cross-study comparisons.13 Proposed solutions to these limitations included: natural and quasi-experimental designs; obtaining data on the most probable alternative explanations for observed trends; and, changing heat action plans incrementally to better measure the effect of individual parameters.13

Heat action plans are an important and popular component of the public health response to extreme heat.13,17,23 Despite this, there remains a limited amount of literature on the effectiveness of these interventions.13,17,23 Additionally, there are significant challenges, especially with data interpretation, as the majority of studies rely on population-level data. In these ecological studies, mortality is measured during or around extreme heat events, with no guarantees that the individuals who make up the data points were directly exposed to a given intervention, potentially affecting the internal validity of the study.13,17,23 Furthermore, it is particularly difficult to

control for external influences, such as adaptation to heat, improved housing, and changes in medical management.13,17,23 In addition, mortality prior to and after the implementation of a heat action plan is often used to compare to the effect of the health action plan; however, Culqui et al. (2014) determined that the severity of the heatwave (i.e., intensity, frequency) complicated the pre- and post-intervention comparison of mortality in studies of heat action plan efficacy.24 Finally, evaluating heat action plans is limited by the difficulty in comparing studies. This is due to diversity in study design, outcome measures, and populations, which all increase variance within meta-analyses of current research.15,17,23

Educational awareness

Educational initiatives, which are a key component of heat action plans, aim to increase individual understanding about the dangers of excessive heat and encourage behaviour modification.17,23 The effectiveness of educational interventions is assessed by measuring changes in awareness, engagement in heat-safe behaviours, drinking water, using fans, and understanding of overall risk.17,23 Mattern et al (2000) provided health education that resulted in an increase in participant knowledge of who to contact for assistance during hot weather from 67% to 94%.23,25 Another study by Nitschke et al (2017) found that after the provision of evidence-based information leaflets, there was an increase in air conditioning use from 63.4% to 74.4% during heatwaves. There was also an increase in the use of cool, wet washcloths, from 8% to 16%.19

Educational and behaviour-focused interventions did not measure outcomes in a manner that could determine if they had a positive effect on heat-associated mortality and morbidity. Instead, these interventions measured behavioural change.17,23 While a behaviour may be protective in terms of reducing the risk of heat-related illness, behaviours cannot be used to measure whether the intervention was effective at reducing heat-related mortality and morbidity.9 Additionally, educational initiatives frequently focused on interventions aimed at older adults, but none of the included studies specifically focused on disabled populations.17,19,20

Air conditioning

Air conditioning is an effective method to reduce exposure to high ambient temperatures.26 Furthermore, heat-related deaths are lower in postal code areas with higher air conditioning prevalence.26 A study examining mortality, average temperature and air conditioner prevalence found that air conditioner prevalence was independently and significantly (p=0.011) associated with lower heat-related mortality risk.27 Furthermore, as air conditioning prevalence increased

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over time, there was an associated decrease in the predicted relative risk of heat-related mortality. In 1975, the prevalence of air conditioning was 49.5% in the USA and the relative risk of heat-related mortality was 1.14. This is contrasted with 2004, when the prevalence of air conditioning had risen to 82.8% and the relative risk of heat-related mortality dropped to 1.05.27 Sera et al. (2020) observed that the increasing prevalence of air conditioning resulted in a decrease in the observed mortality fraction by 16.7% in Canada and the US, 20% in Spain and 14.3% in Japan.24

Additionally, studies that examined air conditioning use within a variety of contexts also found that it reduced the risk of heat-related morbidity and mortality. A recent study in 2022 assessed mortality in Texas prisons with and without air conditioning. The results demonstrated that during extreme heat days, there was a 15.1% increased risk of mortality in prisons without air conditioning, compared to prisons with air conditioning, where there was a weak association with decreased risk of mortality.28 Moreover, a California study examining home air conditioner ownership modelled that a 10% increase in air conditioning in homes led to a weak reduction in excess risk in temperature–mortality relation.29 More specifically, the authors reported an absolute risk reduction of 0.71% and relative risk reduction of 49.1% for cardiovascular disease, and an absolute reduction of 0.51% and relative reduction of 19.9% for respiratory disease.29 Furthermore, in this study, air conditioning use was not correlated with income, reducing the probability that income was a confounding factor in the results.29 During a heatwave in Portugal, the confounder-adjusted hazard ratio of death for hospitalised

patients with access to air conditioning was 0.60 (95% CI 0.37-0.97), compared to 1.05 (95% CI 0.84-1.32) for those without air conditioning.30 Finally, another review found that heating, ventilation and air conditioning installation may improve patient outcomes, including reduced cardiac stress and improved vital signs.31

None of the included studies on air conditioning explicitly addressed whether access to air conditioning improved outcomes for disabled people exposed to extreme heat. At most, the improved outcomes of hospitalised patients with access to air conditioning suggests that access to air conditioning may be protective with regard to medical frailty.

Conclusion

As temperatures increase, preventing heat-related deaths will become increasingly important, with heat action plans being the primary policy framework in this regard. However, the capacity to assess the effectiveness of these programmes is limited by the diverse nature of different heat action plans, study designs, and data availability.13,17,23

A key component of heat action plans is a focus on vulnerable groups, yet outside of older adults, most research on heat action plans, education, and behavioural interventions do not appear to target adults with disabilities.11 Future directions should focus on assessing the impact of heat action plans and educational interventions on mortality, behaviour, and knowledge outcomes in people with disabilities, as well as emphasising the use of quasi-experimental or natural experimental models to ensure that morbidity and mortality are the primary study outcomes for heat action plan research.

References

1. Climate Central. Fingerprints of climate change during Earth’s hottest month. [Internet.] 2023. [cited August 6, 2023.] Available from: https://www.climatecentral.org/climate-matters/climate-shift-index-global-j uly-2023#.

2. Taalas P, Guterres A, World Meteorological Organization. State of the Global Climate 2020. Available from: https://reliefweb.int/report/world/state-global-climate-2020#:~:text=2020 %20was%20one%20of%20the,the%20warmest%20decade%20on%20re cord

3. Government of Quebec. Extreme Heat. Government Information Services. [Internet.] 2023. Available from:

https://www.quebec.ca/en/public-safety-emergencies/emergency-situation s-disasters-and-natural-hazards/what-to-do-before-during-after-emergencydisaster/extreme-heat

4. Met Office. What is a heatwave? [Internet.] Available from: https://www.metoffice.gov.uk/weather/learn-about/weather/types-of-weat her/temperature/heatwave

5. World Health Organisation. Heatwaves. 2023. [Internet.] Available from: https://www.who.int/health-topics/heatwaves#tab=tab_1

6. Ballester J, Quijal-Zamorano M, Méndez Turrubiates RF, Pegenaute F, Herrmann FR, Robine JM et al. Heat-related mortality in Europe during the summer of 2022. Nat Med. 2023;29(7):1857-66.

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7. Armstrong B, Bell ML, Coelho M de SZS, Guo YLL, Guo Y, Goodman P et al. Longer-term impact of high and low temperature on mortality: an international study to clarify length of mortality displacement. Environ Health Perspect. 2017;125(10):107009.

8. Can G, Şahin Ü, Sayılı U, Dubé M, Kara B, Acar HC et al. Excess mortality in Istanbul during extreme heat waves between 2013 and 2017. Int J Environ Res Public Health. 2019;16(22):4348.

9. Fouillet A, Rey G, Laurent F, Pavillon G, Bellec S, Guihenneuc-Jouyaux C et al. Excess mortality related to the August 2003 heat wave in France. Int Arch Occup Environ Health. 2006;80(1):16-24.

10. Chesini F, Herrera N, de los Milagros Skansi M, Morinigo CG, Fontán S, Savoy F et al. Mortality risk during heat waves in the summer 2013-2014 in 18 provinces of Argentina: ecological study. Cien Saude Colet. 2022;27(5):2071-86.

11. Bouchama A, Dehbi M, Mohamed G, Matthies F, Shoukri M, Menne B. Prognostic factors in heat wave related deaths: a meta-analysis. Arch Intern Med. 2007;167(20):2170-6.

12. Son JY, Liu JC, Bell ML. Temperature-related mortality: a systematic review and investigation of effect modifiers. Environmental Research Letters. 2019;14(7).

13. Dwyer IJ, Barry SJE, Megiddo I, White CJ. Evaluations of heat action plans for reducing the health impacts of extreme heat: methodological developments (2012–2021) and remaining challenges. Int J Biometeorol. 2022;66(9):1915-27.

14. WHO Europe. Planning heat–health action. 2023. [Internet.] Available from: https://www.who.int/europe/activities/planning-heat-health-action

15. Kotharkar R, Ghosh A. Progress in extreme heat management and warning systems: a systematic review of heat-health action plans (1995-2020). Sustainable Cities and Society. 2022;76(4):103487.

16. Franziska M, Bickler G, Cardenosa Marin N, Hales S (eds.). World Health Organization Europe. Heat–health action plans: guidance. 2008. [Internet.] Available from: https://www.who.int/publications/i/item/9789289071918

17. Vu A, Rutherford S, Phung D. Heat health prevention measures and adaptation in older populations – a systematic review. Int J Environ Res Public Health. 2019;16(22):4370.

18. Boeckmann M, Rohn I. Is planned adaptation to heat reducing heat-related mortality and illness? A systematic review. BMC Public Health. 2014;14:1112.

19. Nitschke M, Krackowizer A, Hansen AL, Bi P, Tucker GR. Heat health messages: a randomized controlled trial of a preventative messages tool in the older population of south Australia. Int J Environ Res Public Health. 2017;14(9):992.

20. Benmarhnia T, Bailey Z, Kaiser D, Auger N, King N, Kaufman JS. A difference-in-differences approach to assess the effect of a heat action plan on heat-related mortality, and differences in effectiveness according to sex, age, and socioeconomic status (Montreal, Quebec). Environ Health Perspect. 2016;124(11):1694-9.

21. Schifano P, Leone M, De Sario M, De’ donato F, Bargagli AM, Dippoliti D et al. Changes in the effects of heat on mortality among the elderly from 1998-2010: results from a multicenter time series study in Italy. Environ Health. 2012;11:58.

22. Michelozzi P, de’ Donato FK, Bargagli AM, D’Ippoliti D, de Sario M, Marino C et al. Surveillance of summer mortality and preparedness to reduce the health impact of heat waves in Italy. Int J Environ Res Public Health. 2010;7(5):2256-73.

23. Hasan F, Marsia S, Patel K, Agrawal P, Razzak JA. Effective community-based interventions for the prevention and management of heat-related illnesses: a scoping review. Int J Environ Res Public Health. 2021 Aug 2;18(16):8362.

24. Culqui DR, Diaz J, Simón F, Tobías A, Linares C. Evaluation of the plan for surveillance and controlling of the effects of heat waves in Madrid. Int J Biometeorol. 2014;58(8):1799-802.

25. Mattern J, Garrigan S, Kennedy IV SB. A community-based assessment of heat-related morbidity in North Philadelphia. Environmental Res. 2000;83(3):338-42.

26. Gronlund CJ. Racial and socioeconomic disparities in heat-related health effects and their mechanisms: a review. Curr Epidemiol Rep. 2014;1(3):165-73.

27. Sera F, Hashizume M, Honda Y, Lavigne E, Schwartz J, Zanobetti A et al Air conditioning and heat-related mortality: a multi-country longitudinal study. Epidemiology. 2020;31(6):779-87.

28. Skarha J, Dominick A, Spangler K, Dosa D, Rich JD, Savitz DA et al Provision of air conditioning and heat-related mortality in Texas prisons. JAMA Netw Open. 2022;5(11):e2239849.

29. Ostro B, Rauch S, Green R, Malig B, Basu R. The effects of temperature and use of air conditioning on hospitalizations. Am J Epidemiol. 2010;172(9):1053-61.

30. Nunes B, Paixao E, Dias CM, Nogueira P, Flacao JM. Air conditioning and intrahospital mortality during the 2003 heatwave in Portugal: evidence of a protective effect. Occup Environ Med. 2011;68(3):218-23.

31. Shajahan A, Culp CH, Williamson B. Effects of indoor environmental parameters related to building heating, ventilation, and air conditioning systems on patients’ medical outcomes: a review of scientific research on hospital buildings. Indoor Air. 2019;(29(2):161-76.

Sadie Badrie RCSI medical student

Application of artificial intelligence for early detection of breast cancer

Abstract

Breast cancer, the most common malignancy in women worldwide, demands early and accurate detection for optimal outcomes. The incorporation of artificial intelligence (AI) into breast cancer diagnostics offers a transformative approach, potentially revolutionising traditional mammography-based screening methods. AI, driven by algorithms and machine learning, holds the promise to identify patterns and anomalies with higher precision than conventional mammograms. While AI showcases advantages, such as enhanced image analysis and the potential for personalised diagnostics, it also has drawbacks. In its nascent stages, the technology faces challenges in terms of accuracy, variance, and data representativeness. Ethical considerations, especially concerning data privacy and patient consent, further complicate its implementation. Nonetheless, the future of AI in breast cancer diagnosis is promising, with ongoing research aimed at refining the technology and addressing its limitations. This fusion of AI with clinical expertise is expected to usher in an era of advanced, patient-centred breast cancer care.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 76-81.

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FIGURE 1: Overview of artificial intelligence applications in breast cancer imaging.9

CAD: computer-aided detection; BD: breast density.

Introduction

Breast cancer is one of the most commonly diagnosed malignancies, which underscores an urgent need for more efficient detection and treatment strategies. The gravity of this issue is highlighted by World Health Organization (WHO) statistics, with 2.3 million new diagnoses in 2020 added to the existing 7.8 million women diagnosed over the previous five years.1 Approximately 50% of all breast cancer cases occur in women presenting with no distinctive risk factors apart from their gender and age.2 Despite this alarming information, there has been an encouraging increase in survival rates since 1990, which can largely be attributed to advancements in early detection methodologies and the development of effective therapeutic interventions.1

Regular screening and comprehensive clinical evaluations are integral parts of the early detection model for breast cancer. Mammography is the gold standard diagnostic tool and utilises low-dose X-ray technology to provide intricate images of breast tissue, enabling the detection of potential abnormalities before they are physically palpable.3 When mammograms or clinical evaluations raise concerns, additional diagnostic measures, such as ultrasound or biopsy, are initiated to confirm or refute the suspicions. The final diagnosis typically relies on the histopathological examination of biopsy specimens, yielding essential information about the type, grade, and receptor status of the cancer, which plays a vital role in crafting personalised treatment plans.4

However, these traditional diagnostic techniques come with inherent limitations. Mammography has a known false-positive rate of approximately 10%, leading to significant distress and unnecessary testing, and a false-negative rate of roughly 20%, resulting in missed

diagnoses.3 Furthermore, the interpretive nature of histopathological analysis can yield variable outcomes and inconsistencies in diagnosis and treatment, with studies indicating an inter-observer variability of about 48%.4

Given these challenges, the integration of more accurate, reliable, and objective diagnostic tools is warranted. In this regard, the emergence of artificial intelligence (AI), particularly machine learning (ML) algorithms, offers a promising solution.5

This review explores the pivotal role of AI in early breast cancer detection, highlighting its ground-breaking potential as a diagnostic tool and the potential challenges it introduces to breast cancer research and management.

Artificial intelligence: the next frontier in healthcare

AI, characterised by Russell and Norvig as “the science and engineering of making intelligent machines,” 6 is poised to revolutionise healthcare, particularly in disease detection and diagnosis. Integral to this transformation are AI technologies, such as ML, natural language processing (NLP), and deep learning, which have been integrated into medical practices. These technologies are not only enhancing the automation of diagnostics but are also facilitating the creation of personalised treatment plans.7 With the potential to dramatically improve the accuracy and efficiency of diagnosis, AI could shift medical practices and patient care significantly.8

AI’s influence is seen in various diagnostic domains. In medical imaging, algorithms such as convolutional neural networks (CNNs)

Clinical

FIGURE 2: Application of artificial intelligence to breast cancer diagnosis.15

Breast cancer screen

Diagnosis

Staging

Prognosis Mammography

are advancing the detection and interpretation of diseases across multiple specialties, from radiology to pathology. AI’s ability to analyse and learn from complex patterns in imaging data exceeds traditional methods in both speed and accuracy. This leads to earlier and more accurate diagnoses, a critical factor in successful treatment outcomes.9 In pathology, AI is streamlining the examination of tissue samples. By applying algorithms to digital pathology, AI introduces a level of standardisation and objectivity that reduces the variability seen in traditional microscopic analyses. This enhances diagnostic accuracy and improves the consistency of findings across different cases.9 AI is also invaluable in analysing electronic health records (EHRs). Through NLP, AI can extract and synthesise information from vast amounts of unstructured text data, including patient histories and clinical notes. This aids clinicians in making more informed diagnostic decisions, ensuring a comprehensive understanding of the patient’s health status.9

Moreover, AI-driven predictive modelling is becoming a cornerstone in risk assessment. AI tools can predict disease progression and patient outcomes by analysing diverse datasets, including clinical, demographic, and genetic information. This predictive power is instrumental in proactive healthcare, allowing for early intervention and tailored treatment strategies (Figure 1).9

Navigating the artificial intelligence pathways: transforming breast cancer diagnostics

AI is progressively transforming breast cancer diagnostics, profoundly reshaping three critical pathways: the interpretation of mammograms; digital pathology; and, predictive analytics for risk assessment (Figure 2).

Precision treatment

Follow-up

Drug discovery

In the realm of mammography, the integration of CNNs represents a significant advancement in diagnostic medicine. This technology is able to learn from intricate patterns within these images, offering an impressive, remarkable capacity to match and, in some ways, surpass the expertise of experienced radiologists.10 Rodríguez-Ruiz et al (2019) illustrated that AI can effectively detect breast cancer in mammograms, thereby potentially improving both the accuracy and time efficiency of breast cancer diagnoses.11 This heightened ability to detect early signs of breast cancer can considerably enhance patient prognosis.

AI-driven predictive modelling is becoming a cornerstone in risk assessment. AI tools can predict disease progression and patient outcomes by analysing diverse datasets, including clinical, demographic, and genetic information.

In digital pathology, AI enhances objectivity in breast cancer by extracting and analysing thousands of image features from whole slide images (WSI). This analysis is linked to biological phenotypes to create algorithms that recognise disease characteristics similar to genetic profiles. CNNs are pivotal in this process, utilising multi-layered image structures to identify patterns and contours. These networks transform images into features for algorithm development without manual intervention. This technique has

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proven effective for tumour detection, classification, prognostication, and predicting therapeutic responses.12

Additionally, artificial neural networks (ANNs), support vector machines (SVMs), and random forests – all types of ML algorithms –are used for predictive modelling in breast cancer cases. These algorithms use diverse datasets to predict patient outcomes, including clinical, demographic, and genetic information.8 AI capabilities extend beyond diagnostics to predictive analytics for risk assessment, thereby fostering a proactive rather than reactive approach to healthcare.13 Taken together, these promising applications of AI across various critical pathways mark a paradigm shift in the field of breast cancer diagnostics. By improving diagnostic precision, promoting uniformity in interpretation, and enhancing the efficiency of healthcare delivery, AI is poised to revolutionise the landscape of breast cancer care. As these technological advancements continue to evolve and integrate into mainstream healthcare, a brighter and more hopeful future is envisaged for individuals affected by breast cancer worldwide.14

In digital pathology, AI enhances objectivity in breast cancer by extracting and analysing thousands of image features from whole slide images (WSI).

The hurdles ahead: addressing the limitations of artificial intelligence in breast cancer detection

Addressing the challenges in harnessing AI for breast cancer detection involves acknowledging its limitations in comparison with human expertise. Currently, AI systems are evaluated against the performance of radiologists; however, this comparison could prove problematic, as even expert human judgement is susceptible to error.

A seminal study by Rodríguez-Ruiz et al. (2019) compared the performance of an AI system with 101 radiologists in the detection of breast cancer. Interestingly, AI exhibited a higher cancer detection rate. However, AI simultaneously displayed a higher recall rate, hinting at an elevated likelihood of false positives.14 These findings highlight that while the precision of AI in detection could surpass human expertise, it could also potentially increase patient anxiety and healthcare costs due to unnecessary follow-up procedures.

A study by McKinney et al. (2020) revealed that AI systems outperformed radiologists in the UK and USA on a clinically relevant task of breast cancer identification.16 While this remarkable feat underscores the prowess of AI, it also reveals the Achilles heel of such systems – the dependence on the quality and diversity of the training

data. Essentially, the AI’s performance is only as effective as the code or data from which it was built. If the AI model is trained on skewed or non-representative datasets, its ability to apply its ‘learning’ to real-world cases may be significantly hindered.

Another critical consideration revolves around the potential biases and variability in AI and traditional methods. As AI models are trained on datasets reflecting real-world demographics, they may inadvertently incorporate biases present in the data. Furthermore, variability in image interpretation, which may arise due to the idiosyncrasies of an AI model, can lead to disparities in the accuracy of diagnoses, particularly in underrepresented populations. Addressing these biases is essential to ensure equitable and accurate healthcare delivery for all patients.17

Addressing the challenges in harnessing AI for breast cancer detection involves acknowledging its limitations in comparison with human expertise.

Moreover, the challenges of integrating AI into existing healthcare workflows and ensuring seamless collaboration between AI systems and healthcare professionals is of paramount importance. The ‘black-box’ nature – the uncertainty of how AI truly works – can hinder their interpretability, making it challenging for clinicians to trust and comprehend the AI-generated results fully. Transparency and explainability are key factors in fostering trust and acceptance among healthcare providers.18

In light of these challenges, the path forward involves stringent data quality control and openness in the training of AI models. It also demands the establishment of standardised evaluation metrics applicable to both AI systems and human experts.

The challenges of integrating AI into existing healthcare workflows and ensuring seamless collaboration between AI systems and healthcare professionals is of paramount importance.

Challenges and responsibilities in artificial intelligence training and implementation in healthcare

While AI marks a revolutionary change in diagnostics, this evolution brings with it complex challenges related to data quality, ethical dimensions, and the irreplaceable role of human judgment.

A significant challenge stems from the intricacies of AI training. AI efficacy is profoundly influenced by the quality and heterogeneity of

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the training data. Diverse datasets in breast cancer underscore the importance of data quality. Disparities across geographical, racial, and socioeconomic sectors can lead to varied datasets, thus emphasising the importance of representative data in AI models. Without this, there is a heightened risk of AI models making generalisation errors, which might inadvertently perpetuate existing healthcare inequities.19 Emerging from the implementation of AI are ethical dilemmas distinct from traditional medical ethics. While established ethical tenets – autonomy, beneficence, nonmaleficence, and justice – are deeply entrenched in medicine, AI introduces the principle of explicability, which melds intelligibility (‘how does it work?’) and accountability (‘who is responsible for the way it works?’).20 The latter poses a potent query: in scenarios where AI errs, particularly in contexts where it might autonomously triage without human intervention, who assumes responsibility? Is it the AI, its developers, or the clinician? Legal frameworks must evolve to unequivocally address these concerns.19

Furthermore, while AI possesses significant capabilities, it evidently serves as a complement to human expertise rather than a replacement. The role of AI in mammographic screening, while beneficial, mandates meticulous evaluation by physicians to ensure that decisions align with patient welfare and medical prudence.19 The synergy between AI computational prowess and the intuitive expertise of healthcare professionals is essential to harness the full potential of this technology, without sidelining its inherent responsibilities.21 In essence, the integration of AI in healthcare, while promising, necessitates meticulous navigation of data challenges, ethical quandaries, and the commitment to keep human expertise at the forefront of clinical decisions.19

Furthermore, while AI possesses significant capabilities, it evidently serves as a complement to human expertise rather than a replacement.

The future of artificial intelligence in breast cancer detection: balancing innovation with ethics and human expertise

The integration of AI into breast cancer diagnostics and care represents a promising evolution in medical science. Its capabilities, from refining medical image interpretation to uncovering ground-breaking biomarkers and predicting treatment responses, have the potential to redefine early detection and pave the way for tailored treatment regimes.22

These advancements could revolutionise patient outcomes, elevating the standard of breast cancer care to unprecedented levels. However, as the horizon of AI in healthcare expands, the true potential lies in harmonising it with human expertise.23

The synergy between AI computational prowess and the intuitive expertise of healthcare professionals is essential to harness the full potential of this technology, without sidelining its inherent responsibilities.

The future of breast cancer care thus envisions a blended approach, where the analytical prowess of AI seamlessly melds with the discernment of medical professionals. Such a symbiotic relationship amplifies the strengths of both AI and human expertise, creating a robust diagnostic and treatment framework.24,25 Human expertise and AI represent two distinct yet complementary paradigms in healthcare. Human clinicians bring years of training, real-world experience, nuanced understanding, and a profound ability to connect and empathise with patients. Their judgements often consider the subtle complexities of human anatomy and personal histories, making them adept at navigating the grey areas in medicine.26 On the other hand, AI offers unparalleled computational strength, enabling it to process vast amounts of data rapidly and identify patterns or anomalies that might be overlooked by the human eye. By blending the two, we can harness the efficiency and precision of AI while maintaining the invaluable human touch in medical care. This synergy promises not only improved accuracy but also a more holistic approach to patient care, balancing the cold efficiency of algorithms with the warmth and intuition of human experience.27,28

Conclusion

While AI brings transformative potential to breast cancer diagnostics, its true value will be realised when it works hand in hand with a human touch. By fostering an integrated paradigm, the healthcare community can unlock a future where technology and human intuition coalesce to offer the best possible preventive care.

While AI brings transformative potential to breast cancer diagnostics, its true value will be realised when it works hand in hand with a human touch.

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References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.

2. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69(6):438-51.

3. Wilt TJ, Harris RP, Qaseem A. Screening for cancer: advice for high-value care from the American College of Physicians. Ann Intern Med 2015;162(10):718-725.

4. Lehman CD, Arao RF, Sprague BL, Lee JM, Buist DS, Kerlikowske K et al. National performance benchmarks for modern screening digital mammography: update from the Breast Cancer Surveillance Consortium. Radiology. 2017;283(1):49-58.

5. Hosny A, Parmar C, Quackenbush J, Schwartz LH, Aerts HJWL. Artificial intelligence in radiology. Nat Rev Cancer. 2018;18(8):500-10.

6. Russell SJ, Norvig P. Artificial Intelligence: A Modern Approach (3rd ed.). [Internet.] Pearson; 2021. [cited July 26, 2023.] Available from: https://people.engr.tamu.edu/guni/csce421/files/AI_Russell_Norvig.pdf

7. Basu K, Sinha R, Ong A, Basu T. Artificial intelligence: how is it changing medical sciences and its future? Indian J Dermatol. 2020;65(5):365-70.

8. Dileep G, Gianchandani Gyani SG. Artificial intelligence in breast cancer screening and diagnosis. Cureus. 2022;14(10):e30318.

9. Alowais SA, Alghamdi SS, Alsuhebany N et al. Revolutionizing healthcare: the role of artificial intelligence in clinical practice. BMC Med Educ 2023;23:689.

10. Jiang F, Jiang Y, Zhi H et al. Artificial intelligence in healthcare: past, present and future. Stroke Vasc Neurol. 2017;2(4):230-43.

11. Rodríguez-Ruiz A et al. Detection of breast cancer with mammography: effect of an artificial intelligence support system. Radiology, 2019;290(2):305-14.

12. Badve SS. Artificial intelligence in breast pathology – dawn of a new era. NPJ Breast Cancer. 2023;9(1):5.

13. Arora M, Som S, Rana A. Predictive analysis of machine learning algorithms for breast cancer diagnosis. 8th International Conference on Reliability, Infocom Technologies and Optimization (Trends and Future Directions) (ICRITO), Noida, India. 2020:835-39

14. Leibig C et al. Combining the strengths of radiologists and AI for breast cancer screening: a retrospective analysis. Lancet Digit Health. 2022;4(7):e507-19.

15. Zheng D, He X, Jing J. Overview of artificial intelligence in breast cancer medical imaging. J Clin Med. 2023;12(2):419.

16. Rodríguez-Ruiz A et al. Stand-alone artificial intelligence for breast cancer detection in mammography: comparison with 101 radiologists. J Natl Cancer Inst. 2019;111(9):916-22.

17. McKinney SM et al. International evaluation of an AI system for breast cancer screening. Nature. 2020;577(7788):89-94.

18. Adamson AS, Smith A. Machine learning and health care disparities in dermatology. JAMA Dermatol. 2018;154(11):1247-8.

19. Elmore JG et al. Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. BMJ 2017;357:j2813.

20. Carter SM, Rogers W, Win KT, Frazer H, Richards B, Houssami N. The ethical, legal and social implications of using artificial intelligence systems in breast cancer care. The Breast 2020;49:25-32.

21. Morgan MB, Mates JL. Ethics of artificial intelligence in breast imaging. Journal of Breast Imaging. 2023;5(2):195-200.

22. Shinners L, Aggar C, Grace S, Smith S. Exploring healthcare professionals’ understanding and experiences of artificial intelligence technology use in the delivery of healthcare: an integrative review. Health Informatics J. 2020;26(2):1225-36.

23. Taylor CR, Monga N, Johnson C, Hawley JR, Patel M. Artificial intelligence applications in breast imaging: current status and future directions. Diagnostics (Basel). 2-23;13(12):2041.

24. Seth I, Bulloch G, Joseph K, Hunter-Smith DJ, Rozen WM. Use of artificial intelligence in the advancement of breast surgery and implications for breast reconstruction: a narrative review. J Clin Med. 2023;12(15):5143.

25. Najjar R. Redefining radiology: a review of artificial intelligence integration in medical imaging. Diagnostics 2023;13(17):2760.

26. Johnson KB, Wei W-Q, Weeraratne D, Frisse ME, Misulis K, Rhee K et al Precision medicine, AI, and the future of personalized health care. Clin Trans Sci. 2021;14(1):86-93.

27. Nagendran M, Chen Y, Lovejoy CA, Gordon AC, Komorowski M, Harvey H et al. Artificial intelligence versus clinicians: systematic review of design, reporting standards, and claims of deep learning studies. BMJ. 2020;368:m689.

28. Lee J. Is artificial intelligence better than human clinicians in predicting patient outcomes? J Med Internet Res;2020;22(8):e19918.

Sidonie Chard RCSI medical student

Striding toward change: addressing the burden of clubfoot in low- and middle-income countries

Abstract

This comprehensive review addresses the global impact of clubfoot, a prevalent hindfoot deformity, with a focus on low- and middle-income countries (LMICs). Highlighting the clinical presentation, pathoanatomy, and the gold standard Ponseti method for treatment, the review underscores the urgent need for collaborative efforts to overcome barriers hindering access to care in LMICs. Despite the proven efficacy of the Ponseti method, significant challenges persist, leading to preventable disability and long-term consequences. The Ponseti International Association’s role in promoting standardisation, coupled with the engagement of in-country champions and stakeholders, are discussed as essential components of a global strategy. The review concludes by emphasising the necessity of co-ordinated efforts involving governments, non-governmental organisations, international partners, and local communities to raise awareness, provide training, offer financial support, and improve healthcare infrastructure, ultimately working towards the eradication of clubfoot-related disabilities globally.

RCSIsmj staff review

Introduction

Clubfoot is a hindfoot deformity caused by misalignment of the talocalcaneonavicular complex, and is one of the most common lower extremity anomalies globally. Clubfoot is usually an isolated congenital anomaly that occurs in otherwise healthy babies, in which case it is referred to as idiopathic clubfoot or congenital talipes equinovarus. Other classifications of clubfoot include postural, syndromic, and neurologic.1

The global incidence of clubfoot is estimated to be one to two cases per 1,000 births, resulting in 150,000 to 200,000 cases annually. Up to 90% of these cases occur in low- and middle-income countries (LMICs).2 In most cases, clubfoot can be effectively treated using the Ponseti method, which is a minimally invasive method involving manipulation, casting, bracing, and Achilles tenotomy.3 Left untreated, clubfoot can lead to long-term functional disability, deformity, chronic pain, and psychosocial consequences.4,5 Access to appropriate treatment, especially in low-resource settings, remains a significant hurdle.

This review delves into the clinical presentation and underlying pathoanatomy of clubfoot, outlines the Ponseti method for clubfoot treatment, explores the impact of clubfoot in LMICs, and highlights the urgent need for collaborative efforts to ensure that all affected individuals can lead healthier, more productive lives.

Clubfoot is a hindfoot deformity caused by misalignment of the talocalcaneonavicular complex, and is one of the most common lower extremity

anomalies globally.

Clinical presentation and pathoanatomy of clubfoot

Clubfoot is characterised by a turned-in forefoot (adductus), turned-in hindfoot (varus), downward-pointing hindfoot (equinus), and high medial longitudinal arch (cavus), with the calcaneus and navicular bones of the foot rotated around the talus.1 In about 50% of cases clubfoot affects both limbs, and unilateral clubfoot occurs on the right side twice as often as on the left.5 Additionally, boys are two times more likely than girls to be born with idiopathic clubfoot.6 Abnormalities in both morphology and alignment are present, with accompanying soft tissue contractures.

Morphologic and alignment abnormalities

In clubfoot, the talus is smaller than normal and there is medial and plantar deviation of its head and neck.1 However, the whole bone is

externally rotated. Its anteromedial surface articulates with the navicular bone and its anterolateral surface is inarticulate.1 The calcaneus is adducted and inverted inferior to the talus, and has dysplastic facets and an underdeveloped sustentaculum tali.1 The navicular bone is flattened and medially displaced relative to the talar head. In severe cases, the navicular bone articulates with the medial malleolus.1 The cuboid is medially displaced and inverted relative to the talus with joint line obliquity at the calcaneocuboid joint.1 The tibia only articulates with the most posterior part of the talus.1 In those most affected, the posterior tibia may be in contact with the posterior tuberosity of the calcaneus.1

Soft tissue contractures

In clubfoot, muscles and their respective tendons in the deep posterior compartment of the leg (tibialis posterior, flexor digitorum longus, flexor hallucis longus) are contracted, while muscles and respective tendons in the anterior and lateral compartments of the leg (tibialis anterior, peroneus longus, flexor hallucis longus) are elongated.1 The Achilles tendon is thickened and contracted, and is inserted slightly medially on the calcaneus.1 The deep plantar muscles and the abductor hallucis are also contracted.1 The joints of the foot and ankle become contracted over time if the clubfoot is not treated adequately.1 Finally, contractures of the ligaments of the foot and ankle are usually present. The posterior tibiotalar, talofibular, calcaneofibular, and deltoid ligaments, as well as the ligaments on the plantar surface of the foot, may all be affected.1

The gold standard for clubfoot treatment – the Ponseti method

The aim of clubfoot treatment is to achieve a normally aligned foot and ankle that is functional, pain free, and mobile. Ideally, clubfoot treatment is started soon after birth, but this is not always possible, especially in low-resource settings. Thousands of children and adults in LMICs face physical, sociocultural, and psychological consequences of untreated clubfoot due to lack of access to or utilisation of health services.7

The Ponseti method has become a widely recognised treatment for clubfoot worldwide. Developed by Dr Ignacio Ponseti in the 1950s, this minimally invasive approach has demonstrated remarkable success rates in correcting clubfoot in infants and young children.3,8

The Ponseti method minimises the need for complex posterior medial release of multiple tendons and intra-articular interventions, which were once the standard for clubfoot treatment.9

The Ponseti method involves a sequential series of about six gentle manipulations and casting over the course of four to six weeks to

gradually reposition the foot into its correct alignment, aiming to stretch contracted soft tissues and realign bones to achieve a functional and normal foot structure (Figure 1).8 Between 80% and 90% of patients also require a percutaneous tenotomy of the Achilles tendon to correct residual equinus once other deformities are corrected with serial casting.10 Bracing is then required to maintain the treatment corrections (Figure 2). The brace ensures that the foot is kept in an abducted position; it is worn for 24 hours a day for the first three months post treatment, then 12 hours at night and two to four hours throughout the day until the child is four to five years of

age.1,8 Applied appropriately, the Ponseti method is effective in up to 95% of clubfoot cases.7,11

Due to its evidence-based effectiveness, the Ponseti method has become the gold standard in the management of clubfoot worldwide. An article published in the World Journal of Orthopedics in 2014 found that 113 of 193 United Nations member countries were using the Ponseti method.12 Its success in achieving favourable outcomes and minimising the need for surgery ensures that affected individuals can lead healthy, active lives, unrestricted by the limitations previously imposed by the deformity.

Due to its evidence-based effectiveness, the Ponseti method has become the gold standard in the management of clubfoot worldwide.

The

burden of clubfoot in low- to middle-income countries

Despite the known efficacy of the Ponseti method, there exist many barriers to the eradication of clubfoot worldwide, especially in LMICs. Up to 90% of all clubfoot cases occur in LMICs,14 yet most children fail to access adequate treatment. While the Ponseti method has been implemented in numerous LMICs, fewer than 15% of individuals with clubfoot are able to access treatment.2,15 Furthermore, even if initial treatment is accessed, many patients do not adhere to the full course of treatment, leading to relapse and persistent deformities,16 and resulting in a high prevalence of preventable disability.17

The long-term consequences of untreated clubfoot are profound. Left untreated, clubfoot can lead to physical disability, difficulties in

FIGURE 1: Ponseti serial casting allows for gradual repositioning, and improved foot and ankle alignment.13

FIGURE 2: Foot abduction orthoses. The round window at the heel allows parents to ensure that their child’s heel remains down in the brace.1

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Furthermore, individuals with untreated clubfoot may face challenges in accessing education, employment, and in participating fully in their communities. This is especially apparent in LMICs, where transportation and other infrastructure may not be adequately developed, and primary sources of income include agricultural and other forms of manual labour. Also, in many LMICs, people with physical disabilities are stigmatised, excluded from society, and may even experience violence due to cultural norms and beliefs.19,20

Despite the known efficacy of the Ponseti method, there exist many barriers to the eradication of clubfoot worldwide, especially in LMICs.

Many barriers exist to implementing an effective system for Ponseti treatment, especially in LMICs.12,21-24 For example, financial constraints, transportation, difficulties with brace and cast care, self-perceived health status, lack of physical resources, and providers’ lack of knowledge and skill have all been identified as barriers that impact patient care.25 Key solutions to address these barriers have centred on provider and patient education, and financial assistance for patient care and transportation.25

walking and mobility, and increased vulnerability to secondary health issues such as skin infections, chronic pain, and social isolation. As children with untreated clubfoot learn to walk and begin to bear weight, foot position worsens (Figure 3). Weight transmits through the side and top surface of the foot as it twists, and large calluses form on the weight-bearing surface. This makes it very difficult to walk and wear normal shoes, and eventually leads to severe pain (Figure 4).18

In many LMICs, people with physical disabilities are stigmatised, excluded from society, and may even experience violence due to cultural norms and beliefs.

FIGURE 3: A child walking with untreated clubfoot.1

FIGURE 4: Walking on the lateral border of the foot with untreated clubfoot can lead to excessive shoe wear and painful skin lesions.1

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A global effort to decrease the burden of clubfoot

The Ponseti International Association (PIA) was established in 2006, and aims to eliminate disability caused by clubfoot worldwide. The PIA promotes the institutionalisation of the Ponseti method as the standard of care in every country, and provides global leadership in providing high-quality, locally directed, sustainable, and equitable clubfoot care.26 A key component of the PIA’s methods include in-country ‘champions’, who provide leadership and enthusiasm to build their national programme. Programme champions are passionate, knowledgeable, and persuasive; most importantly, they are well respected leaders in the healthcare community. They deliver Ponseti clubfoot care, train other providers, and engage with local and national groups to promote Ponseti treatment.7 Another key component of the PIA’s methods involves the engagement of stakeholders at all levels of society, including health service providers, parents of children who have received Ponseti clubfoot care, health system managers, leaders of professional societies, training institutions, policymakers, and administrators.7

The Ponseti International Association (PIA) was established in 2006, and aims to eliminate disability caused by clubfoot worldwide.

Collaborative efforts involving governments, non-governmental organisations, international partners, and local communities are essential in addressing challenges with clubfoot treatment implementation in LMICs. Initiatives aimed at raising awareness, providing training to healthcare professionals, offering financial support to families, and improving healthcare infrastructure all serve as crucial steps towards reducing the burden of clubfoot in LMICs and ensuring that affected individuals have the opportunity to lead healthier, more productive lives.25

Collaborative efforts involving governments, non-governmental organisations, international partners, and local communities are essential in addressing challenges with clubfoot treatment implementation in LMICs.

Conclusion

In conclusion, congenital talipes equinovarus, or idiopathic clubfoot, is a common lower extremity anomaly that poses significant

challenges, particularly in LMICs. The Ponseti method has emerged as the gold standard for clubfoot treatment, offering a minimally invasive and effective approach to correcting the deformity. However, despite its proven success, barriers to access, adherence, and comprehensive care still persist in LMICs, leading to preventable disability and long-term social, economic, and psychological consequences for affected individuals.

The prevalence of clubfoot in LMICs, coupled with the lack of access to timely and proper treatment, highlights the urgent need for collaborative efforts involving governments, non-governmental organisations, international partners, and local communities. Initiatives aimed at raising awareness, training healthcare professionals, providing financial support to families, and improving healthcare infrastructure are essential to reduce the burden of clubfoot globally.

Congenital talipes equinovarus, or idiopathic clubfoot, is a common lower extremity anomaly that poses significant challenges, particularly in LMICs.

The establishment of organisations like the PIA and the dedication of local champions play a crucial role in promoting the Ponseti method as the standard of care, while also fostering a sustainable and equitable approach to clubfoot treatment. Engaging stakeholders at all levels of society, from healthcare providers to policymakers, is pivotal for the success of these initiatives.

Ultimately, eradicating clubfoot globally, especially in LMICs, requires a comprehensive and holistic approach that addresses the multifaceted challenges faced by individuals with clubfoot and their communities. By working together and prioritising accessible and high-quality care, significant strides can be made in reducing the impact of this condition and ensuring a brighter future for those affected by clubfoot.

Ultimately, eradicating clubfoot globally, especially in LMICs, requires a comprehensive and holistic approach that addresses the multifaceted challenges faced by individuals with clubfoot and their communities.

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References

1 Aroojis A, Pirani S, Banskota B, Banskota AK, Spiegel DA. Clubfoot etiology, pathoanatomy, basic Ponseti technique, and Ponseti in older patients. In: Gosselin RA, Spiegel DA, Foltz M (ed.). Global Orthopedics. Springer; 2020:383-96.

2. Owen RM, Capper B, Lavy C. Clubfoot treatment in 2015: a global perspective. BMJ Glob Health. 2018;3(4):e000852.

3. Ganesan B, Luximon A, Al-Jumaily A, Balasankar SK, Naik GR. Ponseti method in the management of clubfoot under 2 years of age: a systematic review. PloS One. 2017;12(6):e0178299.

4. Bina S, Pacey V, Barnes EH, Burns J, Gray K. Interventions for congenital talipes equinovarus (clubfoot). Cochrane Database Syst Rev. 2020;5(5):CD008602.

5. Balasankar G, Luximon A, Al-Jumaily A. Current conservative management and classification of club foot: a review. J Pediatr Rehabil Med. 2016;9(4):257-64.

6. Dobbs MB, Gurnett CA. Update on clubfoot: etiology and treatment. Clin Orthop Rel Res. 2009;467(5):1146-53.

7. Morcuende JA, Cook TM. The Ponseti method in low and middle income countries: challenges and lessons learned. Foot Ankle Clin. 2015;20(4):547-54.

8. Ponseti IV. Congenital clubfoot. Fundamentals of treatment. New York, Oxford University Press. 1996:21-48.

9. Mishra PK et al. To evaluate the success rate of idiopathic clubfoot management by Ponseti technique under 2 years age group, and to determine the cause of relapse. Int J Life Sci Biotechnol Pharma Res. 2023;12:4-5.

10. Rangasamy K, Baburaj V, Gopinathan NR, Sudesh P. Techniques, anaesthesia preferences, and outcomes of Achilles tenotomy during Ponseti method of idiopathic clubfoot correction: a systematic review. Foot (Edinb). 2022;52:101922.

11. López-Carrero E, Castillo-López JM, Medina-Alcantara M, Domínguez-Maldonado G, Garcia-Paya I, Jiménez-Cebrián AM. Effectiveness of the Ponseti method in the treatment of clubfoot: a systematic review. Int J Environ Res Public Health. 2023;20(4):3714.

12. Shabtai L, Specht SC, Herzenberg JE. Worldwide spread of the Ponseti method for clubfoot. World J Orthop. 2014;5(5):585-90.

13. Walk for Life. Ponseti Solution Bangladesh. 2023. [Internet.] Available from: https://walkforlife.org.bd/en/ponseti-solution/

14. Smythe T, Rotenberg S, Lavy C. The global birth prevalence of clubfoot: a systematic review and meta-analysis. EClinicalMedicine. 2023;63:102178.

15. Smythe T, Mudariki D, Kuper H, Lavy C, Foster A. Assessment of success of the Ponseti method of clubfoot management in sub-Saharan Africa: a systematic review. BMC Musculoskelet Disord. 2017;18(1):453.

16. Owen RM, Kembhavi G. A critical review of interventions for clubfoot in low and middle-income countries: effectiveness and contextual influences. J Pediatr Orthop B. 2012;21(1):59-67.

17. Harmer L, Rhatigan J. Clubfoot care in low-income and middle-income countries: from clinical innovation to a public health program. World J Surg. 2014;38(4):839-48.

18. Bent MA. Congenital talipes equinovarus (Clubfoot). In: Sarwark JF, Carl RL (eds.). Orthopaedics for the Newborn and Young Child: A Practical Clinical Guide. Springer; 2023:47-60.

19. Njelesani J, Hashemi G, Cameron C, Cameron D, Richard D, Parnes P. From the day they are born: a qualitative study exploring violence against children with disabilities in West Africa. BMC Public Health. 2018;18(1):153.

20. Trani J-F, Moodley J, Anand P, Graham L, Maw MTT. Stigma of persons with disabilities in South Africa: uncovering pathways from discrimination to depression and low self-esteem. Soc Sci Med. 2020;265:113449.

21. Tindall AJ, Steinlechner CW, Lavy CB, Mannion S, Mkandawire N. Results of manipulation of idiopathic clubfoot deformity in Malawi by orthopaedic clinical officers using the Ponseti method: a realistic alternative for the developing world? J Pediatr Orthop. 2005;25(5):627-9.

22. Gupta A, Singh S, Patel P, Patel J, Varshney MK. Evaluation of the utility of the Ponseti method of correction of clubfoot deformity in a developing nation. Int Orthop. 2008;32(1):75-9.

23. Spiegel DA, Shrestha OP, Sitoula P, Rajbhandary T, Bijukachhe B, Banskota AK. Ponseti method for untreated idiopathic clubfeet in Nepalese patients from 1 to 6 years of age. Clin Orthop Relat Res. 2009;467(5):1164-70.

24. Ayana B, Klungsøyr PJ. Good results after Ponseti treatment for neglected congenital clubfoot in Ethiopia: a prospective study of 22 children (32 feet) from 2 to 10 years of age. Acta Orthop. 2014;85(6):641-5.

25. Johnson RR, Friedman JM, Becker AM, Spiegel DA. The Ponseti method for clubfoot treatment in low and middle-income countries: a systematic review of barriers and solutions to service delivery. J Pediatr Orthop. 2017;37(2):e134-e9.

26. Ponseti International Association. 2023. Available from: http://www.ponseti.info

Leon Gilligan-Steinberg RCSI medical student

This is your brain on computers: a glimpse into the exciting world of

brain–machine interfaces

Abstract

Brain–machine interfaces (BMIs) have recently been gaining momentum as a novel technology to address a myriad of neurological deficits. Utilising various modalities, BMIs attempt to record and interpret neurological signals and translate them into the desired response. This technology is currently in early clinical trials to address many issues. The most advanced revolve around restoration of motor function or speech in patients dealing with spinal cord injuries or neuromuscular disease. However, researchers are currently looking at applications of this technology in mood regulation, pain management, and various non-medical fields. This article will explain BMI functionality, explore the various proposed applications, and examine obstacles this technology may face when attempting to scale to larger use.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 88-94.

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Introduction

In science fiction novels, authors have dreamed of a distant future where man and machine blend together as one. A human exoskeleton capable of restoring one’s ability to walk and implantable communication devices sound like a tale of science fiction reserved for the silver screen or the pages of a novel, rather than those of a textbook. However, recent progress in brain–machine interfaces (BMIs), also known as brain–computer interfaces, have been pushing these topics to the forefront of scientific discovery. BMIs allow for interpretation of neural signals to create an output that does not rely on the traditional neurocortical pathways. Modern BMIs came to fruition in the early 2000s with the advent of neural multi-electrode recording.1,2 Early research involved animal studies where primates proved their ability to use a BMI to control either a cursor or a motor-operated arm. Advances in this technology have created practical clinical applications, such as restoring motor function and communication skills in those who have suffered neuromuscular disease, cerebrovascular accidents, or traumatic spinal injuries.1 BMIs have proven to be useful in other fields, such as pain medicine and neuropsychiatry. This review will explain the basic guiding concepts behind the development of BMIs, as well as their current and future applications.

Introduction to brain–machine interfaces

BMIs rely on a simple pathway (Figure 1). The brain emits an electrical signal, or input, that gets interpreted by the BMI as a command. This command is then translated into an action by the output arm of the BMI. In essence, the BMI bypasses the neurocortical pathway that has been damaged. Fine-tuning the input and output elements of this process can be exceptionally difficult. For the input, the BMI needs to be taught how to interpret each individual signal. In fact, current BMIs rely on personalisation of the signals emitted by each individual. Essentially, they must learn to interpret the neural output from each specific subject. This slows down the ability to apply them to a large group of patients. Certain factors further complicate the process, such as the level of complexity and precision of each signal. A simple command from an area of the brain that is known to control a process, such as basic movement, can be easily picked up. However, more complex concepts, such as emotions or balancing, require much more rigorous calibration. This is because these more complex commands are often controlled by multiple cortical areas with signals that are not as easily interpreted. As advances in artificial intelligence (AI) blend with these devices, algorithms can be applied to the process of teaching the BMI how to ‘read’ what the brain is signalling.

FIGURE 1: Visual representation of the steps involved in a closed-loop brain–machine interface.18

The strength of the signal can also be modified by the device used to pick it up. The modalities of the input element of a BMI can be stratified as either a non-invasive or an invasive method (Figure 2). Non-invasive methods for receiving the signal emitted from the brain

primarily involve the use of electroencephalograms (EEGs), during which electrodes are attached to the exterior surface of the skull to capture electrocortical signals. Other methods involve the use of functional magnetic resonance imaging (fMRI), MRIs that look

Brain–machine interfaces

Invasive

Electrodes are implanted intracranially. This methodology provides neural signals of the best quality and has a high potential for further improvement. At the same time, it carries risks associated with an invasive surgical procedure.

Single recording site

Several groups have built brain–machine interfaces based on neural recordings from a single cortical area. A single-area brain–machine interface decodes neuronal activity specific to that area, for example motor commands in M1 or cognitive signals in PP.

Small samples

In certain cases, small groups of neurons are sufficient for providing control signals to a brain–machine interface. This design suffers from instability related to variability of neuronal activity and changes in the sampled populations of neurons.

LFPs

Non-invasive

This methodology is based on the recordings of EEGs from the surface of the head. It provides solutions for paralysed people for simple communications with the outside world. However, neural signals have a limited bandwidth.

Multiple recording sites

By recording simultaneously from many areas, this approach takes advantage of distributed processing of information in the brain. Although technically challenging, it is highly promising for both developing brain–machine interfaces and gaining fundamental knowledge.

Brain–machine interfaces based on decoding LFPs suffer less from biocompatibility issues. Their advantage is that they reflect population effects such as neural oscillations. Their bandwidth is, however, limited.

Large ensembles

Large neuronal ensembles (hundreds and, in the future, feasibly thousands of cells) provide a stable signal to control a multi-degree-of-freedom prosthesis. This approach instigates new computational solutions.

FIGURE 2: Classifications of brain–machine interfaces as explained by Lebedev, a leading figure in this field. EEG – Electroencephalogram; LFP – Local field potential; M1 – Primary motor cortex; PP – Posterior parietal cortex.1

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specifically at the areas of the brain receiving the most perfusion. fMRIs interpret increased blood flow as an indication of higher cortical activity. They are less practical and have a temporal delay when compared to EEGs, but they are more accurately able to interpret the area being activated. Invasive methods typically involve the direct implantation of electrodes within the brain or beneath the skull, such as in an electrocorticogram (ECoG). The main distinction between invasive methods of monitoring is whether they are focused on a small area of the brain (small batch) or a large region if there is an increased cortical area measured (large batch). Electrode density is positively associated with the precision of the signal.3 Overall, non-invasive methods have lower spatial resolution than invasive strategies, meaning they are less precisely able to identify what specific area of the brain is emitting the signal. However, they are cheaper and come with less risk of complications, such as infection, neural damage, and intracranial bleeding.4 The output of the BMI varies and depends largely on the specific purpose of the device. Outputs can range from prosthetic arms or computer cursors, to a speaker recreating speech. To replicate natural processes, many BMIs require biofeedback to communicate information about the surrounding environment to the brain and to recreate reflexes that allow for controlled interactions.1

Current leading applications of BMIs revolve around restoring motor function or the ability to communicate in patients with paralysis or neurodegenerative diseases. Gait is one of the most difficult motor functions to restore, as walking requires biofeedback and plasticity.

Applications of brain–machine interfaces in motor control

Current leading applications of BMIs revolve around restoring motor function or the ability to communicate in patients with paralysis or neurodegenerative diseases. Gait is one of the most difficult motor functions to restore, as walking requires biofeedback and plasticity. The main difficulty is that the efferent signal from the extremities must be returned to the brain via the BMI. The interface must then communicate information about proprioception, balance, and trauma to the limb. In 2023, Nature published a clinical study regarding an intervention performed by researchers in Switzerland. The subject of the research was Oskam, a 38-year-old man who had

suffered paralysis due to an incomplete C5/C6 spinal cord injury ten years prior. A bridge was created via the BMI to bypass the area of spinal cord damage. An implanted epidural ECoG was fed to a calibrated decoder that communicated via Bluetooth with electrodes implanted on target muscles. Then, after a six-week calibration utilising a proprietary algorithm and 40 sessions of neurorehabilitation, Oskam could perform activities of daily living, and even traverse complex terrains, including changes in elevation and staircases. Oskam regained the ability to walk freely without the device and relying solely on a front-wheel walker.5

The Walk Again Project, a non-profit established by Duke University’s Center for Neuroengineering, aims to restore mobility in paralysed individuals using BMIs.6 A paper published in 2016 explains the Walk Again Neurorehabilitation study (WA-NR). WA-NR took eight volunteers who had chronic spinal cord injuries that had been present for over one year and engaged them in a neurorehabilitation process. This process involved utilisation of a 16-channel EEG to simulate locomotion. The exoskeleton graduated through progressively difficult tasks, from supported standing to free gait training. To the researchers’ surprise, improvements and partial recovery were noted in sensation, co-ordination, and sensorimotor function in limbs that had previously lost these functions.7,8 Since then, utilisation of BMIs for stroke neurorehabilitation have been explored and show promise.9,10 BMIs can also be combined with neuroprostheses. Similar to how the exoskeletons work, these are attached to the body and allow for controlled action. A study in 2017 looked at an individual with tetraplegia who trained for 13 weeks over 34 training sessions on utilisation of a BMI neuroprosthetic arm.11 The device utilised 96-channel intracortical microelectrodes. The goal was to assess functionality in orientation and grasping. Researchers assessed that seven-dimensional freedom (three-dimensional translation and orientation with one-dimensional grasping) was achieved and competently performed within four months, meaning it could move and orient itself in three dimensions as well as grasp objects, and the participant could perform complicated tasks, such as cone stacking, by the end of the study.11

Applications of brain–machine interfaces in communication

In those with paralytic conditions, amyotrophic lateral sclerosis (ALS), or locked-in syndrome, BMIs have been implemented to assist with communication. There are several currently utilised strategies. These include the utilisation of eye tracking and, in patients with retained upper extremity motor control, handwriting. However, studies have shown that these strategies are up to seven times slower than conventional speech.12,13

These synthesis-based speech BMIs rely on the same initial input process interpreting neural signals as explained earlier. These signals are decoded into speech features, and then into discernible audio. Given both the precision and the large cortical area required for speech, the primary modalities studied are invasive BMIs, often ECoGs with 128 or 32 electrodes.14,15

Interpretation of the speech features involves taking these neural signals and mapping them to elements of speech (Figure 3). After being synthesised into speech, they are transmitted to the exterior world via a vocoder, a device designed to produce a human-like voice using the data it receives. Utilisation of deep learning algorithms, such as the Griffin-Lim Algorithm, have enabled predictive abilities in these vocoders to further decrease the latency involved in communication. Although promising, there have yet to be studies on the long-term viability of these speech synthesis BMIs.16

The future of brain–machine interfaces

BMIs show promise in an exciting range of fields including more general use, pain control, and neuropsychiatry. In 2016, Elon Musk created a company called Neuralink, which originally focused on the restoration of therapeutic communication. He hopes that it might have applications in medicine, such as treating depression and blindness, but also aims to have it serve as a device accessible to the general public, in order to augment their relationship with computers and AI. He has also suggested that the device could eventually extract and store thoughts, as “a backup drive for your non-physical being, your digital soul”.17 Neuralink faces some major hurdles in regulation and there is a significant gap between its current

functionality and Musk’s proposed goals. However, the range of potential applications promises excitement. Other non-medical applications of these BMIs could be in the field of entertainment, such as video games, and as an assistive tool for learning.14,17-19

Another area where BMIs have had an impact has been in the realm of chronic pain control.20 As described in a paper published in 2020, researchers from Cambridge, Oxford, and various institutions in Japan attempted to create a closed-loop BMI to assess pain and treat it via deep brain stimulation (DBS). The initial phase of training the system involved receiving input from fMRIs. The system was subsequently trained by assessing the neural signals emitted during administration of painful electrical stimuli. These painful stimuli correlated with increased information encoding in the pregenual anterior cingulate cortex and decreased encoding in the insula. Afterwards, EEG readings were used for the closed-loop experiment as it was more practical and cost-effective than fMRI. This study further explored the effects of endogenous modulation of pain in this system. Given the complexity of pain interpretation and the effects of the brain’s own autoregulation of pain with endogenous routes, the authors argue that an adaptive system would be more effective for pain control.21

Similarly, BMIs show promise in the treatment of neuropsychiatric and neurologic conditions, such as treatment-resistant major depressive disorder, Parkinson’s disease, and epilepsy. The goal of the system is to create a feedback loop that is responsive to changes in mood. This area of focus faces difficulty in quantifying data points when attempting to create a database of ‘moods’ based on neural readings. This is primarily because it is less clear which specific areas of neural activity align with mood as it

WaveNet

WaveRNN

SamoleRNN

LPCNet

FIGURE 3: Visual representation of the pathway from neural signal to audio synthesis in

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is a more complex and less quantifiable metric. Additionally, it is harder to activate a patient’s emotions when attempting to recreate the signal. However, a study assessing the effect of DBS of the orbitofrontal cortex, an area in the prefrontal cortex theorised to have effects on emotional regulation, in patients with epilepsy and depression, showed dose-dependent improvements in mood. This was assessed with continuous EEG and the Immediate Mood Scaler, a validated questionnaire for assessing mood and depression.22-24

Although less explored, conditions that can be treated by DBS, such as epilepsy and Parkinson’s disease, show initial success when augmented by closed-loop BMIs.25 Studies have begun to assess the functionality of an FDA-approved responsive neurostimulation device (RNS) called NeuroPace for epilepsy. The studies sought to place this electrode in the centromedian thalamus (CM). This served to record electrical activity to detect seizures. The researchers theorised that focused stimulation within this system could disrupt seizure activity. The paper provided evidence of its success in sensing seizure activity and having no recorded short-term side effects when activated.26

Multiple randomised controlled trials of patients with Parkinson’s disease showed improved management of their symptoms with six months of DBS when compared to medical management alone.27,28 Furthermore, a proof-of-principle study involving eight patients showed that selective and controlled employment of this DBS with a BMI proved more effective than continuous DBS.25,29

Challenges to brain–machine interfaces

There is still much to improve for these devices to have a widespread impact due to issues with biocompatibility, safety, and affordability. Many theorised safety issues involve the invasive methods for monitoring neural signals, primarily ECoG. Ideally, with advances in the spatial resolution of non-invasive methods, these could be bypassed completely. However, most of the functionalities discussed in this article would currently require invasive methods for the required resolution. A 2021 review of BMI design identified challenges in biocompatibility, electrical properties, and mechanical properties of implanted electrodes that can be improved. Proposed solutions to issues of biocompatibility include coating the electrodes in substances designed to reduce inflammation, such as hyaluronic acid or hydrogels, or changing the electrodes themselves.18 Although there are not currently enough long-term studies to confidently

References

1. Lebedev MA, Nicolelis MAL. Brain–machine interfaces: past, present and future. Trends Neurosci. 2006;29(9):536-46.

comment on the relative safety of these devices, a 2018 study on the long-term functionality of ECoG as a tool for BMIs showed that it retained effective signalling.30 The 2023 Stentrode with Thought Controlled Digital Switch (SWITCH) study examined the safety of endovascular electrodes for a BMI neurosurgically implanted in the superior sagittal sinus of four paralysed patients. It showed no serious adverse effects when monitored over a 12-month period. The primary adverse effects noted included bruising and hematomas at incision sites, anaemia, and postoperative fatigue. Additionally, signal strength, stability, and fidelity were retained.31 These devices are exceptionally expensive and require complex neurosurgical procedures with specialist follow-up to even implant them. Afterwards, the BMIs need to be calibrated and maintained. Ideally, as continued research and development of these products continues, BMIs will become more accessible and affordable.

Attempting to find ways to make BMIs more affordable, mass-producible, safer, and quicker to calibrate would increase accessibility and widespread use.

Conclusion

BMIs show immense promise as a new technology to serve a myriad of medical and non-medical functions. Understanding the basic structure of a BMI assists in understanding its vast array of applications. The leading areas of research involving BMIs include regeneration and neurorehabilitation of motor functions or assistance in communication, especially in those with spinal cord injuries or neuromuscular disease. However, there are several other medical conditions in which BMIs can be used, including neurologic disease, psychiatric disease, and pain. Other non-medical uses could include elearning, video gaming, integration into computers, and increasing efficiency/safety in transportation, military, or industrial jobs.3 Despite the promise, many BMIs are still in the clinical and pre-clinical phases and will undoubtedly face significant challenges with their application. Attempting to find ways to make them more affordable, mass-producible, safer, and quicker to calibrate would increase accessibility and widespread use. As BMIs continue to advance, they likely will continue to present unique solutions in diverse areas of the medical and non-medical world.

2. Lebedev MA, Nicolelis MAL. Brain–machine interfaces: from basic science to neuroprostheses and neurorehabilitation. Physiol Rev. 2017;97(2):767-837.

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3. Aarabi P, Aarabi P. The impact of electrode density and precision on brain–computer interfaces. Annu Int Conf IEEE Eng Med Biol Soc. 2020;2020:430-3.

4. Padfield N, Zabalza J, Zhao H, Masero V, Ren J. EEG-based brain–computer interfaces using motor-imagery: techniques and challenges. Sensors (Basel). 2019;19(6):1423.

5. Lorach H, Galvez A, Spagnolo V et al. Walking naturally after spinal cord injury using a brain–spine interface. Nature. 2023;618(7963):126-33.

6. Duke Center for Neuroengineering. Walk Again Project. Available from: https://www.walkagainproject.org

7. Donati ARC, Shokur S, Morya E et al. Long-term training with a brain–machine interface-based gait protocol induces partial neurological recovery in paraplegic patients. Sci Rep. 2016;6(1):30383.

8. Shokur S, Donati ARC, Campos DSF et al. Training with brain–machine interfaces, visuo-tactile feedback and assisted locomotion improves sensorimotor, visceral, and psychological signs in chronic paraplegic patients. PLoS One. 2018;13(11):e0206464.

9. Leeb R, Pérez-Marcos D. Brain–computer interfaces and virtual reality for neurorehabilitation. Handb Clin Neurol. 2020;168:183-97.

10. Liu M, Ushiba J. Brain–machine interface (BMI)-based neurorehabilitation for post-stroke upper limb paralysis. Keio J Med. 2022;71(4):82-92.

11. Collinger JL, Wodlinger B, Downey JE et al. High-performance neuroprosthetic control by an individual with tetraplegia. Lancet. 2013;381(9866):557-64.

12. Chang EF, Anumanchipalli GK. Toward a speech neuroprosthesis. JAMA. 2020;323(5):413-4.

13. Pandarinath C, Nuyujukian P, Blabe CH et al. High performance communication by people with paralysis using an intracortical brain–computer interface. Elife. 2017;6:e18554.

14. Musk E. An integrated brain-machine interface platform with thousands of channels. J Med Internet Res. 2019;21(10):e16194.

15. Stavisky SD, Willett FR, Wilson GH et al. Neural ensemble dynamics in dorsal motor cortex during speech in people with paralysis. Elife. 2019;8:e46015.

16. Luo S, Rabbani Q, Crone NE. Brain–computer interface: applications to speech decoding and synthesis to augment communication. Neurotherapeutics. 2022;19(1):263-73.

17. Paul K, Singh M. Elon Musk’s brain implant company is approved for human testing. How alarmed should we be? The Guardian, June 4,

2023. Available from: https://www.theguardian.com/technology/2023/jun/04/elon-musk-ne uralink-approved-human-testing-concern

18. Mridha MF, Das SC, Kabir MM, Lima AA, Islam MdR, Watanobe Y. Brain–computer interface: advancement and challenges. Sensors (Basel). 2021;21(17):5746.

19. Värbu K, Muhammad N, Muhammad Y. Past, present, and future of EEG-based BCI applications. Sensors. 2022;22(9):3331.

20. Gildenberg PL. History of electrical neuromodulation for chronic pain: Table 1. Pain Medicine. 2006;7(Suppl.1):S7-13.

21. Zhang S, Yoshida W, Mano H et al. Pain control by co-adaptive learning in a brain–machine interface. Curr Biol. 2020;30(20):3935-44.e7.

22. Nahum M, Van Vleet TM, Sohal VS et al. Immediate mood scaler: tracking symptoms of depression and anxiety using a novel mobile mood scale. JMIR Mhealth Uhealth. 2017;5(4):e44.

23. Rao VR, Sellers KK, Wallace DL et al. Direct electrical stimulation of lateral orbitofrontal cortex acutely improves mood in individuals with symptoms of depression. Curr Biol. 2018;28(24):3893-902.e4.

24. Shanechi MM. Brain–machine interfaces from motor to mood. Nat Neurosci. 2019;22(10):1554-64.

25. Sun FT, Morrell MJ. Closed-loop neurostimulation: the clinical experience. Neurotherapeutics. 2014;11(3):553-63.

26. Gummadavelli A, Zaveri HP, Spencer DD, Gerrard JL. Expanding brain–computer interfaces for controlling epilepsy networks: novel thalamic responsive neurostimulation in refractory epilepsy. Front Neurosci. 2018;12:474.

27. Weaver FM. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease; a randomized controlled trial. JAMA. 2009;301(1):63-73.

28. Deuschl G, Schade-Brittinger C, Krack P et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. New Engl J Med. 2006;355(9):896-908.

29. Little S, Pogosyan A, Neal S et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann Neurol. 2013;74(3):449-57.

30. Nurse ES, John SE, Freestone DR et al. Consistency of long-term subdural electrocorticography in humans. IEEE Trans Biomed Eng. 2018;65(2):344-52.

31. Mitchell P, Lee SCM, Yoo PE et al. Assessment of safety of a fully implanted endovascular brain–computer interface for severe paralysis in 4 patients: The Stentrode With Thought-Controlled Digital Switch (SWITCH) Study. JAMA Neurol. 2023;80(3):270-8.

Dhruv Jivan RCSI medical student

Creatine and cognition –enhancing the brain through creatine supplementation

Abstract

Creatine, a naturally occurring compound in the human body, has been known for its role in boosting athletic performance. This article explores creatine’s multifaceted nature, delving into its traditional application in physical endeavours and its emerging potential for cognitive improvement. Creatine, chemically termed methylguanidine-acetic acid, is acquired from dietary sources like red meat and seafood, or is synthesised internally in the liver, kidneys, and brain. At its core, creatine plays a vital role in energy metabolism via the phosphagen system; phosphocreatine and adenosine diphosphate are converted into adenosine triphosphate, the body’s primary source of rapid energy replenishment. This quick energy turnaround, crucial for explosive activities like sprinting and jumping, has historically linked creatine supplementation to enhanced athletic performance and muscle hydration. Recent research, however, has uncovered an additional dimension of creatine’s advantages – cognitive enhancement. As the brain utilises a significant portion of creatine for energy production, studies in older adults have demonstrated improved memory performance with creatine supplementation. Furthermore, creatine acts as an antioxidant, enhancing mitochondrial adenosine triphosphate coupling, and elevates essential factors for learning and memory. In conclusion, creatine supplementation offers more than just physical performance enhancements; it also holds potential benefits for mental well-being. By supplying essential adenosine triphosphate energy to critical organs like the brain, creatine enhances mental cognition and reduces fatigue. Research suggests that daily supplementation with 20g of creatine monohydrate shows promise in these areas. As a result, creatine emerges as a compelling natural compound with multifaceted advantages for overall health and well-being.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 95-98.

Introduction

Creatine is a natural chemical that has been known and used for decades, primarily for its athletics benefits.1 However, this wonder supplement is now demonstrating significant benefits and enhancements for cognitive functioning. This article will discuss all aspects of creatine and the latest research on how to use it for both its physical and mental benefits.

What is creatine?

Creatine, also known as methylguanidine-acetic acid, is an essential organic acid crucial for energy production. It is derived from the diet, mainly through consumption of red meat and seafood, or it is synthesised internally by the liver, kidneys, and brain.

Creatine plays a significant role in the body’s energy metabolism through the phosphagen system.2 As shown in Figure 1, the phosphagen system utilises a reversible reaction catalysed by creatine kinase; phosphocreatine and adenosine diphosphate are converted into adenosine triphosphate (ATP), the body’s most rapidly available source of energy.3 It takes 30 seconds to replenish about 70% of creatine and three to five minutes to replenish 100%.2

Creatine, also known as methylguanidine-acetic acid, is an essential organic acid crucial for energy production. It is derived from the diet, mainly through consumption of red meat and seafood,

or it is synthesised internally by the liver, kidneys, and brain.

Physical benefits of creatine

Historically, creatine supplementation has been associated with athletic performance and body building. This is due to its energy enhancement and muscle hydration effects. 4 When exercising, muscles utilise ATP from three metabolic pathways in a stepwise manner. The first energy-producing pathway is the phosphagen system, followed by anaerobic metabolism, and finally aerobic metabolism.1 The ATP produced via the creatine-phosphagen system is used within the first ten seconds of exercise before it is replenished. 1 Therefore, ATP from the phosphagen system is extremely important during short and powerful movements such as throwing, hitting, jumping, and sprinting.2

Supplementation with creatine leads to an increase in muscle creatine stores, ultimately providing the body with optimal energy production in cells. Creatine also hydrates muscles cells by drawing water in through osmosis. Cell hydration is essential for muscle functioning and the aesthetic fullness of the muscle itself.5

Cognitive benefits of creatine

New research is revealing the cognitive benefits of creatine supplementation. After all, the brain is a metabolically demanding organ and uses up to 5% of creatine stores for energy production.4

In 2022, the first systematic review and meta-analysis of randomised controlled trials studying the effects of creatine supplementation on memory in healthy individuals was conducted.4 The results demonstrated enhanced measures of memory performance in healthy individuals, particularly in older adults aged 66-76 years.4 The study revealed significant improvement in memory measures (forward number recall, backward and forward spatial recall, and long-term memory) following supplementation with creatine monohydrate in powder form (SMD=0.35; 95% CI, 0.05-0.66; I2=73%; P=0.02).4

The study revealed significant improvement in memory measures (forward number recall, backward and forward spatial recall, and long-term memory) following supplementation with creatine monohydrate in powder form.

Furthermore, the brain utilises high amounts of energy. Supplementation with creatine increases brain creatine stores and ultimately increases the amount of ATP produced for brain functioning.6 Additionally, creatine acts as an antioxidant, reducing reactive oxygen species by enhancing mitochondrial ATP coupling.6 Creatine also upregulates cAMP-response

FIGURE 1: Phosphagen system – creatine kinase converting ADP to ATP.15

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element binding protein (CREB), a key transcription factor in activity-dependent plasticity, learning, and memory.4 These mechanisms are illustrated in Figure 2

Since the main natural sources of creatine are in meat, a vegetarian diet lacks optimal creatine levels. Therefore, it is not surprising that Rae et al. (2003) found improvements in working memory following creatine supplementation (5g/day for six weeks) among vegetarians.7 In addition, a study done by Benton and Donohoe (2011) found a greater significant effect on memory function following creatine supplementation in vegetarians compared with meat eaters.8 Therefore, based on the current research, vegetarians may receive an increased benefit from creatine supplementation.

Safety of creatine supplementation

Several studies conducted in both athletes and the general population over various time periods (up to five years), provide evidence on the safety of creatine supplementation.9 These studies did not report any negative changes in clinical health markers including total cholesterol values, LDL-cholesterol, high-density lipoprotein cholesterol, lactate dehydrogenase, gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase.9,10 Since creatine is expelled from the body through the kidneys, researchers studied the effects of creatine supplementation on kidney functioning. The literature shows that additional creatine has no long-term detrimental effects on the kidney and other organs.11

Finally, there is a common misunderstanding of creatine-induced weight gain. As discussed above, creatine enhances muscle hydration through osmosis. This results in up to 1kg of weight gain depending on the individual’s muscle mass.12 However, this weight gain is due to beneficial intracellular water retention and not fat mass.

How to supplement with creatine

Creatine supplementation comes in several varieties including creatine monohydrate, magnesium-creatine chelate and creatine citrate, malate, ethyl ester, nitrate, and pyruvate.5 The main differences between these varieties are the additions of different molecules to creatine for absorption purposes. The research shows creatine monohydrate (one creatine molecule per H2O molecule addition) to be the most effective type of creatine for both cognitive and physical benefits.13 This form of supplementation is also financially friendly at just US$0.12/g.

Other types of creatine such as creatine citrate, malate and nitrate, have not been shown to be superior to creatine monohydrate and are often priced higher than the monohydrate version.5 It is unclear why these other forms of creatine exist, with some speculation that it may be for marketing purposes.5

In addition to types of creatine, there are also different forms of creatine such as liquid, powder, and capsules. Fortunately, the form in which creatine is ingested does not affect its absorption into the body.5 The different forms were created to match consumers’ priorities.5 For example, the powder form is easily dissolvable in a liquid and can be

FIGURE 2: Mechanism of creatine on cognitive functioning.6

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taken at any time of the day. Some powder and liquid forms of creatine are flavoured or added to a pre/post-workout supplement. Additionally, the capsular form provides the convenience of being easily transportable and discrete for consumers. Furthermore, how much creatine to supplement with per day is dependent on the individual goal. In the study conducted by Prokopidis et al. (2023), the results demonstrated that elderly study participants (68-85 years) who received 20g of creatine supplementation per day for seven days showed significant improvements in measures of memory (forward number recall, backward and forward spatial recall, long-term memory).4 The same results were observed for vegetarians, as a study by Benton and Donohoe (2011) also found improved memory in this cohort following creatine supplementation of 20g per day.8 However, for physical activity enhancement, the general recommended dosing for creatine is 5g per day.10 There are ongoing discussions about loading doses versus gradual dosing to fill creatine stores. Current research shows no significant benefit to loading doses, as ultimately the muscle creatine stores will be filled on either dosing strategies within a similar timeframe (five days).4

References

1. Bird SP. Creatine supplementation and exercise performance: a brief review. J Sports Sci Med. 2003;2(4):123-32.

2. Morton AR. Chapter 8: Exercise Physiology. In: Pediatric Respiratory Medicine (2nd ed.). 2008:89-99.

3. Wuertz S, Reiser S. Creatine: a valuable supplement in aquafeeds? Rev Aquac. 2023;15(1):292-304.

4. Prokopidis K, Giannos P, Triantafyllidis KK, Kechagias KS, Forbes SC, Candow DG. Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomised controlled trials. Nutr Rev. 2023;81(4):416-27.

5. Fazio C, Elder CL, Harris MM. Efficacy of alternative forms of creatine supplementation on improving performance and body composition in healthy subjects: a systematic review. J Strength Cond Res. 2022;36(9):2663-70.

6. Candow DG, Forbes SC, Ostojic SM, Prokopidis K, Stock MS, Harmon KK, Faulkner P. “Heads up” for creatine supplementation and its potential applications for brain health and function. Sports Med. 2023;53(Suppl.1):49-65.

7. Rae C, Digney AL, McEwan SR et al. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci. 2003;270(1529):2147-50.

8. Benton D, Donohoe R. The influence of creatine supplementation on the

Finally, research on the most beneficial timing of creatine ingestion is inconclusive. Therefore, current recommendations would be to take creatine whenever it is most convenient, although it would be important to be aware that co-ingestion of creatine with carbohydrates and protein may increase creatine accumulation in muscle,14 possibly due to insulin-stimulated sodium-potassium (Na+−K+) pump activity.

Conclusion

In conclusion, the impact of creatine supplementation extends beyond physical performance and encompasses notable health benefits for mental well-being. By providing essential ATP energy to high-functioning organs like the brain, creatine plays a significant role in enhancing mental cognition, and reducing fatigue. Research has shown that a daily supplementation of 20g of creatine monohydrate yields promising results in these areas. Therefore, considering its potential to positively influence both physical and mental performance, creatine emerges as a compelling natural chemical with multifaceted benefits for overall health and well-being.

cognitive functioning of vegetarians and omnivores. Br J Nutr. 2011;105(7):1100-5.

9. Jagim AR, Kerksick CM. Creatine supplementation in children and adolescents. Nutrients. 2021;13(2):1-17.

10. Balestrino M, Adriano E. Beyond sports: efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle. Med Res Rev. 2019;39(6):2427-59.

11. Jäger R, Purpura M, Shao A, Inoue T, Kreider RB. Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids. 2011;40(5):1369-83.

12. Hall M, Manetta E, Tupper K. Creatine supplementation: an update. Curr Sports Med Rep. 2021;20(7):338-44.

13. Escalante E, Gonzalez AM, St Mart D, Torres M, Echols J, Islas M, Schoenfeld BJ. Analysis of the efficacy, safety, and cost of alternative forms of creatine available for purchase on Amazon.com: are label claims supported by science? Heliyon 2022;8(12):e12113.

14. Steenge GR, Lambourne J, Casey A, Macdonald IA, Greenhaff PL. Stimulatory effect of insulin on creatine accumulation in human skeletal muscle. Am J Physiol. 1998;275(6):E974-9.

15. Kreider RB, Kalman DS, Antonio J, Ziegenfuss TM, Wildman R, Collins R et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017;14:18.

Noshin Shermili RCSI medical student

Advances in targeted therapies and immunotherapy for glioblastoma: a glimpse into precise treatment strategies

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive brain tumour with limited effective treatment. This study delves into the genetic heterogeneity and the impact of the tumour microenvironment (TME) on treatment resistance, particularly in IDH-wild-type (IDH-wt) GBM. Molecular subtypes identified within IDH-wt GBM, such as pro-neural, classical, and mesenchymal, provide a basis for more precise therapeutic strategies. This paper reviews innovative treatment approaches, including targeted immunotherapy involving receptor tyrosine kinase (RTK) inhibitors, chimeric antigen receptor (CAR)-T-cell therapy, oncolytic virus (OV) therapy, and immune checkpoint inhibitors (ICIs). Despite challenges and limited success in certain clinical trials, combining diverse therapeutic modalities is suggested to improve overall clinical outcomes. The conclusion explores the ongoing multifaceted efforts and emerging research dedicated to reshaping the treatment modalities for GBM, offering optimism for more effective and targeted interventions against this formidable malignancy.

Introduction

Glioblastoma multiforme (GBM) is a highly malignant tumour of the central nervous system (CNS). It is the most common primary malignant brain tumour in adults, with an annual incidence of three per 100,000.1 On average, GBM is diagnosed at the age of 64, with incidence peaking between the ages of 75 and 84 years.1 Unfortunately, GBM isn’t curable, and patients are faced with a fatal prognosis: the median survival rate

after diagnosis is 15 months.2 If GBM is left untreated, the median survival rate is less than six months, making it a significant health concern for those affected. The current standard of care for GBM consists of maximal surgical resection followed by radiation and adjuvant temozolomide (TMZ) chemotherapy.2,3 This paper aims to explore some of the advances in and challenges of the treatment strategies for GBM.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 99-101.

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Glioblastoma multiforme characteristics

The genetic plasticity and heterogeneity of GBM lends it the ability to adapt to and defend itself against immune responses, resulting in resistance to treatment and an increased chance of aggressive recurrence after surgical resection. The tumour microenvironment (TME) plays a critical regulatory role in brain tumour progression, invasion, and metastasis.4 The GBM TME is a heterogenous collection of non-neoplastic cells, including glial cells, immune cells, microglia, vascular cells, reacting astrocytes, and endothelial cells.3

Due to the heterogeneity of GBM, uniform treatment has demonstrated limited clinical efficacy. Thus, GBM has been characterised using more specific classifications and subtypes, with the hopes of future discoveries of precise treatments. GBM is classified into two groups based on the mutation status of the isocitrate dehydrogenase (IDH) enzyme: IDH-mutant (IDH-mt) GBM; and, IDH-wild-type (IDH-wt) GBM.5 This report will focus on the findings regarding IDH-wt GBM. Recent discoveries highlighting the evolution of gliomas and the influence of TME on immunosuppression have led to further molecular subtyping of IDH-wt GBM into pro-neural, classical and mesenchymal tumours.5 Pro-neural GBMs closely correspond with IDH-mt GBM and are predominantly observed in younger age groups.6 Classical subtype presents with a high level of epidermal growth factor receptor (EGFR) amplification (97%) and few mutations in the tumour suppressor gene TP53. Conversely, mesenchymal subtype is distinguished by its high neurofibromatosis type 1 (NF1) gene mutations, which help regulate cell growth.5 Identification of these subtypes opens up possibilities for more precise and targeted therapeutic strategies.

Novel treatment approaches in IDH-wt glioblastoma multiforme

Targeted immunotherapy offers the potential for more effective treatment of GBM. The current approaches to immunotherapy include kinase targeting, chimeric antigen receptor (CAR)-T-cell therapy, oncolytic virus (OV) therapy, and immune checkpoint inhibitors (ICIs), all of which hold promise for improving the management of GBM.5 The current approaches to immunotherapy are further detailed below.

Receptor tyrosine kinase mutations

Receptor tyrosine kinase (RTK) mutations that lead to aberrant signalling are associated with several malignant cancers. Consequently, the development of small molecule inhibitors that target RTKs has been ground breaking in the cancer field.7 Despite the promising potential of therapeutic kinase pathways, clinical outcomes have shown limited advances in GBM. In IDH-wt GBM, approximately 60% of cases exhibit an overexpression of EGFR.5 EGFR and its active

mutant form EGFRvIII promote the growth and proliferation of tumours. Conversely, in the other 40% of cases, the phosphatase and tensin homolog (PTEN), which plays a crucial role in tumour suppression, is found to be mutated. The RTK inhibitors gefitinib, afatinit and lapatinib have largely been unsuccessful at inhibiting the progression of IDH-wt GBMs.5 Their lack of success has been attributed to their minimal anti-tumour activity, due to the inability to block aberrant signalling of receptors, as theorised.5

Chimeric antigen receptor (CAR)-T-cells

CAR-T-cells are engineered to identify and eliminate cancer cells.8 As a result of its successful outcomes in multiple clinical trials targeting CD19-positive cancers, CAR-T-cell therapy has obtained FDA approval in the treatment of acute lymphoblastic leukaemia and diffuse B-cell lymphoma.8 However, when used to treat GBM, the results have been inconsistent. For instance, long-term tumour eradication was observed in mice through CAR-T-cell therapy.9 Furthermore, evidence indicated that CAR-T-cell therapy led to changes in the TME, resulting in a significant decrease in EGFRvIII expression levels in five out of seven patients.10 However, contrasting findings from the ACT IV trial revealed that less EGFRvIII expression was observed in 60% of patients regardless of their treatment. Additionally, the TME later presented with an increase in other immunosuppressive markers following infusion, thereby restricting prolonged clinical responses.10

Oncolytic virus therapy

OV therapy is a novel strategy that can combat TME immunosuppression. Various OVs like adenovirus, herpes simplex, measles and more have been assessed in GBM. OV has the ability to selectively infect tumour cells via immunogenic cell death, followed by release of pathogen- and damage-associated molecular patterns and proinflammatory cytokines, which activate and recruit immune cells.6 In a phase I clinical trial involving patients with recurrent malignant gliomas, promising results were observed with DNX-2401, an oncolytic adenovirus, as 20% of patients survived beyond three years after treatment.11 Additionally, a clinical trial conducted on patients with recurrent GBM showed that 21% of patients treated with PVS-RIPO, a polio virus OV, were still alive at 36 months, compared to only 4% in the control group.12

Immune checkpoint inhibitors

The utilisation of ICIs to target immune checkpoint proteins in cancer treatment has shown significant clinical advantage in various cancers. In IDH-wt GBM, high expression of the programmed cell death ligand 1 (PD-L1) pathway has been observed, which controls the immune

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tolerance in the TME.5 However, the outcomes of two recent phase III randomised controlled trials (CheckMate-143 and CheckMate-498), involving nivolumab treatments, have been disappointing, as they did not demonstrate a survival benefit.7

Conversely, promising results were seen in a recent multi-centre, randomised, controlled trial that investigated the effects of neoadjuvant and adjuvant anti-PD-L1 blockade in patients with recurrent GBM.5 Although the study had a limited number of patients and insufficient statistical value to evaluate the impact on survival, the neoadjuvant group exhibited enhanced antineoplastic immune responses and increased overall survival rates.8 This was further supported by White et al. (2020), who showed that TMEhigh GBM patients treated with neoadjuvant anti-PD-L1 displayed a significantly improved overall survival.5 Although ICI therapy has not been promising, a combination therapy with OV, or neoadjuvant administration followed by ICI boosting, may enhance clinical outcomes.5 This sequence is currently being tested in different cancer types including GBM trial DNX-2401 with pembrolizumab.5

References

1. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Neuro Oncol. 2018;20(Suppl_4):iv1-86.

2. Kanderi T, Gupta V. Glioblastoma multiforme. [Internet.] StatPearls Publishing; 2022. [cited May 25, 2023.] Available from: https://www.ncbi.nlm.nih.gov/books/NBK558954/

3. American Association of Neurological Surgeons. Glioblastoma multiforme. [Internet.] [cited May 25, 2023.] Available from: https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments /Glioblastoma-Multiforme

4. Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020;30(16):R921-5.

5. White K, Connor K, Clerkin J, Murphy BM, Salvucci M, O’Farrell AC et al New hints towards a precision medicine strategy for IDH wild-type glioblastoma. Ann Oncol. 2020;31(12):1679-92.

6. Wang Q et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell. 2017;32(1):42-56.

7. Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate MA et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med. 2019;25(3):470-6.

Conclusion

The future direction in the battle against GBM will likely involve a multifaceted approach aimed at overcoming the formidable challenges presented by this aggressive brain tumour. Emerging research suggests that a deeper understanding of GBM’s subtypes, such as the recently defined pro-neural, classical, and mesenchymal classifications, will open doors to more targeted therapeutic strategies. While immunotherapy has shown promise in the broader context of cancer treatment, its efficacy in GBM is still a subject of exploration. Efforts to harness the power of CAR-T-cell therapy, combined with OVs to alter the TME, are underway. Recent trials with OVs like DNX-240113 and PVS-RIPO have yielded encouraging results, suggesting that this approach holds potential for GBM treatment. Additionally, the utilisation of ICIs to modulate immune responses shows promise when combined with other therapies, offering hope for more effective GBM management. As research and clinical trials continue, the path forward seeks to turn the tide against this challenging malignancy, providing new avenues for more precise and effective treatments.

8. Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB et al Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477-86.

9. Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT et al. EGFRVIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res. 2014;20(4):972-84.

10. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD et al. A single dose of peripherally infused EGFRVIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017;9(399):eaaa0984.

11. Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS et al. Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol. 2018;36(14):1419-27.

12. Shoaf ML, Desjardins A. Oncolytic viral therapy for malignant glioma and their application in clinical practice. Neurotherapeutics. 2022;19(6):1818-31.

13. University of Toronto. Novel treatment for recurrent glioblastoma shows promising results. [Accessed: October 13, 2023.] Available from: https://www.utoronto.ca/news/novel-treatment-recurrent-glioblastoma-shows -promising-results

India Dhillon RCSI medical student

Telemental health: an effective solution for increasing access to rural mental healthcare

Abstract

Access to quality mental healthcare in rural America is a persistent challenge that results in significantly worsened patient outcomes. The mental healthcare crisis is exacerbated by geographical isolation, limited resources, and a shortage of mental health professionals. One emerging solution to combat this crisis is the use of telemental health (TMH), or the use of technology such as video or phone consultations for mental healthcare. TMH improves accessibility, mitigates stigma, and provides an efficacious treatment modality for the patient. While the use of TMH in rural America is promising, barriers to its widespread implementation include clinician uptake, accessibility, and network connectivity. Further research is needed to explore the role of TMH in treating more complex psychiatric conditions in rural settings, which could have far-reaching implications for bridging the mental healthcare gap in rural America.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 102-104.

Introduction

Access to quality mental healthcare in rural America is a persistent challenge that is exacerbated by geographical isolation, limited resources, and a shortage of mental health professionals.1 The COVID-19 pandemic highlighted the need for novel solutions to the challenges unique to mental healthcare. One such solution that has gained considerable attention is increasing the use of telehealth. Telemental health (TMH) is the use of technology such as video or phone consultations to address mental health needs, and is largely based in community clinics or primary care.2 While TMH has been used for over 15 years, its rapid implementation during the COVID-19 pandemic urges us to revisit its role in rural America. This article will explore the efficacy of TMH in rural primary care, as well as examining the associated challenges faced by both healthcare professionals and patients. Furthermore, this article will discuss the benefits and challenges faced by telehealth in rural settings as well as the general uptake by rural primary care physicians, and will ultimately address its role as a promising solution to bridge the gap in rural mental healthcare.

RCSIsmj staff review

Mental health crisis in rural America

Rural America is experiencing a mental health crisis, yet many rural counties remain underserved. The prevalence of mental illness is equal among Americans living in urban and rural areas; however, rural residents are much less likely to have access to mental healthcare.1 Approximately 20% of Americans live in rural areas; however, only 10% of psychologists practise in these areas.3 Furthermore, over 60% of rural Americans live in designated mental health provider shortage areas.4 Unfortunately, this stark healthcare inequity has dire consequences, with Hofmann et al. (2022) reporting an increased suicide rate among American youths residing in USA counties with mental health professional shortages.5

Barriers to rural mental healthcare

Delivering mental healthcare in rural settings presents unique challenges that impede access to vital services. Geographic isolation combined with sparse population density and transportation barriers limit the availability of mental health facilities. This issue is exacerbated by the persistent shortage of mental health professionals willing to work in rural areas.1,6 An often overlooked issue of accessing mental healthcare in rural settings is the stigma present in small, close-knit communities that may often have limited education and awareness about mental health conditions.7 Mental health stigma is even more apparent among minority groups.7,8 Moreover, social and socioeconomic factors such as high poverty rates and inconsistent insurance coverage also block access to mental health treatment.9 Together, these challenges highlight the pressing need for innovative approaches to ensure equitable mental healthcare delivery in rural settings.

Telemental health in rural mental healthcare

TMH is an emerging solution that can improve accessibility issues, mitigate stigma, and provide an efficacious treatment modality for the patient. TMH is used to facilitate mental healthcare through diagnostic assessment, symptom monitoring, medication management, and supportive psychotherapy, in addition to evidence-based psychotherapy. When used for these purposes, TMH has been shown to be equally or more beneficial than in-person visits. For instance, in a systematic review of nine randomised controlled trials comparing telehealth (telephone, video, or both) versus in-person psychotherapy, Greenwood et al. (2022) found no difference between patient-reported symptom severity, improvement, or function between the two modalities.10 Furthermore, Fortney et al. (2013) compared practice-based versus telemedicine-based collaborative care for treatment-resistant depression in rural American communities. The

study found that patients randomised to the telemedicine-based collaborative care experienced substantially greater remission rates, reductions in depression severity, and overall increases in mental health status and quality of life.11

Benefits of telemental health

TMH is both an effective means of delivering psychotherapy in rural settings, and can have a multitude of additional benefits for patients. First and foremost, telehealth significantly increases access to mental healthcare for underserved communities due to geographical isolation. With TMH, patients can be reached in a matter of minutes, providing both long-term and emergent psychotherapy no matter the location or time zone, if the patient has access to the internet. Additionally, the flexibility of TMH allows patients to schedule appointments that align with their daily routines, enhancing treatment adherence and engagement. Moreover, it mitigates the issue of mental health stigma that is more present in rural areas, as patients can engage in confidential virtual sessions from the comfort and privacy of their home. In turn, this not only heightens psychotherapy accessibility but also promotes earlier intervention.12 TMH also has significant advantages for healthcare providers. For instance, a study in rural Pennsylvania explored the mental healthcare provider’s experiences of using telehealth with youth and older populations, and noted increases in service continuation and parental involvement, and decreases in no-show rates and transportation difficulties.13 They did, however, note several challenges in accessing telehealth, especially among older individuals, those with hearing or learning disabilities, and residents of areas of poor connectivity.13 Similarly, in a study investigating telehealth usage among people with mental illness in rural Louisiana, Sizer et al. (2022) argued that while there appeared to be an overall benefit, there are difficulties with virtual device comprehension, especially for older people, those with lower levels of education, and those with serious and enduring mental illness.14 Altogether, TMH proves to be an effective method of delivering mental healthcare; however, a hybrid approach may best ensure equitable access for all.

Challenges with telemental health

Regardless of the introduction and availability of telehealth for mental healthcare in rural areas, the successful implementation of telehealth critically hinges upon clinician uptake and engagement. Mental health professionals play a pivotal role in establishing the credibility and effectiveness of telehealth services, fostering patient trust and satisfaction. Their integration of these technologies into practice signals a shift toward embracing innovation in order to reach underserved populations in remote areas. A study of 866 mental health, primary care, and specialty care clinicians investigated clinician perception towards TMH and found

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that clinicians’ attitudes towards telehealth quality and ease of use affected their TMH utilisation rates.15 Furthermore, the study also found that in comparison to phone appointments, clinicians more often preferred the use of video appointments to address mental healthcare needs.15 Another study by the same team found that clinician perceptions are largely biased based on their own technology experience, with greater uptake generally by younger generation healthcare workers.16 The importance of clinician engagement in TMH cannot be overstated; it not only enhances access to mental healthcare but also demonstrates a commitment to meeting the diverse needs of rural populations, ultimately contributing to the overall well-being and mental well-being of those who would otherwise face significant barriers to treatment. A significant limitation to implementing TMH in rural mental healthcare is the reliance on network connection, especially in rural areas with insufficient telecommunication infrastructure.

Of note, prior to the COVID-19 pandemic, the use of telehealth for mental healthcare was only covered for patients living in rural settings, and only certain behavioural health and substance use disorders qualified

References

1. Morales DA, Barksdale CL, Beckel-Mitchener AC. A call to action to address rural mental health disparities. J Clin Transl Sci. 2020 Oct;4(5):463-7.

2. Hand LJ. The role of telemedicine in rural mental health care around the globe. Telemed J E Health. 2022;28(3):285-94.

3. Jameson JP, Blank MB. The role of clinical psychology in rural mental health services: defining problems and developing solutions. Clinical Psychology: Science and Practice. 2007;14(3):283.

4. US Dept of Health and Human Services, 2019.

5. Hoffmann JA, Attridge MM, Carroll MS, Simon NJ, Beck AF, Alpern ER. Association of youth suicides and county-level mental health professional shortage areas in the US. JAMA Pediatr. 2023;177(1):71-80.

6. Andrilla CH, Patterson DG, Garberson LA, Coulthard C, Larson EH. Geographic variation in the supply of selected behavioral health providers. Am J Prev Med. 2018;54(6):S199-207.

7. Crumb L, Mingo TM, Crowe A. “Get over it and move on”: the impact of mental illness stigma in rural, low-income United States populations. Mental Health & Prevention. 2019;13:143-8.

8. Williams I, Williams DE, Pellegrino A, Warren JC. Providing mental health services for racial, ethnic, and sexual orientation minority groups in rural areas. Rural Mental Health: Issues, Policies, and Best Practices. 2012:229-52.

9. Gonzalez Jr GE, Brossart DF. Telehealth videoconferencing psychotherapy in rural primary care. Journal of Rural Mental Health. 2015;39(3-4):137.

10. Greenwood H, Krzyzaniak N, Peiris R, Clark J, Scott AM, Cardona M et al

Telehealth versus face-to-face psychotherapy for less common mental health

for coverage, representing an additional barrier for patients.17 In 2019, Medicare expanded its telehealth coverage to include non-rural settings, as well as a more broad list of mental health conditions.17

Conclusion

In conclusion, there is a significant gap in mental healthcare in rural American communities, which is primarily attributable to factors such as geographic isolation, healthcare provider shortages, and socioeconomic challenges. The COVID-19 pandemic accelerated TMH as a major solution to mental healthcare disparities. TMH not only addresses numerous disparities experienced by rural communities but also offers a promising avenue for expanding access to effective mental healthcare. It benefits patients by enhancing accessibility, treatment quality, and scheduling flexibility, while also offering advantages to healthcare providers. However, further research is needed to explore the role of TMH in treating more complex psychiatric conditions in rural settings, which could have far-reaching implications for bridging the mental healthcare gap in rural America.

conditions: systematic review and meta-analysis of randomized controlled trials. JMIR Ment Health. 2022;9(3):e31780.

11. Fortney JC, Pyne JM, Mouden SB, Mittal D, Hudson TJ, Schroeder GW et al Practice-based versus telemedicine-based collaborative care for depression in rural federally qualified health centers: a pragmatic randomized comparative effectiveness trial. Am J Psychiatry. 2013;170(4):414-25.

12. Bashshur RL, Shannon GW, Bashshur N, Yellowlees PM. The empirical evidence for telemedicine interventions in mental disorders. Telemedicine J E Health. 2016;22(2):87-113.

13. Nelson D, Inghels M, Kenny A, Skinner S, McCranor T, Wyatt S et al. Mental health professionals and telehealth in a rural setting: a cross sectional survey. BMC Health Serv Res. 2023;23(1):200.

14. Sizer MA, Bhatta D, Acharya B, Paudel KP. Determinants of telehealth service use among mental health patients: a case of rural Louisiana. Int J Environ Res Public Health. 2022;19(11):6930.

15. Connolly SL, Miller CJ, Gifford AL, Charness ME. Perceptions and use of telehealth among mental health, primary, and specialty care clinicians during the COVID-19 pandemic. JAMA Netw Open. 2022;5(6):e2216401.

16. Connolly SL, Miller CJ, Lindsay JA, Bauer MS. A systematic review of providers’ attitudes toward telemental health via videoconferencing. Clin Psychol (New York). 2020;27(2):e12311.

17. McBain RK, Schuler MS, Qureshi N, Matthews S, Kofner A, Breslau J, Cantor JH. Expansion of telehealth availability for mental health care after state-level policy changes from 2019 to 2022. JAMA Netw Open. 2023;6(6):e2318045.

Arianna Gholami RCSI medical student

Acute ischaemic stroke management with thrombolysis in paediatric patients: a comprehensive review of the literature

Abstract

Acute ischaemic stroke (AIS) is a syndrome that is mostly observed in the adult population. However, substantial literature exists describing this clinical syndrome in children. The current standard of care, according to most guidelines, recommends treatment with 5mg/kg aminosalicylic acid, followed by unfractionated heparin or low-molecular-weight heparin. Due to insufficient validated clinical trial data, thrombolytic therapy is not currently recommended for paediatric patients presenting within the first four-and-a-half-hours; this is the same for the adult population, provided there are no contraindications. This literature review aims to compile evidence from previously published literature along with examples from case reports supporting the use of thrombolysis in paediatric patients who have suffered an AIS. The findings and study designs from multiple clinical trials documenting the use of thrombolysis in paediatric AIS have been included in this review.

Royal College of Surgeons in Ireland Student Medical Journal 2024; 1: 105-110.

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Introduction

Acute ischaemic stroke (AIS) is a medical emergency commonly observed in the adult population. The mechanism of development may vary between cases; however, the end result is always a blockage of perfusion leading to deficits in focal sensory and/or motor neurological function.1 Although adults are vastly more affected by this clinical syndrome, there is a substantial body of literature that documents ischaemic stroke among the paediatric population (patients <18 years old). While ischaemic events in adults can commonly be attributed to large artery atherosclerosis or small vessel occlusions, paediatric ischaemic events are more commonly associated with cardioembolic causes or other congenital disorders.2 It is however important to recognise the increasing frequency of paediatric strokes attributable to risk factors that have traditionally been associated with adult populations, given the increasing prevalence of obesity, hypertension and diabetes mellitus type two worldwide.2 It is also important to note the frequency of stroke mimics in the paediatric population, and how this can affect the proper identification and efficient management of genuine ischaemic events. This literature review aims to compile and analyse cases of paediatric ischaemic strokes to determine the efficacy, safety and optimal dosing of thrombolytic agents such as tissue plasminogen activator (tPA) in their management. To date, there is limited information on the efficacy and guidelines for use of thrombolytic therapy in the management of paediatric ischaemic stroke cases. Despite the lack of a large body of literature on this subject, several large cohort studies will be discussed, and their study designs will be compared to help hypothesise what worked and what did not.

Classification

Paediatric ischaemic strokes can be classified in a number of different ways, and can have a multitude of precipitating factors. Perinatal arterial ischaemic strokes are those that occur in patients from foetal life to 28 days post natal, while childhood strokes are classified as ischaemic events that occur beyond this time frame until 17 years of age.3 While there are a variety of factors that can increase the risk of these events, children under the age of one year have been found to be at a greater risk.3 Other non-modifiable risk factors associated with an increased incidence of ischaemic events in children include male sex as well as being Black and/or of African descent.3 With regard to age-specific categories for paediatric ischaemic strokes, perinatal ischaemic events have been associated with maternal–pregnancy factors impacting coagulability and circulatory interactions.3 For paediatric strokes, ischaemic events are categorised according to the Childhood AIS Standardized Classification and Diagnostic Evaluation (CASCADE) criteria.4 These criteria are used to categorise paediatric strokes

according to their underlying cause, helping to predict the prognosis as well as the risk of recurrence for individual patients.4 Of the risk factors described in the CASCADE criteria, arteriopathies and cardiac disease are the major contributors to acute ischaemic events in children.3 Additionally, the Paediatric National Institutes of Health Stroke Scale (PedNIHSS) is used to help categorise paediatric strokes during emergency assessments, based on their severity.5 This assessment tool evaluates 11 cognitive domains in a patient (level of consciousness, best gaze, visual function, signs of facial palsy, motor function of arms and legs, limb ataxia, sensory functions, language, dysarthria, extinction/inattention) and generates a score between 0 and 56, with a score of zero designating that there is no sign of stroke and a score of greater than 42 indicating severe stroke.6

Diagnosis

Although ischaemic strokes may present similarly in both adults and children, timely diagnoses of strokes in children are often hindered by higher rates of atypical presentation.5 Similar to adults, children with ischaemic strokes may present with clinical sequelae such as hemiparesis, vision changes, and speech or language deficits.5 However, clinical manifestations such as seizures that are typically focal in nature, and changes in tone, have been more frequently reported in children less than 12 months of age.5 Additionally, symptoms such as headaches are more frequently reported in school-aged children.5 Silent episodes have also been reported in all paediatric age groups, representing a major hindrance to proper diagnosis and prompt treatment.5 This is especially prevalent in younger children who may not be able to communicate their symptoms to their caregiver. Although the method of diagnosis for AIS in children versus adults is very similar, important differences do exist. In the adult patient population, guidelines for management of acute ischaemic events recommend treatment based on the National Institutes of Health Stroke Scale (NIHSS), the Alberta Stroke Program Early CT score (ASPECTS), and time from onset of symptoms.7 Based on these assessments, a decision will then be made on whether to revascularise using IV thrombolysis and/or endovascular therapy (EVT).7 In contrast to adult ischaemic strokes, paediatric strokes tend to have delayed diagnoses with a median time of 25 hours, with only 33% of patients being diagnosed within six hours of ischaemic onset.8 This represents a major hindrance to the use and accumulation of data relating to thrombolysis in this population, as current guidelines recommend the use of thrombolysis up to four-and-a-half hours after symptom onset.9 Additionally, while non-contrast computed tomography (CT) scans are the neuroimaging diagnostic tool of choice in adult populations to rule out haemorrhagic strokes in the emergency setting, magnetic

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resonance imaging with diffusion-weighted imaging (MRI-DWI) is considered the gold standard for diagnosing ischaemic stroke in adults and children.8 This distinction in imaging modality is due to the frequently delayed presentation of paediatric strokes, making MRI-DWI a more sensitive and useful diagnostic tool.8 Additional diagnostic tests recommended within the first 24 hours of symptom onset include CT angiography (CTA), magnetic resonance angiography (MRA), or catheter angiography.8 After prompt treatment, it is important to perform additional tests to determine the underlying cause of the ischaemic events to identify the precipitating cause of the stroke. These tests may include electrocardiography (ECG) and transthoracic/ transoesophageal echocardiograms, as well as haemoglobin electrophoresis, and a full work-up for thrombophilia.8

Management

The priority for acute management of paediatric stroke should be to minimise further damage to the penumbra, an area of reversible ischaemia, and to prevent long-term sequelae. Current standard treatment recommended by the majority of guidelines is 5mg/kg aminosalicylic acid (ASA) followed by unfractionated heparin or low-molecular-weight heparin (LMWH), once an indication for anticoagulation has been identified.8 Although there is a risk of haemorrhagic conversion of the infarct, this must be considered in conjunction with the potential benefits of preventing future ischaemic episodes.8 In contrast to adult stroke patients, systemic thrombolysis is not recommended in the paediatric population due to insufficient data on the safety and efficacy of its use. However, there are a variety of case reports describing the successful use of systemic thrombolysis in paediatric ischaemic stroke patients. Table 1 details a selection of case

reports that demonstrate the successful use of thrombolytic therapy in paediatric ischaemic strokes, focusing on the initial management, dosing, and any complications that arose during their hospitalisation. These case reports represent a reservoir of information regarding the successful use of thrombolysis in paediatric AIS and may help guide the study design of future clinical trials focusing on this subject.

Case reports cited

1. Acute ischaemic stroke in a child successfully treated with thrombolytic therapy and mechanical thrombectomy.9

2. Successful treatment of paediatric stroke with recombinant tissue plasminogen activator (rt-PA): a case report and review of literature.10

3. Successful systemic thrombolysis in an adolescent with acute ischaemic stroke.11

4. Management of paediatric strokes with alteplase (tissue plasminogen activator).12

5. Original case (Helios Klinikum, Erfurt, Germany, paediatric ICU patient).13

6. Intravenous thrombolysis at 3.5 hours from onset of paediatric acute ischaemic stroke: a case report.14

7. Endovascular and thrombolytic treatment eligibility in childhood arterial ischaemic stroke.15

8. Risk of intracranial hemorrhage following intravenous tPA (tissue-type plasminogen activator) for acute stroke is low in children.16

Discussion

It has been determined after review of the current literature on use of thrombolytic therapy in paediatric AIS that comprehensive, consistent

Table 1: Case reports demonstrating successful use of thrombolytic therapy in paediatric ischaemic stroke.

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and reliable guidelines related to thrombolytic therapy in this population will depend on the development of proper inclusion and exclusion criteria. The Thrombolysis in Paediatric Stroke (TIPS) study, a multi-centre, phase one cohort study, attempted to outline comprehensive criteria to help clinicians determine the eligibility of paediatric patients for thrombolytic therapy.17 Although the study ended prematurely due to insufficient recruitment of patients, the enrolment protocol serves as a potential guideline for the eligibility of paediatric patients for thrombolysis.17 The target population for the TIPS study was children between the ages of two and 17 years with AIS and a PedNIHSS

Table 2: TIPS inclusion and exclusion criteria.17

Inclusion criteria

n Aged 2-17 years

n Acute ischaemic stroke defined as acute-onset neurological deficit with a pattern consistent with arterial ischaemia

n PedNIHSS ≥4 and ≤24

n Treatment can be administered within 4.5h of stroke onset

n Radiological confirmation of an acute ischaemic stroke by:

(a) MR showing acute stroke on diffusion imaging plus MRA showing partial arterial or complete arterial occlusion of the corresponding intracranial artery

(b) CT and CT angiogram confirmation showing a normal brain parenchyma or minimal early ischaemic change plus partial or complete arterial occlusion of the corresponding intracranial artery

n No evidence of any intracranial haemorrhage

n Children with seizure at onset may be included as long as they fulfil the criteria above

Exclusion criteria

n Unknown time of symptoms onset

n Pregnancy

n Clinical presentation suggestive of SAH even if brain imaging is negative for blood

n Patient who would decline blood transfusion if indicated

n History of prior intracranial haemorrhage

n Known cerebral arterial venous malformation, aneurysm, or neoplasm

n Persistent systolic blood pressure >15% above the 95th percentile for age while sitting or supine

n Glucose <50mg/dL (2.78mmol/L) or >400mg/dL (22.22mmol/L)

n Bleeding diasthesis including platelets <100,000, PT >15s (INR >1.4), or elevated aPTT more than upper limits of the normal range

n Clinical presentation consistent with acute myocardial infarction (MI) or post-MI pericarditis that requires evaluation by cardiology before treatment

n Prior stroke, head major trauma, or intracranial surgery within the past three months

n Major surgery or parenchymal biopsy within 10 days (relative contraindication)

n Gastrointestinal or urinary bleeding within 21 days (relative contraindication)

n Aerial puncture at noncompressible site or lumbar puncture within seven days (relative contraindication). Patients who have had a cardiac catheterisation via a compressible artery are not excluded

n Patient with malignancy or within one month of completion of treatment for cancer

n Patients with an underlying significant bleeding disorder. Patients with a mild platelet dysfunction, mild von Willebrand disease, or other mild bleeding disorders are not excluded

Stroke-related exclusion criteria

n Mild deficit (PedNIHSS <4) at start of tPA infusion or at time of sedation for neuroimaging, if applicable

n Severe deficit suggesting large territory stroke, with pre-tPA PedNIHSS >24, regardless of the infarct volume seen on neuroimaging

n Stroke suspected to be because of subacute bacterial endocarditis, moyamoya, sickle cell disease, meningitis, bone marrow, air, or fat embolism

n Previously diagnosed primary angiitis of the CNS or secondary CNS vasculitis. Focal cerebral arteriopathy of childhood is not a contraindication

Neuroimaging-related exclusions

n Intracranial haemorrhage (HI-1, HI-2, PH-1, or PH-2) on pre-treatment head MRI or head CT

n Intracranial dissection (defined as at or distal to the ophthalmic artery)

n Large infarct volume, defined by the finding of acute infarct on MRI involving one-third or more of the complete MCA territory involvement

Drug-related exclusions

n Known allergy to recombinant tPA

n Patient on anticoagulation therapy must have INR ≤1.4

n Patient who received heparin within four hours must have aPTT in normal range

n LMWH within past 24h (aPTT and INR will not reflect LMWH effect)

aPTT – activated partial thromboplastin time; CNS – central nervous system; CT – computerised tomography; INR – international normalised ratio; LMWH – low-molecular-weight heparin; MCA – middle cerebral artery; MR – magnetic resonance; MRA – magnetic resonance angiography; PedNIHSS – paediatric version of the NIH Stroke Scale; PH – parenchymal haemorrhage; PT – prothrombin time; SAH –subarachnoid haemorrhage; tPA – tissue-type plasminogen activator; TIPS – Thrombolysis in Pediatric Stroke.

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score between four and 24.17 As with adult patients, the administration of thrombolysis was limited to within four-and-a-half hours of symptom onset, with radiological confirmation of ischaemic stroke via MR diffusion imaging, MRA, or CT and CTA.17 Exclusion criteria included factors such as patients for whom symptom onset time was unknown, and potential for haemorrhagic or haematological complications.17 A major concern with regard to the use of thrombolysis in children, as with thrombolytic therapy in adults, is the haemorrhagic conversion of the ischaemic focus. This concern is of even greater importance in young children, as their fibrinolytic system is not yet mature, increasing their risk of haemorrhagic complications.18

Although the TIPS trial inclusion and exclusion criteria are valuable, it is important to analyse whether these criteria are too stringent. A full list of the different inclusion and exclusion criteria can be found in Table 2 17 The trial was well planned and organised, but due to the criteria for recruitment, researchers were forced to end the trial prematurely. For example, the PedNIHSS score required to be recruited into the trial was between four and 24; however, there are recorded cases of successful use of thrombolytic therapy in children with scores above this threshold (e.g., case 5 in Table 1).13 Another example of a criterion that may have been too strict was the exclusion of patients with vascular pathologies such as moyamoya or Kawasaki disease. A case report published by Paediatrics International describes four cases of children with Kawasaki disease being successfully treated with intra-coronary thrombolysis for coronary thrombosis.19 Cases like these are important because they can help shed light on possible adjustments to inclusion and exclusion criteria, thereby increasing the available therapies for a greater population. In terms of time to presentation, the TIPS trial required presentation for treatment within four-and-a-half hours of symptom onset. However, other studies have been conducted, such as that reported by Marecos et al. (2014), where the authors suggested the administration of thrombolysis to children less than eight years old with PedNIHSS scores greater than 10 within a six-hour time frame from symptom onset.20 As previously established, the major concern regarding the use of thrombolysis in children is haemorrhagic conversion of the stroke. Interestingly, a retrospective cohort study spanning from 1998 to 2009 analysed data from 9,257 paediatric patients and concluded that although thrombolysis was associated with an increased risk of intracranial haemorrhage and mortality, the rates of these complications were almost the same as in adult populations.21 This hypothesis is further supported by the TIPSTER study, a retrospective study that collected data from 16 former TIPS sites.16 The study results reported no instances of secondary intracranial haemorrhage (SICH) in children treated with thrombolysis, and also estimated the risk of SICH to be less than 5%, compared to adult SICH rates of 6.4%.16

A retrospective study conducted by gathering data from 13 Turkish hospitals between 2005 and 2019 provides possible alterations to certain exclusion and inclusion criteria for thrombolysis in paediatric patients.22 This study includes case reports describing the use of systemic thrombolysis not only in children with ischaemic strokes, but also in children with other thrombotic diseases such as deep vein thrombosis (DVT), intracardiac thrombosis, non-stroke arterial thrombosis, and pulmonary embolisms.22 The exclusion criteria for this trial included factors such as major surgeries or central nervous system (CNS) bleeds within ten days of administration, platelet count less than 50,000/μL and fibrinogen levels less than 100mg/dL.22 Although these mechanisms of disease differ from each other, the study demonstrates the successful use of thrombolysis in children with numerous “contraindications for thrombolysis”.22 For example, of the 54 children treated in total, seven had an active malignancy, an exclusion criterion outlined by the TIPS trial.22 Additionally, of the 54 children treated, four deaths were reported, with their causes recorded as septicaemia, veno-occlusive disease, and prematurity-related complications – none of which were directly related to use of thrombolysis.22 Interestingly, of the four patients with ischaemic strokes treated with thrombolysis, there were no reported deaths or any haemorrhagic complications, including even minor bleeding.22 Of these four patients, there were also several contraindications to thrombolysis, such as leukaemia (malignancy) and aplastic anaemia.22 The only reported complication for these four patients was the development of unilateral blindness in one patient due to a thrombus formation secondary to otitis media and mastoiditis.22 Additionally, the use of thrombolysis in infants, including preterm infants, was demonstrated in this study: a 32-week-old preterm infant with convulsions and hemiparesis was treated with a 0.1mg/kg infusion over 12 hours with no bleeding complications, resulting in complete resolution of the clot.22 All patients in this study were followed up with a median three-month course of LMWH following discharge from hospital.22

Conclusion

To reach a consensus on whether to give a paediatric patient with AIS thrombolysis, it is necessary to gather more information to help clinicians make informed and evidence-based decisions. Overall, it is not currently possible to make a definitive statement about the efficacy or safety of thrombolysis in the paediatric patient population for AIS, nor what the proper guidelines should include as inclusion and exclusion criteria. This is mostly due to a general lack of systematic data and clinical trials on this topic. However, given the evidence from various case reports documenting its use, a larger, more comprehensive study may help to provide clarification.

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Although the TIPS trial attempted this, due to its strict criteria for treatment, a definitive answer could not be attained. Conversely, the retrospective study conducted in Turkey, discussed above, had much less stringent criteria, allowing more patients to be included in the trial, thereby providing a wealth of data that can now be investigated. The general consensus in terms of optimal dosing seems to follow adult guidelines: a 0.9mg/kg bolus dose followed by an infusion at a rate of 0.9mg/kg over one hour up to a maximum

References

1. Murphy SJX, Werring DJ. Stroke: causes and clinical features. Medicine (Abingdon). 2020;48(9):561-6.

2. George MG. Risk factors for ischaemic stroke in younger adults. Stroke. 2020;51(3):729-35.

3. Rawanduzy CA, Earl E, Mayer G, Lucke-Wold B. Paediatric stroke: a review of common etiologies and management strategies. Biomedicines. 2023;11(1):2.

4. Böhmer M, Niederstadt T, Heindel W, Wildgruber M, Sträter R, Hanning U et al. Impact of childhood arterial ischaemic stroke standardized classification and diagnostic evaluation classification on further course of arteriopathy and recurrence of childhood stroke. Stroke. 2019;50(1):83-7.

5. Mastrangelo M, Giordo L, Ricciardi G et al. Acute ischaemic stroke in childhood: a comprehensive review. Eur J Pediatr. 2022;181(1):45-58.

6. Hidalgo MJ, Muñoz D, Balut F, Troncoso M, Lara S, Barrios A et al Paediatric arterial ischaemic stroke: clinical presentation, risk factors, and Pediatric NIH Stroke Scale in a series of Chilean patients. Cell Med. 2018;10:215517901876033.

7. Herpich F, Rincon F. Management of acute ischaemic stroke. Crit Care Med. 2020;48(11):1654-63.

8. Rosa M, De Lucia S, Rinaldi VE, Le Gal J, Desmarest M, Veropalumbo C et al. Paediatric arterial ischaemic stroke: acute management, recent advances and remaining issues. Ital J Paediatr. 2015;41:95.

9. Souto Silva R, Rodrigues R, Reis Monteiro D, Tavares S, Pereira JP, Xavier J et al. Acute ischaemic stroke in a child successfully treated with thrombolytic therapy and mechanical thrombectomy. Case Rep Neurol. 2019;11(1):47-52.

10. Cremer S, Berliner Y, Warren D, Jones AE. Successful treatment of paediatric stroke with recombinant tissue plasminogen activator (rt-PA): a case report and review of the literature. CJEM. 2008;10(6):575-8.

11. Viaro F, Manara R, Farina F, Palmieri A, Rocca FD, Ballotta E et al. Successful systemic thrombolysis in an adolescent with acute ischaemic stroke. Neurologist. 2015;20(3):48-50.

12. Filatov A, Alvarez J, Seibert J, Swerdloff M. Management of paediatric

dose of 90mg. From the selected cases in this paper, there were no instances of major or even minor intracranial bleeding; however, the small sample size for this analysis must be taken into account. Analysing aspects of retrospective clinical trial designs separately, such as outcomes, dosages, and inclusion or exclusion criteria, may allow future prospective trials to safely include more patients, while also avoiding unnecessary harm to those who may be predisposed to complications.

strokes with Alteplase (tissue plasminogen activator). Cureus. 2021;13(8):e17088.

13. Gholami A. (Undergraduate medical programme, RCSI, Dublin, Ireland, medical student.) Conversation with: Shuerer K (Helios Klinikum, Erfurt Germany, MD). August 3, 2023.

14. Waring ED, Milling TJ, Warach S. Intravenous thrombolysis at 3.5 hours from onset of paediatric acute ischaemic stroke: a case report. Paediatr Emerg Care. 2020;36(1):34-7.

15. Hutchinson ML, Beslow LA, Shih EK, Licht DJ, Kimmel AC, Granath C et al Endovascular and thrombolytic treatment eligibility in childhood arterial ischaemic stroke. Eur J Paediatr Neurol. 2021;34:99-104.

16. Amlie-Lefond C, Shaw DWW, Cooper A, Wainwright MS, Kirton A, Felling RJ et al. Risk of intracranial hemorrhage following intravenous tPA (tissue-type plasminogen activator) for acute stroke is low in children. Stroke. 2020 Feb;51(2):542-8.

17. Rivkin MJ, deVeber G, Ichord RN, Kirton A, Chan AK, Hovinga CA et al Thrombolysis in pediatric stroke study. Stroke. 2015;46(3):880-5.

18. Parmar N, Albisetti M, Berry LR, Chan AK. The fibrinolytic system in newborns and children. Clin Lab. 2006;52(3-4):115-24.

19. Harada M, Akimoto K, Otaka M, Sato K, Oda H, Otsuki M et al Thrombolytic therapy in Kawasaki disease: a report of four cases. Paediatr Int. 2013;55(5):e111-5.

20. Marecos C, Gunny R, Robinson R, Ganesan V. Are children with acute arterial ischaemic stroke eligible for hyperacute thrombolysis? A retrospective audit from a tertiary UK centre. Dev Med Child Neurol. 2015;57(2): 181-6.

21. Alshekhlee A, Geller T, Mehta S, Storkan M, Al Khalili Y, Cruz-Flores S. Thrombolysis for children with acute ischaemic stroke: a perspective From the Kids’ Inpatient Database. Paediatr Neurol. 2013;49(5):313-8.

22. Zengin E, Sarper N, Yazal Erdem A, Odaman Al I, Sezgin Evim M, Yaralı N et al. Thrombolysis with systemic recombinant tissue plasminogen activator in children: a multicenter retrospective study. Turk J Haematol. 2021;38(4):294-305.

RCSIsmj narrative medicine

Torn

Kira Antonyshyn RCSI medical student

On February 24, 2022, Russia launched a full-scale invasion of Ukraine – home to my friends, my family, my ancestors. On this same day, I interviewed for RCSI’s Graduate Entry Medicine (GEM) Programme. Unlike most of the diaspora in Canada who watched reports of the invasion live, I had gone to bed early on the night of the invasion in preparation for my interview. On February 24, I awoke to the news of Russia’s genocidal attack. Instead of the last-minute preparations I had planned, I read the news in horror. I cried. I interviewed with RCSI. Then, I went to work.

At that time, I was employed by a Canadian-Ukrainian charity, and so the weeks between my interview and my offer were filled with work, checking in on loved ones in Ukraine, volunteering, rallies, and very little sleep. I did not stop to think about the possibility of joining RCSI’s GEM class of 2026 until I received my offer. The choice became to pursue my lifelong dream of becoming a doctor, or make a meaningful difference in the lives of Ukrainians suffering in a brutal unprovoked war. Choosing to accept my medical school offer felt like I was giving up on Ukraine. Choosing to continue my employment felt like I was giving up on me.

A world away

On February 24, a world away, Ivan was a man leading a normal

civilian life in Ukraine. He spent time with his wife and daughter. He worked as an IT specialist, but loved cooking, and dreamed of one day becoming a chef. At approximately 5.00am that morning, Ivan returned home from his job. Just as he was falling asleep, it began. He immediately got his wife and five-year-old daughter to safety. Later that morning, he lined up at the nearest military enlistment office to register. He was handed a rifle, a helmet, and a pair of socks. By the 25th he was on active service. As soon as the missiles hit Ukrainian soil, Ivan knew he would be joining the fight. The Ukrainian Government was not mandating young and fit men to enlist. However, his country, his home, his daughter’s life, his family, and his identity were under attack. Over the ensuing months, he became a seasoned soldier – a sniper – on active duty. While on patrol with his unit, shrapnel from a tank blast avulsed his face, adding him to the list of casualties in Russia’s war. He does not remember much, but he remembers craving a cigarette. He remembers the faces of his comrades. He remembers seeing blood.

Ivan lost the entire lower third of his face. He underwent an urgent field tracheotomy to preserve his airway, and several surgeries that addressed his critical injuries to ensure his survival. He was left without a mandible, chin, or lip, and he required long-term tube feeding. The surgeons in Ukraine did not have the resources, time, or expertise for

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a reconstruction. The psychological burden on Ivan cannot be overstated. No longer fit to serve his country, he went home. Here, he hid behind a mask. He believed he looked like a monster. He wanted to protect his daughter from seeing his face.

Guilt

I do not regret my decision to pursue medicine, but I feel an enormous amount of guilt. Medical school is filled with new experiences, intellectually challenging and stimulating material, and the development of lasting personal and professional relationships. However, I am constantly aware of the growing death toll in Ukraine.

Emphasising the dichotomy between these two worlds are my social media platforms inundated with posts about RCSI society events contrasted against posts detailing the endless suffering of Ukrainians. The war is not a topic I shy away from, but when meeting my classmates for the first time, conversations about war, rape, and death seem ill suited. While I keep conversations light, my heart feels heavy. I remain determined to somehow continue to help Ukrainians throughout my medical education.

Perspective

I recently joined the Canada Ukraine Surgical Aid Program (CUSAP) as a researcher. CUSAP is a humanitarian initiative that involves a Canadian multidisciplinary team travelling to Poland to deliver complex post-traumatic reconstructive surgery to victims of Russia’s war against Ukraine. I had the opportunity to witness world-class experts deliver complex and life-changing surgical and medical care, as well as listen to the stories and perspectives of all those involved. My research project relied on information derived from hour-long semi-structured interviews with patients, nurses, physicians, and others. Through them, I relived February 24, 2022, and its aftermath, this time through the lens of each Canadian volunteer and Ukrainian patient that I interviewed. Ivan was one of those patients. The CUSAP volunteers who met Ivan on his first mission described the stark contrast between the man they met then and the man he is now. Prior to his first surgery, Ivan was described as an angry, frustrated, and distrusting individual. The person I met, on his second mission, was an entirely different man. Although the lower third of his face was covered by a mask, his eyes were full of life and he made me feel instantly at ease. He was kind, personable, and hopeful. He underwent a staged reconstruction. In the first stage, a scapular free tissue transfer provided vascularised bone to reconstruct his mandible and skin to repair the defect in his chin and floor of mouth. In the second stage, a free tissue transfer from the forearm reconstructed his lip. About two months later, the team received a message from Ivan

with two file attachments. In one, he proudly demonstrated the use of his new jaw – a video of himself slurping soup. This was the first time he had been able to consume food orally since his injury. The second was a photo of himself smiling with his daughter. He was no longer hiding behind his mask. CUSAP gifted Ivan with the confidence to show his face to his daughter.

Privilege

Missions are emotionally draining. Ivan was just one of 40 patients. Each had their own unique story to tell. Each had their own trauma. The days are long. Internists work 12-hour shifts, managing patients with several comorbidities following complex traumatic surgical reconstructions. Surgeons spend up to 15 hours in the operating room daily. The internists, anaesthetists, and surgeons involved are experts in their respective fields, but the cases on these missions are complex. They are dramatically different from those patients who are seen and treated in Canada. As such, physicians rely heavily on innovative problem-solving and a multidisciplinary approach. Despite these taxing days, participants consistently described this work as their most gratifying life experience. Each person I interviewed vividly recounted their personal experiences of February 24, 2022. This date dramatically altered the course of not only my life and that of Ivan, but also the lives of CUSAP patients and volunteers, as well as others within Ukraine, the diaspora, and the broader global population. This date also, devastatingly, brought a premature end to countless lives. While my heart continues to ache for the endless suffering of Ukrainians, my experience with CUSAP reaffirmed that I made the right decision in choosing RCSI. I joined the mission for three days. These were the most awe-inspiring and humbling days I have ever experienced. I want to be the physician who successfully manages patients with complicated multidrug-resistant infections. I want to be the surgeon who helps a woman walk again. I want to be the doctor who volunteers her time and expertise to help the people of Ukraine, despite having no personal connection to Ukraine. I want to be part of a medical team that generates the same unwavering trust that the patients have in the CUSAP team’s expertise and intentions. I am confident RCSI will help me get there. Through my research, I am not only able to stay connected to Ukraine, but I can remind people of the ongoing atrocities committed every day. I can raise awareness of a worthy humanitarian effort and provide a framework for others responding to public health emergencies. I feel privileged to be working towards a career that will equip me with the skills to become involved in humanitarian medical aid as a future medical doctor.

RCSIsmj book review

Talking to Strangers

Talking to Strangers is an exploration of failures in communication, says Senior Staff Writer LEON GILLIGAN-STEINBERG.

Talking to Strangers: what we should know about the people we don’t know

By: Malcolm Gladwell

Publisher: Little, Brown and Company

Published: 2019

ISBN-10: 0316478520

ISBN-13: 978-0316478526

Talking to Strangers is not about medicine. However, the messages delivered by Malcolm Gladwell touch on a topic that is often criminally under-addressed in medical textbooks: communication.

Why do we so often fail to communicate with those from other cultures?

Gladwell embarks on a journey through countless, seemingly unconnected, stories. We travel from Europe, learning how Adolf Hitler tricked the world leaders around him, to the clandestine dance of the Cold War, to the arrival of Hernán Cortés in the hanging gardens of Tenochtitlan. Like a beguiling lawyer wooing a jury, Gladwell enthrals his reader with vivid storytelling only to unveil another lesson about the origins of miscommunication deftly woven into the grand tapestry of his argument.

Gladwell employs strong communication skills by signposting each of his lessons.

Why can’t we tell when the stranger in front of us is lying to our face?

Gladwell’s argument revolves around Dr Timothy Levine’s ‘Truth Default Theory’, which posits that we default to believing that those around us are telling the truth. According to this theory, the average human tends to require an immense burden of proof before they

believe that they are being deceived.1 This concept, Gladwell argues, is how Cuban double agents managed to humiliate American spy agencies from within, and why British politicians mistakenly believed that Hitler would not thrust the world into World War II. To emphasise the importance of a threshold for detecting lies, Gladwell introduces Bernie Madoff, a man who created a Ponzi scheme worth an estimated $65 billion USD. Numerous parties on Wall Street noted significant discrepancies in Madoff’s story, but failed to act because they did not meet the burden of suspicion.

In medicine these deceptions can be seen all around. An age-old adage in medicine, popularised by the infamous television character Dr House is: “Everyone lies”. A study from the Association of American Medical Colleges revealed that over 80% of patients have “concealed relevant information” from their healthcare team. The study goes on to explore the reasons behind these omissions, with the primary reasons being that patients want to avoid judgement and lectures from their doctors.2

The story of Madoff serves as a platform for Gladwell to explain the ‘holy fool’, a canonical figure in many stories who acts as the sceptic. The holy fool, he writes, is someone who spots liars everywhere and constantly believes he is being deceived. Though rare, Gladwell argues they are critical to society.

RCSIsmj book review

Again, Gladwell refers to Dr Levine: “What we get in exchange for being vulnerable to an occasional lie is efficient communication and social co-ordination. The benefits are huge and the costs are trivial in comparison. Sure, we get deceived once in a while. That is just the cost of doing business”.3

To put this in familiar terms, a healthcare professional may equate the ability to catch a lie to positive predictive value (PPV). The PPV is the likelihood that a positive result on a test actually corresponds with the presence of a disease, or that it is a ‘true positive’. As the burden of disease increases in a tested population, the PPV increases. In the everyday world, it is simply not practical to engage in paranoia and question every truth one receives. However, what happens when the burden of lies increases? Think of it as the CT scan on a paediatric patient following head trauma. When there is low suspicion for serious injury, the cost of ordering extra imaging to investigate for a potential hidden injury cannot be justified when compared to the risks of radiation associated with this CT scan. However, if the investigator has a high level of suspicion for a cerebral haemorrhage, for instance, the investigation is warranted. The true question is: if 80% of patients fail to disclose the truth to doctors, should we be holy fools? Or will the suspicion further impair our relationships?

Why does physically meeting a stranger sometimes impair our ability to read them?

Gladwell follows a team comprised of scientists, an economist, and a bail expert, who crafted an artificial intelligence (AI) algorithm to identify flight risks and threats to public safety when considering bail. They then tested this model against the historical rates of judges’ bail decisions throughout the United States of America. They found that “the algorithm could reduce crime by 18.8% holding the release rate [essentially releasing the same percentage of defendants as the historical rates of judges], or holding the crime rate constant [and aiming for a similar threshold for tolerable levels of crime as achieved by the judges’ decisions], the algorithm could jail 24.5% fewer people”.4 Gladwell asks: how is this algorithm able to outperform experienced judges? These judges would have access to greater amounts of data and information, including in-person interactions with the defendants. In an explanation for the results of the study, the researchers proposed the theory that the ‘unobserved variables’ the judges are exposed to actually cloud their judgement. The answer lies in Gladwell’s ‘Transparency Fallacy’. Another experiment from Dr Levine found that subjects were terrible at detecting when others were lying if their displayed actions did not match with the content of their speech. Even with trained law enforcement officers,

Levine reported, only 20% were able to identify which interviewees had their behaviour mismatched with the honesty of their statements. As advancing technology continues to integrate itself firmly in the medical world, from AI models to telemedicine, these tools will distance physicians from their patients. What effects will this distance, often thought of as negative, have on the physician–patient relationship? Ultimately, Talking to Strangers is a book full of interesting examinations of our daily interactions. It touches on a myriad of other topics relevant to the medical world, such as alcohol use and its relation to sexual assaults, and the ‘coupling’ of context to suicide attempts (explaining why the removal of firearms could significantly reduce suicides in the USA). There are some who take issue with the book. Most notably, Carol Tavris from the Wall Street Journal examines the research that Gladwell put into the book. Her counterpoints are worth reading in conjunction with this book as they provide a useful perspective. Part of her argument relies on what she deems ‘lazy’ research and thinking, claiming that Gladwell sometimes fails to fully research or disclose elements of the story he is telling.5 Regardless, this book serves as an entertaining examination of the essential interactions we have with those around us, by anchoring memorable stories to insightful studies. It is certainly worth a read for anyone interested in the art of communication in their personal and professional lives.

Ultimately, Talking to Strangers is a book full of interesting examinations of our daily interactions. It touches on a myriad of other topics relevant to the medical world, such as alcohol use and its relation to sexual assaults, and the ‘coupling’ of context to suicide attempts.

References

1. Levine TR. Truth-Default Theory (TDT). J Lang Soc Psychol. 2014;33(4):378-92.

2. Fagerlin A. When patients lie. Association of American Medical Colleges. [Internet.] Available from: https://www.aamc.org/news/viewpoints/when-patients-lie

3. Gladwell M. Talking to Strangers. Little, Brown and Company, 2019.

4. Kleinberg J, Lakkaraju H, Leskovec J, Ludwig J, Mullainathan S. Human Decisions and Machine Predictions. Q J Econ. 2918:133(1):237-93.

5. Tavris C. ‘Talking to Strangers’ Review: Fool Me Once, Shame on Me. The Wall Street Journal. September 13, 2019.

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