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Bioengineered transplants:stem cell reversal ofchronic kidney disease

RCSI Royal College of Surgeons in Ireland

Student Medical Journal

smjVolume 12: Number 1. 2019

ISSN 2009-0838Inside: Bipolar disorder: the highs and lows

RCSI DEVELOPING HEALTHCARE LEADERS WHO MAKE A DIFFERENCE WORLDWIDE

AcknowledgementsThank you to the RCSI Alumni for their continued support of us as students – providing career advice, acting as mentors, enabling

electives and research, and supporting the publication of the RCSIsmj since its inception in 2008.

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

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

support of the annual debate.

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

constant endorsement and assistance.

The RCSIsmj was extremely privileged to have a number of professors and clinicians involved in this year’s journal clubs. We would very

much like to thank the following individuals for their support of, and participation in, the journal club, and to express our appreciation of

their time, knowledge, and expertise:

Prof. Arnold Hill

Dr Mark Murphy

Prof. Alf Nicholson

Mr David O’Brien

Dr Joseph Galvin

Prof. David Henshall and the team at FutureNeuro

4 Editorial

4 Director’s welcome

RCSI Ethics Challenge5 RCSIsmj Ethics Challenge 2019/2020

6 RCSIsmj Ethics Challenge winner 2018/2019

Research spotlight10 FutureNeuro: translating research into action – Prof. David Henshall

Interview13 Prof. Orla Hardiman

Case reports16 Maxillary sinus cancer

21 A case of a knee slip and slide

Book review26 The Inflamed Mind

Original articles27 Can proprioception influence gait abnormalities in Parkinson’s disease?

32 Post-discharge decisions: prolonged VTE prophylaxis for colorectal cancer surgery

39 The role of lymphoscintigrams in breast cancer – a retrospective audit from Beaumont

Hospital

Review articles44 The burden of paediatric asthma in urban United States populations

50 Chronic obstructive pulmonary disorder in adult Chinese women

56 Fasting fiction: is intermittent fasting superior to conventional dieting?

62 ‘Joint’ decision-making: how to determine the best approach for total hip arthroplasty

68 The role of rapid autopsy in oncology

72 Pharmacologic management of diabetes during Ramadan

78 Influence of the gut microbiome on brain health and function

Staff reviews84 Bipolar disorder: the highs and lows

91 The intersection of depression and chronic illness

96 Bioengineered transplants: stem cell reversal of chronic kidney disease

101 The big and the small of it: paediatric implantable cardioverter-defibrillators

107 An evolving strategy for cardiovascular intervention: a hybrid approach

113 Six degrees of genetic identification

118 Against all odds: ethical dilemmas in modern peri- and neonatal medicine

Perspectives124 How fitness can fuel the brain

128 Donate or do not? Strategies to increase organ donation rates

132 E-cigarettes: a new age of smoking

Abstracts136 Novel developments in cancer immunotherapy: an analysis of compounds that inhibit

indoleamine 2,3-dioxygenase

137 Eradicating bacterial biofilms with cold air plasma under simulated wound conditions

138 An aberrant phagosomal pH impairs neutrophil microbial killing in cystic fibrosis

139 Effect of long-term storage on disintegration and dissolution of over-encapsulated

penicillin V tablets

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

Royal College of Surgeons in Ireland Student Medical Journal

Executive CommitteeDirector Suzanne MurphyEditor-in-Chief Rachel AdilmanPeer Review Director Cameron ChalkerSenior Editor Alyssa ContiAssistant Peer Review Director Magar GhazarianExecutive Secretary Harishitaa PrithivirajWebmaster Gemma Wright Ballester

Assistant Webmaster Tiffany Yeretsian

Peer ReviewersDavid SeligmanAlison HuntOluwabunmi AdesanyaDeena ShahClaire GalliboisTessa WeinbergSakshi KirpalaneyShaghayegh (Sherry) EsfandniaAlexandra MitchamAidan McKeeAlexandr (Sacha) MagderHannah SuchyDonal RocheHannah O’NeillCarol RizkallaJeremy LauAlexa HigginbothamAnanya PentaparthySamantha Tso

Senior Staff WriterKatie Nolan

Staff WritersJessica MillarLaura StauntonMonika CieslakOla MichalecVladimir DjedovicJeffrey Lam

Director of EducationSri Sannihita Vatturi

Education OfficersMatthew PatelKassandra Gressman

Public Relations Joseph Saleh Fraser Jang-Milligan

The Malthouse, 537 NCR, Dublin 1.T: 01-856 1166 F: 01-856 1169www.thinkmedia.ieDesign: Tony Byrne, Tom Cullen and Niamh ShortEditorial: Ann-Marie Hardiman, Paul O’Grady andColm Quinn

RCSIsmjcontents

JOURNALISM CONTENT DESIGN

Volume 12: Number 1. 2019 |

RCSIsmjeditorial and director’s welcome

| Volume 12: Number 1. 2019

“The very first step towards success in anyoccupation is to become interested in it.”

William Osler

It is with much pride that I welcome you to the latest edition of the

RCSIsmj. Now in our twelfth year, we have undergone many changes

and have been lucky enough to chronicle the changing face of medicine

and research.

As ever, the RCSIsmj is an entirely student-run endeavour and I am always

blown away by the creativity and commitment of my peers. In my past

three years with RCSIsmj, I have been privileged to get to know so many

amazing students who are actively involved in research across the globe.

From Beaumont to Beijing, the diversity of this research is clear to see

throughout this issue. Involvement in research during their undergraduate

career is a testament to our students’ commitment to becoming the best

possible healthcare professionals. This is something we are encouraged in

from day one at RCSI, where inspiration is all around us. Prof. David

Henshall and the team in FutureNeuro are just one example of this.

I know that I leave the RCSIsmj in the hands of a strong and capable team

who will continue to encourage RCSI students to engage in research.

As ever, the RCSIsmj is grateful for the support and encouragement we

receive from the Dean’s office and the faculty of RCSI, without whom

none of this would be possible. I hope you enjoy reading this issue as

much as we did working on it, and perhaps it might even inspire you.

Medicine in 2019 abounds with ever-advancing tools and technology,

in everything from diagnostics, genealogy, and research, to

conservative and invasive therapeutics, and we are increasingly faced

with the question: “just because we can do something, does that really

mean we should?” The scope of practice of healthcare personnel today

– what we are capable of carrying out – is impressive, somewhat

daunting, and worth pausing to reflect upon. In Volume 12 of the

RCSIsmj, our authors explore this issue from birth to beyond the grave.

Monika Cieslak examines ethical dilemmas in neonatology, giving

readers a unique lens through which to contemplate the implications of

recent technological progress. Senior staff writer Katie Nolan teaches us

about modern genetic sequencing, and warns of the generational risks

posed by gaps in the interpretation and protection of our genomic data.

Today, with minimal effort, we can decode our DNA, but whether this

practice is secure or wise remains controversial.

With such comprehensive diagnostic and therapeutic advancements,

we must remain cognisant of and purposeful in our efforts to advocate

and foster the art of medicine. In this vein, Ola Michalec provides

essential insight into the consequences of chronic illness for patients’

mental health, reminding us that compassionate, holistic care

necessitates managing patients beyond mere physical symptoms and

lab values. What’s more, scientific resources now enable philanthropic

action even in death; Matthew Patel and Brian Li, respectively, discuss

the need for organ donation and rapid-autopsy tissue banking amidst

the ever-present burden of refractory disease.

We are thrilled, as always, to share Volume 12’s varied articles with you,

and thank you for your continued engagement with the RCSIsmj.

Rachel Adilman

Editor-in-Chief, RCSIsmj 2018-2019

Balancing possibility with responsibility

Director’s welcome

Suzanne Murphy

Director, RCSIsmj 2018-2019

RCSIsmjprize


A child is born at term with hypoplastic left heart syndrome. He is

initially stable and placed on a prostaglandin infusion to maintain

systemic blood flow. His parents are informed that there is roughly a

75% chance of survival at five years, but this will require at least three

separate surgical procedures and extensive hospital time. Some

neurologic disability, although probably not severe, is likely should he

survive, and there is a small chance of significant neurologic disability.

In addition, should he survive, there is a possibility that he might

require a heart transplant later in life. The cardiology service has

recommended that the surgery be performed, but the parents have

requested that the prostaglandin infusion be stopped and the child be

allowed to die.

Questions

1. What are the ethical and legal issues involved in this case?

2. How should the clinical team proceed?

3. Is the clinical team obligated to withdraw support, as requested by

the parents, even if they disagree with the parents, and believe

surgery is the appropriate course of action?

Ethics challenge 2019/2020

CONFLICTING CLINICIAN AND PARENTAL WISHES

This is the eleventh instalment of the RCSIsmj Ethics Challenge.

The editorial staff would like to congratulate Alyssa Conti on her

winning essay in the 2018/2019 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 2020 print edition of the RCSIsmj. The deadline for submission

of entries will be separate from the general submission deadline for

the 2020 edition of the RCSIsmj. Please visit our website at

www.rcsismj.com for specific dates. Please contact us at

[email protected] with any questions or concerns.

Submission guidelines

Please construct a lucid, structured and well-presented discourse for

the issues raised by this scenario. Please ensure that you have

addressed all the questions highlighted and discuss these ethical

issues academically, making sure to reference when necessary.

Your paper should not exceed 2,000 words.

Your essay will be evaluated on three major criteria:

1. Ability to identify the ethical issues raised.

2. Fluency of your arguments.

3. Academic quality with regard to depth of research, appropriateness

of references and quality of sources.

Good luck!

The winning entry will be presented with a prize at the launch

of the next issue.

RCSIsmjethics challenge

Introduction

Conscientious objection in the field of medicine has sparked moral

and ethical debates regarding the role of healthcare professionals

(HCPs) in medical care delivery. Conscientious objection refers to the

right of HCPs to refuse participation in certain legal, safe, and

medically indicated services on the basis of the physician’s moral or

religious beliefs. Commonly, these services include abortion,

contraception, euthanasia, and organ donation; however, controversy

around conscientious objection has also arisen in the discussion of

vaccinations, non-therapeutic male circumcision, and the provision of

blood transfusions. In 1948, at the United Nations General Assembly,

conscientious objection was introduced to international law in Article

18 of the Universal Declaration of Human Rights.1 This declaration

gives the “right to freedom of thought, conscience, and religion” and

includes the right to “manifest this religion or belief in teaching,

practice, worship, and observance”.1 Historically, these rights were

practised in the context of military service, whereby an individual’s

religious or moral objection to active duty and combat was resolved

by assigning the objector to an alternative military duty.2 As it applies

ETHICS CHALLENGE WINNER 2018/2019

Alyssa ContiRCSI medical student


Conscientious objection in medicine



to medicine, conscientious objection allows HCPs to refuse, on the

grounds of personal or religious beliefs, the provision of certain

medical services requested by their patients.3 In the United Kingdom,

the Conscientious Objection (Medical Activities) Bill protects medical

practitioners with a conscientious objection from participating in

services such as the withdrawal of life-sustaining treatment, any

activity under the Human Fertilisation and Embryology Act 1990, or

any activity under the Abortion Act 1967.4 This applies to all medical

practitioners participating in such activities, including those in the

General Medical Council, the Nursing and Midwifery Council, the

Health and Care Professions Council, and the General Pharmaceutical

Council.4 Therefore, conscientious objection does not solely apply to

physicians; the rights of all HCPs including nurses, midwives,

pharmacists, and medical students, are equally included.

In 1948, at the United Nations GeneralAssembly, conscientious objection wasintroduced to international law in Article18 of the Universal Declaration of Human

Rights. This declaration gives the “right to freedom of thought, conscience,and religion” and includes the right to“manifest this religion or belief in

teaching, practice, worship, and observance”.

In the United States (US), federal statutes and professional guidelines

allowing physicians to refuse participation in legalised abortions were

instituted after Roe v. Wade in 1973, when the US Supreme Court

ruled that the banning of abortion by individual states was

unconstitutional.5 Since then, conscientious clauses have been

adopted by numerous states; some states even allow medical

professionals to refuse to refer patients to alternate, willing providers,

as that could be considered participation in the medical procedure

itself.5 In Canada, however, a recent court ruling placed restrictions on

conscientious objection by implementing the policy of “effective

referral”, wherein objecting doctors must refer patients to

non-objecting physicians to ensure access to care and protect

vulnerable patients from harm.6

Ethical implications

Medical ethics defines the set of non-hierarchical moral principles that

guide HCPs through all stages of patient care. The ethical debate

regarding the legality, practicality, and morality of conscientious

objection in medicine can be examined and interpreted using the

core principles of autonomy, beneficence, non-maleficence, and

justice.

Autonomy and beneficence

Autonomy is the right of an informed, competent adult to

independently make decisions about their own medical care.7 While

the respect for patient autonomy remains a fundamental principle in

medical ethics, conflict ensues when attempting to determine the

limitations within which this right can be espoused and applied. In

conscientious objection, difficulty arises when a physician’s ethical or

moral values directly conflict with the care requested or required by a

patient, which would result in the physician upholding patient

autonomy at the expense of their own. Therefore, the essence of the

conscientious objection discussion is determining whose autonomy

supersedes. The ethical principle of beneficence addresses the

concept of acting for the benefit of others. In professional settings,

this principle has established the fiduciary relationship wherein work

always, without exception, favours the client’s rights and wishes over

those of the professional carrying out the work.8

Resurgence of paternalism

As patient expectations and the role of doctors in the doctor-patient

relationship have changed, medicine has evolved from its historic

paternalistic roots. Paternalism in medicine stems from the notion

that doctors have greater knowledge of diseases and medical

treatments compared to the general public, and therefore should

decide which course of action is appropriate for their patients.

With the introduction of ethically sound principles such as autonomy

and informed consent, patient participation in healthcare decisions

has increased tremendously, shifting the doctor-patient relationship

away from patient passivity. However, by allowing a doctor to

conscientiously object to a treatment or service that is within the

patient’s legal right, are we reverting to paternalism? If a doctor

imposes their personal morals and opinions onto a patient’s

therapeutic decision by refusing care, is the physician’s individual

autonomy being valued more highly than their patient’s?

Is there a neutral ground?

In order to mitigate the debate over conscientious objection, a middle

ground must be established. Medicine, both at its core and in

concordance with the principle of beneficence, is an act of service. A

physician’s primary obligation is to their patient. Therefore, denying a



patient a requested service that is both legally available and medically

indicated could be viewed as a direct contradiction to the principle of

beneficence. Fundamentally, it is unethical for a doctor to make moral

judgements on behalf of their patients, nor should a physician’s

beliefs be imposed upon a patient or restrict their access to medical

care. In a world of absolutes, where no middle ground can be found,

a healthcare provider’s professional obligation should be prioritised

over their personal beliefs. Comparatively, in a healthcare market

consisting of numerous providers holding diverse moral and religious

views, allowing conscientious objection with the stipulation of

mandatory referral could mitigate the debate between professional

obligations and individual physician rights. However, in an

emergency or any situation in which a referral is not possible, for

example due either to time or geographic constraints, it is the

physician’s professional obligation to provide the requested or

required medical service regardless of their personal beliefs.

Non-maleficence

Non-maleficence originates from the Hippocratic tenet of primum non

nocere, meaning first do no harm.9 Commonly, non-maleficence is

thought to represent the hazardous aspect of a risk–benefit analysis

when making healthcare decisions. The complexity of this principle

lies within the definition of ‘harm’. Proponents of conscientious

objection argue that certain services requested by patients would

cause the patient harm, thus resulting in the physician acting as the

source of that harm. However, the reverse can also be argued; in the

example of euthanasia, would refusal to withdraw life-sustaining

treatment cause more harm to the patient by prolonging their life,

rather than performing that service at the patient’s wish, to end their

suffering? Evidently, within the principle of non-maleficence it is

plausible to argue both for and against conscientious objection

depending on the interpretation of ‘harm’.

In circumstances where conscientious objection is not permitted, such

as emergencies, if a service or treatment is within a physician’s scope

of practice, they are obligated to attend to the patient’s needs or

wishes over personal moral or religious beliefs. In order to avoid

causing harm in such scenarios, medical students and doctors in

training should not be permitted to conscientiously object to

life-saving or emergent procedures performed within their field. Even

if a medical student is a conscientious objector, there may come a

time when they are required, in an emergent setting, to perform the

service to which they object. Therefore, lack of prior experience due

to conscientious objection during their training years could place

patients in potentially harmful situations.

If a doctor imposes their personal morals and opinions onto a patient’stherapeutic decision by refusing care, is the physician’s individual autonomy

being valued more highly than their patient’s?

Justice

The current stipulation wherein prompt referral is necessary in the

event of conscientious objection raises concern with respect to the

ethical principle of justice. The need for justice and equality in both

humanity and medicine has been a core philosophical concept for

centuries. Aristotle’s formal theory of justice requires, in equal parts,

consideration, fairness, and impartiality.10 Before introducing

overarching laws and regulations for conscientious objection in

medicine, it is important to consider all patient populations and

healthcare settings. Healthcare systems are diverse, ranging from

public to private, and population density and infrastructure vary,

meaning that there are often large discrepancies in access to

healthcare. The requirement of prompt patient referral to

non-objecting physicians is grounded in, and reliant upon, two large

assumptions. First, the healthcare setting must be densely populated

with sufficient physicians to enable such referrals. Second, the

stipulation assumes that all patients have the financial and physical

ability to be selective and flexible in the healthcare market they utilise

and the physician they see. This concept of ‘doctor shopping’ may be

impossible in certain public healthcare systems, or impractical due to

resource and finance limitations. In light of this, suggestions have

been made to implement hiring regulations that allow regional

authorities to allocate physicians based upon their conscientious

objection morals.

RCSIsmj


ethics challenge

Even if a medical student is aconscientious objector, there may

come a time when they are required, in an emergent setting,

to perform the service to which they object.

Arguments can be made for the potentially discriminatory nature of

mandating formal documentation of one’s conscientious objections in

the physician hiring process. However, in order to ensure that patients

retain access to legal, safe, and medically appropriate health services,

the first step is to ensure that they have access to physicians capable

of and willing to perform those services. Therefore, the identity and

‘moral scope’ of those physicians must be documented. It must be

clarified that this identification is not intended to promote

discrimination against a physician’s moral or religious views (and

indeed it mustn’t), but rather to emphasise that the primary duty of

both physicians and regulatory bodies is to ensure that all patients

have appropriate access to care. The allowance for such regional

authorities to address conscientious objection in this way might be

the next step to ensure that all medical communities are properly

serving the needs of all patients.

Conclusion

In the field of medicine, conscientious objection allows healthcare

providers to excuse themselves from providing patients with legal, safe,

and medically indicated services on the basis of personal moral or

religious beliefs. Medical practices commonly impacted by

conscientious objection include abortion, euthanasia, organ donation,

and male circumcision. There have been debates regarding which HCPs

have the right to conscientiously object, including medical students,

consultant physicians, nurses, midwives, and pharmacists. Additionally,

it has been suggested that physicians should perhaps be required to

disclose their objections, so that regulatory and hiring bodies can ensure

a sufficient mix of physicians within an area in order to cater to the full

scope of patient needs within a population. From an ethical standpoint,

in order for HCPs to have a legal right to conscientiously refuse certain

medical practices, they must be obligated to refer patients, in a timely

manner, to another practitioner who is willing to perform the

treatment. This referral must not cause the patient any emotional harm,

nor can it delay their access to timely care. In situations where referrals

are not possible, such as emergencies or lack of referral opportunities, it

is the HCP’s duty to carry out the service themselves. As stated in the

Hippocratic Oath,11 and many modernised versions used today, a

doctor’s primary obligation is towards their patients, and it is this

privilege of service and ethical responsibility that ultimately transcends

personal beliefs.

References

1. United Nations General Assembly. Universal Declaration of

Human Rights, 217 A (III). December 10, 1948. [Internet].

Available at:

http://www.un.org/en/universal-declaration-human-rights/.

2. Lippman M. The recognition of conscientious objection to military

service as an international human right. Cal W Int’l L J. 1990;21:31.

3. Shaw D, Gardiner D, Lewis P, Jansen N, Wind T, Samuel U et al.

Conscientious objection to deceased organ donation by healthcare

professionals. J Intensive Care Soc. 2018;19(1):43-7.

4. UK Parliament. Conscientious Objection (Medical Activities) Bill [HL]

2017-2019. [Internet]. Available from:

https://services.parliament.uk/bills/2017-19/conscientiousobjectionm

edicalactivities.html.

5. Misna L. Stem cell based treatments and novel considerations for

conscience clause legislation. Ind Health L Rev. 2011;8:471.

6. Symons X. Canadian court tells doctors they must refer for

euthanasia. February 3, 2018. [Internet]. Available from:

https://www.bioedge.org/bioethics/canadian-court-tells-doctors-they-

must-refer-for-euthanasia/12585.

7. Gillon R. Medical ethics: four principles plus attention to scope. BMJ.

1994;309(6948):184-8.

8. Kinsinger FS. Beneficence and the professional's moral imperative. J

Chiropr Humanit. 2009;16(1):44-6.

9. Summers J, Morrison E. Principles of healthcare ethics. Health Care

Ethics (2nd ed.). Sudbury: Jones and Bartlett Publishers,

2009:41-58.

10. Gillon R. Philosophical medical ethics. Rights. Br Med J (Clin Res Ed).

1985;290(6485):1890-1.

11. British Medical Association. BMA updates Hippocratic Oath. 1997.

[Internet]. [cited 2016 May 17]. Available from:

http://web.bma.org.uk/pressrel.nsf/wall/776B5BE6D9D1D2D0802568

F50054301D?Open.

RCSIsmj


research spotlight

One in four people in Ireland will be directly affected by a neurological

disorder during their lifetime. An enormous gap remains in translating

neuroscience, genetics, and diagnostic discoveries into patient care; the

current system for diagnosing, treating, and managing chronic and rare

neurological diseases is inadequate and largely fails patients.

FutureNeuro is the Science Foundation Ireland (SFI) Research Centre for

Chronic and Rare Neurological Diseases, based at the Royal College of

Surgeons in Ireland (RCSI), and brings together an internationally

recognised multidisciplinary team. FutureNeuro includes neuroscientists,

clinical neurologists, geneticists, cell biologists, and analytical and

materials chemists from five different third-level institutions’ research

teams including RCSI, Trinity College Dublin (TCD), University College

Dublin (UCD), Dublin City University (DCU), and National University of

Ireland Galway (NUIG). FutureNeuro currently has eight dedicated

principal investigators.

The vision of FutureNeuro is to provide a uniquely integrated centre that

will accelerate translatable discoveries on genetic diagnosis and advanced

molecular treatments supported by enabling eHealth technology for

chronic and rare neurological diseases. Researchers in FutureNeuro

connect to a national clinical network spanning major tertiary referral

centres across Ireland, which in turn are linked via national disease-specific

electronic health systems. This is globally unique and provides an edge

over similar initiatives and a platform to deliver world-leading research.

Further, given the size and nature of the healthcare system in Ireland, this

is scalable to other neurological disorders.

FutureNeuro: translatingresearch into action

FutureNeuro Director Prof. DAVID

HENSHALL of RCSI describes this

groundbreaking project to

improve the treatment of

neurological disorders.

RCSIsmj


research spotlight

Defining the problem

Brain diseases are hugely costly for health and society. It is estimated

that as many as 800,000 people in Ireland live with some form of

neurological condition, with a healthcare and societal cost of €3

billion.1

The problem – and solution – is threefold:

1. Diagnosis: Genomic medicine will provide a molecular diagnosis

and guide therapy so that patients receive the right drug sooner with

fewer side effects.

2. Therapy: Many patients fail to respond to available drugs, and for

most rare neurological diseases there is simply no effective treatment.

New therapeutics will control or correct the gene networks in the

brain that underlie the disease or drug resistance.

3. eHealth infrastructure: This is largely absent and has not been

leveraged for research in Ireland to date. National electronic health

record infrastructure connects individuals to their records, improves care

outcomes, and facilitates world-class research, including clinical trials.

FutureNeuro’s research aims to change patient journeys, to result in

faster, more precise diagnosis, and fewer hospital and emergency

department admissions. For people who do not respond to current

treatments, the centre will help drive the development of new

therapies that work to restore normal brain function. Clinical decision

support systems will be developed using electronic health records to

provide insights into how a person’s disease progresses, their

response to treatment, and to assess risk factors to inform a more

individualised treatment plan.

The vision of FutureNeuro is to provide auniquely integrated centre that willaccelerate translatable discoveries on

genetic diagnosis and advanced moleculartreatments supported by enabling

eHealth technology for chronic and rareneurological diseases.

The team

The centre’s director, Prof. David Henshall, is a neuroscientist whose

research focuses on discovering new treatments and biomarkers of

epilepsy. Also based in RCSI is Prof. Gianpiero Cavalleri, a human

geneticist interested in the genetic underpinnings of brain diseases

and predictors of drug responses, and Prof. Jochen Prehn, a

world-leading researcher on neurodegeneration and mathematical

modelling to predict drug responses.

The research team in TCD includes Prof. Orla Hardiman, Prof. Colin

Doherty, and Prof. Matthew Campbell. Prof. Hardiman is a world

RCSIsmjresearch spotlight


leader in clinical amyotrophic lateral sclerosis (ALS) research, and

developed the longest running and possibly most successful

population-based ALS register in the world. Prof. Doherty is the

national clinical lead in Ireland for epilepsy, and is a pioneer in

biobanking of blood and brain tissues for research into neurological

diseases. Prof. Campbell researches the molecular technology to

deliver large molecules and drugs directly to the brain, crossing the

blood–brain barrier – this poses a significant challenge for treatment

of neurological disease.

Another nucleic acid specieshas been discovered that

rises in the blood ahead of aseizure, suggesting thatseizure forecasting mayone day be possible.

In NUIG, Prof. Sanbing Shen is a cell biologist and introduced

neuronal stem cell technology to Ireland. His research will focus on

developing brain cells from the skin tissue of rare diseases to screen

the effect of different drug treatments, thus reducing the amount of

trial and error in current therapeutic practice. Prof. Robert Forster,

based in DCU, is a materials chemist and is currently developing ways

to detect some of the ultra-low levels of diagnostic brain molecules in

blood. The ultimate goal is to develop a rapid point-of-care test for

epilepsy and other neurological diseases.

The centre is supported by research-active clinicians across Ireland.

Leading on clinician research is Prof. Norman Delanty, a neurologist

based in Beaumont Hospital specialising in the difficult-to-treat

neurological disease.

A key player in the FutureNeuro programme is eHealth and

specifically the Epilepsy Electronic Patient Record (EPR), developed as

a ‘lighthouse project’ by the HSE and led out by Mary Fitzsimons. The

EPR contains detailed clinical information and patient-reported

disease insights from 10,000 people living with epilepsy in Ireland.

This, combined with genomic data, can improve clinical

decision-making and support better research into the disease.

Flagship Irish research

Funding for FutureNeuro is secure for at least six years, with an

investment of over €13.6 million by SFI. It is one of 17 research

centres now operating across science and technology fields. These

are the flagship funding instruments for SFI – they provide

large-scale, long-term support for basic and applied research that is

strategically important for Ireland’s economic and societal progress.

A major part of the research activities of such centres is partnerships

with industry, ranging from small and medium enterprises to large

multinational companies.

FutureNeuro has now been operating for nearly 18 months. Nine

PhD-driven research projects are up and running, and the Centre’s

headcount has reached nearly 50. Progress has been made across all

three thematic areas.

Among the therapeutics projects, researchers have tested

oligonucleotide inhibitors of non-coding RNAs (part of the genome’s

‘dark matter’) and found promising anti-seizure effects in preclinical

models, and research is looking at how the blood–brain barrier can be

bypassed to deliver these to the brain.

Another nucleic acid species has been discovered that rises in the

blood ahead of a seizure, suggesting that seizure forecasting may one

day be possible. The centre is also investigating how the brain’s

endocannabinoid system responds to seizures, and testing the effects

of cannabinoids, a recently approved medicine for intractable

epilepsy.

Although FutureNeuro is still in its early days, research findings

have already been published. This includes the discovery that a

set of nucleic acids are released from the brain into the blood of

patients with epilepsy, and the development of a prototype test that

could be a useful addition to EEG, MRI, and other clinical

assessments.2

References

1. Clarke S, Craven A, Doig H, Gill M, Hardiman O, Lynch T et al. Building a

Supportive Framework for Brain Research in Ireland. Irish Brain Council.

2017. [Internet]. [cited 2019 February 16]. Available from:

https://www.nai.ie/assets/25/0425F95F-FE1F-4D25-

BE47D8C6D75756C2_document/IBC_position_paper_final_for_print_

March2017.pdf.

2. Raoof R, Bauer S, Naggar HE, Connolly NM, Brennan GP, Brindley E et al.

Dual-center, dual-platform microRNA profiling identifies potential

plasma biomarkers of adult temporal lobe epilepsy. EBioMedicine

2018;38:127-41.

RCSIsmjinterview


Prof. Orla Hardiman is Professor of Neurology in Trinity College Dublin

(TCD). She recently stepped down as Academic Director of the Trinity

Biomedical Sciences Research Institute. She is a Consultant Neurologist

at the National Neuroscience Centre, where she is Director of the

National Amyotrophic Lateral Sclerosis (ALS) Clinic and the Irish ALS

Research Group, and is about to take up her new role as Clinical Lead

for Neurology in the HSE. Prof. Hardiman’s primary research interests are

the genomics, epidemiology, and disease phenotyping of ALS. Her

research aims to elucidate the mechanisms of disease heterogeneity,

with a particular focus on identifying new target genes and drug targets

for patient treatment.

Can you tell us about your path from medical school?

I always knew that I wanted a job that included both research and

clinical practice. My own experience of being female, and not really

having any mentors, made me want to be a good mentor for younger

people coming up behind me.

When I graduated in 1983, the landscape was fairly barren. There were

no proper specialist training schemes, and most contracts were either six

months or one year in duration. People really had to find their own way.

This was difficult as money was tight in those days, and moving from

city to city was very challenging. I was lucky as I had a one-year

internship in St Vincent’s, and then spent two years in the old Richmond

Hospital in both neurology and neuropathology.

But further training was going to be difficult at home, and emigration

was essential. I am one of five siblings, and by that time four of us had

emigrated.

After a trip to the US to look at job opportunities, my husband and I

settled on Boston, as I had matched to a good residency in the Harvard

programme, and he was able to get a job as a lawyer. I trained in

neurology and then in neuromuscular disease and cell biology.

By 1991, the Irish economy was beginning to pick up again. I already

had a BSc in Physiology, and I returned to Ireland as a Newman Scholar

in UCD in human anatomy and physiology, and used my training in

muscle biology to set up a lab. I also taught physiology to

physiotherapists and medical students.

But I really missed the clinical work, and in 1996 I applied for and was

successful in my application for Consultant Neurologist in Beaumont. I

All about the brainSenior staff writer KATIE NOLAN spoke with Prof. Orla Hardiman about

her career and her research into ALS.

RCSIsmjinterview


worked hard for 11 years as a full-time clinician (by that time I also had

four children). There were only 11 neurologists in the country, and I was

seeing over a hundred patients a week, with a 1:3 on-call schedule. I

re-oriented my research towards epidemiology, clinical phenotyping

and genomics. I had received a good training in amyotrophic lateral

sclerosis (ALS) in Boston, as I had worked as a Fellow with one of the

leaders in the field, Bob Brown.

In 2007, I was successful in my application for a Clinician Scientist Award

(CSA) from the Health Research Board (HRB). At that time, I moved my

academic affiliation from RCSI to TCD, as I was already collaborating

with the Smurfit Institute of Genetics in TCD, and I had a strong

affiliation with Trinity College Institute of Neuroscience (TCIN). My CSA

allowed me to buy out 50% of my time, and to concentrate on building

a research programme in ALS. I had a very supportive Head of School in

TCD. He put me in touch with TCD Development Officer Zhanna

O’Clery, with whom I worked to build a new Academic Unit of

Neurology using philanthropic support. My HRB grant, and my research

output, facilitated my contract adjustment to that of Academic

Consultant, and my appointment in 2013 as the first full Professor of

Neurology in TCD (actually, in all of the Republic of Ireland). From

2015-2018 I was also the Academic Director of the Biomedical Science

Institute in TCD – a great job that opened up a whole range of

interesting collaborative opportunities.

I now have my dream job. I am still active as a clinician. This is very

important to me, as my core identity is that of a doctor. But I am also

very active in research design and development, clinical trials, and

mentoring, and most recently in service planning for neurology. There

are now over 35 people working in my research group, and I have taken

huge pleasure in attracting many extremely bright young people to

work with us, and to watch in awe as their careers blossom.

Did you know you wanted to study neurology while in

medical school? When did the desire to study the brain

become apparent?

I was always interested in the brain. Also, I have a background in

physiology. I don’t have a particularly good factual memory, and I liked

subjects I could work through by deductive logical reasoning. I also

hated being in a position where I would have to make critical decisions

in a short timeframe, so emergency medicine and intensive care were

not attractive options. My original plan was to go into psychiatry, but

after an internship in which I rotated through a service that was heavily

psychoanalytic in nature, I decided to move over to the ‘nuts and bolts’

of neurology. But in a way, my career has come full circle, as we have

recently shown a biological association between ALS and schizophrenia.

Being Irish, of a certain age and female, Iam afraid that there was not a lot of

mentoring available at the time. But I haveworked with some very able people, andlearned important skills along the way.

Have you had any great mentors throughout your career?

Being Irish, of a certain age and female, I am afraid that there was not a

lot of mentoring available at the time. But I have worked with some very

able people, and learned important skills along the way (some of these

points of learning were about how NOT to behave!)

The most positive influences on my life were the late Hugh Staunton,

who set up the very successful Irish epilepsy programme with a

combination of forceful intelligence and sheer determination, Bob

Brown in Boston, who showed me what a really successful clinician

scientist can look like, and some very strong female colleagues with

whom I have had the privilege of working along the way: Aileen Barrett,

who was Head of Physiotherapy in Beaumont when I was a young

consultant, Rozanne Barrow, who was Head of Speech and Language

Therapy in Beaumont, and Audrey Craven, who set up the Migraine

Association of Ireland. I still count all three among my close friends.

You completed part of your training in America – would you

recommend this experience to other Irish graduates?

Yes, I would. In some ways, it is tougher today than it was when I was

going through. As there were very few ‘systems’ or regulations back

then, there was a lot of flexibility, and one could receive an entire

training overseas and have it recognised here.

Now, I would recommend completing the basic training and SpR

training here, and then moving overseas for Fellowship training. Young

doctors should also look at the Wellcome-HRB ICAT programme, which

RCSIsmjinterview


focuses on the combined academic and clinical specialist. Residency

training in neurology is still possible in the US, but engagement with the

Royal College of Physicians in advance is advisable to ensure that all the

Irish requirements for Specialist Registration are met.

When did you know you wanted to combine your clinical

skills with your passion for research?

I always liked the idea of combining clinical engagement with scientific

curiosity. I did an intercalated BSc halfway through medical school, in

UCD. This really confirmed my interest in applied clinical research.

How do you balance the demands of a medical career with

staying on track in the research lab?

In my opinion, it isn’t really possible to run a first-class basic science lab

and be a first-class clinician in Ireland. Even in the US people generally

choose between one or the other. But it is possible to run applied

research programmes that focus on “bedside-to-bench” research. In this

scenario, we set the clinical parameters and clinical questions, and work

with our basic laboratory colleagues to translate back and forth.

What is the most rewarding part of your work?

Making a difference. This can be in improving patient care, finding a

new disease mechanism through genomic analysis, or helping a

younger colleague move up the ladder.

What advice do you have for future clinician researchers?

Work hard and don’t be afraid of failing. Believe in yourself. Most new

ideas take 10-15 years to embed into the general scientific zeitgeist. Be

honest, and keep your integrity and your humility. Remember that

sometimes you are just plain wrong, and there is no honour in trying to

publish a piece of flawed research, no matter how compelling the

justification. Counter-intuitive results are there to keep us humble. And

above all, be nice to people, especially those coming up behind you.

Your lab has a diverse range of research interests. Of

particular importance is the ongoing research into the rates

and causes of familial ALS within the Irish population. The

motor neuron disease (MND) register you created has been

collecting patient data since 1994, and is a powerful research

tool. What does the genetic profile of Irish patients tell us? Is

that profile similar to patient cohorts from other countries?

The Register has helped us to define the entire range of disease, and has

enabled quite a few new observations, including the relationship

between ALS and other neurological and neuropsychiatric conditions.

The genomic profile of Irish ALS patients differs slightly from other

countries. For example, we do not have any patients in Ireland with the

SOD1 variants. Instead, 50% of our families carry the C9orf72 expanded

repeat. We don’t yet have a genetic explanation for the remaining 50%.

Our studies in epidemiology have also made another important

observation, which is that populations that are genetically admixed

seem to be protected. We have shown this in Cuba, and the work has

been replicated in other parts of Latin America. The ‘mulatto’ (most

genetically admixed) population has a 50% lower rate of ALS compared

to ‘whites’. This proves the complex genetic basis of ALS.

You set up the ALS DNA bank in 1999, which contains

genome-wide association study (GWAS) data from the Irish

patient cohort. Do you think genealogical data and the

advancing techniques in gene profiling will help identify

future drug targets for ALS? Has familial gene clustering

data been important for identifying new target genes or

mechanisms of disease progression?

Up to a point. I think that future therapeutics will certainly have a

pharmacogenomic component. But I think that our genealogical work

will also help us to identify different patterns of degeneration. Our data

suggests that the relationship with neuropsychiatric conditions is not

uniformly distributed; these conditions tend to cluster within families.

Our more recent work in neuroimaging (now led by Dr Peter Bede), and

more recently in neuro-electric signal analysis (now led by Dr Bahman

Nassereloslami), has convinced me that we should be thinking about

ALS (and probably the other neurodegenerations) as disorders of brain

networking. The genomic basis to this may provide clues, but I could

envisage a class of drugs that work to stabilise/modulate brain

networking as being of therapeutic value.

Your research has identified links between ALS and

psychiatric illnesses such as schizophrenia. This research is

expanding the field of neurology and identifying the role of

genetic pleiotropy in neurological disorders. Do you think

advances in neuropsychiatry research will help scientists and

clinicians understand the brain and neurodegeneration

better?

Absolutely – it is all about the brain! Dichotomising into ‘neurological’

and ‘psychiatric’ conditions is biologically irrational. How the brain fails

can be a function of neurodevelopmental errors, acquired disruptions in

cellular function, synaptic function, cell–cell interaction, or neuronal

connectivity, or disruptions in essential glial function (there is an

evolving literature on oligodendrocytes in this regard), etc.

There is still a huge amount to discover, and there is no reason why

neurologists and psychiatrists cannot learn from one another.

Bharti M. Kewlani1

Dr Carlos S. Gracias2

Prof. James P. O’Neill3

1RCSI medical student

2Medical intern, University

Hospital Galway

3Professor of Otolaryngology,

Head and Neck Surgery,

Beaumont Hospital, Dublin

Introduction

Cancers of the nasal cavity and paranasal sinuses

are rare and account for fewer than 1% of all

human malignancies.1 Up to 60-70% of sinonasal

malignancies are maxillary sinus cancers, with

squamous cell carcinoma (SCC) being the most

common subtype.1 Patients with maxillary sinus

cancer remain largely asymptomatic until the

tumour reaches a large size with widespread local

tissue destruction or metastasis.2 These tumours

thus present very late in the disease course, leaving

surgery as the primary treatment option despite

limited scientific rationale and weak clinical

evidence regarding treatment guidelines. Regional

lymphatic spread in the context of this malignancy

is relatively uncommon, although involvement of

the submandibular, upper jugular, and

occasionally retropharyngeal nodes may occur.

Fewer than 5% of these cancers present with

distant metastasis.2,3

In terms of risk factors, chronic irritation of the

sinus lining can lead to squamous transformation

of the epithelial cells within the sinus cavity, such

as in the case of long-term cigarette smoking or

alcohol consumption. Occupational exposure to

wood dust, nickel dust, mustard gas, isopropyl oil,

chromium, and other substances may also

Maxillary sinus cancer

Abstract

Maxillary sinus cancers are the most common type of sinonasal malignancies. These cancers are

locally aggressive, and patients generally remain asymptomatic until the tumour reaches an

advanced stage. Multimodality therapy is the gold standard for treating these cancers. This report

presents the case of a 60-year-old male, Mr GA, who received a diagnosis of advanced-stage

maxillary sinus carcinoma following biopsy of the lesion after it was incidentally discovered on a

computed tomography (CT) scan ordered in the primary care setting. Mr GA underwent elective

removal of the primary tumour followed by extensive reconstructive surgery and adjuvant

radiotherapy. This case highlights the significance of a multidisciplinary team and evidence-based

approach in achieving successful outcomes for patients with maxillary sinus cancer.

Royal College of Surgeons in Ireland Student Medical Journal 2019; 1: 16-20.

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RCSIsmjcase report


contribute to squamous transformation of the sinus lining and

subsequent development of malignancy. Therefore, individuals

working in the furniture-making, leather, and textile industries are at

higher risk of malignant transformation due to chronic inhalation of

such microparticles.4 Additionally, human papillomavirus (HPV) or

Epstein-Barr virus (EBV) infection may also be an early event in the

multistep progression towards malignancy.4 Multimodality therapy,

including surgery, radiation therapy, and chemotherapy, is used to

treat such cancers.

Case summary

A 60-year-old Irish businessman, Mr GA, presented to his local general

practitioner (GP) in June 2017, complaining of mild sinusitis-like

symptoms ongoing for four months. The patient had a 50 pack-year

smoking history and an average weekly intake of 20 units of alcohol.

His symptoms included occasional red-orange nasal discharge and

nasal congestion. However, apart from these mild episodes, the

patient had no other complaints. Mr GA’s past medical history was

significant for hypertension, controlled on propranolol, and he denied

any known drug allergies. His past surgical history was insignificant

apart from bilateral varicose vein removal in 2017.

To thoroughly investigate this patient’s symptoms, the GP ordered an

electrocardiogram (ECG), blood tests, and a chest x-ray, all of which

revealed no abnormalities. However, a non-contrast computed

tomography (CT) scan of the paranasal sinus revealed a mixed

intensity, expansile mass in the left maxillary sinus (Figure 1a).

Medially, the mass invaded the middle and inferior turbinates of the

nasal cavity, causing obliteration of the left middle meatus. Superiorly,

invasion of the infraorbital region was apparent, with sparing of the

orbit. Involvement of the oral cavity and gingivobuccal sulcus was

also noted inferiorly. Furthermore, transverse section of the CT scan

(Figure 1b) showed the mass breeching the confines of the maxillary

sinus, extending into the nasal cavity, and invading the posterior wall

of the maxillary sinus.

Mr GA was subsequently referred to the ear, nose and throat (ENT)

department, where a biopsy of the left maxillary sinus and nasal

polyps was conducted.

Occupational exposure to wood dust,nickel dust, mustard gas, isopropyl oil,chromium, and other substances may

also contribute to squamoustransformation of the sinus lining and subsequent development ofmalignancy. Individuals working in the furniture-making, leather, and textile industries are at higher risk of malignant transformation due

to chronic inhalation of such microparticles.

FIGURE 1a: Coronal section of a CT scan showing a mixed-intensity mass in the leftmaxillary sinus.

FIGURE 1b: Transverse section of a CT scan showing the tumour invading theposterior wall of the left maxillary sinus and causing obliteration of the left middle meatus.

RCSIsmjcase report


Table 1: American Joint Committee on Cancer (AJCC) criteria for tumour (T) staging of maxillary sinus carcinoma.5

T stage Criteria

T1 Tumour limited to the maxillary sinus mucosa with no erosion or destruction of bone

T2 Tumour causing bone erosion or destruction, including extension into the hard palate and/or middle nasal meatus,

except extension to the posterior wall of the maxillary sinus and pterygoid plates

T3 Tumour invades any of the following: bone of the posterior wall of the maxillary sinus, subcutaneous tissues, floor or

medial wall of the orbit, pterygoid fossa, or ethmoid sinuses

T4a Tumour invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate,

sphenoid, or frontal sinuses

T4b Tumour invades any of the following: orbital apex, brain, middle cranial fossa, cranial nerves other than maxillary

division of trigeminal nerve, nasopharynx, or clivus

FIGURE 2: Elective neck dissection incorporating levels 1-4. FIGURE 3a: Intra-operative tumour resection using a globe-sparing total ethmoidmaxillectomy.

RCSIsmj

The histopathology report that followed described a T3/4a N0 M0

poorly differentiated, non-keratinising SCC in the left maxillary sinus

(Table 1). In addition, there was confirmed bone invasion by the

tumour both laterally (through the maxilla into the pterygoid fossa)

and medially (into the nasal cavity). No vascular or perineural invasion

was reported.

The patient was then referred to the Department of Otolaryngology,

Head and Neck Surgery at Beaumont Hospital, where a complete

head and neck examination was performed, and a repeat head and

neck CT scan with contrast and positron emission tomography (PET)

scans were conducted to further delineate the extent of malignancy.

Mr GA’s case was then discussed at a multidisciplinary team (MDT)

meeting involving the pathology, ENT, plastic surgery, and oncology

teams. The patient continued to remain stable and well with no

further deterioration of his initial symptoms.

Management

At the MDT meeting, a therapeutic decision was made to proceed

with surgical excision of the primary tumour and associated lymph

nodes followed by radiotherapy, in keeping with the National

Comprehensive Cancer Network (NCCN) guidelines.6

The extirpative component of this case included a prophylactic

left-sided elective neck dissection (END) incorporating levels 1-4

(Figure 2), and a globe-sparing total ethmoid maxillectomy (Figure

3a). The reconstructive element of the surgery included orbital floor

repair using a titanium mesh and subsequent coverage with a

temporalis pedicled muscle flap.

This was followed by insertion of an oral obturator, fashioned by a

prosthodontist prior to the operation, to seal the oral cavity from the

adjacent paranasal sinus (Figure 3b).

Histopathology on the excised tumour confirmed a SCC that was

removed with clear circumferential margins (Figure 4). Neck

dissection did not reveal any tumour dissemination. The MDT then

decided that adjuvant radiation without chemotherapy was the best

therapeutic strategy for this patient. Six weeks postoperatively, Mr GA

commenced six weeks of adjuvant radiotherapy amounting to 60Gy.

This case provides an example of an MDT approach to a patient withadvanced sinonasal malignancy,requiring the collaboration ofhead and neck cancer surgeons,plastic surgeons, prosthodontists,

radiation oncologists, neuro-radiologists,and pathologists.


case report

FIGURE 3b: Intra-operative reconstruction of the infra-orbital floor and oral cavity. FIGURE 4: Macroscopic appearance of the resected lesion.

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Discussion

Complete surgical excision followed by postoperative radiation therapy

remains the primary treatment option for locally aggressive, resectable

maxillary sinus tumours. Aggressive surgical resection would

theoretically increase functional and cosmetic morbidity, but this has

improved significantly with modern reconstructive techniques such as

microvascular free flaps, pedicled flaps, and prosthetic obturators such

as the one used in the above case.7

Tumour dissemination to cervical lymph nodes is one of the most

important prognostic factors in maxillary sinus cancer.8 Patients with

evident metastasis to regional lymph nodes undergo neck dissection,

where lymph nodes from different anatomical levels are removed.

However, whether or not patients with clinically negative neck nodes

should undergo an END remains debatable.

This case reports a patient who had a T3/4a N0 M0 locally invasive

maxillary sinus cancer, with no evidence of regional lymph node

dispersion of the tumour (Table 1). Nonetheless, an END was

performed. According to one study, local control of the primary

tumour was deemed more important compared to neck management

via END, and it concluded that the incidence of occult cervical

metastasis of maxillary SCC was not high enough to recommend END.9

Another study, however, concluded that advanced T stage tumours

pose a much higher risk for cervical metastases compared to early T

stage tumours.10 As such, the authors recommended that an END of

levels I to III should be performed for all patients with T3/4 N0

disease.10 This is expected to significantly reduce tumour recurrence

rates and improve survival outcomes for these maxillary SCC patients.10

In the case of this patient, Mr GA’s tumour involved the gingivobuccal

sulcus, which increased the chances of tumour invasion to regional

lymph nodes, according to the latter study.10 For this reason, Mr GA

was managed with an END.

Conclusion

The complex anatomy of the paranasal sinus region, together with

the tendency for late clinical presentation due to an asymptomatic

early phase, makes maxillary cancer treatment particularly difficult.

Unlike many other cancers, standard treatment guidelines and

randomised data to guide management in maxillary sinus cancer are

lacking. This case provides an example of an MDT approach to a

patient with advanced sinonasal malignancy, requiring the

collaboration of head and neck cancer surgeons, plastic surgeons,

prosthodontists, radiation oncologists, neuro-radiologists, and

pathologists. This case also required specialised care from nursing

staff, speech and language therapists, and physiotherapists,

highlighting the importance of a holistic team approach to

evidence-based medicine and complex patient care.

References

1. Grant RN, Silverberg E. Cancer Statistics 1970. New York; American

Cancer Society, 1970.

2. Turner JH, Reh DD. Incidence and survival in patients with sino-nasal

cancer: a historical analysis of population-based data. Head Neck.

2012;34:877-85.

3. Robin T, Jones B, Gordon O, Phan A, Abbott D, McDermott J et al. A

comprehensive comparative analysis of treatment modalities for sinonasal

malignancies. Cancer. 2017;123(16):3040-9.

4. American Cancer Society. What are the risk factors for nasal cavity and

paranasal sinus cancers? 2019. [Internet]. [cited 2018 September 3].

Available from:

https://www.cancer.org/cancer/nasal-cavity-and-paranasal-sinus-cancer/ca

uses-risks-prevention/risk-factors.html.

5. Oralcancerfoundation.org. NCCN Clinical Practice Guidelines in Oncology:

Head and Neck Cancers. 2019. [Internet]. [cited 2018 September 3].

Available from: https://oralcancerfoundation.org/wp-content/

uploads/2016/09/head-and-neck.pdf.

6. Popovic D, Milisavljevic D. Malignant tumors of the maxillary sinus. A

ten-year experience. 2004. [Internet]. [cited 2018 September 3]. Available

from: http://facta.junis.ni.ac.rs/mab/mab200401/mab200401-07.pdf.

7. Capote A, Escorial V, Muñoz-Guerra MF, Rodríguez-Campo FJ, Gamallo C,

Naval L. Elective neck dissection in early-stage oral squamous cell

carcinoma – does it influence recurrence and survival? Head Neck.

2007;29(1):3-11.

8. Park J, Nam W, Kim H, Cha I. Is elective neck dissection needed in

squamous cell carcinoma of maxilla? J Korean Assoc Oral Maxillofac Surg.

2017;43(3):166.

9. Zhang W, Wang Y, Mao C, Guo C, Yu G, Peng X. Cervical metastasis of

maxillary squamous cell carcinoma. Int J Oral Maxillofac Surg.

2015;44(3):285-29.

10. Deschler DG, Moore MG, Smith RV (eds.). Quick Reference Guide to TNM

Staging of Head and Neck Cancer and Neck Dissection Classification (4th

ed.). Alexandria, VA; American Academy of Otolaryngology–Head and

Neck Surgery Foundation, 2014.

case report


Campbell Shaw1


Introduction

Tibiofemoral knee dislocation is a rare and serious

injury that occurs in 0.02-0.1% of all

musculoskeletal injuries.1 Blunt trauma to the

lower extremity is associated with a 28-46% injury

rate to the popliteal artery.2 Ligament instability

and absent pedal pulses (i.e., posterior tibial artery

and dorsalis pedis) are signs of a critical injury

requiring urgent vascular consultation.2 In the case

of a posterior dislocation of the tibia on the femur,

the popliteal artery is particularly susceptible to

trauma as it is anatomically anchored by

landmarks above and below the knee, rendering it

vulnerable to any movement of those points.2 The

femoral artery passes through the tight opening of

the adductor hiatus, between the femur and fascia

of the adductor magnus, to enter the popliteal

fascia and become the popliteal artery. It is at this

transition that the popliteal artery is fixed in place

A case of a knee slip and slide

Abstract

A posterior knee dislocation can present with various complications ranging from simple fractures to

vascular damage requiring immediate medical attention. Compartment syndrome is a potential

serious complication and medical emergency, involving increased pressure within a muscular

compartment that can result in diminished blood flow, compromised nerve conduction, and

impaired muscle function. Discussed here is the case of a 22-year-old female who presented with

popliteal thrombosis and compartment syndrome following a tibiofemoral knee dislocation. The use

of diagnostic imaging, including angiography and magnetic resonance imaging (MRI), is essential to

determine the complications associated with traumatic injuries. Clinical scenarios such as this

highlight the importance of thorough neurovascular assessment in complex orthopaedic injuries.


RCSIsmjcase report

RCSIsmjcase report

and therefore vulnerable to damage if the femur becomes displaced.3

Additionally, as the artery moves towards the foot, it travels in close

proximity to the soleus tendon, anchoring it distally.4

Compartment syndrome is a differential cause of injury to the

popliteal artery, as well as a known complication of knee trauma. As

muscles are organised into fascia-bound compartments around the

thigh, pathologies that raise intracompartmental pressure, such as

oedema due to injury, can lower vascular perfusion. Capillary collapse

occurs when the compartment pressure is raised above the capillary

perfusion pressure, resulting in ischaemia and cellular necrosis.5

Ultimately, compartment syndrome lasting one hour can result in

neuropraxia, the temporary loss of nerve conduction due to

pressure-mediated nerve damage.5

The severity and range of complicationsthat can arise following an injury to

the lower limb highlight the importance ofconsidering neurovascular function

in addition to motor ability in orthopaedicinjuries.

Popliteal aneurysms and pseudoaneurysms are additional causes of

popliteal artery damage. Popliteal aneurysms often occur in the lower

limb following trauma and therefore must be considered in the event

of disrupted perfusion following knee injury.6 Similarly,

pseudoaneurysms result in vessel wall damage with blood contained

within the tunica adventitia.6 Common peroneal neuropathy is a

frequent consequence of popliteal artery pseudoaneurysm as it

compresses the peroneal nerve.7 Patients experiencing peroneal

neuropathy often present with ‘drop foot’ (inability to dorsiflex the

foot) and sensory loss along the lateral side of the lower limb.7

The severity and range of complications that can arise following an

injury to the lower limb highlight the importance of considering

neurovascular function in addition to motor ability in orthopaedic

injuries. This case report presents a 22-year-old female with a

posterior knee dislocation resulting in popliteal thrombosis and

compartment syndrome, emphasising the traumatic neurovascular

effects that can arise due to injury involving the contents of the

popliteal fossa.

Case report

A 22-year-old Caucasian female presented by ambulance to the

emergency department of St. Catharine’s General Hospital in Ontario,

Canada, with sharp pain in her right lower extremity following a water

park accident. The patient reported sliding down a rope swing at a

local water park when her right leg became entangled in the rope. She

twisted due to the catching action of the rope and fell to the platform

directly below. The pain was described as sharp with rapid onset and a

severity of 10/10. There were no associated symptoms and no

exacerbating or relieving factors. Her past medical history was non

contributory and she had no previous surgical history. The patient was

taking the oral contraceptive pill and reported an allergy to amoxicillin.

On examination, the patient was distressed and in severe pain,

although she was conscious and oriented. On inspection of her right

leg, there was an obvious deformity and effusion of the knee.

Regarding her vital signs, the patient was tachycardic; however, her

blood pressure was stable and no signs of shock were appreciated. A

neurological examination of the right lower extremity revealed intact

motor function in the peroneal and tibial nerve distributions. Her right

dorsalis pedis and posterior tibial artery pulses were not palpable, and

her foot was cold in temperature. The patient had extremely limited

range of motion due to pain and swelling.

X-rays on initial admission to the emergency department revealed a

right knee dislocation and tibial plateau fracture (Figure 1). Emergency

FIGURE 1: X-ray of right knee indicating a right posterior knee dislocation of thetibia (distally) on the femur (proximally).


RCSIsmjcase report

room physicians were able to reduce the dislocation under conscious

sedation (Figure 2). While pedal pulses remained absent to palpation,

vascular consultation confirmed their presence by Doppler

ultrasound. Computed tomography (CT) angiography of the right

lower extremity revealed an abrupt disruption of blood flow affecting

the right popliteal artery extending for 5cm distally, and of the right

posterior tibial artery extending for 2.5cm distally (Figure 3). There

was normal blood flow in the anterior tibial and peroneal arteries.

This case report presents a female with aposterior knee dislocation resulting inpopliteal thrombosis and compartmentsyndrome, emphasising the traumatic

neurovascular effects that can arise due toinjury involving the contents of the

popliteal fossa.

The patient was admitted to hospital, prescribed heparin, and observed

overnight. Throughout the evening, she experienced worsening knee

swelling, pain, and paraesthesia. The next morning she was taken to the

operating room for vascular bypass surgery to improve circulation in the

right lower extremity. During surgery, muscular oedema was immediately

apparent upon division of the fascia, indicating compartment syndrome as

a differential cause of the arterial stenosis. Since the muscular

compartments in the leg are separated by non-elastic fascia, injury

resulting in swelling of the muscles cannot be accompanied by a

compensatory increase in volume. Therefore, increased pressure causes

compression of the arteries in that compartment, posing a serious threat

to blood flow. In such conditions, an urgent fasciotomy is performed to

relieve pressure and restore circulation.

In addition to compartment syndrome, an arteriotomy of the popliteal

artery revealed significant intimal injury and thrombus, indicating the

need for a saphenous vein graft. While the anastomosis was successful

in reperfusing the foot, the surgeon was unable to close the incision

medially due to significant muscle oedema. A lateral fasciotomy was

then performed to alleviate the compartment syndrome; however,

closure of that incision was also not possible due to the extent of

oedema. The wound was cleaned and dressed, as closure of the

fasciotomy was to be postponed until she returned to her home town.

FIGURE 3: CT angiogram of the right knee indicating thrombosis of the rightpopliteal artery extending 5cm (right), and of the right posterior tibial arteryextending 2.5cm (left).

FIGURE 2: Anterior x-ray of the right knee showing realignment of the knee joints.


RCSIsmjcase report

In addition to compartment syndrome, an arteriotomy of the

popliteal artery revealed significantintimal injury and thrombus,

indicating the need for a saphenous vein graft. While the anastomosis was successful in reperfusing the foot, the surgeon was unable to

close the incision medially due to significantmuscle oedema.

The following day, postoperative magnetic resonance imagining

(MRI) of the right knee confirmed the diagnosis of a complete

posterior cruciate ligament (PCL) tear and a radial tear of the

medial meniscus. The anterior cruciate ligament (ACL) was

intact. Additionally, an osteochondral impaction injury to the

anterior aspect of the lateral tibial plateau was discovered. It

was determined that the cause of compartment syndrome in this

case was a large knee joint effusion with extensive inter- and

intramuscular oedema (Figure 4).

For the following five days, the patient was placed in a knee

immobiliser and was observed in hospital for infection and

ischaemia. On orthopaedic follow-up examination, the dorsalis

pedis pulse was palpable; however, the posterior tibial pulse was

absent, likely due to extensive swelling.

The patient’s foot appeared warm and well perfused. On motor

examination, the patient was able to flex and extend her toes and

ankle. Light touch sensation was intact in the superficial peroneal,

deep peroneal, and tibial nerve distributions. The following

morning, after nine days of hospital admission, the patient was

transferred and repatriated to her home town.

At this time, she was fitted for a hinged knee brace (Figure 5) and

would still require PCL and medial meniscal surgery, closure of her

fasciotomy, and subsequent orthopaedic rehabilitation. To close the

open fasciotomy, a skin graft was crafted in theatre and placed over

the open wound.

The fasciotomy would then heal naturally as her leg was stabilised

within the brace.

FIGURE 4: Postoperative MRI of the right knee showing extensive effusion andmuscular oedema.

FIGURE 5: Hinged knee brace to stabilise the right knee joint.


RCSIsmjcase report

Discussion

This case describes a traumatic orthopaedic injury that resulted in

compartment syndrome, emphasising the level of severity that can

accompany a simple knee dislocation. It is evident that detailed

anatomical knowledge is necessary in order to consider and decipher

the full range of complications that could arise from a joint

dislocation. Diagnosis of such complications requires proper history

taking and physical examination, as well as numerous imaging

modalities, including angiograms to identify thrombosis, and x-rays

and MRIs to diagnose fractures and ligament tears.

Compartment syndrome was first detected in this patient by the

presence of muscular oedema during surgery. Subsequently, a

postoperative MRI was ordered to monitor the swelling. As swelling

within lower limb compartments can cause serious neurovascular

injury, early diagnosis is essential to prevent limb ischaemia and

long-term damage.8 Acute compartment syndrome is a medical

emergency and requires immediate fasciotomies to relieve pressure

within the muscular compartment.8 Indeed, this patient required both

a lateral and medial fasciotomy due to the extent of muscle oedema.

Conclusion

This case highlights the numerous possible complications of a

posterior knee dislocation. Extensive damage to surrounding

structures, including the popliteal artery, cruciate and collateral

ligaments, and the tibial plateau was discovered following further

diagnostic tests. Urgent vascular surgery was required to restore

normal blood flow to the lower limb. Due to extensive muscular

swelling, fasciotomies were performed to reduce intracompartmental

pressure. The patient was stabilised in a knee brace and sent home for

a future PCL and MCL corrective operation as well as fasciotomy

closure. This case emphasises the importance of neurovascular

assessment following traumatic orthopaedic injuries, as damage

within the popliteal fossa can have significant and emergent distal

implications.

References

1. Bakia J, Tordoir J, Heurn E. Traumatic dissection and thrombosis

of the popliteal artery in a child. J Pediatr Surg. 2012;47(6):1299-301.

2. Godfrey AD, Hindi F, Ettles C, Pemberton M, Grewal P. Acute thrombotic

occlusion of the popliteal artery following knee dislocation: a case report

of management, local unit practice, and a review of the literature. Case

Rep Surg. 2017;2017:5346457.

3. Philippose S, Jacinth JS, Muniappan V. The anatomical study of popliteal

artery and its variations. Int J Anat Res. 2017;5(4.3):4679-85.

4. Parker S, Handa A, Deakin M, Sides E. Knee dislocation and vascular

injury: 4 year experience at a UK major trauma centre and vascular hub.

Injury. 2016;47(3):752-6.

5. Cone J, Inaba K. Lower extremity compartment syndrome. Trauma

Surgery & Acute Care Open. 2017;2(1):e000094.

6. Corriere MA, Guzman RJ. True and false aneurysms of the femoral artery.

Semin Vasc Surg. 2005;18(4):216-23.

7. Ersozlu S, Ozulku M, Yildirim E, Tandogan R. Common peroneal nerve

palsy from an untreated popliteal pseudoaneurysm after penetrating

injury. J Vasc Surg. 2007;45(2):408-10.

8. Reverte MM, Dimitriou R, Kanakaris NK, Giannoudis PV. What is the

effect of compartment syndrome and fasciotomies on fracture healing in

tibial fractures? Injury. 2011;42(12):1402-7.



book review

The Inflamed Mind:

A radical new approach to depression

Edward Bullmore

Hardcover: 224 pages

Publisher: Short Books Ltd

Published: 2018

ISBN-13: 978-1780723501

Depression is a prevalent mood disorder that spans all age groups and

is estimated to affect nearly 300 million people worldwide. The

mainstay of treatment involves a combination of cognitive therapies

and antidepressant medications. These antidepressant drugs act to

modulate neurotransmitters in the brain and, in turn, regulate mood

and emotion. While the triggers of depression are often varied and

unique, much of its management has focused on a few antidepressant

medications, which can have mixed results in different patient

populations.

The Inflamed Mind describes a chronological timeline in the history of depression, from its

early description as melancholia in 400BC, to the discovery of Prozac

(fluoxetine) in the 1980s.

An evolving field

Research in the field of depression and other mental health disorders is

evolving, and studies are focusing on new theories of disease progression

and novel treatment paradigms. One such researcher is Prof. Edward

Bullmore, a psychiatrist who published The Inflamed Mind in 2018 to

introduce a new theory about the links between inflammation and

depression. Prof. Bullmore’s research incorporates immunology,

neuroimmunology, and psychiatry to suggest that infection and

inflammation in the body and brain can result in depression.

The case that sparked his interest occurred early in his career, when

he met Mrs P, a middle-aged lady with severe rheumatoid arthritis.

During her consultation and through careful questioning he was able

to determine that she was also depressed. While his superiors posited

that Mrs P was depressed because she knew she was suffering with a

chronic inflammatory disorder, Prof. Bullmore, at the time only a

trainee physician, wondered if her inflammatory state was in fact the

cause of Mrs P’s depression.

Bullmore’s research incorporatesimmunology, neuroimmunology, and

psychiatry to suggest that infection andinflammation in the body and brain can

result in depression.

Focus on inflammation

Research is moving away from the older model of depression, which

focused primarily on the role of serotonin regulation. New evidence

shows that the blood–brain barrier (BBB) is more penetrable than

initially thought. In times of stress and inflammation, cytokines can

cross the BBB and induce microglia activation in the brain, which

damages neurons in the amygdala and cingulate gyrus. This model of

depression opens up many new avenues and routes of exploration

into causes, effects, and treatment of depression.

The Inflamed Mind describes a chronological timeline in the history of

depression, from its early description as melancholia in 400BC, to the

discovery of Prozac (fluoxetine) in the 1980s. Prof. Bullmore’s

approach is methodical and well explained even for those who may

not understand all the minutiae and facets of immunology. He

examines the pharmaceutical industry’s hesitation about pursuing

development of new treatments, and discusses the emerging field of

independent research. The Inflamed Mind is an engaging, informative,

and accessible read for students, healthcare providers, and non-clinical

individuals alike who share a curiosity about the history and treatment

of one of this century’s most prevalent disorders.

An inflammatory theory of depression?

RCSIsmj

In The Inflamed Mind, Edward Bullmore presents a new theory about

possible links between inflammation and depression,

says Senior Staff Writer KATIE NOLAN.

Mary Tien-Yi Wang1

Rebecca Chow2

Alanna Crawford1

Quincy Almeida2

1RCSI medical students

2Wilfrid Laurier University,

Waterloo Ontario

Can proprioception influencegait abnormalities inParkinson’s disease?

Abstract

Freezing of gait (FOG), clinically defined as the transient inability to move one’s feet off the ground,

is a symptom of Parkinson’s disease (PD) associated with changes to gait parameters. Since

proprioception is impaired in PD, relying on proprioception alone to guide locomotion, when

walking in the dark for example, may lead to greater gait impairments such as FOG and gait

variability. To date, no study has demonstrated whether differences in the accuracy of proprioception

in participants who experience FOG (‘freezers’) can influence gait impairment when walking in the

dark. This study aimed to identify a correlation between the degree of proprioception impairment

and frequency of freezing episodes to determine whether improving proprioception could improve

FOG. In this study, freezers performed walking trials in both dark and lit conditions. FOG severity,

step variability, and proprioception (joint position matching of the upper limbs) were measured.

Participants were divided into two groups, classified as either ‘high’ or ‘low’ proprioception error,

using a median split of error scores on the joint position matching task. High error and low error

groups were not significantly different in step time variability, FOG episode duration, or FOG

frequency in dark walking trials. However, there was a significant group by condition interaction

effect (p=0.02). This suggests that having better proprioception can mitigate the effects of a

proprioceptive processing challenge while walking, which may have clinical applications in PD.


RCSIsmjoriginal article




Introduction

Freezing of gait (FOG) is a common and debilitating symptom of

Parkinson’s disease (PD).1 FOG is clinically defined as a transient period

during which an individual feels that their feet are “stuck to the

ground”.2 Those who experience FOG also tend to have increased gait

variability, measured by step time (ST) and step length (SL) variability

during periods of walking when FOG is absent.3 Gait variability

parameters have also been independently associated with FOG and an

increased fall risk in older adults.4,5,6 Additionally, FOG can lead to

impaired mobility, which may result in adverse consequences such as

fractures and other injuries.7 Investigating step variability parameters is

thus important when studying freezing in patients with PD.

The pathophysiology of FOG is not fully understood. Unlike

bradykinesia, tremor, rigidity, and postural instability, FOG is relatively

resistant to improvement with dopaminergic therapy.8 This suggests

that the pathophysiology underlying this feature of PD is distinct from

the dopaminergic pathway deficits that are known to cause

bradykinesia, tremor, rigidity, and postural instability. One proposed

mechanism is that impairments in sensorimotor integration cause an

increased processing demand on the sensorimotor loop of the basal

ganglia, which produces routine and automatic movements, thus

depleting processing resources necessary for motor output.8 It has been

argued that a deficit in proprioception underlies the impairments in

sensorimotor processing in individuals with PD.9

A previous study investigated this by asking patients with PD who

experience FOG (commonly referred to as ‘freezers’ in current research)

to walk in the dark and thus rely primarily on proprioception to guide

walking.10 Freezers demonstrated a greater number of FOG episodes

when walking in complete darkness, compared to well-lit settings

when visual information about their limbs or an external reference

point was available.

This suggests that when such patients are forced to rely solely on this

distorted proprioceptive feedback without compensatory visual

feedback, sensorimotor processing challenges arise. It is this

impairment in processing that leads to FOG.10 However, it remains

unclear whether differences in FOG severity and step variability in dark

walking conditions are related to differences in proprioceptive

accuracy, a parameter that was not evaluated in the previous study.

The present study investigated the relationship between proprioceptive

accuracy and performance in walking trials in both lit and dark

conditions, by measuring FOG severity (determined by FOG frequency

and duration) and step variability (measured by SL and ST variability).

It was hypothesised that participants with poor proprioception would

experience more negative impacts on gait parameters in dark walking

conditions compared to those with accurate proprioception.

Materials and methods

Ethics approval was obtained from the Wilfrid Laurier University

Research Ethics Board and all patients provided written consent prior to

study participation. Participants with PD (n=18) who experienced FOG

were recruited from the Wilfrid Laurier University Movement Disorders

Research and Rehabilitation Centre database. Participants underwent

proprioception testing, walking trials, and assessments on the Unified

Parkinson’s Disease Rating Scale (UPDRS III) as conducted by a

movement disorder specialist.11

Montreal Cognitive Assessment

Participants’ cognition was assessed using the Montreal Cognitive

Assessment (MoCA).12 The MoCA involves a series of tasks that are

graded out of 30, with higher scores indicating better cognitive

function. This test has been validated for use in PD.12 All participants

were included regardless of MoCA score. There was no significant

difference in MoCA score between groups. No participants were unable

to complete tasks due to deficits in cognition or ability to understand

instructions.

Proprioception and group allocation

Proprioception was measured using a passive contralateral joint position

matching (JPM) task.13 Participants were seated with their forearms fixed

on two rotating platforms such that both elbow joints were resting at a

90º angle. Visual and auditory feedback were eliminated using a blindfold

and noise-cancelling headphones. Participants then had one arm passively

rotated laterally at the elbow joint to one of three positions: 10º, 30º, or

60º from the starting position. The contralateral arm was moved next in

the same fashion, and participants were instructed to notify the researcher

when they believed the angle of both elbow joints was equal. Absolute

and relative error were recorded for three trials of each of the three angle

conditions for both upper limbs. Participants’ overall proprioception error

scores were calculated by summing the absolute error from all of their 18

trials. The participants were then divided into two groups, either ‘accurate

proprioception’ (low error) or ‘poor proprioception’ (high error) through

a median split. The participant on the median score was randomly

assigned to the high error group.

Walking trials

Participants performed three walking trials of approximately 9.75m

in two walking conditions: well lit and dark. Participants were asked

to walk in a straight path that was 0.3m wide. The dark condition

was intended to induce a challenge to the sensorimotor system (SMS),

as participants would be forced to use primarily SMS feedback without

visual information to compensate.


Eight OptiTrack13 cameras were used to record the frequency and

duration of FOG episodes during walking trials, as well as SL and ST

variability. Infrared light-emitting diodes (IREDs) were placed over

each participant’s xiphoid process, tibial tuberosities, lateral malleoli,

and fifth metatarsals.

FOG episodes were defined as “any period where the centre of mass

velocity measured by the IRED on the xiphoid process dropped below

10% of the participant’s baseline” velocity.2 This definition allowed for

the inclusion of freezing episodes that present as a pronounced

festinating gait rather than a complete cessation of lower limb

movement.

Results

Proprioception and group allocation

Participants were divided into high proprioception error and low

proprioception error groups (see Table 1). Mean proprioception score

was significantly different between the two groups (low error group

92.9 ± 17.7; high error group 284.3 ± 209.6; p<0.05).

Independent t-tests were performed to determine whether any

significant differences in demographic characteristics existed between

the two groups.

There were no significant differences in terms of mean age

(p=0.192), mean UPDRS III score (p=0.093), or mean MoCA score

(p=0.147).

FOG results from dark condition walking trials

The frequency and duration of FOG episodes were analysed in only

the dark condition, since no FOG episodes occurred in the lit

condition. Independent sample t -tests were performed between

the high and low proprioceptive error groups and found no

significant difference in mean FOG frequency (p=0.28) or duration

(p=0.24). However, both mean FOG frequency and duration were

higher in the high error group compared to the low error group

(see Table 2).

Step time variability

A mixed repeated-measures ANOVA was performed to determine

differences between groups, conditions (dark vs lit), and trials for

mean ST variability. There was only a significant effect of condition

(dark vs light) on gait parameter outcomes (p=0.018). There was no

significant difference between the high and low error groups with

respect to ST variability (see Figure 1).

Table 1: Group demographics.

Group Gender Mean age UPDRS Mean MoCA Proprioception

(M:F) III Score score error score

High error 7:2 74.6 ± 8.98 29.2 ± 8.98 22.1 ± 5.16 284.3 ± 209.55(n = 9)

Low error 6:3 69.7 ± 9.37 22.3 ± 7.26 25.2 ± 3.31 92.9 ± 17.66(n = 9)

Table 2: Frequency and duration of FOG episodes duringdark walking trials.

Results High error group Low error group

Mean number x = 1.2 episodes x = 0.44 episodesof FOG episodes (p = 0.28) Mean FOG duration x = 389.2 seconds x = 146.7 (p = 0.24)

seconds

FIGURE 1: Step time (ST) variability in light and dark conditions in high and lowproprioception error groups, by trial.

100

80

60

40

20

0

-20

-40

Trial: 1 Trial: 2

DV_1

CONDITIO*TRIAL*PROP_ERROR; LS MeansCurrent effect: F(2, 20) = 1.1621, p = 0.33306

Effective hypothesis decompositionVertical bars denote 0.95 confidence intervals

Trial: 3

PROP_ERRO

R:

LOW

HIGH

PROP_ERRO

R:

LOW

HIGH

PROP_ERRO

R:

LOW

HIGH

CONDITIO 1

CONDITIO 2




Step length variability

A mixed repeated-measures ANOVA was performed to determine

differences between groups, conditions (dark vs lit), and trials for the mean

SL variability (see Figure 2). The high error group had significantly higher

SL variability compared to the low error group in all trials and conditions

(p=0.039). There was a significantly greater SL variability in the dark

condition in all trials and groups compared to the lit condition (p<0.001).

There was also a significant interaction effect, i.e., group by condition

(p=0.02) (see Figure 3). The high error group had significantly greater SL

variability in dark compared to well-lit conditions, while the low error

group did not demonstrate changes between light and dark conditions.

Discussion

This study aimed to investigate whether differences in proprioceptive

accuracy among those with PD could influence walking performance in

conditions that increase one’s dependency on proprioceptive feedback,

thus challenging sensorimotor processing. Overall, the findings are in

line with this study’s hypothesis, and suggest that the degree of

proprioceptive accuracy in individuals with PD influences FOG and gait

behaviour in a proprioceptive processing challenge. Although there

was a lack of a significant difference in FOG outcomes between high

and low error groups, this could be explained by the small number of

FOG episodes captured in total, or by the small sample size. Higher

FOG frequency and duration were observed in the high error group,

which supports this assumption despite the findings not achieving

statistical significance. However, it could also be argued that

proprioceptive accuracy does not impact FOG outcome measures in

these conditions due to the lack of significance. Ultimately, repeat

studies with a larger sample size are required.

Nevertheless, proprioceptive ability did have a significant impact on SL

variability when the proprioceptive processing challenge was introduced.

Those with accurate proprioception (low error group) were less impacted

by the challenge posed by the dark environment and exhibited a

negligible decline in gait control. This group also had significantly less SL

variability than those with poor proprioception (high error group) in dark

conditions. This supports the hypothesis that an individual’s

proprioceptive ability can influence the degree to which freezing and gait

behaviour change under proprioceptive processing challenges.

SL variability has been shown to be a better indicator of gait

impairment in freezers than ST variability, although both parameters

are measures of automaticity in gait.14,15 It is known that freezers

attempt to control SL to enable gait adjustments, often using visual

cues and landmarks in their environment to guide their movement.9 SL

can be consciously controlled in order to reduce freezing behaviour

severity, and hence SL variability is theorised to be a superior indicator

of gait quality in patients who experience freezing compared to ST

variability.16 Previous work has shown ST variability in freezers to be less

correlated with gait impairments than SL variability.14 The

non-significant differences between groups for ST variability could be

due to the lower relevance that this measure has to freezing of gait.

Limitations

The study’s sample size was small due to the low prevalence of PD

freezers. This could be the reason for a lack of significant differences

FIGURE 2: Step length (SL) variability in light and dark conditions in high and lowproprioception error groups, by trial.

FIGURE 3: Interaction effect of proprioceptive ability by walking condition on SLvariability.

120

100

80

60

40

20

0

-20

Trial: 1 Trial: 2

DV_1

CONDITIO*TRIAL*PROP_ERROR; LS MeansCurrent effect: F(2,20) = 0.99366, p = 0.38777


Trial: 3

PROP_ERRO

R:

LOW

HIGH

PROP_ERRO

R:

LOW

HIGH

PROP_ERRO

R:

LOW

HIGH

CONDITIO 1

CONDITIO 2

90

80

70

60

50

40

30

20

10

0

-10

-20

Conditio

DV_1

CONDITIO*PROP_ERROR; LS MeansCurrent effect: F(1,10) = 7.6260, p = 0.02008


Prop error low

Prop error high

1 2


References

1. Stuart S, Lord S, Hill E, Rochester L. Gait in Parkinson’s disease: a

visuo-cognitive challenge. Neurosci Biobehav Rev. 2016;62:76-88.

2. Cowie D, Limousin P, Peters A, Hariz M, Day BL. Doorway-provoked

freezing of gait in Parkinson’s disease. Mov Disord. 2012;27(4):492-9.

3. Nieuwboer A, Giladi N. Characterizing freezing of gait in Parkinson’s disease:

models of an episodic phenomenon. Mov Disord. 2013;28(11):1509-19.

4. Bloem BR, Hausdorff JM, Visser JE, Giladi N. Falls and freezing of gait in

Parkinson’s disease: a review of two interconnected, episodic phenomena.

Mov Disord. 2004;19(8):871-84.

5. Mortaza N, Abu Osman NA, Mehdikhani N. Are the spatio-temporal

parameters of gait capable of distinguishing a faller from a non-faller

elderly? Eur J Phys Rehabil Med. 2014;50(6):677-91.

6. Hausdorff JM. Gait variability: methods, modeling and meaning. J

Neuroengin Rehabil. 2005;2:19.

7. Okuma Y. Freezing of gait and falls in Parkinson’s disease. J Parkinsons Dis.

2014;4(2):255-60.

8. Lewis SJ, Barker RA. A pathophysiological model of freezing of gait in

Parkinson’s disease. Parkinsonism Relat Disord. 2009;15(5):333-8.

9. Almeida QJ, Frank JS, Roy EA, Jenkins ME, Spaulding S, Patla AE et al. An

evaluation of sensorimotor integration during locomotion toward a target

in Parkinson’s disease. Neuroscience. 2005;134(1):283-93.

10. Ehgoetz Martens KA, Pieruccini-Faria F, Almeida QJ. Could sensory

mechanisms be a core factor that underlies freezing of gait in Parkinson’s

disease? PloS One. 2013;8(5):e62602.

11. Fahn S, Mardsen CD, Jenner P, Teychenne P (eds.). Recent Developments

in Parkinson’s disease. New York; Raven Press, 1986:375pp,.

12. Gill DJ, Freshman A, Blender JA, Ravina B. The Montreal Cognitive

Assessment as a screening tool for cognitive impairment in Parkinson’s

disease. Mov Disord. 2008;23(7):1043-6.

13. Measurement Sciences. Optotrak Certus – Measurement Sciences. 2019.

[Internet]. [Accessed 2019 January 22]. Available at:

https://www.ndigital.com/msci/products/optotrak-certus/.

14. Lebold CA, Almeida QJ. Evaluating the contributions of dynamic flow to

freezing of gait in Parkinson’s disease. Parkinsons Dis. 2010;2010:732508.

15. Gabell A, Nayak US. The effect of age on variability in gait. J Gerontol.

1984;39(6):662-6.

16. Han J, Waddington G, Adams R, Anson J, Liu Y. Assessing proprioception: a

critical review of methods. J Sport Health Sci. 2016;5(1):80-90.

17. Tan T, Almeida QJ, Rahimi F. Proprioceptive deficits in Parkinson’s disease

patients with freezing of gait. Neuroscience. 2011;192:746-52.


between the high and low error groups in terms of FOG duration and

frequency. Another limitation is that only one method was used to

assess proprioception, and proprioception was only measured in one

joint. Participants’ scores on JPM for forearm positioning were

assumed to be indicative of the person’s overall proprioceptive

accuracy. Other methods for measuring proprioception exist, which

have higher validity and conceptual purity.16 However, JPM has

the benefit of being easy to perform and interpret (little equipment

or tester expertise is required to run JPM testing). Ideally,

other proprioception testing methods could have been used, and

multiple joints, especially joints of the lower limbs, could have been

tested. The degree of degradation in proprioceptive ability in PD

could vary across different joints, so measuring proprioceptive ability

in a single joint may not have been indicative of total body

proprioception.17

The study could also have benefited from the inclusion of healthy

age-matched controls in order to provide a gauge against which to

measure the high and low error groups’ proprioception. This would

have indicated each groups’ proprioceptive accuracy relative to ‘normal’

levels.

Conclusion

This information has great clinical significance for devising

novel treatment strategies that can ameliorate FOG behaviours.

FOG is relatively resistant to common PD treatments, such as

dopaminergic therapy, and warrants further research.8 This lack of

dopaminergic response causes FOG to be a significant contributor

to morbidity and mortality, even in patients who are on

appropriate pharmacological therapy with clinical improvement. Thus,

there exists the potential to improve quality of life in those who

experience FOG if other treatment modalities can be found to decrease

FOG episodes. The results of this study suggest that proprioception

may contribute to FOG behaviour and to other gait impairments.

Further research is needed to expand on these clinical findings. Certain

training programmes have demonstrated an improvement in

proprioception and could therefore potentially improve FOG and gait

abnormalities. This would greatly improve PD patient safety through

reducing the risk and occurrence of falls.7 The findings of this study

could be complemented by further research examining whether

improvements in proprioception among PD patients can decrease FOG

behaviour.

Caitlin Gibson1,2

Vera Dounaevskaia3

Sandra de Montbrun4

Ori Rotstein2,4


2Keenan Research Centre for

Biomedical Science, Li Ka Shing

Knowledge Institute, St. Michael’s

Hospital, Toronto, Ontario,

Canada

3Department of Medicine,

Thromboembolism, University of

Toronto, Toronto, Ontario,

Canada

4Department of Surgery,

University of Toronto, Toronto,

Ontario, Canada

Post-discharge decisions:prolonged VTE prophylaxis forcolorectal cancer surgery

Abstract

The connection between venous thromboembolism (VTE) and cancer was first described in the

1860s by Armand Trousseau. Postoperative VTE remains one of the leading complications and causes

of mortality in patients undergoing surgery for colorectal cancer. While there is evidence that

continuation of VTE prophylaxis beyond the hospital stay can reduce overall VTE incidence in select

groups of surgical patients, local hospital guidelines for prescribing post-discharge prophylactic

medication to prevent VTE vary. Current guidelines from the American College of Chest Physicians

(ACCP) recommend 30-day postoperative thromboprophylaxis for cancer patients undergoing major

abdominal or pelvic surgery.

This project aimed to develop an evidence-based protocol for post-discharge VTE prophylaxis in

colorectal cancer patients undergoing surgical resection at St. Michael’s Hospital, Toronto. The project

consisted of a literature review to define the indications for post-discharge VTE prophylaxis, a chart

review of 100 patients with colorectal cancer undergoing colorectal surgery to determine compliance

with best practice, and possible implementation of a new thromboprophylaxis protocol. After review

of the 100 cases, 21 cases were excluded as the patients did not have a laparotomy or laparoscopic

procedure, or were on anticoagulation therapy at time of/during admission. Only two of the 79

remaining patients (2.53%) were prescribed post-discharge thromboprophylaxis. This demonstrates a

gap in the use of recommended guidelines for VTE prevention in cases of colorectal cancer resection.

A protocol for implementing post-discharge VTE prophylaxis in cancer patients undergoing colorectal

surgery at St. Michael’s Hospital, Toronto, was developed and will be discussed.






Introduction

Venous thromboembolism (VTE) presents as a major complication for

patients with malignancy, especially those undergoing invasive

surgery.1 The @RISTOS project demonstrated that 40% of VTE events

occurred after 21 days postoperatively, highlighting that the risk of an

event remains elevated long after a typical postoperative hospital

stay.2 Despite continued evidence that cancer patients undergoing

major operations are at high risk for VTE, prevention with

pharmacological thromboprophylaxis is still largely underutilised.3

Possible explanations for this trend include shorter hospital stays,

earlier mobilisation of patients, and improved surgical techniques.2

Additionally, patients undergoing laparoscopic procedures, or those

without complications following surgery, are usually discharged

quickly and may not stay in hospital to receive the minimum seven to

ten days of postoperative prophylaxis.

The risk of a VTE event increases depending on the presence of other

comorbidities, patient age, type of operation, duration of surgery,

chemotherapy treatment, and other patient-, cancer-, and

treatment-related factors.4 The interrelatedness of these factors allows

patients to be divided into low-, moderate-, higher-, and high-risk

groups.5 Individuals with colorectal cancer undergoing resection

surgery are categorised as high risk for VTE events, for which the

current guidelines have recommended extended thromboprophylaxis

use.5 This patient population is deemed high risk due to the presence

of malignancy, a prothrombotic condition, as well as the longer

duration of major abdominal surgery. It has also been suggested that

extended VTE prophylaxis for 30 days postoperatively may replace

the traditional seven to ten days’ postoperative thromboprophylaxis

protocol as the new standard of care in patients undergoing major

abdominal surgery.1,6,7

The risk of a VTE event increases depending on the

presence of other comorbidities, patient age, type of operation, duration

of surgery, chemotherapy treatment, and other patient-, cancer-, and

treatment-related factors.

The underutilisation of these guidelines demonstrates a gap between

current research and clinical practice. There is a clear need for quality

communication and adjustments to be made in order to provide the

safest and most effective treatment to these vulnerable patients. The

purpose of this work was to identify best practice in this field, to

quantify the frequency of post-discharge prophylaxis in patients with

colorectal cancer who underwent surgery in a single institution, to

identify gaps relative to accepted guidelines, and to suggest

implementation of a new approach to lessen these gaps.

FIGURE 1: Consort Flow diagram.

100 colorectal cancer surgeryresection patients betweenAugust 2017 and April 2018

85 eligible patients:• 35 Laparotomy• 50 Laparoscopy

6 patients excluded

79 eligible patientsincluded in final analysis

15 patients excluded:8 colonoscopy only

3 EUA only3 trans-anal only1 exploratory only

Not eligible for post-discharge prophylaxis because:

• 5 continued anticoagulation therapy prescribed prior to admission(for prior VTE or pre-existing prothrombotic mutation)

• 1 had VTE postoperatively while still in hospital – discharged on therapeutic anticoagulation



Table 1: Literature review.

Type of study Study title Results

RCT Duration of prophylaxis against venous 28/332 had postoperative VTE thromboembolism with enoxaparin after • 12% incidence in placebo group (20/167) surgery for cancer1 • 4.8% incidence in enoxaparin group (8/165) Absolute RR of 7.2% Conclusion: use enoxaparin for 4 weeks postoperatively

RCT A randomised study on one-week versus 11/225 had postoperative VTE during four-week prophylaxis for venous randomisation period thromboembolism after laparoscopic • 11/113 VTE in short treatment group surgery for colorectal cancer6 • 0/112 VTE in extended treatment group Extended follow-up: • 1 VTE in extended treatment group-confirmed VTE Conclusion: prolonged treatment is preferential when compared to short-duration treatment

RCT Prolonged prophylaxis with dalteparin to Cumulative VTE incidence between 7 and 28 days was: prevent late thromboembolic complications • 16.3% in short-term treatment in patients undergoing major abdominal surgery: • 7.3% in long-term treatment a multicentre randomised open-label study7 Prolonged treatment was shown to have a significant effect at reducing VTE without increasing bleeding risk

RCT Extended prophylaxis with bemiparin for Primary efficacy outcome (DVT, non-fatal PE, and the prevention of venous all-cause mortality) at end of double-blind period: thromboembolism after abdominal or • 25 (10.1%) in bemiparin group pelvic surgery for cancer: the • 32 (13.3%) in placebo group CANBESURE randomised study8 not statistically significant Major VTE: • 2 in bemiparin group • 11 in placebo group statistically significant: P = 0.010 Conclusion: “Prolonging LMWH up to 4 weeks in patients undergoing major abdominal and/or pelvic surgery is associated with a favorable benefit-to-risk ratio”8 without increasing the risk of bleeding Guideline American Society of Clinical Oncology – Patients undergoing cancer surgery should receive ASCO4 (2015) (updated) prophylaxis before surgery and continuing for at least 7-10 days • Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features

Guideline International Clinical Practice LMWH qd or low dose UFH TID Guidelines3 (2012) • Commence 2-12 hours preoperatively and continue for at least 7-10 days postoperatively • Extended prophylaxis of 4 weeks to prevent postoperative VTE after major laparotomy/ laparoscopy in cancer patients may be indicated with high VTE risk and low bleeding risk

Guideline European Society of Medical Oncology – Enoxaparin 4,000U or dalteparin 5,000U or UFH ESMO9 (2011) 5,000U for at least 10 days postoperatively for surgery >30 minutes Guideline American College of Chest Physicians – “For high-risk patients undergoing abdominal or ACCP 9th edition5 (2012) pelvic surgery for cancer who are not otherwise at high risk for major bleeding complications, we recommend extended-duration pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis”



Methods

A literature review of relevant background material and current

guidelines was initially performed. Subsequently, a chart review of

100 patients from St. Michael’s Hospital, Toronto, was conducted and

analysed. Analysis of both the articles and charts led to the proposal

of a novel protocol for post-discharge thromboprophylaxis in patients

with colorectal cancer undergoing surgical resection.

Literature review

PubMed and Google Scholar were used to conduct the literature review.

The following keywords were included in the search:

thromboprophylaxis, colorectal, cancer, venous thromboembolism,

guidelines, and duration. The following types of studies were utilised:

four randomised controlled trials (RCTs); four existing guidelines; and

three cohort studies.

Patient chart review

Medical charts of 100 patients with colorectal cancer undergoing

surgery from August 2017 to April 2018 at St. Michael’s Hospital,

Toronto, were obtained and subjected to review. Patient records were

stored in Soarian Clinicals and Sovera databases. Information was

collected by analysing pathology reports, consultation notes, operative

summaries, discharge letters, operating room records, anaesthesia

records, and electronic medication administration records. Patients

were excluded if the operation was exploratory, trans-anal, or

colonoscopy only. All laparotomy and laparoscopy surgeries for

confirmed colon or rectal cancer were included (Figure 1).

Results

Literature review

The literature review revealed a favourable benefit-to-risk ratio when

patients were prescribed extended thromboprophylaxis after

undergoing surgery for abdominal and/or pelvic cancer in the four

RCTs reviewed. The current guidelines recommend a minimum of

seven to ten days of postoperative thromboprophylaxis, or a total

duration of four weeks unless otherwise contraindicated. The cohort

studies summarised in Table 1 revealed an overall rate of 2.0-2.83%

VTE events, which is closely related to the rate of 3.8% found in this

Cohort Risk of Post-Discharge Venous Comparison of 90-day in-hospital VTE, 90-day Thromboembolism and Associated post-discharge VTE, and 90-day mortality Mortality in General Surgery: A • “Major organ resections had the greatest Population-Based Cohort Study Using odds of VTE”10

Linked Hospital and Primary Care Data • Post-discharge VTE accounted for 64.8% of all in England10 recorded VTE (hospital and primary care databases) – 35.2% were in-hospital. • Overall VTE rate for colorectal cancer resection = 2.11% (55.5% post discharge)

Cohort A Clinical Outcome-Based Prospective Incidence of clinically overt VTE within 30 ±5 days Study on Venous Thromboembolism postoperatively in patients undergoing cancer surgery (or longer if longer hospital stay) After Cancer Surgery – • 2.83% of general surgery patients developed The @RISTOS Project2 postoperative VTE • 40% of all studied VTE events occurred after 21 days postoperatively • The colon was the second most common site of primary tumour with the third highest incidence of VTE Thromboembolism was the most common cause of death in this cohort

Cohort Timing and Perioperative Risk Factors 2% of patients developed a VTE within 30 days for In-Hospital and Post-Discharge (0.6% post-discharge) Venous Thromboembolism After Median time to diagnosis of VTE was 9 days Colorectal Cancer Resection11 post-operatively or 9 days from day of discharge UFH: unfractionated heparinLMWH: low-molecular-weight heparinDVT: deep vein thrombosisPE: pulmonary embolismTID = three times daily qd = four times daily

Type of study Study title Results

Table 1: Literature review (continued).

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study. Overall, the literature supported the aim of this study, and

showed resemblance to the findings within the St. Michael’s cohort.

Of note, the RCTs used venography to detect VTE events and thus

asymptomatic cases were also detected.

St. Michael’s Hospital chart review

A total of 100 charts were reviewed and, of these, 21 were excluded.

Fifteen patients were excluded because they did not undergo a

laparotomy or laparoscopic procedure and thus the risk of VTE was

unknown. There were six patients on anticoagulation therapy during

their admission, five of whom were admitted on anticoagulation

therapy for a pre-existing condition, and one who had a VTE event

during the index admission. This rendered these individuals ineligible

for thromboprophylaxis as they were receiving therapeutic doses.

The purpose of this work was to identify best practice in this field, to

quantify the frequency of post-dischargeprophylaxis in patients with colorectalcancer who underwent surgery in a single institution, to identify gaps

relative to accepted guidelines, and tosuggest implementation of a newapproach to lessen these gaps.

Table 2: Post-discharge VTE prophylaxis.

Yes No

Received post-discharge prophylaxis 2 77

Length of stay (days)

Patient 1 18

Patient 2 74

Average 46 8.31

Of the 79 patients analysed, two were prescribed dalteparin 5,000U

subcutaneously (SC) once nightly for post-discharge prophylaxis

(2.53%) (Table 2). The orders for dalteparin 5,000U were written on

the discharge summary, but an additional note stating “prescription

not given” was included with the orders and the duration of

prophylaxis was not specified. It is unclear whether these patients had

already filled the prescription or whether the patient never received

the prescription upon discharge. The reason for extended-duration

thromboprophylaxis for these two patients was not specified in the

medication order or in the documents reviewed.

Table 3: Post-discharge VTE events.

Received post-discharge prophylaxis

Yes No

Developed Yes 0/2 3/77

post-discharge VTE No 2/2 74/77

Additionally, three of the 79 patients (3.8%) suffered a

post-discharge VTE event (Table 3). These cases were discharged

without extended thromboprophylaxis and suffered a postoperative

event within 7, 13, and 50 days after the index operation. These

events occurred at 1, 6, and 25 days post discharge, respectively

(Table 4). The increased rate of VTE in patients not receiving

post-discharge prophylaxis was not significantly different from those

that did, but agrees with current research that the risk of VTE remains

elevated after discharge from hospital in those undergoing colorectal

cancer resection.

Analysis of both the articles and chartslead to the proposal of a novel protocolfor post-discharge thromboprophylaxis

in patients with colorectal cancerundergoing surgical resection.

Table 4: Length of stay and VTE presentation.

Post-discharge No post-discharge

VTE event (n=3) VTE event (n=76)

Average length 14.67 9.05

of stay (days)

Median length 7.00 6.00

of stay (days)

Number of 7 (1), 13 (6), 50 (25)

postoperative

(post-discharge)

days before VTE

presentation

original article

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A newly proposed VTE protocol

A protocol for post-discharge VTE prophylaxis in patients undergoing

colorectal cancer surgery was established following thorough

examination of both the current literature and the chart review, which

was then presented at the morbidity and mortality (M and M)

meeting at St. Michael’s Hospital, Toronto. In order to determine the

best approach to improve the current system, experts at the M and

M meeting had the opportunity to share their insight, and the

potential obstacles and limitations to the proposed protocol. The new

protocol will be implemented with guidance from Thrombosis

Canada, which includes staff education and patient education. Based

on post-implementation results within the first three to six months,

the protocol may be adjusted.

As per the new VTE protocol, low-molecular weight heparin (LMWH)

will be administered for 30 days following discharge from hospital for

all patients with colorectal cancer who have undergone laparoscopic

or laparotomy colorectal cancer resections, unless contraindicated.

Each patient will be taught how to self-administer the injections by a

member of the nursing staff prior to discharge, and will receive the

LMWH free of charge. Medication access is outlined in Figure 2.

Review of patient outcomes will be carried out at 3, 6, and 12 months

following protocol implementation, with the aim of reducing or

eliminating post-discharge VTE events after colorectal surgery for

colorectal cancer patients. Once a consensus has been reached, the

protocol will be disseminated to hospital administrators, nurses,

physicians, and pharmacists. Educational seminars will be held in

order to prepare hospital staff for the incoming changes and to

address concerns. As the proposed protocol is still in development,

results are not yet available.

FIGURE 2: Access to medication.

Prescription is covered

Pharmacistprovides Pfizer discount cards, which makesprescriptioncovered

Prescription is covered

Patient is >65 y/o

Patient is <65 y/o withoutprivate insurance

Patient is <65 y/o withprivate insurance

Doctorsprescribe 30 days

of Fragmin® (dalteparin)5,000U on

discharge order

original article

References

1 Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-Amrani

A et al. Duration of prophylaxis against venous thromboembolism with

enoxaparin after surgery for cancer. N Engl J Med. 2002;346(13):975-80.

2 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ.

Executive Summary. Chest. 2012;141(2):7S-47S.

3 Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, Bonizzoni E et al. A

clinical outcome-based prospective study on venous thromboembolism

after cancer surgery: The @RISTOS Project. Ann Surg.

2006;243(1):89-95.

4 Frere C, Farge D. Clinical practice guidelines for prophylaxis of venous

thomboembolism in cancer patients. Thromb Haemost.

2016;116(10):618-25.

5 Lyman GH, Bohlke K, Falanga A. Venous thromboembolism prophylaxis

and treatment in patients with cancer: American Society of Clinical

Oncology Clinical Practice Guideline Update. J Oncol Pract.

2015;11(3):e442-4.

6 Vedovati MC, Becattini C, Rondelli F, Boncompagni M, Camporese G,

Balzarotti R et al. A randomized study on 1-week versus 4-week

prophylaxis for venous thromboembolism after laparoscopic surgery for

colorectal cancer. Ann Surg. 2014;259(4):665-9.

7 Rasmussen MS, Jorgensen LN, Wille-Jørgensen P, Nielsen JD, Horn A,

Mohn AC et al. Prolonged prophylaxis with dalteparin to prevent late

thromboembolic complications in patients undergoing major abdominal

surgery: a multicenter randomized open-label study. J Thromb Haemost.

2006;4(11):2384-90.

8 Kakkar VV, Balibrea JL, Martínez-González J, Prandoni P. Extended

prophylaxis with bemiparin for the prevention of venous

thromboembolism after abdominal or pelvic surgery for cancer: the

CANBESURE randomized study. J Thromb Haemost. 2010;8(6):1223-9.

9 Mandalà M, Falanga A, Roila F. Management of venous

thromboembolism (VTE) in cancer patients: ESMO clinical practice

guidelines. Ann Oncol. 2011;22(Suppl.6):85-92.

10 Bouras G, Burns EM, Howell A-M, Bottle A, Athanasiou T, Darzi A. Risk of

post-discharge venous thromboembolism and associated mortality in

general surgery: a population-based cohort study using linked hospital

and primary care data in England. PLoS One. 2015;10(12):e0145759.

11 Davenport DL, Vargas HD, Kasten MW, Xenos ES. Timing and

perioperative risk factors for in-hospital and post-discharge venous

thromboembolism after colorectal cancer resection. Clin Appl Thromb.

2012;18(6):569-75.



Discussion

The literature review demonstrated that the incidence of

post-discharge VTE in patients undergoing colorectal surgery for

resection of colorectal cancer remains elevated, and is a cause of

significant morbidity and mortality for these individuals. In addition,

prolonged VTE prophylaxis in colorectal cancer patients following

surgery appears to be well supported by the literature. This study was

limited as it consisted of a chart review of only 100 patients over a

one-year period. The chart review allowed for analysis of VTE events

that presented post discharge to a single hospital institution. The

professionals present at the M and M meeting showed concern

regarding the following aspects of the proposed protocol: training

nursing staff on patient education for self-administered injections;

patient compliance with self-injected medication; and adverse

outcomes. These concerns were addressed and have been integrated

into the revised proposed protocol.

Conclusion

The results of the chart review were in line with the current incidence

rates of post-discharge VTE events in colorectal cancer surgery

patients, and demonstrated a gap in prescribing habits based on

current guidelines for this patient population. The main finding from

this chart review was that only 2.53% of patients received

post-discharge prophylaxis. By contrast, the @RISTOS project

showed a post-discharge prescribing rate of 30.7%.2 The chart

review also showed that 3.8% of patients developed VTE

post discharge. The @RISTOS project demonstrated clinically overt

VTE in 2.83% of the general surgery patients included within the

study.2

The next steps of this project are to implement the newly proposed

VTE prophylaxis prescribing protocol and subsequently analyse the

incidence of post-discharge VTE events and adherence to the

thromboprophylaxis prescribing protocol. Future research aimed at

the cost–benefit ratio of prolonged post-discharge

thromboprophylaxis and the use of new oral anticoagulant agents is

recommended.

Acknowledgements

The author wishes to acknowledge the RCSI and the Keenan Research

Summer Student programme for their contribution.


Bharti M. Kewlani

RCSI medical student

The role of lymphoscintigramsin breast cancer – aretrospective audit fromBeaumont Hospital

Abstract

Introduction: Lymphoscintigram scans have been used, along with the technetium-99m and blue

dye injection, to locate sentinel lymph node(s) in breast cancer patients undergoing surgery at

Beaumont Hospital. However, the value of lymphoscintigrams for accurately identifying potentially

malignant lymph nodes in the clinical setting remains controversial.

Aim of study: To evaluate the role of pre-operative lymphoscintigrams in female breast cancer

patients at Beaumont Hospital.

Methods: Hospital database records of 100 breast cancer patients’ lymphoscintigrams, from August

2015 to November 2017, were evaluated retrospectively. These findings were correlated with

histology results and operative reports of ‘hot and/or blue’ lymph nodes.

Results: The mean number of nodes on lymphoscintigrams and histology reports was 2.42 and 2.63,

respectively. Some 6% of patients (n=6) had negative lymphoscintigram scans but were found to

have malignant lymph nodes on histological assessment.

Conclusion: Lymphoscintigraphy did not enhance the accuracy of detecting sentinel lymph nodes in

this study. Given these findings, further randomised controlled trials are recommended to guide

eventual elimination of lymphoscintigrams at Beaumont Hospital.



RCSIsmj

Introduction

Breast cancer is the most common malignancy in females, with an

annual incidence of 2,890 cases diagnosed in Ireland.1 Lymph from

the breast tissue drains via a system of ducts into lymph nodes in the

upper limb and thorax, and this lymphatic system serves as a possible

route for cancer metastasis. The sentinel lymph node(s) (SLN) is the

very first draining lymph node, and would thus be the first node to

which cancer would spread.2 An SLN biopsy is therefore performed

before or alongside surgical removal of the tumour, to confirm or

exclude the spread of breast cancer to regional lymph nodes and thus

pathologically stage the disease.2 One method for identifying the SLN

is to inject an isosulfan blue dye intra-operatively to directly visualise

the blue node(s).3 A second method involves injecting a radioactive

colloid tagged with technetium-99m near the areola for

intra-operative detection with a gamma probe.4,5 If the latter is done,

a lymphoscintigram (a nuclear medicine technology for imaging the

lymphatic system) is often obtained pre-operatively to aid

identification of the SLNs.5 There is no single unanimous protocol in

Irish hospitals for pre-operative SLN assessment in breast cancer.

Currently, at Beaumont Hospital in Dublin, both lymphoscintigraphy

and the isosulfan blue dye visualisation technique are used to identify

SLNs. Clinical guidelines at Beaumont Hospital have not been

updated in recent years to reflect available evidence, and the

usefulness of lymphoscintigrams has not been evaluated. A literature

review around this topic has shown that this area of research is

relatively underexplored; over the past ten years, only a handful of

studies have probed this question of lymphoscintigram efficacy. In

2010, studies conducted in New Zealand and the UK concluded that

the blue dye method alone is sufficient and pre-operative

lymphoscintigraphy is not required.6,7 However, these studies

indicated that further research looking at survival patterns and

recurrence rates should be done to confidently eliminate

lymphoscintigrams from clinical practice.7

In 2010, Sun et al. also concluded that lymphoscintigrams neither

improved the identification rate of SLNs nor reduced the chances of

missing SLNs during excisional surgery.8 It was further noted that

patients with metastatic breast cancer to the axilla had lower SLN

detection rates via lymphoscintigraphy compared to those without

metastasis.8

A 2015 study conducted in St Vincent’s Hospital in Ireland did not find

any benefit to injecting the blue dye post lymphoscintigraphy to

detect SLNs.3 The authors suggested avoiding the use of blue dye due

to possible anaphylactic reactions, skin tattooing, and interference

with pulse oximetry, and recommended that the blue dye method

should be reserved for patients with negative lymphoscintigrams or

who have undergone neoadjuvant chemotherapy.3

The aim of this present study was to retrospectively audit 100 female

patients who received breast cancer treatment at Beaumont Hospital

in Ireland between August 2015 and November 2017, and compare

their lymphoscintigram findings to histology findings. Subsequently,

the number of ‘hot and blue’ nodes identified intra-operatively was

also reviewed to assess for any correlations or discrepancies.

Methods

Search strategy

A search of the relevant databases (PubMed, CINAHL, and Cochrane)

was conducted, with results initially limited to articles published in the

last five years, but revised and expanded to articles published in the

last ten years due to a lack of publications on this topic in recent years.

The Medical Subject Headings (MeSH) used were as follows:

“lymphoscintigram – sentinel lymph node – breast cancer – English –

10 years – humans”. A total of 17 papers were found from the 3

databases used (PubMed – 10; CINAHL – 3; Cochrane – 4). Returned

search results were screened for duplicates, leaving a total of 13

papers that were then sorted based on title and abstract. Eventually,

7 papers were retained; the remaining 6 were discarded, as they were

deemed irrelevant for this study.

original article



RCSIsmj

Patient selection

Upon request, the Picture Archiving and Communication System

(PACS) office at Beaumont Hospital ran a search to extract a list of all

patients who underwent lymphoscintigraphy between January 2015

and December 2017. This list included 295 patients and was exported

into a working Excel spreadsheet. Data was extracted from the patient

seen most recently (2017), and data collection proceeded

retrospectively. Exclusion criteria included males, lymphoscintigrams

done for patients with melanoma, and cases where data was

insufficiently recorded. The final cohort of patient data included cases

from August 2015 to November 2017. Information was retrieved

from a total of 100 patients and 101 lymphoscintigram scans. Four

patients had bilateral malignancy and thus bilateral breast surgery,

but only two of these four patients had bilateral lymphoscintigraphy

performed (n=102 scans). However, one lymphoscintigram scan was

unavailable or unreported (n=101 scans). Finally, operative notes from

patients’ charts were reviewed manually, where possible, to record

the number of ‘hot and blue’ lymph nodes detected during surgery.

Upon request, the Picture Archiving andCommunication System (PACS) office atBeaumont Hospital ran a search to extract a list of all patients who

underwent lymphoscintigraphy betweenJanuary 2015 and December 2017.

Data analysis

Data was recorded and analysed using an Excel spreadsheet. Information

was obtained from lymphoscintigram imaging reports (from the hospital’s

PACS software) and histology reports (from the hospital’s WinPath

system). The data collected included: patient demographics; tumour

type and size; histological grade; lymphovascular invasion; oestrogen,

progesterone, and HER2 receptor status; lymphoscintigraphy results;

type of surgery; number of nodes positive for malignancy on

histology; and, number of ‘hot and/or blue’ lymph nodes detected

intra-operatively.

Results

This audit included data from 100 female patients (96 outpatients; 4

inpatients) who received treatment for breast cancer at Beaumont Hospital

between August 2015 and November 2017. The mean patient age was

58.3 years (range: 31-91 years). The average size of the invasive tumour

was 27.68mm (range: 0-210mm). The most common histological type

was invasive ductal carcinoma (IDC) grade 2, and 6% of patients had

multifocal disease. Thirteen patients (13%) had carcinoma in situ. For the

remaining 87 patients with invasive carcinoma, 16 had definitive

lymphovascular invasion, and 9 had probable lymphovascular invasion.

The remaining 62 patients did not have lymphovascular invasion.

Comparing the number of SLN(s) detected via different methods

All patients had a lymphoscintigram scan performed pre-operatively, and

were given the radioactive technetium-99m injection as well as the

isosulfan blue dye injection to aid the SLN biopsy. A total of 101

lymphoscintigrams were reported and analysed; nodes were counted

manually on scans retrieved from the PACS system. The average number

of SLNs per lymphoscintigram was 2.42 nodes (range: 0-13 nodes). The

average number of SLNs from 100 corresponding histology reports was

2.63 (range: 1-9 nodes).

It was noted that only 74 of the 87 surgical chart notes reviewed had

information regarding SLNs sufficiently recorded. This data was either

missing from the remaining operative notes, or was very poorly written

and could not be interpreted accurately, and was thus omitted. The

average number of ‘hot and/or blue’ nodes detected during surgery, as

calculated from the 74 available and legible operative notes, was 1.71

(range: 1-4). It was also noted that 6 of these 74 patients had nodes that

were hot (i.e., technetium-99m was detected via intra-operative gamma

probe), but not blue. In two cases, there was no evidence of hot and/or

blue nodes. These results are illustrated in Figure 1. A standard error of 5%

was included.

FIGURE 1: Comparing the average number of positive sentinel lymph nodesdetected pre-operatively and intra-operatively. Lymphoscintigraphy scans detected2.42 nodes (range 0-13, n = 101); histology reports detected 2.63 nodes (range1-9, n = 100 as one histology report was unavailable); surgery detected 1.71 hotand/or blue nodes (range 1-4, n = 74).

original article

3.5

3

2.5

2

1.5

1

0.5

0

Average number of lymph nodes

Lymphoscintigram Histology Surgery (hot/blue)

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Consistency of lymphoscintigraphy and histology findings

Analysis revealed that 30 patients had lymphoscintigram scans that

were consistent with histology report findings, meaning the number

of nodes detected on lymphoscintigram exactly matched the number

of nodes seen on histology. However, 34 patients had histology

reports that revealed more nodes than their respective

lymphoscintigram scans, and another 34 patients had histology

reports that revealed fewer nodes than their respective

lymphoscintigrams (see Table 1).

Table 1: Number of positive lymph nodes detected via

lymphoscintigram versus histology.*

Number of Comparing the number of positive patients lymph nodes detected

30 Lymphoscintigram = Histology

34 Lymphoscintigram < Histology

34 Lymphoscintigram > Histology

Interpreting the histology findings for patients with negative

lymphoscintigrams

Of the 101 lymphoscintigrams performed, reported, and interpreted,

it was noted that six patients had a negative scan, meaning no lymph

nodes were identified. However, the histology reports for these six

patients were positive and indeed detected lymph nodes. Four of

these six patients had one sentinel node on histology, while the

remaining two patients each had six sentinel nodes detected on

histology (see Table 2).

Table 2: Histology results for six patients withnegative lymphoscintigram scans.

Number of Number of positive sentinel nodes patients on histology

4 1

2 6

Histological lymph node analysis

This audit revealed that 22 out of 100 patients had lymph nodes

positive for cancer on histological assessment. The average number of

positive nodes on histology was 0.233 (range: 0-2 nodes). Axillary

lymph node clearance was performed on 21 of these 22 patients.

Figure 2 summarises the number of nodes that were positive for

cancer among the 100 patients evaluated in this study; 20 patients

had one positive node, and two patients had two positive nodes.

Of note, 14% of the patients in this study were negative for the

oestrogen, progesterone, and HER2 receptors (i.e., triple negative),

and four of these patients had positive lymph nodes on histology.

Discussion

Lymphoscintigrams are nuclear medicine scans, and are only

performed in certain institutes where this imaging technology is

available. The 100 patients included in this study had a pre-operative

lymphoscintigram scan performed for further evaluation of their

breast cancer prior to surgery. In the majority of cases, the imaging

scan was done one day prior to surgery. Results showed that the

average number of SLNs detected on lymphoscintigram (2.42) was

almost the same as that seen histologically (2.63). The difference

noted was found not to be statistically significant (see Figure 1).

All lymphoscintigrams assessed in this study were interpreted

manually by one individual, via counting the number of lymph nodes

seen on the scan. As such, any judgement calls made by the

researcher regarding number of visible nodes were consistent.

However, approximately 10% of the scans were of average or poor

image quality, which introduced some degree of error since the nodal

assessment and count was based on only one individual’s

interpretation skills.

Based on data extrapolation from 2015, the Power Performance

Manager (PPM) costing system estimates that the average cost of

providing nuclear imaging for the year 2017 was €307.25/service,

which includes directly attributable running costs. By eliminating


original article

0 nodes (79%)

1 node (19%)

2 nodes (2%)

FIGURE 2: Number of positive (malignant) lymph nodes on histological analysis.

*One lymphoscintigram was unavailable or not performed, and one histologyreport was missing or unavailable, so numeric figures do not sum to the 100patients included in the study.


References

1. Breast Cancer Ireland. Facts and figures. 2019. [Internet]. [cited 2019

January 5]. Available from:

https://www.breastcancerireland.com/education-awareness/facts-and-

figures/.

2. Borgstein PJ, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S.

Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of

lymphoscintigraphy and gamma probe detection. J Am Coll Surg.

1998;186(3):275-83.

3. O’Reilly EA et al. The value of isosulfan blue dye in addition to isotope

scanning in the identification of the sentinel lymph node in

breast cancer patients with a positive lymphoscintigraphy: a

randomized controlled trial (ISRCTN98849733). Ann Surg.

2015;262(2):243-8.

4. Caruso G, Cipolla C, Costa R, Morabito A, Latteri S, Fricano S et al.

Lymphoscintigraphy with peritumoral injection versus

lymphoscintigraphy with subdermal periareolar injection of

technetium-labeled human albumin to identify sentinel lymph nodes in

breast cancer patients. Acta Radiologica. 2014;55(1):39-44.

5. Schaafsma BE, Verbeek FP, Rietbergen DD, van der Hiel B, van der Vorst

JR, Liefers GJ et al. Clinical trial of combined radio- and

fluorescence-guided sentinel lymph node biopsy in breast cancer. Br J

Surg. 2013;100(8):1037-44.

6. McMasters K, Wong S, Tuttle T, Carlson D, Brown C, Dirk Noyes R et al.

Preoperative lymphoscintigraphy for breast cancer does not improve the

ability to identify axillary sentinel lymph nodes. Ann Surg.

2000;231(5):724-31.

7. Mathew MA et al. Pre-operative lymphoscintigraphy before sentinel

lymph node biopsy for breast cancer. Breast. 2010;19(1):28-32.

8. Sun X et al. Roles of preoperative lymphoscintigraphy for sentinel lymph

node biopsy in breast cancer patients. Jpn J Clin Oncol. 2010;40:722-5.

9. Vaz S, Silva Â, Sousa R, Ferreira T, Esteves S, Carvalho I et al.

Breast cancer lymphoscintigraphy: factors associated with sentinel

lymph node non visualization. Rev Esp Med Nucl Imagen Mol.

2015;34(6):345-9.

lymphoscintigraphy, a technology that, based upon these results,

appears to provide no significant additional benefit to breast cancer

patient management, funds could be redirected towards research and

other areas of hospital patient care.

Of note, lymphoscintigrams have played an integral role in the

identification of SLNs in melanoma, which, unlike breast cancer, has

an unpredictable route of lymphatic drainage and spread.6 McMasters

et al. therefore argue that routine use of lymphoscintigrams in breast

cancer is not justified due to its predictable pattern of spread.6

One final limitation of this study is that the author would have liked to

assess patients’ body mass index (BMI), due to a possible correlation

between obesity and negative lymphoscintigram scans; however, this

data could not be evaluated due to limited resource availability.9

After evaluating the data collected and processed in this

retrospective audit, it is evident thatconducting a pre-operative

lymphoscintigram scan did not improveSLN detection rates in Beaumont Hospital breast cancer patients.

Conclusion

After evaluating the data collected and processed in this retrospective

audit, it is evident that conducting a pre-operative lymphoscintigram

scan did not improve SLN detection rates in Beaumont Hospital breast

cancer patients. Lymphoscintigrams are costly, and their continued

use in everyday practice should be carefully evaluated further. We

propose that lymphoscintigrams should be reserved for patients who

have a negative technetium-99m result (i.e., no SLNs detected using

radioactive technetium-99m colloid) or for patients with a history of

anaphylactic reaction to intra-operative use of the blue dye. Further

retrospective audits and randomised controlled trials with larger

patient cohorts are warranted before the complete elimination of

lymphoscintigrams for breast cancer patients at Beaumont Hospital is

carried out.

Acknowledgements

Professor Arnold D.K. Hill, Head of School of Medicine/Professor of

Surgery, Royal College of Surgeons in Ireland

Mr Chwanrow M.K. Baban, general surgeon, Beaumont Hospital,

Dublin

Mrs Aisling Hegarty, Research Nurse Manager, Beaumont Hospital,

Dublin


Jaclyn A. Croyle

Francesco Bartoloni Saint Omer

Sari F. Yordi

Tara E. Dowd

Jesse M. Connors

Taylor C. Cunningham

RCSI medical students

The burden of paediatricasthma in urban United States populations

Abstract

Within the United States (US) paediatric population, asthma is the most common chronic disease. Its

impact is most greatly appreciated with respect to quality of life. The importance of this condition

has been recognised in the US with a significant national response; however, prevalence, morbidity,

and mortality continue to rise. This review explores the extent of asthma in the US paediatric

population, as well as strategies undertaken by US health services to address this childhood illness.

In addition, this review assesses the efficacy of three evidence- and population-based asthma

prevention strategies, namely immunotherapy, reduction of environmental triggers, and prevention

of viral infections.


RCSIsmjreview


RCSIsmjreview


Introduction

Asthma is the most common chronic disease impacting the paediatric

population in the United States (US).1 The major burden of this

disease is its significant impact on quality of life (QOL).

Physiologically, asthma is characterised by airway inflammation and

hyperresponsiveness, and reversible bronchoconstriction, as a result

of inappropriate activation of the immune system to a nonspecific

particle.1 These processes lead to a decrease in airway lumen

diameter, causing the characteristic asthmatic symptoms of cough,

wheeze, and sputum production.1 Managing these symptoms

requires lifelong medication, and in acute exacerbations may require

presentation to the emergency room (ER).2 This impacts on the US

population via school and work absenteeism, and places a strain on

the healthcare system through the need for resources and

medication.3 Additionally, patients experience a reduced QOL as they

try to avoid triggering their symptoms.

Currently, approximately 10% of children aged 5 to 19 years in

the US have asthma. Interventionstrategies aimed at preventing asthma in children in urban areas

would be advantageous for the US population, from both a financial and QOL perspective.

The diagnosis of asthma is becoming more prevalent due to

improved understanding of the disease pathogenesis and better

diagnostic techniques. Asthma is more prevalent in urban areas,

which may be due to differences in environmental exposures and

lifestyle factors.4 Despite significant national responses in the US to

address this condition, the prevalence, morbidity, and mortality of

asthma have remained high in this population. Currently,

approximately 10% of children aged 5 to 19 years in the US have

asthma.5 Intervention strategies aimed at preventing asthma in

children in urban areas would be advantageous for the US

population, from both a financial and QOL perspective. These

strategies could reduce disease burden and mortality secondary to

asthma.

In this literature review, the epidemiology of childhood asthma in

urban US populations was assessed. Subsequently, three

evidence-based, population-based prevention strategies were

explored for their potential application in this patient population.

Methods

To complete this literature review, prospective and retrospective

studies, and online information, were evaluated for eligibility. No

language or date restrictions were applied. The paediatric population

was defined as ages 1 to 18 years, inclusive, as per the Medical

Subject Headings (MeSH) search criteria. PubMed was the main

source used to search for relevant data. This yielded 473 articles for

review. In addition, Science Direct, the clinical summary website

UpToDate, and the US Centers for Disease Control and Prevention

(CDC) website were also used to gather sources.

Titles and abstracts were reviewed for eligibility by each author.

Full-length articles for those deemed appropriate were accessed, and

bibliographies for these articles were investigated to identify

additional relevant studies.

Results

Epidemiology

The collection of epidemiological statistics on asthma poses

challenges, particularly with regard to collating and representing the

data in a standardised manner. Using a clinician’s diagnosis in health

questionnaires has been shown to be both sensitive and specific.6 This

strategy was utilised in the National Health Interview Survey (NHIS)

by asking patients if they had been diagnosed with asthma by a

physician, including the timeline and presentation of their diagnosis.7

In 2010, the CDC analysed data from the NHIS and found that 25.7

million people had asthma in the US, of which seven million were

children under 18 years of age.8 The data also showed that the

prevalence of asthma has increased; however, visits to primary care

settings for asthma symptoms decreased from 2001-2009 in the US.8

Moreover, children under 18 years of age with asthma are more likely

to attend primary care clinics or the ER than asthmatic adults, but

adults have a seven times higher mortality rate compared to

children.8 These statistics further highlight the importance of

recognising asthma risk factors, and using that information to

generate and promote prevention strategies that would likely reduce

the disease burden.8

Risk factors

Genetic and environmental factors have been attributed to the

development and severity of asthma. Although no single gene is

responsible for causing asthma, genetic mutations involving the

immune system play a role in predisposition to the disease.9,10

Interactions between genetic and environmental factors, both

prenatally and postnatally, are key in the risk of asthma development.

Polymorphisms in certain toll-like receptors, combined with exposure

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to traffic-related air pollution as seen in urban environments, may

increase the risk of childhood asthma.11

A child’s geographic, demographic, and social environment are

important factors when assessing the risk of developing asthma and

its severity. Children from urban households and of lower

socioeconomic status are at greater risk of an asthma diagnosis and

asthma-related exacerbations.12,13 Multiple factors may explain this,

including exposure to environmental pollutants, decreased physical

activity, poor diet, treatment non-adherence, and a high-stress

setting.12-15 Additionally, early introduction to microorganisms and

allergens, like those found on animals or a farm, can cause

desensitisation, preventing future hypersensitivity reactions.16 An

urban environment does not permit the same opportunity for gradual

exposure to these allergens, which is known to be a protective factor

in the development of asthma.

It is also crucial to consider the prenatal environment, as

maternal smoking status, paracetamol use, urban-type surroundings,

and a lower socioeconomic status have all been shown to increase

the risk of a child developing asthma.10 Furthermore, short-term

breastfeeding, postnatal tobacco smoke exposure, and antibiotic

use as a newborn have also been shown to increase paediatric

asthma.9,16

National health system response

In 1999, the CDC recognised the increased prevalence and burden of

asthma, and launched the National Asthma Control Program (NACP)

to provide funding to states, cities, school programmes, and

non-governmental organisations.3 Funds are used to perform regular

asthma surveillance, improve healthcare training in asthma

management, and develop education strategies.3 The goals of this

initiative are to reduce the morbidity and mortality of asthma, limit

missed school and work days, and improve QOL for asthma patients

in the US.3 It is estimated that for every US dollar spent through the

NACP, $71 US are saved, highlighting the success of this programme.3

In order to achieve its goals, the NACP improved surveillance

techniques for asthma data collection through telephone surveys and

a partnership with the National Centre for Disease Statistics.3

The NACP also directs funding for intervention programmes in all

participating districts.3 This has included initiatives such as asthma

education, funding for medication, healthcare training, and risk

reduction strategies including smoking cessation training and

promotion.3 Additionally, the NACP collaborated with the National

Institutes of Health, among others, to generate National Asthma

Education and Prevention Program Guidelines.3 Other partnerships

with the American Lung Association and the Asthma and Allergy

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Foundation of America have been important for supporting policy

changes in the US, including legislation allowing youth to self-carry

and self-administer asthma medications in the school setting,

promoting affordable and quality care, and advocating for outdoor

and indoor air quality improvement.17,18 Future aims of the NACP are

to tackle racial and ethnic disparities, and improve reimbursement

schemes for asthma education and environmental management

strategies.3,19

In 1999, the CDC recognised the increasedprevalence and burden of asthma, andlaunched the National Asthma ControlProgram (NACP) to provide funding tostates, cities, school programmes, andnon-governmental organisations.

Prevention strategies

Specific immunotherapy

Immunotherapy is effective in children monosensitised to house dust

mites by preventing sensitisation to other allergens that could

otherwise lead to asthma.20 For individuals with rhinoconjunctivitis

and hay fever, immunotherapy reduces the risk of progression to

asthma.20,21 Of note, children who are untreated have at least a two

times greater risk of developing asthma or new asthma

sensitisations.20-22 According to Calderón and Brandt, the mechanism

of action of specific immunotherapy drugs, such as Grazax, is not fully

understood, but is believed to involve modulation of the immune

response by regulating immunoglobulin E (IgE) production and

generating anti-IgE antibodies that competitively inhibit the

allergen-IgE interaction.23 There is a dose-response curve with Grazax

in relation to antibodies.23 Additionally, there is a change from Th2

cells to regulatory T cells, and the mechanism that allows antigens to

be presented by specific T cells is inhibited.23

Nasser et al. determined the cost-effectiveness of Grazax in relation to

quality-adjusted life years (QALYs) in patients with existing

rhinoconjunctivitis.24 They found that productivity loss and healthcare

resource use as a result of asthma symptoms and complications were

much higher in the untreated group.24 Grazax was thus determined

to be a highly cost-effective treatment when compared to standard

management.24 The three-year treatment course would target

high-risk asthma patients, defined as those with pre-existing asthma

monosensitisation, or with a respiratory allergic response other than

asthma to one or more allergens.

This immunotherapy has already been shown to be effective in

Europe, making it a promising prevention strategy for the US

paediatric population. The greatest advantage of its introduction

would be its potential to reduce chronic asthma diagnoses and

disease burden. The main limitation, however, is that the long-term

side effects are unknown.

Reducing environmental triggers in the home

Many triggers for childhood asthma can be found in the home

environment, especially in urban settings. Home-based education

programmes serve to reduce the burden of disease in high-risk

paediatric asthma patients via proper home cleaning and repair.

These home-based programmes typically target the primary

caretakers of children with asthma in the urban environment, where

they are caring for those who have been diagnosed with asthma by a

physician and who have been to the hospital twice within a one-year

period. Healthcare workers visit the primary residence of the child to

assess for potential asthma triggers and educate the family on how

best to eliminate them. These programmes have proved to be

successful in several US urban populations.25-27 Other studies in the US

measured the reduction in asthma triggers and allergens, rather than

overall asthma improvement, to evaluate the effectiveness of these

home-based interventions. These studies found that a

multicomponent intervention strategy reduced levels of asthma

triggers in the home, including dust mites and cockroach excrement,

in both the short and long term.28-30 Adherence rates for these

programmes has been as high as 93%, suggesting that the

intervention is manageable, which is vital for lasting success.25 In

addition, this proposed programme has been shown to result in

substantial healthcare cost savings.27

Preventing viral infection

A third way to reduce the burden of paediatric asthma is to dampen

the allergic response to viral infections. Studies have shown that lower

respiratory tract viral infections, combined with aeroallergen

sensitisation, increase the probability of inducing asthma

symptoms.31-34 Over time, this can lead to the development of

persistent asthma. Certain viral infections have been strongly

associated with asthma exacerbations, including respiratory syncytial

virus and rhinovirus. 31-34

IgE plays a key role in the allergic response to these respiratory viruses,

making it a critical target for treatment. The US Inner City Asthma

Consortium published data strongly supporting the use of monthly

anti-IgE therapy (omalizumab) in high-risk subjects with atopy.33 A

randomised controlled trial recently published data supporting

anti-IgE therapy, showing that it not only reduced the number of

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References

1. Sawicki G, Haver K. Asthma in children younger than 12 years:

epidemiology and pathophysiology. In: Post T (ed.). UpToDate, Waltham,

MA. 2017. [Internet]. [Accessed 2017 November 25]. Available from:

https://www.uptodate.com/contents/asthma-in-children-younger-than-12-

years-initial-evaluation-and-diagnosis?search=asthma-in-children-younger-t

han-12-years-epidemiology-and-pathophysiology&source=search_result&s

electedTitle=1~150&usage_type=default&display_rank=1.

2. Fanta CH. An overview of asthma management. In: Post T (ed.).

UpToDate, Waltham, MA. 2017. [Internet]. [Accessed 2017 November 15].

Available from:

https://www.uptodate.com/contents/an-overview-of-asthma-management

?search=An%20overview%20of%20asthma%20management&source=sear

ch_result&selectedTitle=1~150&usage_type=default&display_rank=1.

3. Centers for Disease Control and Prevention. CDC’s National Asthma

Control Program: An investment in America’s health. Atlanta, GA. 2013.

[Internet]. Available from:

https://www.cdc.gov/asthma/pdfs/investment_americas_health.pdf.

4. Milligan KL, Matsui E, Sharma H. Asthma in urban children: epidemiology,

environmental risk factors, and the public health domain. Curr Allergy

Asthma Rep. 2016;16(4):33.

5. Centers for Disease Control and Prevention. Most Recent Asthma Data.

2017. [Internet]. Available from:

https://www.cdc.gov/asthma/most_recent_data.htm.

6. Litonjua A, Weiss S. Epidemiology of asthma. In: Post T (ed.). UpToDate,

Waltham, MA. 2018. [Internet]. [Accessed 2019 January 29]. Available

from:

https://www.uptodate.com/contents/epidemiology-of-asthma?search=epid

emiology%20of%20asthma%20litonjua&source=search_result&selectedTitl

e=1~150&usage_type=default&display_rank=1.

7. Centers for Disease Control and Prevention. NHIS Data, Questionnaires

and Related Documentation. Atlanta, GA. 2017. [Internet]. Available from:

https://www.cdc.gov/nchs/nhis/data-questionnaires-documentation.htm.

8. Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA et al.

Trends in asthma prevalence, health care use, and mortality in the United

States, 2001-2010. NCHS Data Brief. 2012;(94):1-8.

9. Dietert RR. Maternal and childhood asthma: risk factors, interactions, and

ramifications. Reprod Toxicol. 2011;32(2):198-204.

10. Savenije OE, Kerkhof M, Reijmerink NE, Brunekreef B, de Jongste JC, Smit

HA et al. Interleukin-1 receptor-like 1 polymorphisms are associated with

serum IL1RL1-a, eosinophils, and asthma in childhood. J Allergy Clin

Immunol. 2011;127(3):750-6.e1-5.

11. Kerkhof M, Postma DS, Brunekreef B, Reijmerink NE, Wijga AH, de Jongste

JC et al. Toll-like receptor 2 and 4 genes influence susceptibility to adverse

effects of traffic-related air pollution on childhood asthma. Thorax.

exacerbations but also the number of symptomatic days spent in

hospital.35 Targeted therapy such as this has its disadvantages,

however, which include the time required to educate healthcare

providers and implement the new protocol. Moreover, the cost of

therapy needs to be addressed in order to ensure that asthma patients

of all socioeconomic groups in the US can benefit.36 Supplying this

therapy seasonally (i.e., in the autumn and winter months), could

make IgE therapy more cost-effective.33-35

Conclusion

It is clear that childhood asthma carries a significant burden in the US

population. The prevalence of asthma has increased in recent years; as

of 2010, 10% of children aged 5 to 19 years in the US were reported

to have asthma.5 Although it is a multifactorial disease, many risk

factors have been identified, including lower socioeconomic status

and urban residences.11 As with other chronic conditions, there seems

to be an interplay between genetics and the environment; however,

the extent of this interaction is not yet fully understood.

In 1999, the NACP was founded with clear objectives to address and

tackle this rising health problem.3 It has helped to reduce the

prevalence, morbidity, and mortality of paediatric asthma by enabling

funding for intervention programmes across the US.3

In this review, three evidence-based prevention strategies were

discussed. The first aims to reduce asthma prevalence by using targeted

immunotherapy in high-risk children, while the other two strategies aim

to lessen the disease burden by reducing symptoms and exacerbations.

Although many of these strategies have currently been tested or

implemented in populations outside the US, their application to the

US is valid. Exposure to the allergens in urban environments is likely to

be similar worldwide, and the asthmatic response to these triggers is

universal within the human body. The key factors that will determine

the success of these strategies are adherence rates and long-term

costs. Since these interventions will reduce the prevalence of asthma,

as well as lessen the need for medication or hospital and ER visits, the

long-term savings will outweigh the initial financial investment,

making them a viable option for the US population.

RCSIsmjreview


2010;65(8):690-7.

12. Cardet JC, Louisias M, King TS, Castro M, Codispoti CD, Dunn R et al.

Income is an independent risk factor for worse asthma outcomes. J Allergy

Clin Immunol. 2018;141(2):754-60.

13. O’Connor GT, Lynch SV, Bloomberg GR, Kattan M, Wood RA, Gergen PJ et

al. Early-life home environment and risk of asthma among inner-city

children. J Allergy Clin Immunol. 2018;141(4):1468-75.

14. Abajobir AA, Kisely S, Williams G, Strathearn L, Suresh S, Najman JM. The

association between substantiated childhood maltreatment, asthma and

lung function: a prospective investigation. J Psychosom Res.

2017;101:58-65.

15. Oland AA, Booster GD, Bender BG. Psychological and lifestyle risk factors

for asthma exacerbations and morbidity in children. World Allergy Organ J.

2017;10(1):35.

16. Liu AH, Babineau DC, Krouse RZ, Zoratti EM, Pongracic JA, O’Connor GT

et al. Pathways through which asthma risk factors contribute to asthma

severity in inner-city children. J Allergy Clin Immunol.

2016;138(4):1042-50.

17. Jones SE, Wheeler L. Asthma inhalers in schools: rights of students with

asthma to a free appropriate education. Am J Public Health.

2004;94(7):1102-8.

18. Asthma and Allergy Foundation of America. Advocacy and Public Policy.

2017. [Internet]. Available from: http://www.aafa.org/page/advocacy.aspx.

19. Centers for Disease Control and Prevention. Asthma self-management

education and environmental management: Approaches to enhancing

reimbursement. 2013. [Internet] Available from:

https://www.cdc.gov/asthma/pdfs/Asthma_Reimbursement_Report.pdf.

20. Pajno GB, Barberio G, De Luca FR, Morabito L, Parmiani S. Prevention of

new sensitizations in asthmatic children monosensitized to house dust

mite by specific immunotherapy. A six-year follow-up study. Clin Exp

Allergy. 2001;31(9):1392-7.

21. Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, Halken S, Høst A et al.

Five-year follow-up on the PAT study: specific immunotherapy and

long-term prevention of asthma in children. Allergy. 2006;61(7):855-9.

22. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A et al.

Specific immunotherapy has long-term preventive effect of seasonal and

perennial asthma: 10-year follow-up on the PAT study. Allergy.

2007;62(8):943-8.

23. Calderón M, Brandt T. Treatment of grass pollen allergy: focus on a

standardized grass allergen extract – Grazax®. Ther Clin Risk Manag.

2008;4(6):1255-60.

24. Nasser S, Vestenbæk U, Beriot-Mathiot A, Poulsen PB. Cost-effectiveness of

specific immunotherapy with Grazax in allergic rhinitis co-existing with

asthma. Allergy. 2008;63(12):1624-9.

25. Gruber KJ, McKee-Huger B, Richard A, Byerly B, Raczkowski JL, Wall TC.

Removing asthma triggers and improving children’s health: The Asthma

Partnership Demonstration project. Ann Allergy Asthma Immunol.

2016;116(5):408-14.

26. Baezconde-Garbanati L, Lienemann BA, Robles M, Johnson E, Sanchez K,

Singhal R et al. Implementation of HPV vaccination guidelines in a diverse

population in Los Angeles: results from an environmental scan of local HPV

resources and needs. Vaccine. 2017;35(37):4930-5.

27. Turcotte DA, Alker H, Chaves E, Gore R, Woskie S. Healthy homes: in-home

environmental asthma intervention in a diverse urban community. Am J

Public Health. 2014;104(4):665-71.

28. Adgate JL, Ramachandran G, Cho SJ, Ryan AD, Grengs J. Allergen levels in

inner city homes: baseline concentrations and evaluation of intervention

effectiveness. J Expo Sci Environ Epidemiol. 2008;18(4):430-40.

29. McConnell R, Milam J, Richardson J, Galvan J, Jones C, Thorne PS et al.

Educational intervention to control cockroach allergen exposure in the

homes of hispanic children in Los Angeles: results of the La Casa study.

Clin Exp Allergy. 2005;35(4):426-33.

30. Morgan WJ, Crain EF, Gruchalla RS, O’Connor GT, Kattan M, Evans R 3rd

et al. Results of a home-based environmental intervention among urban

children with asthma. N Engl J Med. 2004;351(11):1068-80.

31. Beigelman A, Bacharier LB. Early-life respiratory infections and asthma

development: role in disease pathogenesis and potential targets for disease

prevention. Curr Opin Allergy Clin Immunol. 2016;16(2):172-8.

32. Feldman AS, He Y, Moore ML, Hershenson MB, Hartert TV. Toward primary

prevention of asthma. Reviewing the evidence for early-life respiratory viral

infections as modifiable risk factors to prevent childhood asthma. Am J

Respir Crit Care Med. 2015;191(1):34-44.

33. Holt PG, Sly PD. Viral infections and atopy in asthma pathogenesis: new

rationales for asthma prevention and treatment. Nat Med.

2012;18(5):726-35.

34. Jackson DJ. Early-life viral infections and the development of asthma: a

target for asthma prevention? Curr Opin Allergy Clin Immunol.

2014;14(2):131-6.

35. Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH et al.

Randomized trial of omalizumab (anti-IgE) for asthma in inner-city

children. N Engl J Med. 2011;364(11):1005-15.

36. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for

asthma in adults and children. Cochrane Database Syst Rev.

2014;13(1):Cd003559.

Alexander Bonte

Lisa Gilmore

Kalu Long

Jessica Pian

Natalie Smith

Jason Royal

RCSI medical students

Abstract

Background: Chronic obstructive pulmonary disorder (COPD) is a major cause of increasing

mortality and morbidity worldwide, particularly in low- and middle-income countries where 90% of

deaths attributed to COPD occur. In China, the prevalence of COPD is 8.2% and there is a

disproportionately high mortality rate due to COPD. Chinese women in particular experience specific

risk factors, such as lifestyle and occupational exposures, and are a historically understudied and

underdiagnosed demographic. Opportunities for interventions specifically targeted at women are of

special interest in China.

Objective: The aim of this review is to examine the existing literature to quantify the disease burden

of COPD on Chinese females, to determine their specific risk factors, and to evaluate evidence-based

public health interventions at both local and national levels to mitigate the disease burden on this

demographic.

Methods: A comprehensive literature review was performed in the electronic databases of MEDLINE

PubMed and Cochrane Library, using the search terms COPD, China, and female/women. Articles

not available in English were removed from the analysis.

Results: The prevalence of COPD in Chinese women is 5.1%. Public health interventions such as the

provision of cleaner stoves to improve household ventilation and early screening programmes to

diagnose COPD have proven effective in both Chinese populations and in other countries. The

Chinese national health system response has been largely inadequate in meeting international

standards recommended to decrease the incidence of COPD.

Conclusions: The incidence and mortality of COPD, particularly in Chinese women, is a growing

concern. Public health interventions have demonstrated the potential for success in Chinese

populations. Additional effective public health interventions are needed to mitigate the incidence,

morbidity, and mortality of COPD, particularly for women. Nationwide large-scale studies of

epidemiological data are urgently needed to better inform public health decision-making.


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Chronic obstructivepulmonary disorder in adult Chinese women

RCSIsmjreview


Introduction

Chronic obstructive pulmonary disorder (COPD) is an increasing

cause of morbidity and mortality worldwide. Studies estimate a global

prevalence of 11.7%, with a 68.9% increase between 1990 and 2010.

While global prevalence is on the rise, incidence and mortality in

high-income countries are declining. The same is not true for middle-

and low-income countries where risk factors remain pervasive;

according to the World Health Organisation (WHO), 90% of COPD

deaths occur in low- and middle-income countries.1

The aetiology of COPD is complex, comprised of modifiable and

non-modifiable risk factors that are both environmental and genetic.

In high-income countries, tobacco smoke is the predominant COPD

risk factor, while in lower-income countries the aetiology is more

complex. In China, environmental pollutants are on the rise and other

risk factors like malnutrition, poor ventilation, and infectious diseases

remain ubiquitous.2

The estimated COPD prevalence in China is 8.2%.3 Globally, COPD in

women is of particular concern and has gained significant attention

as a threat to public health.4 In China, this risk to women is further

compounded by continued indoor air pollution and unique

occupational exposure.2,4

This review sets out to assess the current landscape of the burden of

COPD in China with a specific focus on adult Chinese women, and to

examine evidence-based interventions that may mitigate that burden.

While China’s health system has implemented various strategies to

combat COPD, additional interventions are needed to mitigate the

incidence, morbidity, and mortality of COPD, particularly for women.

Search methodology

To assess the breadth of epidemiological information on adult

Chinese women with COPD, searches were performed in MEDLINE

PubMed using Medical Subject Headings (MeSH) and subheadings.

Exact search terms and refinements resulted in an initial body of

literature comprising 46 results.

To explore existing interventions targeting COPD, the Cochrane

Library was searched for “COPD” as a MeSH descriptor with

“Prevention & Control” as a qualifier. Sixty-nine results were found

that addressed COPD interventions, and 37 results were found that

specifically centred on interventions relevant to China. The literature

searches described above are all limited by the exclusion of

Chinese-language search terms.

While global prevalence is on the rise, incidence and mortality

in high-income countries are declining.The same is not true for middle- and low-income countries where risk factors remain pervasive; according to the World Health

Organisation (WHO), 90% of COPD deaths occur in low- and middle-income countries.

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Epidemiology

China has produced the highest number of COPD epidemiological

studies among emerging countries, yet data are inconsistent due to

discrepant diagnostic criteria, diverse study populations, and differing

geographic estimates (see Table 1).5-7 One of the largest

population-based studies estimates an overall 8.2% prevalence

(12.4% for men and 5.1% for women) using Global Initiative for

Chronic Obstructive Lung Disease (GOLD) criteria.3,5 Findings from

this study fit well within global averages; however, mortality due to

COPD in China is significantly greater than in other parts of the

world.8 Research estimates age-standardised mortality in China as

179.9 per 100,000 person-years for men and 141.3 per 100,000

person-years for women.2

COPD is the third highest cause of disability-adjusted life years

(DALYs) in China and is projected to rise with increased smoking

prevalence.1 While female smoking (2.4%) is low in comparison to

male smoking levels (52.9%), disproportionate exposure to biofuels,

increasing social acceptability of female smoking, and potential

genetic susceptibility place women at particular risk for COPD.4,9,10

Table 1: Estimated COPD prevalence by geographic

location in China based on GOLD criteria.

Region Total prevalence (95% CI)

Beijing 8.0 (7.1-9.0)

Tianjin 9.6 (8.6-10.7)

Liaoning 7.4 (6.6-8.3)

Shanghai 6.5 (5.6-7.4)

Guangdong 9.4 (8.4-10.4)

Shanxi 5.5 (4.6-6.4)

Chongqing 13.7 (11.9-15.5)

Average 8.2 (7.9-8.6)

Source: Zhong et al., 20075

COPD risk factors

Tobacco smoke

Smoking is the leading risk factor for COPD in China. China is the

world’s largest producer and consumer of cigarettes, consuming 40%

of the cigarettes in the world.11 Estimated consumption of cigarettes

in China increased by 260% between 1970 and 1990, with recent

data citing continually high prevalence in males.11,12 While the same

study found a decrease in smoking uptake by women, these

researchers also express concern that more acceptable attitudes

towards female smoking may reverse this trend.11 Other publications

have found a rise in young female smokers.13

In addition to active smoking, second-hand smoke exposure in

China is common. Some 51.3% of female non-smokers reported

exposure to second-hand smoke at home.14 Passive smoking, as well

as biofuel exposure, may explain COPD rates in Chinese women that

are higher in proportion to their active smoking rates.15 Additionally,

research conducted globally and in China suggests that

genetic factors may place women at greater risk of developing

COPD, with an earlier onset and higher mortality than their male

counterparts.4,16

In contrast to more economicallydeveloped countries, inefficient biomass combustion is the second

leading risk factor for COPD in China, due to pollutants produced by heating and cooking in poorly

ventilated areas.

Indoor pollutants

In contrast to more economically developed countries, inefficient

biomass combustion is the second leading risk factor for COPD in

China, due to pollutants produced by heating and cooking in poorly

ventilated areas.17 One study that measured indoor and outdoor

pollutants based on spirometry from rural and urban households

concluded that the use of biofuels is widespread in rural China and

negligible in urban areas (88.1% vs 0.7% of households).18

Additionally, the prevalence of COPD among non-smokers was

significantly higher in rural households, where biofuels are more

commonly used, than in urban ones (7.4% vs 2.5%).18 Zhong et al.

also observed a significantly higher COPD prevalence in rural areas

(8.8%) compared with urban areas (7.8%).5 Rural Chinese women are

disproportionately exposed to indoor air pollution in comparison to

men, as they spend more time at home and do the majority of

household cooking.17

National health system response

In 2012, the WHO endorsed a new health goal intending to

achieve a 25% reduction in COPD-related premature death by the

year 2025.8 In China, health officials acknowledge the severity

of this problem, yet there remains no centralised plan to combat

the burden of the disease and no direct efforts targeting women.

The WHO established the Framework Convention on Tobacco

Control (FCTC), which came into effect in 2006.19 The MPOWER

policy tracks compliance with FCTC regulations on tobacco

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monitoring, smoke-free policies, cessation programmes, health

warnings and mass media, advertising bans, and cigarette

taxation.19 China’s implementation of and adherence to FCTC

requirements is considered very poor based on quantitative markers

of MPOWER.19

For example, in 2007 the Chinese Government approved WHO

guidelines prohibiting smoking in the workplace and indoor public

places.20 However, the Ministry of Health did not introduce a

nationwide ban on smoking in indoor public places until 2011.21 In

a WHO survey, 89% of respondents observed smoking in banned

public areas, emphasising that without legal penalties there is poor

compliance with the law.22 Beijing has been more successful after

implementing fines for individuals and establishments, public

shaming tactics, and hiring inspectors to enforce the ban.21

Notably, in China’s most recent 2017 WHO profile, it received the

lowest possible rating for its smoke-free policies.19 Article 11 of the

FCTC requires that large, graphic, and pictorial warnings of the

health hazards of smoking cover at least 50% of a cigarette

package.23 China has failed to comply with guidelines, providing

only small text-only warnings that cover 35% of the package.

To reduce risk from indoor air pollution, the Ministry of Agriculture

introduced the National Improved Stove Program (NISP) in the

1980s and distributed 200 million stoves to households in rural

China. The stoves required less fuel and were installed with

chimneys and grates to increase ventilation in the home in efforts

to reduce household air pollution.24

Evidence-based public health interventions

In China, locally established COPD interventions are delivered at

different tiers of prevention, including primordial, primary, and

secondary levels. Outcome data supporting regulatory cigarette

legislation and early screening suggests promising adaptation to the

Chinese population.25,26 A second iteration of the NISP could also help

to minimise COPD risk for women.

Reduction of household air pollution

Given the large percentage of the population who live in rural China,

interventions that improve cook stove quality and household

ventilation can reduce COPD risk for women and the entire

household.15 Chinese studies have highlighted these benefits,

including better air quality measurements in homes, reduced decline

in forced expiratory volume (FEV1), reduced COPD risk, and

decreased COPD incidence.24,27-29 Studies conducted in other

countries show similar results and note additional benefits, including

a rise in infant birth weight, decreased rates of childhood pneumonia,

and an improvement in self-reported respiratory symptoms.28

While the NISP is regarded as a successful public health intervention,

technological advancements have led to more efficient, cleaner

stove models.24 Environmental monitoring studies show persistent levels

of household air pollution above national safety standards for indoor air,

including homes that previously participated in the programme.27

While the main aim of this intervention is to reduce COPD risk in

women, the intervention would additionally benefit other household

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Early screening programmes

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of patients who have diagnosable COPD but are asymptomatic or

unaware of their condition.32,33 Prevalence data from China support

the need for COPD screening; one study showed that of participants

meeting COPD diagnostic criteria, 35.5% were asymptomatic and

only 35.1% had a previous diagnosis before study enrolment.5

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physicians.4

Numerous COPD screening strategies exist worldwide, with the

majority conducted in the primary care setting.33 A randomised

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concluded that implementation of the Respiratory Health Screening

Questionnaire (RHSQ), with follow-up diagnostic spirometry in

high-risk patients, was an effective early COPD detection strategy.

Preliminary cost estimations found this intervention economically

feasible.26 Implementation of a similar screening programme in China

could help to identify high-risk women.

While the RHSQ has been validated in a Western setting, it would

need to be replaced by a locally developed screening tool, such as the

COPD Screening Questionnaire, or adjusted and translated for a

Chinese population.34 For example, the RHSQ does not assess for

biomass smoke exposure, one of the leading COPD risk factors for

women in China. In primary care facilities that lack resources for full

spirometry, case-identification spirometry can be used to refer

patients for follow-up rather than diagnosis.35

Slowed disease progression, better symptom control, and integration

of useful maintenance treatments are just some advantages to early

COPD detection and diagnosis. This will ultimately lead to long-term

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and decreased health expenditure.33

Conclusion

Previously understudied, COPD in women is gaining attention

worldwide as a public health threat, including in China. Several factors

make Chinese women of particular interest, including their

disproportionate rates of biofuel exposure, the potential rise in female

smokers, and high exposure to second-hand smoke. COPD

prevalence data in women contradicts the low percentage of female

smokers; this inconsistency highlights the impact of indoor pollution

and questions if there are genetic factors that make women more

susceptible to COPD. Further studies should examine this theory,

which is a topic of significant controversy within the literature.

Furthermore, although a large task given its population size, a

nationwide epidemiological study would clarify differing reports

on COPD in China, with focused analysis on distinct populations

like women. Meanwhile, a large-scale meta-analysis of the literature

to date could synthesise current data to better inform public

health decision-making. The Chinese Government should also

increase health sector capacity to detect, manage, and treat

COPD.

Finally, no risk factor operates independently; like other disease states

and health outcomes, COPD risk is multifaceted and occurs at

multiple tiers of influence. The confluence of individual behaviours,

society/community, and larger socioeconomic, cultural, and

environmental conditions, all contribute to health.36 This includes

overarching national health efforts like public health policies and

legislation. China’s compliance with WHO regulations will reduce the

burden of disease on individuals and communities, and decrease the

economic burden on the public healthcare system.

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7. Halbert RJ, Isonaka S, George D et al. Interpreting COPD prevalence

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smoking among Chinese adult men and women: findings of the 2010

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12. Chan-Yeung M, Aït-Khaled N, White N et al. The burden and impact of

COPD in Asia and Africa. Int J Tuberc Lung Dis. 2004;8(1):2-14.

13. Ho MG, Ma S, Chai W et al. Smoking among rural and urban young

women in China. Tob Control. 2010;19(1):13-8.

14. Gu D, Wu X, Reynolds K et al. Cigarette smoking and exposure to

environmental tobacco smoke in China: The international collaborative

study of cardiovascular disease in Asia. Am J Public Health.

2004;94(11):1972-6.

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pulmonary disease in China. Respirology. 2013;18(Suppl.3):4-9.

16. Xu F, Yin X, Shen H et al. Better understanding the influence of cigarette

smoking and indoor air pollution on chronic obstructive pulmonary

disease: a case-control study in mainland China. Respirology.

2007;12(6):891-7.

17. Chapman RS, He X, Blair AE et al. Improvement in household stoves and

risk of chronic obstructive pulmonary disease in Xuanwei, China:

retrospective cohort study. BMJ. 2005;331(7524):1050.

18. Liu S, Zhou Y, Wang X et al. Biomass fuels are the probable risk factor for

chronic obstructive pulmonary disease in rural South China. Thorax.

2007;62(10):889-97.

19. World Health Organisation. WHO Report on The Global Tobacco

Epidemic. MPOWER Packag. 2008:1-336.

20. Yamato H, Jiang Y, Ohta M. WHO Framework Convention on Tobacco

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21. Fong GT, Sansone G, Yan M et al. Evaluation of smoke-free policies in

seven cities in China, 2007-2012. Tob Control. 2015;24(Suppl. 4):iv14-20.

22. World Health Orgnization Western Pacific Region and University of

Waterloo, ITC Project. Smoke-free policies in China: Evidence of

effectiveness and implications for action. Manila: 2015.

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Article 11 of the WHO Framework Convention on Tobacco Control

(Packaging and labelling of tobacco products). Tob Control. 2008.

24. Smith KR, Keyun D. A Chinese national improved stove program for the

21st century to promote rural social and economic development. Energy

Policy Res. 2010;1:24-5.

25. Hammond D, Fong GT, McNeill A et al. Effectiveness of cigarette warning

labels in informing smokers about the risks of smoking: findings from the

International Tobacco Control (ITC) Four Country Survey. Tob Control.

2006;15(Suppl.3):19.

26. Dirven JAM, Tange HJ, Muris JWM et al. Early detection of COPD in

general practice: patient or practice managed? A randomised controlled

trial of two strategies in different socioeconomic environments. Prim Care

Respir J. 2013;22(3):331-7.

27. Sinton JE, Smith KR, Peabody JW et al. An assessment of programs to

promote improved household stoves in China. Energy Sustain Dev.

2004;8(3):33-52.

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interventions to reduce household air pollution in low and middle income

countries: a descriptive systematic review. BMC Public Health.

2015;15:650.

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obstructive pulmonary disease after improved cooking fuels and kitchen

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2014;11(3):e1001621.

30. Bruce N, Smith K, Ezzati M et al. Addressing the impact of household

energy and indoor air pollution on the health of the poor: implications for

policy action. 2002. [Internet]. Available from:

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31. Mehta S, Shahpar C, Appia A et al. The health benefits of interventions to

reduce indoor air pollution from solid fuel use: a cost-effectiveness analysis.

Energy Sustain Dev. 2004;8(3):53-9.

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Christopher S. Lozano


Abstract

Objective: The obesity epidemic presents a major challenge to health and chronic disease, most

notably cardiovascular disease. With the global burden of obesity expected to continue to increase,

many strategies for weight loss have been developed. Intermittent fasting (IF) is a weight loss

technique characterised by short periods of semi-restricted food intake interspersed with extended

periods of fasting. This is in contrast to continuous restriction (CR) diet regimens, which reduce the

total number of calories consumed in a conventional eating schedule. There is some evidence,

particularly in animal studies, that IF is more effective for weight loss compared to CR. This systematic

review aims to compile and evaluate all the human trials of IF and CR to determine whether there is

a clear advantage of one technique over the other.

Methods: A search using relevant keywords yielded 659 articles, of which seven were found to meet

the inclusion criteria for this analysis. These seven articles investigated a variety of different fasting

regimens.

Results: None of the studies demonstrated a significant difference in weight loss between the IF and

CR groups. There is some evidence to suggest that IF might be more effective than CR because it is

more conducive to diet adherence.

Conclusions: Within the current literature, there is no definitive answer as to whether IF is superior

to CR for weight loss. Additional human studies should be conducted to better clarify this clinically

relevant question, and should include adherence as part of their analysis.


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Fasting fiction: is intermittent fasting superior toconventional dieting?

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Introduction

Intermittent fasting (IF) is defined as a diet regimen that cycles

between periods of fasting (low or no food intake) interspersed

with periods of less restricted or unrestricted food intake.1 Fasting

in various forms has been around for thousands of years, rooted

in asceticism or for spiritual purposes in various religions.2 While

fasting for religious reasons persists, modern-day fasting is often for

the purpose of weight loss. The theory behind weight loss in IF is

similar to conventional dieting in that it creates a caloric deficit.

The key difference between IF and conventional diets lies in the

timing of caloric ingestion. Most conventional diets rely on a

continuous restriction (CR) of calories (e.g., reductions in daily caloric

intake by 25% each day) or simply the complete restriction of certain

types of food.

It is widely accepted that beingoverweight or obese carries a number of negative health effects. Increasedbodyweight is associated with anincreased risk for chronic diseasesincluding cardiovascular disease, diabetes, kidney and liver disease,

osteoarthritis, and cancer.

Various methodologies for IF have been studied; however, there is no

definitive regimen established as IF has only recently come under

mainstream scientific interest. The interval of fasting and degree of

restriction vary greatly across different studies. One IF regimen

restricts all eating to an eight-hour period during the day, which

typically results in the participant skipping one or more meals.3 Some

diets involve alternate-day fasting, characterised by zero food intake

every other day or a moderate restriction (50-70%) every other day.4-6

Another popular approach is the 5:2 method, in which fasting takes

place for two days of the week and the other five days have less

restriction or ad libitum food intake.7 On the more extreme end, some

studies have tested longer fasting periods of four to six days.8 Many

of these studies of IF for weight loss have been conducted in humans;

however, it is also important to note that studies in animals have

investigated IF in the context of far-reaching metabolic benefits for

health and disease beyond that of body composition and weight.1

It is widely accepted that being overweight or obese carries a number

of negative health effects. Increased bodyweight is associated with an

increased risk for chronic diseases including cardiovascular disease,

diabetes, kidney and liver disease, osteoarthritis, and cancer.9 A large

meta-analysis consisting of nearly three million subjects across 97

studies found a significant increase in all-cause mortality in

overweight individuals compared to non-overweight subjects.10 With

the global burden of obesity-related illness on the rise, there is an

increasing urgency to devise safe and effective ways for people to lose

excess weight.11 The question remains: what role should IF play in the

arsenal of weight management techniques?

Methods

Search strategy

The Scopus database (www.scopus.com) was used to search original

research articles on the use of IF and CR for weight loss. The search

was conducted in August 2018. A search string was designed using

the following terms: intermittent fasting; alternate day fasting;

whole-day fasting; time-restricted eating; continuous restriction;

consistent restriction; (long-term) caloric restriction; and (long-term)

energy restriction. These terms were combined with the terms weight

loss, weight reduction, fat mass loss, overweight, and obese/obesity.

Complete search results, including citation information and abstracts,

were exported as an RIS file and imported into Colandr

(www.colandr.com), a web-based platform for investigators to collect

research articles and keep track of which ones have been included or

excluded during the stages of a systematic review.

Inclusion criteria

Articles in this analysis were limited to randomised controlled trials

(RCTs) in human subjects. Review articles and basic science articles

(including animal studies) were excluded. Articles required

overweight or obese subjects (BMI ≥25) over 18 years of age. Studies

were included if they compared a variation of IF with a conventional

CR diet. Studies were deemed acceptable if the intervention was at

least four weeks long and included at least ten subjects in each

treatment group. Initially, abstracts were scrutinised to generate a

smaller list of potentially relevant articles. Of these relevant articles,

full texts were retrieved and examined. Articles that did not meet the

inclusion criteria were discarded. Figure 1 shows a PRISMA diagram

of the stages of systematic review in this study.

Results

Study identification

The search of the Scopus database yielded 659 articles in total. Abstracts

of these articles were reviewed for relevance and suitability based on the

inclusion criteria. This initial screen of abstracts left 15 articles that

warranted additional review. After scrutiny of these full texts, eight

articles were excluded and seven were included for final analysis.

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Systematic review

The following information was extracted from each article: study

design and duration; study population characteristics (sex, age, and

BMI); prescribed treatments; weight change from baseline; and,

participant adherence. This data is shown in Table 1.

Demographics

Based on the inclusion criteria, all seven studies examined overweight

and/or obese individuals. Three studies recruited obese individuals

(BMI >30) exclusively,12-14 three studies allowed overweight

participants (BMI ≥2515,16 or BMI >2717), and one study did not specify

a BMI cut-off, although the average body fat percentage of

participants was noted to be 47%.18 The age of participants also

varied across studies. Four studies included a general adult population

(females ≥18, and males and females ages 18-55, 18-64, or 21-70).

The other three studies included more specific populations, such as

postmenopausal females and males aged 55-75 (war veterans).

Group size varied across the different studies, ranging from 10 to 58

participants.

Variations in IF diet

In four out of the seven studies, a 5:2 IF diet was employed. In the 5:2

diet structure, two non-consecutive days per week are assigned to

fasting and the remaining five days allow ad libitum eating. The

degree of caloric restriction on the fasting days varies. Of these 5:2

studies, three instructed participants to consume a fixed amount of

energy on the fasting days (1,670-2,500kJ,17 600kcal,13 or

400-600kcal14), while another study instructed subjects to eat 25% of

their energy requirement on fasting days.16

Conversely, in the alternate-day fasting technique, participants

alternated between a large caloric restriction on one day (‘fast day’)

followed by increased eating the next day (‘feast day’). Again, there

was some variability in the allocation of calories. For example, one

study allowed for caloric intake equivalent to 25% of the energy

requirement on fast days, followed by 125% caloric intake on feast

days.15 Another study instructed zero caloric intake on fast days and

ad libitum intake on feast days.12 One study did not specify their IF

protocol, although the authors indicated that the intervention was

designed to reduce bodyweight by 1% per week.18 In each study, the

IF group was compared to a CR group in which participants were

required to have a consistent daily restriction that was of less

magnitude. The degree of caloric restriction in these continuous

groups varied slightly, but most involved a 25-30% calorie deficit

per day.

Weight loss assessment

All studies examined demonstrated weight loss in both their IF groups

and their CR groups, though the degree of weight loss varied

between studies. The length of intervention and follow-up across the

different studies ranged from eight weeks to six months. All but one

study measured the change in bodyweight as the average number of

kilograms lost over time, while the other study measured the loss as

Articles from initial Scopusdatabase search

(n=659)

Review articles, basic science oranimal studies, and off-topic

articles (n=644)

Abstracts obtained and reviewed(n=659)

Studies not meetinginclusion criteria

(n=8)

Studies meeting inclusioncriteria used in review

(n=7)

Articles selected for full-textreview (n=15)

FIGURE 1: PRISMA diagram showing the process of inclusion and exclusion of articles for this systematic review.

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an average percentage of the participants’ baseline bodyweights.

The largest weight loss was reported by Arguin et al., where the IF

group lost 10.7±3.0kg on average after five weeks of IF followed by

five weeks of energy maintenance.18 Interestingly, the authors did not

give a detailed breakdown of the dietary intervention employed other

than to say it was designed to reduce bodyweight by 1% each week.

They did, however, include the macronutrient composition of the

diet: 55% carbohydrates, 30% fat, and 15% protein. The CR group in

this study experienced a similar weight loss of 9.5±2.1kg.18

The least amount of weight loss from IF was seen in the study by

Carter et al., where participants had an average 2.0±1.9kg reduction

in bodyweight at the end of an eight-week programme (and

negligible change at 12-month follow-up).17 The IF methodology

used in this study was a 5:2 day ‘feed-fast’ protocol in which subjects

consumed 1,670-2,500kJ (400-600kcal) on fast days. In this study, the

CR group experienced an average loss of 3.2±2.1kg after eight weeks

on a 5,000-6,500kJ (1,200-1,550kcal) daily diet. This difference in

weight loss between the CR and IF treatment groups was ultimately

found to be non-significant.

An important finding is that none of the studies demonstrated a

significant difference in weight loss between the IF and CR groups. A

detailed breakdown of study follow-up and weight loss results can be

found in Table 1.

Discussion

The purpose of this systematic review was to examine different RCTs

that explored the use of IF versus CR for weight loss. Of the existing

human literature, only seven studies have directly compared IF to CR

diets, and none of them have shown a significant difference. There

are a number of underlying considerations that need to be taken into

account with this result. First and foremost, the most important factor

at play appears to be calories consumed versus calories expended. In

each study, there was a comparable caloric deficit between the CR

and IF groups. In other words, the small differences in weight change

that were observed most likely come from factors other than energy

input. For example, adherence to the diet likely played a large

role. This is evidenced by the fact that some studies reported their

results ‘per protocol’, meaning that they only measured results in

subjects who adhered to the prescribed treatment, while other

studies reported their results as ‘intention to treat’, meaning that

they included all subjects regardless of diet adherence. Adherence is

a major issue in the efficacy of weight loss diets and there is

some evidence to suggest that IF might be conducive to better

adherence, although more research is needed on this topic to better

understand the importance of adherence.19 Overall, the exclusion of

non-adherent participants in some of the trials examined makes it

difficult to compare their results to those from trials that used an

intention to treat analysis.

The current literature indicates that IF may impart two benefits over

conventional CR. First, IF appears to be more tolerable than CR and

therefore results in improved long-term adherence. The second

proposed benefit is that IF incites some metabolic processes that

impart additional benefits beyond weight loss, such as reducing

oxidative stress.20 Animal studies of IF have demonstrated a potential

benefit for cardiovascular disease, type 2 diabetes, and even cancer.1

While there have been extensive studies of these effects in animals,

less work has been done in humans. Until more research is conducted

in these areas, a definitive answer regarding the efficacy of IF over CR

cannot be given.

Conclusion

IF is a safe and effective method of weight loss as demonstrated by

several human studies. This systematic review did not find evidence

that IF was superior to CR for weight loss in overweight subjects;

however, this conclusion comes with a caveat. Further studies must

include the role of adherence as well as the benefits of IF outside pure

caloric deficit to accurately determine the diet regimen of choice.

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review

Author Year Study Study Groups Intervention Weight Adherence Conclusion design population change

Arguin et al.18

Carter et al.17

Catenacciet al.12

Conley et al.13

Harvie et al.16

Sundfør et al.14

2012

2016

2016

2018

2011

2018

RCT; 10-20-weekintervention,1-year FU

RCT; 8-weekinterventionand12-month FU

RCT; 8-weekintervention,24-week FU

RCT; 6months

RCT; 6months

RCT; 6-monthweight lossphase,6-monthweightmaintenancephase

F; post-menopausal(average age= 60.5),obese(average BF%= 47.2)

F; age ≥18,BMI ≥27

M and F; age= 18-55, BMI≥30

M; age =55-75, BMI≥30

F; age =30-45, BMI = 25-40

M and F; age= 21-70, BMI = 30-45

IF: N = 12CR: N = 10

IF: N = 39CR: N = 36

IF: N = 14CR: N = 14

IF: N = 12CR: N = 12

IF: N = 53CR: N = 54

IF: N = 54CR: N = 58

After weight loss phase:*IF: -4.0±1.4kgCR: -3.5±1.5kg

After weight maintenancephase:*IF: -10.7±3.0kgCR: -9.5±2.1kg

After 8 weeks ofintervention:*IF: -2.0±1.9kg

CR: -3.2±2.1kg(mean ± SD)At 12-month FU:*IF: -2.1±3.8kg

CR: -4.2±5.6kg(mean ± SD)

At 8 weeks:*IF: -8.2±0.9kg

CR: -7.1±1.0kgAt 32 weeks:*IF: -5.7±1.5kgCR: -5.0±1.6kg

At 6 months:**IF: -5.3±3.0kgCR: -5.5±4.3kg

At 1 month:*IF: -1.8kgCR: -1kg

At 3 months:*IF: -4.1kgCR: -3kg

At 6 months:*IF: -5.7kgCR: -4.5kg

At 3 months:**IF: -7.1 ± 3.7kgCR: -7.4 ± 3.8kg

At 6 months:**IF: -9.1 ± 5.0kgCR: -9.4 ± 5.3kg

Changes between 6- and12-month FU:**IF: +1.1 ± 3.8kgCR: +0.4 ± 4.0kg

2 participantsfrom CR and 1participant from IF excluded fromanalysis (due tofactors other thanadherence)

Attrition duringfollow-up period:IF = 12CR = 12

Attrition:IF = 3CR = 22 participantswithdrew beforestarting theintervention

Attrition:IF = 1CR = 0

Attrition:IF = 11CR = 7

Attrition: WLphase:IF = 1CR = 2

WM phase:IF = 3CR = 1

Differencesin weightloss betweengroups werenotsignificant






Table 1: Summary of design and findings of IF versus CR trials included in this review.

IF: 5-week energyrestriction period followedby a 5-week energymaintenance period

CR: 15-week energyrestriction period followedby a 5-week energymaintenance periodBoth diets were designedto reduce body weight by1%/week during weightloss phase

IF: 1,670-2,500kJ/day for2/7 days per week;unrestricted 5/7

CR: 5,000-6,500kJ/day for7/7 days per week

IF: alternating days of 0kcalintake with unrestrictedintake days

CR: 400kcal caloric deficiteach day

IF: 600kcal/day for 2/7non-consecutive days perweek; unrestricted 5/7

CR: 500kcal/day restrictionfrom required amount for7/7 days per week

IF: 25% of energyrequirement for 2/7 daysper week; unrestricted 5/7

CR: 75% of energyrequirement for 7/7 daysper week

IF: 400-600kcal/day for 2/7non-consecutive days perweek; unrestricted 5/7

CR: reduction by ~30% ofenergy requirement perday

Author Year Study Study Groups Intervention Weight Adherence Conclusion design population change

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References

1. Patterson RE, Sears DD. Metabolic effects of intermittent fasting. Annu Rev

Nutr. 2017;37:371-93.

2. Persynaki A, Karras S, Pichard C. Unraveling the metabolic health benefits of

fasting related to religious beliefs: a narrative review. Nutrition.

2017;35:14-20.

3. Gabel K, Hoddy KK, Haggerty N et al. Effects of 8-hour time restricted feeding

on body weight and metabolic disease risk factors in obese adults: a pilot

study. Nutr Healthy Aging. 2018;4(4):345-53.

4. Horne BD, Muhlestein JB, Lappé DL et al. Randomized cross-over trial of

short-term water-only fasting: metabolic and cardiovascular consequences.

Nutr Metab Cardiovasc Dis. 2013;23(11):1050-7.

5. Johnson JB, Summer W, Cutler RG et al. Alternate day calorie restriction

improves clinical findings and reduces markers of oxidative stress and

inflammation in overweight adults with moderate asthma. Free Radic Biol

Med. 2007;42(5):665-74.

6. Varady KA, Bhutani S, Klempel MC et al. Alternate day fasting for weight loss

in normal weight and overweight subjects: a randomized controlled trial.

Nutr J. 2013;12(1):146.

7. Patterson RE, Laughlin GA, LaCroix AZ et al. Intermittent fasting and human

metabolic health. J Acad Nutr Diet. 2015;115(8):1203-12.

8. Safdie FM, Dorff T, Quinn D et al. Fasting and cancer treatment in humans: a

case series report. Aging (Albany NY). 2009;1(12):988-1007.

9. Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121(6):21-33.

10. Flegal KM, Kit BK, Orpana H et al. Association of all-cause mortality with

overweight and obesity using standard body mass index categories. JAMA.

2013;309(1):71.

11. Cummings J, Aisen PS, DuBois B et al. Drug development in Alzheimer’s

disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.

12. Catenacci VA, Pan Z, Ostendorf D et al. A randomized pilot study comparing

zero-calorie alternate-day fasting to daily caloric

restriction in adults with obesity. Obesity (Silver Spring). 2016;24(9):1874-83.

13. Conley M, Le Fevre L, Haywood C et al. Is two days of intermittent energy

restriction per week a feasible weight loss approach

in obese males? A randomised pilot study. Nutr Diet. 2018;75

(1):65-72.

14. Sundfør TM, Svendsen M, Tonstad S. Effect of intermittent versus continuous

energy restriction on weight loss, maintenance and cardiometabolic risk: a

randomized 1-year trial. Nutr Metab Cardiovasc Dis. 2018;28(7):698-706.

15. Trepanowski JF, Kroeger CM, Barnosky A et al. Effect of alternate-day fasting

on weight loss, weight maintenance, and cardioprotection among

metabolically healthy obese adults. JAMA Intern Med. 2017;177(7):930-8.

16. Harvie MN, Pegington M, Mattson MP et al. The effects of intermittent or

continuous energy restriction on weight loss and metabolic disease risk

markers: a randomized trial in young overweight women. Int J Obes (Lond).

2011;35(5):714-27.

17. Carter S, Clifton PM, Keogh JB. The effects of intermittent compared to

continuous energy restriction on glycaemic control in type 2 diabetes; a

pragmatic pilot trial. Diabetes Res Clin Pract. 2016;122:106-12.

18. Arguin H, Dionne IJ, Sénéchal M et al. Short- and long-term effects of

continuous versus intermittent restrictive diet approaches on body

composition and the metabolic profile in overweight and obese

postmenopausal women: a pilot study. Menopause. 2012;19(8):870-6.

19. Harvie M, Howell A. Potential benefits and harms of intermittent energy

restriction and intermittent fasting amongst obese, overweight and normal

weight subjects – a narrative review of human and animal evidence. Behav Sci

(Basel). 2017;7(1):pii:E4.

20. Wegman MP, Guo MH, Bennion DM et al. Practicality of intermittent fasting

in humans and its effect on oxidative stress and genes

related to aging and metabolism. Rejuvenation Res. 2015;18(2):

162-72.


review

Trepanowskiet al.15

2017 RCT, 6-monthweight lossphase followedby 6-monthweightmaintenancephase

M and F;age = 18-64,BMI =25-39.9

IF: N = 34CR: N = 35Ctrl: N = 31

At 6 months**:IF: -6.8% BWCR: -6.8% BW

At 12 months**:IF: -6.0% BWCR: -5.3% BW

Attrition: WLphase:IF = 9CR = 6

WM phase:IF = 4CR = 4

Differences inweight lossbetween theinterventiongroups werenotsignificant

IF: 25% of energy needs onfast days; 125% of energyneeds on ‘feast days’,alternating each day.

CR: 75% of energy needsevery day

Ctrl: no restriction

BF = body fat; BW = bodyweight; Ctrl = control group; RCT = randomised controlled trial; F = female; M = male; FU = follow-up; SD =standard deviation; WL = weight loss; WM = weight maintenance.*reported per protocol**reported as intention to treat

David Seligman


Abstract

Osteoarthritis of the hip is a leading cause of chronic disability worldwide. Total hip arthroplasty

reduces pain, increases mobility, and has very high patient-reported satisfaction rates postoperatively.

Three of the common surgical techniques include the posterior approach, the direct lateral approach,

and the direct anterior approach (DAA). The DAA is unique in that it utilises both an intermuscular

and internervous plane; however, the procedure may come with drawbacks including a steeper

surgical learning curve and increased risk of intraoperative fracture. The posterior approach is the

most common technique with reports demonstrating shorter surgical times but greater dislocation

rates. The direct lateral approach allows for greater exposure to the femur; however, it is associated

with postoperative Trendelenburg gait. There remains no consensus among surgeons regarding the

best technique or which outcomes are most important. Meta-analyses comparing these three

techniques have mostly failed to determine the superiority of one over another, with the exception

of one study supporting the direct lateral approach. There remains a need for more robust

randomised controlled trials and a better defined standard for outcomes of interest in order to

establish the most advantageous approach for both short- and long-term recovery, joint functionality,

and pain reduction.


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‘Joint’ decision-making:how to determine thebest approach for totalhip arthroplasty

RCSIsmjreview


Introduction

Osteoarthritis (OA) is the most common chronic condition of the

joints and is a leading cause of chronic disability in the elderly

population worldwide.1 OA of the knees and hips can cause

significant impairment in activities of daily living, creating barriers to

engagement in regular exercise and maintenance of a healthy

lifestyle. OA is a progressive disease and many treatment options,

such as anti-inflammatory medications and intra-articular steroid

injections, are aimed at symptomatic relief without altering the

underlying pathophysiology. In more severe and debilitating cases,

patients may decide to receive a total joint replacement in order to

reduce pain and restore functionality.2

Total hip arthroplasty (THA) is an increasingly popular procedure,

with over 90% of patients reporting satisfaction with their results

after surgery.3 Factors including an ageing population, increased

life expectancy, and the obesity epidemic have contributed to an

increased need for joint replacement surgery, and greater

expectations for longevity in the lifespan of prostheses.4 In fact,

it is estimated that the demand for hip replacements in Organisation for

Economic Co-operation and Development (OECD) countries

will rise by 1.2% per year, reaching roughly 2.8 million implants

per year in 2050.5 In order to combat this issue of longevity, an

abundance of research has been done that focuses on optimising

durable and longer-lasting materials such as stainless steel, titanium, and

ceramic variations for the ball and socket joint components.6 In addition

to modifying the materials used, continued advancements

in surgery, such as minimally invasive techniques and computer- assisted

sizing, have improved short- and long-term outcomes and reduced the

incidence of intraoperative complications and postoperative pain.7

Despite the ubiquity of the THAprocedure, there is a lack of consensusregarding the gold standard techniqueamong surgeons, with many lookingtowards newer, minimally invasive

approaches.

Shorter post-surgery recovery times prove to be advantageous to both

patients and hospitals. As fewer days are required for in-hospital recovery,

patients can return to their daily commitments sooner, allowing the

procedure to be less of an imposition on their lives and schedules. The

decreased hospital stays also alleviate strain on the hospital by utilising

fewer resources and freeing up beds designated for recovery.8

Despite the ubiquity of the THA procedure, there is a lack of

consensus regarding the gold standard technique among surgeons,

with many looking towards newer, minimally invasive approaches.

These modern approaches can further decrease recovery time,

allowing patients to get back on their feet and out of the hospital

more promptly.9 This review will compare three commonly used THA

techniques, assess the benefits and drawbacks of each, and

summarise the findings from several key meta-analyses in the field.

Surgical approaches

The most commonly used surgical approaches to THA include the

posterior approach, the direct lateral approach, and the newly

popularised direct anterior approach (DAA) (Figure 1).10 Several

variables may inform both patient and physician preference. For

example, surgeons may weigh short- and long-term functional

FIGURE 1: Schematic representation of the common approaches to total hip arthroplasty (THA): A. Posterior approach; B. Direct lateral approach; and C. Direct anteriorapproach. Adapted from Orthobullets.com – https://www.orthobullets.com/recon/12116/tha-approaches.

Gluteus maximus

t

Short rotators

Femoral neck

t

Gluteus medius

t

t

Quadratus femoris

t

Vastus lateralis

t

Fascia lata

t

tt

Tendon of gluteusminimus

Joint capsule

t t t

Incised tendon ofgluteus medius

Greatertrochanter

Vastus lateralis(incised)

tt

SartoriusGluteus medius

Ascending branch oflateral femoralcircumflex artery

t

t

Tendon of rectusfemoris(cut)

t

Iliopsoas

Femoral head and neck

t

Rectus femoris

t

Tensor fasciae latae

t

A B C

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outcomes against the intraoperative risks and technical difficulty

associated with each technique. Of particular interest, many studies

have emphasised short-term recovery, length of hospitalisation,

reported pain, and long-term functionality as important

decision-making variables.11

Posterior approach

The posterior approach to THA gained popularity in the 1950s and is

used ubiquitously today. A recent survey across 57 countries revealed

that 45% of surgeons prefer the posterior approach.12

Technique

The patient is placed in the lateral decubitus position. An incision

is made 5cm distal to the greater trochanter and centred on the

femoral diaphysis. Fascia overlying the gluteus maximus is divided and

the muscle is split. The gluteus maximus is retracted and the sciatic

nerve is protected. The short external rotators and piriformis are incised

at their insertion on the greater trochanter (Figure 1A). The posterior

joint capsule is incised to expose the femoral head and neck.13

Discussion

This technique provides good visualisation of both the acetabulum and

femur, and spares the abductor muscles, which are involved in lateral

and anterior approaches.13 A major drawback to the posterior approach

is a significantly higher postoperative dislocation rate compared to the

other techniques. A 2002 meta-analysis reported a dislocation rate of

3.23% in posterior THA compared to 0.55% in the direct lateral

approach and 2.18% in the anterolateral approach.14

Direct lateral approach

The direct lateral approach originated in the 1980s and has gained

popularity since. In fact, it is the most commonly used technique in

Canada. Worldwide, it is the second most popular approach with

42% of surgeons preferring this method.12

Technique

The patient is placed in the lateral decubitus position. The lower leg

and foot are bagged to allow for manipulation during the procedure.

A longitudinal incision of roughly 10cm is made, extending over the

greater trochanter. The fascia is split in the area that divides the tensor

fascia lata (TFL) and gluteus maximus (Figure 1B). The gluteus

minimus is exposed and divided with one-third anteriorly and

two-thirds posteriorly. The gluteus minimus and the joint capsule are

then split to visualise the femoral head.13

Discussion

This approach allows considerable exposure of the femur, improving

visualisation into the femoral shaft. This eases the process of reaming

(widening and smoothing) the canal in preparation for the insertion of the

stem (femoral joint component).13 It is associated with very low dislocation

rates.14 However, one well-documented complication associated with this

approach is damage to the superior gluteal nerve, which can lead to a

Trendelenburg gait.15 This deficit is often short term, with most cases

improving spontaneously by 12 months postoperatively.

Direct anterior approach

The DAA has gained tremendous popularity in recent years both in

the surgical community and in the media. Interestingly, it is not a new

procedure, but rather was first described in the 1940s and later

modified in the 1950s.13 In a 2013 survey, roughly 10% of surgeons

favoured this approach in their practice, which has likely increased in

the last five years.12 The allure of this approach relates to its utilisation

Table 1: Summary of reported benefits and drawbacks for three common approaches to total hip arthroplasty. Adaptedfrom Petis et al., 2015.

Posterior approach Lateral approach Direct anterior approach

Advantages • Shorter surgical time • Low dislocation rate • Intermuscular and internervous plane • Shorter learning curve • Excellent exposure of the (muscle sparing)

• Less blood loss femur for stem insertion • Shorter recovery time

• Spares abductor muscles • Shorter length of stay in hospital

Disadvantages • Greater dislocation rate • Greater risk for damage to • Steeper learning curve • Greater risk of sciatic the superior gluteal nerve • Longer surgical time

nerve injury resulting in Trendelenburg gait • Damage to LFCN

• Greater muscle damage • Greater risk for heterotopic • Intraoperative fractures (femur, ankle)

ossification • Limited exposure of the proximal femur

LFCN = Lateral femoral cutaneous nerve.

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of an intermuscular and internervous plane to access the joint. The

DAA allows the surgeon to enter through the Hueter interval between

the sartorius and TFL without incising the muscle.10

The DAA has gained tremendouspopularity in recent years both in the surgical community and in the media. Interestingly, it is not a new procedure, but rather was firstdescribed in the 1940s and later

modified in the 1950s.

Technique

The patient is placed in the supine position with or without a

specialised surgical table. The leg is attached to a mobile element that

allows for controlled movement of the limb intraoperatively.16 An

incision is made 3cm lateral and 3cm distal to the anterior superior

iliac spine down to the level of the fascia. The TFL and sartorius

muscle are separated (Figure 1C), and major vessels in this region are

ligated. Fat is removed to visualise the capsule and the head of the

rectus femoris is reflected for better exposure.

Capsulectomy/capsulotomy is performed to expose the femoral neck.

The surgical table allows better elevation of the femur for stem

insertion. The positioning of the joint implant can also be confirmed

using intraoperative x-ray.10

Discussion

Reported benefits for this approach include reduced pain, improved

function, faster discharge, faster return to mobility, and better stride

time and cadence speed.17,18 However, some studies reported difficult

learning curves among surgical trainees, new intraoperative fracture

risks, and increased risk for infection due to proximity of the moist

groin area.10,19 Other reported complications include damage to the

lateral femoral cutaneous nerve (LFCN), dissection of the

neurovascular bundle of the femoral triangle, and ankle fractures

associated with the special surgical table.20 Additionally, there is

greater difficulty visualising the femoral canal using the DAA.

Therefore, many joints are being reconstructed using shorter stem

designs, which are newer and consequently do not have the same

proven performance history as the more conventional stems.21

Weighing the options

Several prospective and retrospective studies have compared

outcomes across patients having undergone THA with these three

surgical approaches. The commonly reported advantages and

drawbacks are summarised in Table 1. Some studies have suggested

that the DAA results in less muscle damage and better gait

mechanics.18,22 Other studies have reported reductions in

postoperative pain scores, length of hospitalisation, and earlier

discontinuation of ambulatory devices with the DAA.23 Most studies

found similar long-term outcomes with respect to functionality and

revision rates.24 Noted pitfalls of the DAA include a reportedly difficult

learning curve for surgeons, as well as complications such as ankle

fractures and damage to the LFCN, drawbacks that are not noted in

other techniques.16,25 Many of the studies reporting complication

rates are retrospective and non-comparative.

A research group based in Melbourne, Australia, has commenced a

parallel three-arm randomised controlled trial (RCT) comparing the

posterior, direct lateral, and direct anterior approaches in a sample

size of 243 patients.24 They will be assessing patient-reported pain

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and function at two years postoperatively using the Oxford Hip Score

(OHS). Secondary outcomes will include length of stay and rates of

dislocation, infection, intraoperative fractures, and various other

complications.24

Meta-analyses

The following selected meta-analyses provide comparisons for these

procedures, outlining various outcomes of interest.

Anterior vs posterior approach

In their 2015 meta-analysis, Higgins et al. looked at 17 studies

assessing the anterior vs posterior approach.4 The authors concluded

that there was insufficient evidence to support the superiority of one

approach over another. The anterior approach may demonstrate

reductions in early patient-reported pain, function, and narcotic

consumption. The study also found significant reductions in length of

stay and dislocation rates in the anterior group.4 The posterior

approach trended towards lower estimated blood loss and operation

time without statistical significance. There was no difference in gait

function recovery or intraoperative fractures.4

Direct anterior vs direct lateral approach

Yue et al. included 12 studies in a meta-analysis comparing the direct

anterior and direct lateral approaches.26 The results of this

meta-analysis suggested that the DAA was associated with lower

reported pain in the early postoperative period, shorter length of

hospital stay, and greater functional rehabilitation in the early period.

It was also found that the DAA was associated with longer average

surgical time. There was no significant difference between the groups

with regard to perioperative complication rates, transfusions, and

radiological outcomes.26

Posterior vs direct lateral approach

Berstock et al. performed a meta-analysis of five studies comparing

the posterior and direct lateral approaches.27 The study failed

to determine superiority of one approach over another in terms

of functional outcomes. The results of this meta-analysis favoured

the posterior approach for reduction in the risk for Trendelenburg

gait as well as stem malposition. The posterior group trended

insignificantly towards reduced heterotopic ossification and

dislocation rates.27

Cross comparisons

Putananon et al., in their 2018 meta-analysis, included the following

comparative studies: four anterior vs direct lateral approach; four direct

anterior vs posterior approach; and five direct lateral vs posterior

approach.28 The overall recommendation of this review was in favour of

the direct lateral approach, which was found to be most favourable for

postoperative pain, complications, and postoperative functionality.28

Discussion

Relative to other techniques, the DAA is more technically demanding

with a steeper surgical learning curve. Thus far, the evidence for

long-term functionality following the DAA appears to be comparable to

other techniques.19 Although proponents in the media and surgical

community have emphasised its benefits, it is crucial to acknowledge

and assess new risks associated with the DAA, including intraoperative

fracture and neurovascular damage.29 Despite the promise of shorter

recovery times, surgeons and patients must also consider the cost

associated with this potential benefit. One study suggests that it may

take a surgeon, on average, 100 cases to become proficient in the

procedure.30 In reality, this means that during the first 100 operations,

patients may be at greater risk for complications, longer operative time,

and conversion to other techniques. If the DAA is indeed superior to

other techniques, then perhaps this early risk is outweighed by the

long-term potential benefit.

Despite the promise of shorter recoverytimes, surgeons and patients must alsoconsider the cost associated with thispotential benefit. One study suggeststhat it may take a surgeon, on average,

100 cases to become proficient.

Conclusion

It is evident that there are several viable techniques for THA, and there

are many advantages and drawbacks associated with each one. The

growing interest in the DAA among both patients and surgeons will

continue to provide short- and long-term data, which will better

inform the surgical community on the risk:benefit ratio between all

approaches. There remains a need for larger and more extensive

RCTs, which may shed light on the potential benefit of one technique

over another.26 Most review articles have advocated for physician

preference until more convincing evidence is available.4 Alternatively,

others have advocated for the direct lateral approach on the basis of

pain scores, functionality, and complications.28 Ultimately, the onus is

on the surgical team to adequately educate their patient and make a

joint decision on the technique that will improve outcomes, minimise

risk for complications, and give the best chance for longevity.

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after direct lateral approach to the hip. Clin Orthop Relat Res.

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17. Schweppe ML, Seyler TM, Plate JF, Swenson RD, Lang JE. Does surgical

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patients treated by minimally invasive direct anterior approach: a gait analysis

study. Clin Biomech (Bristol, Avon). 2009;24(10):812-8.

19. Kagan R, Peters CL, Pelt CE, Anderson MB, Gililland JM. Complications and pitfalls

of direct anterior approach total hip arthroplasty. Annals of Joint. 2018;3(5).

20. Barrett WP, Turner SE, Leopold JP. Prospective randomized study of direct

anterior vs postero-lateral approach for total hip arthroplasty. J Arthroplasty.

2013;28(9):1634-8.

21. Panichkul P, Parks NL, Ho H, Hopper Jr RH, Hamilton WG. New approach and

stem increased femoral revision rate in total hip arthroplasty. Orthopedics.

2016;39(1):e86-92.

22. Müller M, Tohtz S, Springer I, Dewey M, Perka C. Randomized controlled trial

of abductor muscle damage in relation to the surgical approach for primary

total hip replacement: minimally invasive anterolateral versus modified direct

lateral approach. Arch Orthop Trauma Surg. 2011;131(2):179-89.

23. Christensen CP, Jacobs CA. Comparison of patient function during the first six

weeks after direct anterior or posterior total hip arthroplasty (THA): a

randomized study. J Arthroplasty. 2015;30(9):94-7.

24. Talia AJ, Coetzee C, Tirosh O, Tran P. Comparison of outcome measures and

complication rates following three different approaches for primary total hip

arthroplasty: a pragmatic randomised controlled trial. Trials. 2018;19(1):13.

25. Goulding K, Beaulé PE, Kim PR, Fazekas A. Incidence of lateral femoral

cutaneous nerve neuropraxia after anterior approach hip arthroplasty. Clin

Orthop Rel Res. 2010;468(9):2397-404.

26. Yue C, Kang P, Pei F. Comparison of direct anterior and lateral approaches in

total hip arthroplasty: a systematic review and meta-analysis (PRISMA).

Medicine (Baltimore). 2015;94(50):e2126.

27. Berstock JR, Blom AW, Beswick AD. A systematic review and meta-analysis of

complications following the posterior and lateral surgical approaches to total

hip arthroplasty. Annals R Coll Surg Engl. 2015;97(1):11-6.

28. Putananon C, Tuchinda H, Arirachakaran A, Wongsak S, Narinsorasak T,

Kongtharvonskul J. Comparison of direct anterior, lateral, posterior and

posterior-2 approaches in total hip arthroplasty: network meta-analysis. Eur J

Orthop Surg Traumatol. 2018;28(2):255-67.

29. Lee GC, Marconi D. Complications following direct anterior hip procedures:

costs to both patients and surgeons. J Arthroplasty. 2015;30(9):98-101.

30. de Steiger RN, Lorimer M, Solomon M. What is the learning curve for the

anterior approach for total hip arthroplasty? Clin Orthop Rel Res.

2015;473(12):3860-6.

Brian Li1

Elysia Grose2

Shawn Khan3

Caberry Weiyang Yu4


2University of Ottawa

3University of Toronto

4Queen’s University

Abstract

Clinical autopsies are conducted to further investigate a patient’s cause of death and often include

sampling tissue for educational or research purposes. However, standard autopsies preclude the

collection of the high-quality tissue necessary for advanced laboratory assays due to the degree of

tissue necrosis that occurs after death. Rapid autopsies differ from standard procedures in that they

are conducted shortly after a patient’s death, thus preserving the structural integrity of important

biomolecules. The goal of this review is to outline the logistics of rapid autopsy programmes, and to

discuss the advantages of rapid autopsies and their relevance in the field of cancer research. To

ascertain the number and variety of studies that have utilised rapid autopsy-obtained tissue for cancer

research, a search was conducted on Ovid MEDLINE for all records from 1946 to January 4, 2017.

The majority of studies focused on molecular genetics, clinical research, and tumour heterogeneity,

most frequently using prostate, breast, and pancreas tissue. This article highlights the need for a

more robust and comprehensive systematic review on the impact of rapid autopsy programmes to

better inform and advise researchers on the value of rapid autopsies for oncology research.


RCSIsmjreview


Introduction

Rapid autopsy is an advanced method of

biospecimen procurement whereby autopsies are

conducted within six hours post mortem.1-3 This

technique was first introduced in the late 1980s;

however, its popularity has grown in recent years

due to its invaluable role in oncology research.4-6

Tissue obtained from rapid autopsies experiences a

much shorter post-mortem interval, defined as the

time between death and tissue preservation,

allowing scientists to collect high-quality specimens

for advanced laboratory analyses that require tissue

to have low levels of cellular degradation.7-9 Rapid

autopsies also allow for the collection of a much

larger volume of tissue, a biopsy option that is not

possible in living patients. Specimens from standard

The role of rapid autopsyin oncology

RCSIsmjreview


autopsies are snap frozen in liquid nitrogen and/or preserved in

formalin-fixed paraffin-embedded blocks.3 Rapid autopsies provide the

additional option of immediate fresh tissue distribution to cancer

research facilities, permitting analyses that are incompatible with

archival frozen or fixed tissue.7

Institutions capable of executing the collection and maintenance of

such a repository of high-quality biospecimens are invaluable resources

for clinicians and researchers who are interested in investigating tumour

biology, metastatic disease, and treatment resistance. Secondary to

significantly furthering our understanding of tumourigenesis, rapid

autopsy programmes offer a unique opportunity for advanced-stage

cancer patients to donate their bodies to cancer research. The purpose

of this review article is to inform current and future oncology

researchers of the enormous potential and utility of rapid

autopsy-obtained tissue. This review will also outline the rapid autopsy

process from patient recruitment to transport of the deceased.

Methods

A search was run on Ovid MEDLINE for all records from 1946 to

January 4, 2017, using the search terms rapid autopsy, rapid tissue

donation, and warm autopsy. The search strategy yielded 173

publications. After removing duplicates, 138 references underwent

title and abstract review, yielding 53 potentially relevant references on

the analysis of rapid autopsy tissue in the context of cancer research.

In total, 44 unique records relevant to oncology were identified upon

full-text review. Studies were then organised by tissue type as well as

topic of research, with some articles being included in multiple

categories. Studies regarding patient perspectives on rapid autopsies

or body donations were excluded. A PRISMA flow chart of the data

extraction process is shown in Figure 1.

Results – literature search

The majority of rapid autopsy programmes worldwide are located in

the United States (>90%). Over half of the studies analysed tissue

obtained from rapid autopsy programmes at Johns Hopkins Hospital

(26%) and the University of Michigan (26%). The mean sample size

was 17 patients (range: 1-76). Patients ranged from 14-90 years of age.

Autopsies were conducted 1 to 48 hours post mortem, although the

majority were performed within 6 hours. The top three most studied

rapid autopsy tissues were from the prostate, breast, and pancreas, as

shown in Figure 2. The top three research fields that utilised rapid

autopsy tissue included molecular genetics (54%), clinical research

(18%), and tumour heterogeneity (16%), as shown in Figure 3.

Results – rapid autopsy process

Recruitment

The eligibility criteria for rapid autopsies typically include patients

with advanced cancer and a ‘do not resuscitate’ status.3 The consent

process should include the patient’s family members and next of kin

or person with power of attorney, as they will have a role in

supporting the patient and facilitating later steps of co-ordination.3

The topic of tissue donation can be difficult, particularly for patients

diagnosed with terminal illnesses such as cancer. As such, the timing

and language of the discussion must be carefully chosen. Patients

should be approached by their medical oncologist or palliative care

physician only after a strong relationship has been established and

initial treatments have been unsuccessful.10 The label “rapid autopsy

programme” should also be avoided in clinical environments as

patients and family members may find the term too abrasive; “tissue

donation programme” has been suggested as an acceptableFIGURE 1: PRISMA flow chart of data extraction process.

FIGURE 2: Distribution of primary disease sites studied using rapid autopsy samples.

Prostate

Breast

Pancreatic

Renal cell carcinoma

Diffuse intrinsicpontine glioma

Other (embryonalrhabdomyosarcoma,intrahepaticcholangiocarcinoma,melanoma, multiple myeloma,ovarian)

173 total records identified through adatabase search – OVID MEDLINE(R)

138 records after duplicates removed

53 records identified after screeningby title and abstract

44 records identified upon full text review

t

t

t

9 records excluded

85 records excluded

tt

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alternative.11 Patients should also be reassured that their decision to

participate in, or decline, rapid autopsy will not have any effect on

their treatment options or quality of life.12

Patient tracking

Patients from either inpatient or outpatient settings can participate in

rapid autopsy programmes.3 It is important to track the patient’s

whereabouts to ensure that the correct individual will be contacting

the rapid autopsy team at the time of the patient’s death. For

instance, families of patients who are transferred to a hospice may ask

the nursing staff to contact the autopsy team at the time of death.

Transport of the deceased

Members of the rapid autopsy team are notified by the patient’s

healthcare provider, family member, next of kin, or person with

power of attorney so that immediate transport can be arranged.3 This

can be a difficult stage in the process since a balance must be found

between allowing family members ample time to grieve and ensuring

timely transport of the body for autopsy before significant tissue

degradation occurs. Extraneous factors such as traffic and weather

conditions can also lead to delays.

Autopsy

Biobanking is concurrently conducted during the autopsy and is

guided by the patient’s past radiology reports to locate primary

tumours and metastatic sites. Standard autopsy procedures are

applied, including a Y-shaped incision from the shoulders to the

sternum and pubic bone, evisceration of internal organs, and a

systematic examination of all organs. Biobanking may consist of snap

freezing tissue in liquid nitrogen or preserving the tissue in

formalin-fixed paraffin-embedded blocks. Labs may request that

specimens be placed in specific media for testing.

Transport of the deceased to funeral home

Once the autopsy is complete, the body is transported to the family’s

designated funeral home. The body can be restored to a state suitable

for an open casket viewing, the details of which are discussed at the

time of consent.3 Since rapid autopsy programmes are sponsored by a

combination of grants and hospital resources, there are no costs to the

family for transport of the deceased. A letter of appreciation can be sent

to the family several weeks after the procedure.3

Discussion

Rapid autopsy programmes appear to be few and far between, with

the vast majority located in the United States. Within oncology

research, there is a wide scope of applications for tissue obtained from

rapid autopsy, ranging from drug resistance to xenograft studies.1,13-15

Overall, studies to date that have utilised rapid autopsy tissue

primarily investigated the molecular genetics of cancer, as genomic

instability enables neoplastic cells to resist programmed cell death,

sustain proliferation signals, and activate invasion and metastasis.16

In the age of personalised cancer medicine, genomic characterisation

of tumours is of paramount importance to determine the appropriate

treatment plan for oncology patients. Unfortunately, this is

complicated by significant variations in genomic instability. Tumour

heterogeneity has been found between different regions within a

single tumour, as well as between the primary tumour and its

metastases.17 Evidence for tumour heterogeneity has also been found

between patients of the same histological cancer subtype.18

Therefore, removal of tumour tissue from a living patient, either

through biopsy or surgical excision, may prove to be insufficient in

obtaining an accurate genetic representation of the patient’s entire

disease. There is much to uncover about the clinical implications of

interpatient and intratumour heterogeneity on diagnosis, prognosis,

treatment selection, and combating treatment resistance.19 Rapid

autopsies may thus prove to be pivotal in furthering our understanding

of genetic cancer lineages, since they allow for high-volume,

low-degradation sampling of multiple neoplastic sites.20-22

Conclusion

The procurement of tissue through rapid autopsies has enabled

significant advancements in oncology research, particularly for

prostate, pancreatic, and breast cancer. The majority of published

research appears to be centred on studying molecular genetics in

FIGURE 3: Distribution of studies utilising rapid autopsy specimens in their analysesaccording to research interests.

Molecular genetics

Clinical

Tumour heterogeneity

Drug resistance

Xenograft

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References

1. Rubin MA, Putzi M, Mucci N, Smith DC, Wojno K, Korenchuk S et al.

Rapid (“warm”) autopsy study for procurement of metastatic prostate

cancer. Clin Cancer Res. 2000;6(3):1038-45.

2. Wu JM, Fackler MJ, Halushka MK, Molavi DW, Taylor ME, Teo WW et al.

Heterogeneity of breast cancer metastases: comparison of therapeutic

target expression and promoter methylation between primary tumors and

their multifocal metastases. Clin Cancer Res. 2008;14(7):1938-46.

3. Alsop K, Thorne H, Sandhu S, Hamilton A, Mintoff C, Christie E et al. A

community-based model of rapid autopsy in end-stage cancer patients.

Nat Biotechnol. 2016;34(10):1010-14.

4. Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M et al.

Androgen-independent prostate cancer is a heterogeneous group of

diseases: lessons from a rapid autopsy program. Cancer Res.

2004;64(24):9209-16.

5. Lindell KO, Erlen JA, Kaminski N. Lessons from our patients: development

of a warm autopsy program. PLoS Med. 2006;3(7):e234.

6. Beltran H, Eng K, Mosquera JM, Sigaras A, Romanel A, Rennert H et al.

Whole-exome sequencing of metastatic cancer and biomarkers of

treatment response. JAMA Oncol. 2015;1(4):466-74.

7. Walker DG, Whetzel AM, Serrano G, Sue LI, Lue LF, Beach TG.

Characterization of RNA isolated from eighteen different human tissues:

results from a rapid human autopsy program. Cell Tissue Bank.

2016;17(3):361-75.

8. Sun H, Sun R, Hao M, Wang Y, Zhang X, Liu Y et al. Effect of duration of

ex vivo ischemia time and storage period on RNA quality in biobanked

human renal cell carcinoma tissue. Ann Surg Oncol. 2016;23(1):297-304.

9. Birdsill AC, Walker DG, Lue L, Sue LI, Beach TG. Postmortem interval effect

on RNA and gene expression in human brain tissue. Cell Tissue Bank.

2011;12(4):311-8.

10. McIntyre J, Pratt C, Pentz RD, Haura EB, Quinn GP. Stakeholder

perceptions of thoracic rapid tissue donation: an exploratory study. Soc Sci

Med. 2013;99:35-41.

11. Achkar T, Wilson J, Simon J, Rosenzweig M, Puhalla S. Metastatic breast

cancer patients: attitudes toward tissue donation for rapid autopsy. Breast

Cancer Res Treat. 2016;155(1):159-64.

12. Quinn GP, Murphy D, Pratt C, Muñoz-Antonia T, Guerra L, Schabath

MB et al. Altruism in terminal cancer patients and rapid tissue

donation program: does the theory apply? Med Health Care Philos.

2013;16(4):857-64.

13. Almendro V, Kim HJ, Cheng YK, Gönen M, Itzkovitz S, Argani P et al.

Genetic and phenotypic diversity in breast tumor metastases. Cancer

Res. 2014;74(5):1338-48.

14. Udager AM, Alva A, Chen YB, Siddiqui J, Lagstein A, Tickoo SK et al.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a rapid

autopsy report of metastatic renal cell carcinoma. Am J Surg Pathol.

2014;38(4):567-77.

15. Xie T, Musteanu M, Lopez-Casas PP, Shields DJ, Olson P, Rejto PA et

al. Whole exome sequencing of rapid autopsy tumors and xenograft

models reveals possible driver mutations underlying tumor

progression. PloS One. 2015;10(11):e0142631.

16. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation.

Cell. 2011;144(5):646-74.

17. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell

plasticity. Nature. 2013;501(7467):328-37.

18. Cancer Genome Atlas Network. Comprehensive molecular portraits

of human breast tumours. Nature. 2012;490(7418):61-70.

19. Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in

the clinic. Nature. 2013;501(7467):355-64.

20. Avigdor BE, Cimino-Mathews A, DeMarzo AM, Hicks JL, Shin J,

Sukumar S et al. Mutational profiles of breast cancer metastases from

a rapid autopsy series reveal multiple evolutionary trajectories. JCI

insight. 2017;2(24):pii: 96896.

21. Pisapia DJ, Salvatore S, Pauli C, Hissong E, Eng K, Prandi D et al.

Next-generation rapid autopsies enable tumor evolution

tracking and generation of preclinical models. JCO Precis Oncol.

2017;1:1-3.

22. Savas P, Teo ZL, Lefevre C, Flensburg C, Caramia F, Alsop K et al.

The subclonal architecture of metastatic breast cancer: results from

a prospective community-based rapid autopsy program “CASCADE”.

PLoS Med. 2016;13(12):e1002204.


review

cancer. However, despite its clear potential to make significant

contributions to cancer research, rapid autopsy is still relatively

unknown among oncology clinicians and researchers. Currently, there

are no published systematic reviews on the usage of rapid autopsy

tissue; such publications could prove useful for the development of

novel programmes to guide oncology researchers on how rapid

autopsy tissue samples should be collected and utilised. Based on the

this preliminary search, a more comprehensive, systematic review of

the literature should be completed to improve future clinical trials and

basic science research using rapid autopsy-obtained tissue.

RCSIsmj


Abstract

Fasting during the lunar month of Ramadan is regarded as an integral pillar of Islam. During this holy

month, many Muslims around the world abstain from eating and drinking from sunrise to sundown.

Depending on geography, these fasts can range from 12 to 20 hours. Fasting in itself causes many

physiological changes within the body, but individuals with diabetes who observe the month of Ramadan

are at risk of many additional physiologic complications, ranging from hypoglycaemia and ketoacidosis to

thrombosis due to dehydration. Healthcare professionals not accustomed to or familiar with Ramadan lack

knowledge regarding the pharmacologic modifications required for patients with diabetes during the fast.

While some guidelines do exist, they are not widely known or followed, and such data is not published in

any medication reference text such as the British National Formulary (BNF) or Lexicomp. Presented here

are the current guidelines implemented by the International Diabetes Federation (IDF) and the Diabetes

and Ramadan (DAR) International Alliance, compiled from a range of studies regarding fasting and its

implications for individuals with diabetes.

review

Ranya Buhamad

RCSI pharmacy student


Pharmacologic managementof diabetes during Ramadan

RCSIsmj


Introduction

According to the World Health Organisation (WHO), there are 422 million

people living with diabetes worldwide.1 It is estimated that 50 million

individuals with diabetes observe the holy month of Ramadan, an Islamic

lunar month during which an absolute fast is observed.2 Fasting has many

benefits for diabetics and non-diabetics, such as reducing insulin resistance

and providing better blood glucose control.3 While there are many types

of fasting, most studies have explored intermittent fasting, also known as

a wet fast, during which water can be consumed. During Ramadan,

however, the type of fast performed is a dry fast. This absolute fast involves

abstaining from both eating and drinking, from sunrise to sunset, for one

month. Managing diabetes during Ramadan is a challenge for patients as

well as healthcare providers (HCPs) due to a lack of data and

epidemiological studies.4

During a dry fast, a healthy individual’s body undergoes physiologic

changes, predominantly in metabolic pathways, which result in

ketogenesis.5 Usually, periods of eating stimulate insulin secretion.

However, during fasting, the absence of ingested food causes insulin

secretion to drop. In order for the body to maintain homeostasis, glycogen

stores are broken down to promote gluconeogenesis so that glucose can

be used to fuel body tissues and organs.5 As the fast continues, glycogen

stores are depleted, and the body turns to utilising fatty acids as an energy

source in a process known as ketosis or ketogenesis.5 Healthy individuals

are able to regulate these processes to maintain normal blood glucose

levels.5 People with diabetes, on the other hand, lack the ability to

effectively regulate blood glucose levels.5

An Epidemiology of Diabetes and Ramadan (EPIDIAR) study conducted in

2005 highlighted the many risks associated with fasting in patients with

diabetes, including hypoglycaemia, hyperglycaemia, diabetic ketoacidosis

(DKA), dehydration, and thrombosis.6,7 In order to ensure that patients

with diabetes have optimal blood glucose control and quality of life, HCPs

should familiarise themselves with the unique pharmacologic

modifications required for adequate diabetes management during

Ramadan, as well as after, especially as populations become increasingly

culturally diverse.

Eid-Al-Fitr is a holiday marking the end of the fast. During this celebratory

period, many people tend to overindulge in carbohydrate-rich foods and

snacks.8 Therefore, this post-Ramadan transitional period must also be

considered, and patients with diabetes should be educated and monitored

by HCPs to ensure maintenance of blood glucose control.

Determining patient risk categories

Due to a previous lack of data on the consequences of fasting among

patients with diabetes during Ramadan, an inaugural consensus meeting

was held in 1995 in Casablanca, which aimed to propose a set of

recommendations for fasting diabetics. The meeting included

endocrinologists and diabetes experts, as well as Muslim scholars and

clerks. During the conference, a standard guideline was outlined regarding

the risk assessment of patients with diabetes, and patients were risk

stratified based on expert opinion.3,9

The Muslim community took well to the recommendations, which, in a

religious context, were based on the interpretation of the Holy Quran

(Al-Baqarah 183-185), which exempts sick individuals from fasting and

reiterates the concept of ease.10 Muslim diabetics who still choose to fast

during Ramadan despite this religious exemption should be respected on

the basis of patient autonomy, but should also be made aware of the risks

associated with fasting.8

Figure 1 summarises the risk categories for patients with diabetes, as

outlined at the 1995 conference. It is recommended that patients

who are deemed very high or high risk should abstain from fasting

review

FIGURE 1: Risk categorisation of patients with diabetes. Adapted from Al-Arouj et al.6

Severehypoglycaemia ordiabeticketoacidosis threemonths prior toRamadan

Patients withhypoglycaemiaunawareness

Patients with type1 diabetes

Patients with poorblood glucosecontrol

Patients with renalinsufficiency

Patients livingalone (e.g.,elderly)

Patients who aretreated withinsulin orsulfonylureas

Patients withwell-controlleddiabetes treatedwith short-actinginsulinsecretagogues

Patients withwell-controlleddiabetes managedwith diet alone ormetformin

VERY HIGH RISK

HIGH RISK

MODERATE RISK

LOW RISK

RCSIsmj


during Ramadan and otherwise.6 Furthermore, it is recommended that

a patient should break their fast if a blood glucose measurement is less

than 3.3mmol/L, or if their blood glucose rises above 16.7mmol/L.6

Ramadan-focused diabetes education

According to the EPIDIAR study, one-third of patients with diabetes did

not receive any counselling regarding fasting during Ramadan from

their HCPs.3 Of the HCPs who did provide counselling, only 63%

adhered to the recommended guidelines.11 The primary aim of the

IDF-DAR guidelines is to reduce the risks associated with diabetes and

fasting.12 Education and counselling is not limited to the patient, but

must also extend to the HCP so that they can familiarise themselves

with the various aspects of fasting during Ramadan, in order to better

care for their patients.12 According to the IDF-DAR guidelines, the

crucial areas of diabetes education include: risk quantification; blood

glucose monitoring; advice regarding fluids, diet, and exercise;

medication adjustments; and, when to break the fast.12

According to the IDF-DAR guidelines, the crucial areas of diabetes educationinclude: risk quantification; blood

glucose monitoring; advice regardingfluids, diet, and exercise; medication

adjustments; and when to break the fast.

In a UK-based study entitled Ramadan Education and Awareness in

Diabetes (READ), a group of general practitioners attended an

educational workshop on this issue.11 Following the workshop,

physician participants counselled their patients with type 2 diabetes

(n=57) and relayed the newly acquired advice and

recommendations.11 Patients’ weights and incidence of

hypoglycaemic events before and after Ramadan were compared to

those of a control group that did not receive any counselling.12 The

results demonstrated weight loss (mean -0.7kg, p<0.001) and a

decrease in hypoglycaemic events in the experimental group that

received educational counselling.12 Conversely, the control group

reported weight gain (mean +0.6kg, p<0.001) and an increase in

hypoglycaemic events.12 This demonstrates the importance and

effectiveness of proper education and counselling in reducing

hypoglycaemic episodes among fasting individuals.

HCPs should also encourage a highly structured self-monitoring

programme for their fasting patients with diabetes. According to

recommendations published by the Diabetes Research and Clinical

Practice journal, self-monitoring blood glucose should be carried out

at seven distinct times throughout the day:8,12

1. At the sunrise meal (suhoor).

2. Morning.

3. Midday.

4. Mid afternoon.

5. At the sunset meal (iftar).

6. Two hours following iftar.

7. Any time the patient feels unwell.

Fasting management of type 1 diabetes

Patients with type 1 diabetes are classified as high risk with respect to

fasting, and thus it is not recommended that these patients fast

during Ramadan due to possible complications, most notably

hypoglycaemia.13 Islamic clerks have approved this medical

recommendation as it aligns with Islamic teaching. Despite this, many

Muslims experience peer pressure to fast during Ramadan, according

to the DAR International Alliance.12 In fact, it is reported that 42.8%

of patients with type 1 diabetes indeed fast during Ramadan.3 If such

patients do make the choice to fast, HCPs must be responsible for

educating them regarding the risks associated with fasting and any

advised medication adjustments. With regard to pharmacologic

management of type 1 diabetes, the IDF-DAR alliance has set out

guidelines relating to recommended adjustments for insulin regimens

during Ramadan. In addition, HCPs must provide patients with advice

regarding proper hydration and nutrition.

Insulin therapy

Insulin administration during a fast carries a risk of hypoglycaemia.8

Typical insulin regimens for insulin-dependent diabetics (either type 1

or type 2) include a long- or intermediate-acting basal insulin and a

short-acting bolus insulin dose administered with meals.8 Another

treatment regimen utilises twice-daily pre-mixed insulins. There is

limited data available concerning the optimal insulin regimen during

Ramadan. Recent guidelines state that with proper monitoring and

individualisation of therapy, either regimen would be considered safe

during Ramadan.8 In terms of dosage adjustments, long/

intermediate-acting basal insulins should be administered twice daily,

with the usual pre-Ramadan ‘morning dose’ to be taken instead at

iftar, and the pre-Ramadan ‘evening dose’ to be reduced by 50% and

taken instead at suhoor.8 For three-times-daily short-acting insulin

boluses, the therapy should be adjusted to only twice-daily dosing:

one bolus to be administered at iftar, while the suhoor dose should be

reduced by 25-50% according to the IDF-DAR guidelines.8

review

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For patients who take pre-mixed insulins, dose adjustments are also

necessary. For the twice-daily regimen, the normal dose should be

administered at iftar, and the suhoor dose should be reduced by

25-50%.8,14 A three-times-daily regimen should be switched to the

twice-daily dosing schedule just described.

Dose titrations should be performed every three days for all insulin

regimens, and adjusted based on self-monitored blood glucose levels.8 A

summary of these titrations is listed in Table 1. Of note, all of the insulin

recommendations stated above apply to both type 1 and type 2 diabetes.

Insulin pumps

Patients with poor blood glucose control can benefit from insulin

pumps. According to the IDF-DAR guidelines, studies demonstrated

that insulin-dependent diabetics can safely perform a fast using

insulin pumps with the following rate adjustments:8

n basal rate: reduce the dose by 20-40% during the last three to four

hours of fasting, and increase the dose by 30% after iftar; and,7,14

n bolus rate: patients should continue to administer regular doses

based on the carbohydrate content of the meal.7,14

Fasting management of type 2 diabetes

Patients with type 2 diabetes often require multiple medications in

order to manage their disease.15 The added challenges posed by

fasting during the holy month of Ramadan mean that various

treatment modifications may be required.

Diet and exercise therapy

Patients who are managed on dietary therapy alone are well able to

reap the many benefits that fasting has on blood sugar. The main area

for adjustment with this mode of therapy, as recommended by the

IDF-DAR guidelines, is exercise. The intensity of physical activity

should be reduced during the hours of fasting, and adequate

hydration should follow during the hours of iftar.8

Metformin

Metformin is the first-line agent for treatment of type 2 diabetes.8 This

medication works by decreasing both hepatic glucose production and

glucose absorption.16 Although there are no randomised controlled

trials (RCTs) investigating the use of metformin during Ramadan, it is

considered a safe agent since it carries a low hypoglycaemic risk.8

Metformin is available in immediate- and prolonged-release

preparations. In terms of adjusting a patient’s metformin dosage

during fasting, once-daily immediate-release or prolonged-release

regimens require no modifications.8 For twice-daily dosing, the first

dose is to be taken at suhoor, and the second dose at iftar.6,8 For

patients on a three-times-daily dosing regimen, the morning dose

should be taken at suhoor, and the remaining dosages should be

combined and administered at iftar.6,8

Thiazolidinediones

Thiazolidinediones (TZDs) reduce blood glucose by activating

peroxisome proliferator activated receptor γ. Pioglitazone

was evaluated in a study of fasting Muslims during Ramadan.12

In comparison to placebo, pioglitazone showed no difference

in incidence of hypoglycaemic events.12 During Ramadan, no

dose adjustments are necessary due to TZDs’ low risk of

hypoglycaemia.12

Short-acting insulin secretagogues

This class of medication works by stimulating pancreatic beta cells to

secrete more insulin. The IDF-DAR guidelines recommend that

three-times-daily dosing should be reduced to twice-daily dosing

during Ramadan, with no other dose adjustments necessary.8

Sulfonylureas

Sulfonylureas (SUs) are a second-line treatment for type 2 diabetes

following metformin.15 SUs stimulate insulin secretion from pancreatic

beta cells in a glucose-independent process.8 This carries a higher risk

review

Table 1: Dose titrations of insulin during Ramadan. Adapted from Hassanein et al.6,10,13

Pre-iftar Post-iftar/post-suhoor

Fasting blood glucose basal insulin bolus insulin Pre-mixed insulin

<3.9mmol/L Reduce by 4 units Reduce by 4 units Reduce by 4 units

3.9-5.0mmol/L Reduce by 2 units Reduce by 2 units Reduce by 2 units

5.0-7.0mmol/L No change required No change required No change required

7.0-11.1mmol/L Increase by 2 units Increase by 2 units Increase by 2 units

>11.1mol/L Increase by 4 units Increase by 4 units Increase by 4 units

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of hypoglycaemia depending on the specific medication used due to

a difference in receptor interactions.8 According to an observational

study of patients treated with SUs, the highest incidence of

hypoglycaemic events was associated with glibenclamide, a

first-generation agent.8,17 This study thus recommended that

second-line agents such as gliclazide be used to treat type 2 diabetes

during Ramadan.8,17 In terms of dose adjustments for the twice-daily

regimen, the suhoor dose should be reduced while keeping the iftar

dose the same.8

SGLT2 inhibitors

This class of oral medications works by increasing glucose excretion

via the kidneys.8 The risks associated with SGLT2 inhibitors include

urinary tract infections and dehydration; the risk of dehydration is

augmented when a patient is fasting. To date, only one study has

assessed the use of SGLT2 inhibitors during Ramadan; it advises

caution with use of these medications, and emphasises that patients

must be informed to stay well hydrated after iftar.8,18

DPP4 inhibitors

As a result of DPP4 enzyme inhibition, the levels of circulating

glucagon-like-peptide-1 (GLP1) are increased. GLP1 plays a pivotal

role in stimulating insulin secretion.8 IDF-DAR guidelines recommend

no dosage adjustment during Ramadan.12

GLP1 receptor agonists

By mimicking the incretin hormone, GLP1 receptor agonists are able

to increase glucose uptake in muscles. When used as monotherapy,

the risk of hypoglycaemia is low in comparison to their use alongside

SUs or insulin.8 Newer agents such as lixisenatide and dulaglutide

have since come to market, but there have been no trials regarding

their use during Ramadan. The IDF-DAR guidelines state that as

long as GLP1 receptor agonists are well titrated to the therapeutic

dose six weeks prior to Ramadan, they are considered safe to use

while fasting.8

Table 2 summarises the IDF-DAR guidelines on oral diabetes

medication adjustments during Ramadan.

As global populations becomeincreasingly diverse, it is paramount that healthcare professionals educatethemselves on cultural and religiouspractices that influence healthcare

and pharmacotherapy.

Conclusion

As global populations become increasingly diverse, it is paramount

that healthcare professionals educate themselves on cultural and

religious practices that influence healthcare and pharmacotherapy.

Physicians and allied health professionals involved in managing

patients with diabetes should counsel patients prior to Ramadan,

liaise with them throughout the fast, and continue patient monitoring

during Eid-Al-Fitr in the weeks following Ramadan. Guidance during

review

Table 2: Pharmacologic modifications for fasting patients with type 2 diabetes during Ramadan.

Pharmacologic agent/class Treatment modification during Ramadan

Metformin OD – no modification

BD – dose to be taken at suhoor and iftar

TID – first dose to be taken at suhoor, and remaining doses to be combined at iftar

Thiazolidinediones No adjustments necessary

Short-acting insulin secretagogues TID – switch to BD dosing

Sulfonylureas Switch to second-generation agent

BD – reduce suhoor dose

SGLT2 inhibitors Use with caution

Advise patient to stay hydrated

DPP4 inhibitors No adjustments necessary

GLP1 receptor agonists No adjustments necessary if well titrated six weeks prior to Ramadan

OD = once daily

BD = twice daily

TID = three times daily

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Eid-Al-Fitr should include advice against overindulgence, along with

counselling regarding medication readjustment to pre-Ramadan

dosages. Regular self-blood glucose monitoring is vital during this

readjustment period in order to prevent adverse complications such

as hypo- or hyperglycaemia.

Although the Diabetes and Ramadan International Alliance and

International Diabetes Federation have put tremendous effort into

creating guidelines for diabetes management during the holy

month of Ramadan, additional long-term studies with larger sample

sizes are much needed in order to create an internationally known

and accredited guideline. There are many gaps concerning some

new diabetes medications and their effects during fasting; these

areas of uncertainty must be clarified to maximise patient safety. The

scope of such research could also extend to other illnesses, since a

majority of patients living with diabetes have other co-morbidities.

As newer medications and more advanced therapies continue to be

brought to the market, guidelines must expand and progress to

include them.

review

References

1. World Health Organisation. Diabetes. 2018. [Internet]. [cited 2018

November 1]. Available from:

http://www.who.int/news-room/fact-sheets/detail/diabetes.

2. Almalki M, Alshahrani F. Options for controlling type 2 diabetes during

Ramadan. Front Endocrinol (Lausanne). 2016;7:32.

3. Salti I, Benard E, Detournay B, Bianchi-Biscay M, Le Brigand C, Voinet C

et al. A population-based study of diabetes and its characteristics during

the fasting month of Ramadan in 13 countries: results of the

Epidemiology of Diabetes and Ramadan 1422/2001 (EPIDIAR) study.

Diabetes Care. 2004;27(10):2306-11.

4. Arnason T, Bowen M, Mansell K. Effects of intermittent fasting on health

markers in those with type 2 diabetes: a pilot study. World J Diabetes.

2017;8(4):154-64.

5. Longo V, Mattson M. Fasting: molecular mechanisms and clinical

applications. Cell Metab. 2014;19(2):181-92.

6. Al-Arouj M, Bouguerra R, Buse J, Hafez S, Hassanein M, Ibrahim M et al.

Recommendations for management of diabetes during Ramadan.

Diabetes Care. 2005;28(9):2305-11.

7. Hassanein M, Al-Arouj M, Hamdy O, Bebakar W, Jabbar A, Al-Madani A et

al. Diabetes and Ramadan: practical guidelines. Diabetes Res Clin Pract.

2017;126:303-16.

8. Hassanein M, Al-Arouj M, Ben-Nakhi A. Management of diabetes during

Ramadan. 2016. [Internet]. [cited 2019 January 8]. Available from:

https://www.daralliance.org/daralliance/wp-content/uploads/2018/01/ID

F-DAR-Practical-Guidelines_15-April-2016_low_8.pdf.

9. Akram J, De Verga V. Insulin lispro (Lys(B28), Pro(B29)) in the treatment

of diabetes during the fasting month of Ramadan. Diabet Med.

1999;16(10):861-6.

10. Sadikot S, Hassanein M. Diabetes and Ramadan: Practical Guidelines.

Brussels: DAR-IDF; 2016. [Internet]. [cited 2019 January 8]. Available

from: http://Diabetes and Ramadan:Practical Guidelines.

11. Bravis V, Hui E, Salih S, Mehar S, Hassanein M, Devendra D. Ramadan

Education and Awareness in Diabetes (READ) programme for Muslims

with type 2 diabetes who fast during Ramadan. Diabet Med.

2010;27(3):327-31.

12. Hassanein M, Ahmedani, M. IDF-DAR Practical Guidelines. Brussels:

International Diabetes Federation, 2016: Chapter 6. [ebook]. [Accessed

2019 January 3]. Available at: https://www.daralliance.org/daralliance/

wp-content/uploads/2018/01/IDF-DAR-Practical-Guidelines_15-April-201

6_low_6.pdf.

13. Diabetes Control and Complications Trial (DCCT)/Epidemiology of

Diabetes Interventions and Complications (EDIC) Study Research Group.

Intensive diabetes treatment and cardiovascular outcomes in type 1

diabetes: The DCCT/EDIC Study 30-year follow-up. Diabetes Care.

2016;39(5):686-93.

14. Hassanein M, Al-Arouj M, Hamdy O. Insulin dose modifications for

patients with diabetes. 2017.

15. Canadian Agency for Drugs and Technologies in Health. Optimal second-

and third-line therapy in type 2 diabetes. Ottawa, 2013:1-2. [Internet].

Available from: https://www.cadth.ca/sites/default/files/pdf/C1111_

Project_in_Brief_e.pdf.

16. DrugBank. Metformin. 2019. [Internet]. [cited 2019 January 8]. Available

from: https://www.drugbank.ca/drugs/DB00331.

17. Aravind S, Tayeb K, Ismail S, Shehadeh N, Kaddaha G, Liu R et al.

Hypoglycaemia in sulphonylurea-treated subjects with type 2 diabetes

undergoing Ramadan fasting: a five-country observational study. Curr

Med Res Opin. 2011;27(6):1237-42.

18. Beshyah S, Chatterjee S, Davies M. Use of SGLT2 inhibitors during

Ramadan: a survey of physicians’ views and practical guidance. Br J

Diabetes. 2016;16(1):20.

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review

Abstract

Recent research has identified the human microbiome as a key modulator of the gut–brain axis, influencing

both physiological brain function and the development of neurologic and psychiatric pathologies. A

number of studies have investigated whether differences exist in the microbial composition within the

gastrointestinal tracts of individuals with certain neuropsychiatric conditions compared to neurotypical

controls. Indeed, findings support the idea that abnormalities in gut microbiota composition can have

pathological implications both within the gastrointestinal system and extra-intestinally. This review aims to

examine the mounting evidence with respect to certain neuropsychiatric conditions, namely major

depressive disorder, generalised anxiety disorder, early- and late-onset autism spectrum disorder, and

Parkinson’s disease. There appears to be a higher incidence of gastrointestinal issues among patients with

these conditions compared to the general population. In addition, altered gut microbial composition in

psychiatric patients has been found to hinder the therapeutic benefit of certain drugs commonly used for

symptom management. The gut microbiota may thus be a potential therapeutic target with broad clinical

relevance, from enhanced understanding of neuropsychiatric pathophysiology, to therapeutic applications

in both gastrointestinal and neurological conditions.

Emily Panteli



Influence of the gutmicrobiome on brain healthand function

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Introduction

The human microbiota is defined as all microorganisms that live on or

within the body, with its corresponding genome being the microbiome.1

This vast population outnumbers an individual’s own cells tenfold, and

accounts for 2-3% of body weight. Most of these microorganisms reside

within the gastrointestinal tract (GIT). The role the human microbiome

plays in health and disease is becoming increasingly recognised, with

numerous studies showing that these species impact human nutrition,

immunity, behaviour, and disease.2 The United States Institutes of Health

initiated the Human Microbiome Project (HMP) in 2008, with the aim of

generating a resource that would enable improved comprehension of the

human microbiota and its role in human health and disease.3 By the end

of 2017, HMP researchers had published over 650 papers discussing the

structure, function, and diversity of the microbiome.3 The second phase of

the HMP is currently in progress, and aims to analyse host–microbiome

interactions through longitudinal studies of disease-specific cohorts.4

The gut–brain axis

Currently, the gut microbiota is viewed as a key regulator of the gut–brain

axis, whereby microorganisms in the GIT lumen modulate many brain

processes, including pain perception, stress reactivity, immune responses,

and the emotional motor system (EMS).5 This axis is bidirectional; the

central nervous system (CNS) is capable of altering gut flora populations

and other GIT-related factors such as motility, rate and composition of

secretions, mucosal permeability, and nutrient delivery (Figure 1). This is

achieved through the hypothalamic-pituitary-adrenal (HPA) axis and the

autonomic nervous system (ANS). Enterochromaffin cells are essential

bidirectional transducers that facilitate communication between the gut

lumen and nervous system; afferent innervation of these cells via the vagus

nerve provides a direct signalling pathway.6

Recent studies indicate a strong correlation between dysbiosis and manyhealth conditions, including obesity,

autoimmunity, allergies, andgastrointestinal problems such as irritablebowel syndrome (IBS) and inflammatory

bowel disease (IBD).

Dysfunction of the gut–brain axis can lead to dysbiosis, defined as a

change or imbalance in microbiota composition with consequent

pathophysiological outcomes.8 Recent studies indicate a strong correlation

between dysbiosis and many health conditions, including obesity,

autoimmunity, allergies, and gastrointestinal problems such as irritable

bowel syndrome (IBS) and inflammatory bowel disease (IBD).9 Evidence is

also accumulating to support the hypothesis that dysbiosis may have a role

in the progression of neuropsychiatric disorders, such as major depressive

disorder (MDD), generalised anxiety disorder (GAD), autism spectrum

disorder (ASD), and Parkinson’s disease (PD).2

review

FIGURE 1: Schematic representation of bidirectional brain–gut–microbe interactions.7

Direct and indirectmodulation of entericmicrobiota by the CNS

Modulation of nervoussystem function byenteric microbiota

Enteric microbiota

GI motility, secretion,permeability

Mucosal immune function

Viscerosensorymechanismt

t

t

t

Enteric microbiota

Visceral stimuli perception – emotion

t

tt

t

tt

t

HPA axisANS

EMS

t

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Dysbiosis can arise through the use of antibiotics, vaccinations,

disinfectant cleaning products, and a high-calorie diet.10 These ‘modern

advances’ decrease one’s contact with microorganisms, especially during

childhood, and hence can result in significant changes in the composition

of an individual’s intestinal microbiota. This is supported by the ‘hygiene

hypothesis,’ which suggests a causal relationship between decreased

contact with microorganisms and an increased incidence of allergic

diseases.10 The Western diet, which is high in calories, fat, and sugar, was

demonstrated to cause dysbiosis in a humanised mouse model.11

Microbial composition shifted to an overgrowth of Firmicutes such as

Clostridium innocuum and Eubacterium dolichum, with a reduction in several

Bacteroides species.11 As demonstrated by rodent studies, the high

comorbidity of stress-related psychiatric symptoms and gastrointestinal

impairment is further evidence of the significant role of the gut–brain axis

in pathological states.12

Major depressive disorder

MDD, also known as clinical depression, is a mood disorder affecting

approximately one in five individuals at some point in their life, with over

85% of sufferers relapsing within ten years.13 Symptoms include

persistent low mood, loss of interest in previously enjoyable activities,

disturbances in sleep or appetite, and suicidal ideations.14 With MDD

being one of the leading causes of morbidity and mortality worldwide,

much research has been done to understand its pathophysiology.

Modern research reveals that MDD is a ‘physiological’ pathology, with

biological origins such as neurotransmitter imbalances or abnormal

neuronal circuitry.13

A systematic review by Lee et al. estimated the co-occurrence of

functional gastrointestinal disorders, such as IBS, and MDD to be 30%.15

A literature review by Mudyanadzo et al. described an undeniable

association between IBS and mood disorders that has long been

documented.16 The dysbiosis-induced inflammation that occurs in IBS

may contribute to the physiological stress that, in some cases, damages

areas of the brain such as the hippocampus and amygdala, leading to

MDD.17 The inflammation observed in IBS is due to increased levels of

cytokines, immune proteins that disrupt glutamate levels.17 Glutamate

is a neurotransmitter that, when overproduced, can exert an excitotoxic

effect, leading to pathological changes in neuronal circuits. These

findings are highly clinically relevant, as recognition of the relationship

between IBS and MDD has led to the collaborative management of

these two conditions. Antidepressants, mainly selective serotonin

reuptake inhibitors (SSRIs), are now routinely used to treat IBS.16 The

precise mechanism of action of SSRIs is still unknown in the treatment

of MDD and other mood disorders; however, they are believed to limit

serotonin reabsorption in the synaptic cleft in order to increase

extracellular levels and chemical activity.18 SSRIs have also been found

to increase gut motility, influence sympathetic and parasympathetic

relays to the GIT via the HPA axis, reduce levels of pro-inflammatory

cytokines such as interleukin-1, and increase levels of the

anti-inflammatory interleukin-10.16 It is speculated that the

anti-inflammatory action of SSRIs reduces the damaging effects of

dysbiosis, thereby contributing to SSRIs’ effectiveness in treating

depression; this provides further evidence of an association between the

microbiome and brain function.16

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Generalised anxiety disorder

GAD is defined as “excessive anxiety and worry occurring more days

than not for at least six months, about a number of events or

activities”.19 For a clinical diagnosis of GAD, the anxiety cannot be

attributable to another pathology or substance, and impairs daily

functioning.19 It is well known that physical manifestations of anxiety

occur often, especially in the GIT. Multiple researchers have found

statistically significant positive correlations between GAD and

gastrointestinal problems, including acid reflux and ulcerative colitis.20

Indeed, evidence supporting the notion that gut microbiota

abnormalities contribute to GAD pathophysiology is accumulating.21 A

systematic comparative analysis conducted by Jiang et al. identified

dysbiosis in GAD patients, specifically overabundances of the bacteria

Escherichia, Shigella, Fusobacterium, and Ruminococcus gnavus.22 Another

experiment performed by Guzman et al. – which aimed to demonstrate

that gut microbiota from patients with GAD can induce anxiety in

neurotypical mice – found that the GAD-colonised mice had increased

brain-derived neurotrophic factor (BDNF) expression in the amygdala

and decreased BDNF expression in the hippocampus accompanying

their dysbiosis-induced anxiety symptoms.21 Both the amygdala and

hippocampus have roles in emotional processing.21 BDNF is a protein

that regulates synaptic plasticity in neurons through control of their

growth, maturation, and survival. Certain polymorphisms in the BDNF

gene are associated with an increased risk of developing psychiatric

conditions such as bipolar disorder, GAD, and eating disorders.23 The

findings of Guzman et al. support the relationship between gut

microbiota dysbiosis and the occurrence of GAD, and may pave the way

for the development of genetic testing for BDNF gene polymorphisms as

a novel biomarker for psychiatric disorders.

Autism spectrum disorder

ASD is a range of neurodevelopmental and behavioural disorders of

varying severity, characterised by restrictive repetitive behaviours and

impaired social interaction and communication.24 Interestingly, many

children with ASD suffer from gastrointestinal issues such as diarrhoea,

constipation, and abdominal pain.25 Three surveys conducted in the US

described a high prevalence of gastrointestinal problems in children with

ASD when compared to neurotypical children.24 This has sparked

numerous investigations into possible dysbiosis in individuals with autism.

It has been demonstrated that faecal samples obtained from a group of

children with autism contained ten times more gram-positive bacteria

under the Clostridium genus compared to samples from the general

population.6 However, these findings are not always replicable; a study

conducted by Gondalia et al. did not show significant differences in the

gut microbiota of children diagnosed with ASD compared to their

neurotypical siblings.25 Rather, this study concluded that other

explanations for gastrointestinal dysfunction in the autistic population

ought to be considered, such as elevated anxiety levels and self-restricted

diets.25 Hence, the existence of dysbiosis as a factor in the pathogenesis of

ASD remains a complex and controversial topic, undoubtedly warranting

further investigation.

Three surveys conducted in the USdescribed a high prevalence of

gastrointestinal problems in children withASD when compared to neurotypicalchildren. This has sparked numerous

investigations into possible dysbiosis inindividuals with autism.

In most ASD cases, early symptoms emerge in infancy. However, a

subset of children receives a diagnosis of regressive or late-onset ASD.

Typically, these children initially reach developmental milestones

normally, and then, at an older age, exhibit a deterioration of previously

acquired skills, with autistic signs becoming apparent.26 Sandler et al.

speculated that gut microorganism disruption may contribute to the

symptomatology in regressive ASD by promoting colonisation of

neurotoxin-producing bacteria.27 This hypothesis is supported by the

fact that many parents recall antibiotic exposure preceding chronic

persistent diarrhoea prior to their child’s ASD diagnosis.27 Several bodies

of evidence confirm that antibiotic administration can result in

dysbiosis, with broad-spectrum antibiotics affecting the abundances of

30% of gut bacteria.28 Once antibiotic treatment is stopped, the

microbiome is often able to recover and return to its pre-treatment

composition; however, the initial state is not always fully restored.29

Sandler et al. tested their hypothesis by recruiting 11 children with

regressive ASD for an interventional trial using oral vancomycin. As

faecal samples from children with ASD have been found to contain

significant overgrowth of bacteria under the Clostridium genus,

vancomycin was the chosen intervention as it is widely used to treat C.

difficile infections, the most common cause of healthcare- associated

infectious diarrhoea in developed countries.6,30 Short-term

improvement of participants in the Sandler et al. trial was evaluated

using paired videotapes analysed by a clinical psychologist, who

concluded that behaviour improved in 80% of children in the

intervention group.27 However, the long-term benefits are still unclear

and are yet to be investigated. This randomised controlled trial indicates

that a possible dysbiosis exists in late-onset ASD, a finding that warrants

further research.27

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References

1. The National Human Genome Research Institute. The Human Microbiome

Project: Extending the definition of what constitutes a human. 2012.

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at-constitutes-a-human/.

2. Medical News Today. What is the gut microbiota? What is the human

microbiome? Brighton: Medical News Today. 2016. [Internet]. [cited 2018

June 10]. Available from: https://www.medicalnewstoday.com/articles/307998.php.

3. The NIH Common Fund. Human Microbiome Project. Maryland: National

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4. Proctor L. The Integrative Human Microbiome Project: dynamic analysis of

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5. Mayer E. The neurobiology of stress and gastrointestinal disease. Gut.

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6. Mangiola F, Ianiro G, Franceschi F, Fagiuoli S, Gasbarrini G, Gasbarrini A.

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7. Rhee S, Pothoulakis C, Mayer E. Principles and clinical implications of the

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Parkinson’s disease

PD is a neurodegenerative condition characterised by akinesia,

bradykinesia, muscle rigidity, tremor, and depression. This is due to loss of

dopaminergic neurons in the pars compacta of the substantia nigra, one

of the basal ganglia in the brain. However, there is a well-established

co-existence of extranigral pathologies.31 Much research examining the

pathophysiology of PD has reported dysbiosis in patients with PD.32,33 Like

the other neuropsychiatric conditions discussed above, sufferers of PD

often have comorbid gastrointestinal dysfunction; for instance,

approximately 80% of PD patients suffer from constipation.31 Other

gastrointestinal conditions that have a higher incidence in patients with

PD compared to the general population include Helicobacter pylori

infection, a leading cause of ulcers, and small intestinal bacterial

overgrowth (SIBO), affecting nearly 25% of all PD sufferers.31 H. pylori

infections have negative implications for PD treatment because this

bacterium hinders absorption of levodopa, a drug routinely used for PD

symptom management.31 Fasano et al. found that patients receiving

levodopa who also had SIBO suffered from more Parkinson’s motor

symptoms, and experienced delayed onset of action of levodopa.32 Upon

eradication of SIBO, an increase in levodopa’s therapeutic efficacy was

observed in these patients, highlighting the clinical significance of

dysbiosis and its implications for the pharmacologic management of

certain neurological illnesses.32

Therapeutic potential: faecal microbiota transplantation

Faecal microbiota transplantation (FMT) is the process of transplanting

faeces from a donor with healthy gut flora to a recipient in order to treat

dysbiosis and impaired gastrointestinal function.34 This procedure is

commonly used to treat gastrointestinal diseases such as C. difficile

infection, Crohn’s disease, and ulcerative colitis.35 Although recent studies

in animals concluded that gut microbiota transplantation can transfer a

behavioural phenotype, there have been no clinical studies to date

investigating its efficacy in neuropsychiatric disorders in humans.10 The

findings of one study, conducted by Hsiao et al., support gut–brain axis

involvement in mice displaying symptoms of ASD, and identify a potential

target for probiotic therapy in this neurodevelopmental condition.36

Treating these mice with Bacteroides fragilis was found to correct

behavioural abnormalities associated with ASD.36 However, these findings

have not yet been applied to humans with ASD. Additionally, case reports

of FMT demonstrated favourable outcomes and neurological symptom

alleviation in patients suffering from PD.37,38 Accumulating research

supports FMT as a promising approach for the treatment of dysbiosis in

both gastrointestinal and extra-intestinal disorders, broadening the

procedure’s clinical applications.39 However, further studies in humans are

essential to ensure its therapeutic efficacy.

Conclusion

The human microbiome is an essential modulator of the gut–brain axis,

and hence the gut microbiota is involved in a variety of both physiological

and psychological processes. Ever-increasing evidence suggests that

alterations in the composition of these microorganisms can have

pathological consequences within and beyond the GIT. This accounts, in

part, for the high incidence of gastrointestinal comorbidities in many

neuropsychiatric conditions, from anxiety and depression to PD. The

microbiome influences both the pathogenesis and treatment of disease,

making gut flora a potential therapeutic target in a vast number of

conditions. With such clinical and therapeutic possibility, further research

is warranted and eagerly anticipated.

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11. Brown K, Daniella DeCoffe D, Molcan E, Gibson D. Diet-induced dysbiosis

of the intestinal microbiota and the effects on immunity and disease.

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12. Reber S. Stress and animal models of inflammatory bowel disease – an

update on the role of the hypothalamo-pituitary-adrenal axis.

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13. Liang S, Wu X, Hu X, Wang T, Jin F. Recognizing depression from the

microbiota–gut–brain axis. Int J Mol Sci. 2018;19(6):E1592.

14. National Institute of Mental Health. Depression – Overview. Bethesda,

Maryland: U.S. Government Printing Office. 2018. [Internet]. [cited 2018

September 7]. Available from: https://www.nimh.nih.gov.

15. Lee C, Doo E, Choi J, Jang S, Ryu H, Lee J et al. The increased level of

depression and anxiety in irritable bowel syndrome patients compared

with healthy controls: systematic review and meta-analysis. J

Neurogastroenterol Motil. 2017;23(3):349-62.

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2018;10(8):e3178.

17. Kiecolt-Glaser J, Derry H, Fagundes C. Inflammation: depression fans the

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18. Preskorn S, Ross R, Stanga C. Selective serotonin reuptake inhibitors.

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19. Reynolds C, Kamphaus R. Diagnostic and Statistical Manual of Mental

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21. Guzman E, Anglin R, De Palma G, Lu J, Potts R, Amber M et al. A301 Gut

microbiota from a patient with generalised anxiety disorder induces

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Can Assoc Gastroenterol. 2018;1(1):523-4.

22. Jiang H, Zhang X, Yu Z, Zhang Z, Deng M, Zhao J et al. Altered gut

microbiota profile in patients with generalized anxiety disorder. J Psychiatr

Res. 2018;104:130-6.

23. US National Library of Medicine. Genetics Home Reference – BDNF gene.

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24. Horvath K, Perman J. Autistic disorder and gastrointestinal disease. Curr

Opin Pediatr. 2002;14(5):583-7.

25. Gondalia S, Palombo E, Knowles S, Cox S, Meyer D, Austin D. Molecular

characterisation of gastrointestinal microbiota of children with autism

(with and without gastrointestinal dysfunction) and their neurotypical

siblings. Autism Res. 2012;5(6):419-27.

26. Stefanatos G. Regression in autistic spectrum disorders. Neuropsychol Rev.

2008;18(4):305-19.

27. Sandler R, Finegold S, Bolte E, Buchanan C, Maxwell A, Väisänen M et al.

Short-term benefit from oral vancomycin treatment of regressive-onset

autism. J Child Neurol. 2000;15(7):429-35.

28. Dethlefsen L, Relman D. Incomplete recovery and individualized responses

of the human distal gut microbiota to repeated antibiotic perturbation.

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29. Francino M. Antibiotics and the human gut microbiome: dysbioses and

accumulation of resistances. Front Microbiol. 2015;6:1543.

30. Isaac S, Scher J, Djukovic A, Jiménez N, Littman D, Abramson S et al.

Short- and long-term effects of oral vancomycin on the human intestinal

microbiota. J Antimicrob Chemother. 2017;72(1):128-36.

31. Parashar A, Udayabanu M. Gut microbiota: implications in Parkinson’s

disease. Parkinsonism Relat Disord. 2017;38:1-7.

32. Fasano A, Bove F, Gabrielli M, Petracca M, Zocco M, Ragazzoni E et al. The

role of small intestinal bacterial overgrowth in Parkinson’s disease. Mov

Dis. 2013;28(9):1241-9.

33. Scheperjans F, Aho V, Pereira P, Koskinen K, Paulin L, Pekkonen E et al. Gut

microbiota are related to Parkinson’s disease and clinical phenotype. Mov

Disord. 2015;30(3):350-8.

34. Gupta S, Allen-Vercoe E, Petrof E. Fecal microbiota transplantation: in

perspective. Therap Adv Gastroenterol. 2016;9(2):229-39.

35. Fond G, Boukouaci W, Chevalier G, Regnault A, Eberl G, Hamdani N et al.

The “psychomicrobiotic”: targeting microbiota in major psychiatric

disorders: a systematic review. Pathol Biol (Paris). 2015;63(1):35-42.

36. Hsiao E, McBride S, Hsien S, Sharon G, Hyde E, McCue T et al. Microbiota

modulate behavioral and physiological abnormalities associated with

neurodevelopmental disorders. Cell. 2013;155(7):1451-63.

37. Dinan T, Cryan J. Gut feelings on Parkinson’s and depression. Cerebrum.

2017;pii:cer-0417.

38. Shi Y, Yang Y. Fecal microbiota transplantation: Current status and

challenges in China. JGH Open. 2018;2(4):114-6.

39. Xu M, Cao H, Wang W, Wang S, Cao X, Yan F et al. Fecal microbiota

transplantation broadening its application beyond intestinal disorders.

World J Gastroenterol. 2015;21(1):102-11.

review


staff review

Abstract

A renewed global interest in research on mental health disorders has been sparked, as the number of

individuals suffering from mental or behavioural disorders now amounts to approximately 450 million.

Additionally, the World Health Organisation (WHO) estimates that one million people suffering from mental

health issues die by suicide each year. Bipolar disorder (BD) is a chronic mental illness defined by repeated

episodes of depressive and manic episodes that impact patients’ overall health, including daily functioning

and quality of life. BD commonly presents in adolescence or early adulthood, and is further divided into

Bipolar I, dominated by manic episodes, and Bipolar II, dominated by hypomanic episodes. Current

practice guidelines and detailed algorithms used for the diagnosis and management of BD are not user

friendly and require a skilled team to navigate. This results in underdiagnosis of BD, leaving many patients

undertreated. Symptom complexity, duration, and intensity make reaching a conclusive diagnosis for

manic, hypomanic, and depressive states challenging. While there is no single unifying theory that

encompasses the genetic, pharmacological, biochemical, and anatomical components of BD’s

pathophysiology, an array of categorical theories currently exists. After accurately confirming a BD

diagnosis, identifying appropriate treatment is crucial, as symptomatic improvement generally takes one to

four weeks. Currently, pharmacologic treatments include mood stabilisers, antidepressants, and atypical

antipsychotics. Unfortunately, lifetime management of BD is extremely challenging due to its dynamic and

fluctuating nature. The WHO has called on regional governments to identify the current barriers to mental

health and well-being, as this is a crucial step towards improving the morbidity and mortality associated

with mental illnesses on a global scale. This review aims to dissect the complexity of BD from diagnosis to

management, including the prevailing theories, diagnostic methods, and pharmacologic therapies.

Jessica Millar

RCSI pharmacy student


RCSIsmj

Bipolar disorder: the highs and lows


Introduction

Renewed interest in research on mental health disorders has been

driven by a plethora of factors. The World Health Organisation (WHO)

estimates that approximately one million people die by suicide as a

result of mental illness each year.1 Additionally, those suffering from

mental illnesses are also victims of human rights violations, stigma,

and discrimination throughout daily life.1 It is estimated that one in

four families have a member suffering from a mental health condition

to whom the family provides the majority of care.1 It is therefore in

the best global interest to address misconceptions, reduce

prevalence, and improve the lives of those living with such conditions.

Bipolar disorder (BD) is a chronic mentalillness defined by repeated episodes ofdepressive and manic symptoms, whichhave a significant impact on the overall

health status of the patient.

Bipolar disorder (BD) is a chronic mental illness defined by repeated

episodes of depressive and manic symptoms, which have a significant

impact on the overall health status of the patient, including daily

functioning and quality of life.2 BD involves six clinical parameters,

including two states (depression and mania) and four phase changes

(depression to mania, mania to depression, depression to mixed

states, and mixed states to depression).3 Most commonly, BD

presents in adolescence or early adulthood, between 18 and 22 years

of age.4 BD can be further divided into Bipolar I, dominated by manic

episodes, and Bipolar II, dominated by hypomanic episodes.5

Unfortunately, many of the current practice guidelines, decision trees,

and detailed algorithms used in the diagnosis and management of BD

are complex and not entirely user friendly, requiring a skilled team to

navigate appropriately.4 This further complicates an already difficult

diagnosis and management process, prolonging the period to

effective therapeutic management.

Aetiological theories

There is currently no single unifying theory that encompasses the

genetic, pharmacological, biochemical, and anatomical components

of BD’s pathophysiology.4 Pre-existing theories included the

electrolyte disturbance and serum fluid theory, which was revised in

the late 1960s. This theory suggested that lower amounts of sodium,

haemoglobin, and albumin were present during manic episodes,

while those levels were increased in depression.6 Hochman et al.

revisited this theory in 2014, and found evidence of an imbalance in

both electrolytes and fluid homeostasis throughout bipolar episodes.6

The monoamine hypothesis theorises that depression results from

underactivity or deficiency of monoamines such as dopamine,

serotonin, and noradrenaline, while mania occurs with excess of these

monoamines.4 This theory arose in the 1970s as the dopaminergic

theory, hypothesising that additional dopamine contributed to mania

while deficits led to depressive episodes.7 Current research, however,

has isolated serotonin as the crucial monoamine involved in the

neurophysiology of depression.8 It is owing to this prevailing

understanding that selective serotonin re-uptake inhibitors (SSRIs),

which act as serotonin agonists, are commonly used as

antidepressants in the management of mood disorders.3,9,10

Furthermore, management of BD with lithium has created a further

chemical imbalance theory. Lithium is thought to be neuroprotective

against urea toxicity, which is a pathophysiological mechanism

underlying the clinical presentation of BD.11,12

The neurodevelopmental theory suggests that differences in cerebral

pathophysiology are the cause of mood disorder development. It is

proposed that a combination of genetic predisposition and

adverse events early in life, such as insults during gestation, could

develop into psychosis in adolescence or early adulthood,

when normal maturational changes ‘unmask’ the insult.13 Such

neurodevelopmental conditions involve functional abnormalities,

such as accelerated volume loss in brain areas essential for mood

regulation, and dysregulation of glial-neuronal connections.14

Neuroimaging studies, most commonly magnetic resonance imaging

(MRI), show larger lateral ventricles in patients suffering multiple

bipolar episodes compared to those who experience a single episode,

or healthy controls.14

Genetic theories go a step further in that they map the incidence and

patterns of BD inheritance. Data collected from twin studies suggests

the current heritability of BD to be between 60 and 80%; however,

this statistic is much lower in family studies and larger patient

cohorts.15 Clinicians have since found that positive family histories of

BD are rare in everyday practice, and it is uncommon to have

multiple family members affected over several generations.15

However, genetic risk factors alone increase susceptibility with small

to moderate effects, indicating the role of non-genetic risk factors,

such as alcohol, drug dependence, and physical and sexual abuse in

the aetiology of BD.15

The single nucleotide polymorphism CACNA1C is the most replicated

and studied polymorphism for BD, appearing in all ethnic populations

(present in 31% of European, 6% of Asian, and 56% of African

populations).15 However, since many individuals who carry this allele

are considered healthy, further research is required to confirm

staff reviewRCSIsmj


CACNA1C’s contribution to the pathology of BD.15 Genetic

vulnerability and episodic recurrence must both be explained by a

neurological hypothesis in order to make a genetic diagnosis of BD.

Current linkages are being studied on chromosomes 18 and 21q for

their role in genetic vulnerability to the development of BD.3,16-19

Diagnosing bipolar disorder

While symptom complexity, duration, and intensity vary greatly, a

high index of clinical suspicion for BD is necessary for further

substantiation into diagnosis (Figure 1).5 Generally, an initial

presentation is described as episodes of mania or depression

separated by periods that are deemed ‘well’.5 However, during these

symptom-free periods patients may still experience decreased

functioning, which can be detected via MRI to further support a

diagnosis of BD.5

The diagnosis is further supported when the patient presents with

mood-related symptoms such as depression, mood swings, irritability,

anxiety, or difficulty sleeping.5 The Diagnostic and Statistical Manual

of Mental Disorders 5th Edition (DSM-5) criteria specifically define the

manic, hypomanic, and depressive states that must be identified

during BD diagnosis. Manic episodes are defined as distinct periods of

erratic and prolonged elevation of mood or irritable mood, with

increased goal-directed activity or energy, for the majority of days

within at least one week.5 The presence of at least three other

symptoms, such as inflated self-esteem, decreased need for sleep,

talkativeness, flight of ideas, increased distractibility, or excessive

involvement in activities with painful consequence, must also be

present and severe enough to cause marked impairment of functioning

and potential hospitalisation.5 The episodes must not be attributable to

other substances such as illicit drugs, medication, or alcohol.5

Hypomanic episodes are defined as a distinctive period of erratic and

prolonged elevation with increased goal-directed activity or energy,

lasting at least four consecutive days, present for most of the day and

nearly all four days.5 Similarly, at least three other symptoms as seen above

should be noted.5 However, the episode should not be severe enough for

marked impairment or hospitalisation.5 Hypomanic episodes are often

overlooked, and may incorrectly be deemed a symptom-free period.5

BD is underdiagnosed due to cautionthroughout the diagnostic process, to

avoid incorrect labelling. This often results in manic episodes being overlooked and undermanaged.

Depressive episodes are defined as five or more symptoms present in

the same two-week period, showing a change from previous

functioning, with at least one of the symptoms being either depressed

mood or loss of interest.5 The mood should be present for most of the

day and nearly every day, with a markedly decreased interest in

activities, unintentional weight loss, insomnia or hypersomnia,

psychomotor agitation or retardation, fatigue, feelings of

worthlessness or inappropriate guilt nearly every day, diminished

ability to think or concentrate, and/or recurrent thoughts of death.5

Currently, BD is underdiagnosed due to caution throughout the

diagnostic process, to avoid incorrect labelling.3,20 This often results in

manic episodes being overlooked and undermanaged; the same is

true for mixed states, hypomania, and/or bipolar depression.3 Studies

looking at the diagnostic patterns within a community approximate

that 60% of hospitalised patients who are diagnosed with BD by

researchers also received a confirmed clinical diagnosis.3

staff reviewRCSIsmj

FIGURE 1: The diagnostic process for bipolar disorder. Case-based tools such as themood disorder questionnaire (MDQ) and the composite international diagnosticinterview (CIDI) are used to differentiate mood disorders.5

No Continue managementin primary care

Yes Specialistreferral/collaborative care

Suspect bipolar disorder

n Presentation: depressive symptomsn Risk factors: history of manic or hypomanic symptoms

Verify suspicion of bipolar disorder by:

n Patient interview: detailed personal (onset, frequency, severityof mood symptoms), family and social history

n Case-based finding tools (e.g., M3, MDQ, CIDI)

Confirm bipolar disorder diagnosis:

n Detailed clinical interview: using DSM-IV-TR/DSM-5 criteria;determine bipolar I vs bipolar II; assess for mixed state

t t

Evidence of:

n Suicide risk n Harm to self/others n Comorbidities


Management of bipolar disorder

After accurately confirming a BD diagnosis, identifying an

appropriate treatment strategy is crucial, as symptomatic

improvement generally takes up to two weeks for antipsychotics and

antidepressants, in comparison to a seven-day delay of therapeutic

effects with mood stabilisers.21-23 Diagnostic challenges and

concomitant delays may result in ineffective treatment for initial

episodes, and the potential for biological and psychological ‘scars’

from these early episodes to linger, further complicating BD.2-4 It has

been found that only 50-60% of patients treated with mood

stabiliser monotherapy respond adequately, meaning that the rest of

the patient cohort will require polypharmacy or multiple treatment

modalities, such as pharmacotherapy in conjunction with cognitive

behavioural therapy (CBT).4,24 Currently, the mainstays of

pharmacologic treatment include medications such as mood

stabilisers (lithium, valproate, lamotrigine, and carbamazepine),

antidepressants, and an array of atypical antipsychotics, as

outlined below.25

Non-pharmacologic therapy

Non-pharmacologic therapies, such as electroconvulsive therapy,

magnetic seizure therapy, magnetic stimulation, sleep deprivation,

bright light therapy, and psychosocial interventions, have been seen

as efficacious alternatives to current pharmacological methods.26

Psychotherapy is one of the most commonly utilised adjuvants, as it

has been proven to be more efficacious than medication alone in

mood relapse prevention.26 The Systematic Treatment Enhancement

Program for Bipolar Disorder (STEP-BD), involving 15 clinical

sites, found that recovery from depressive episodes was 110 days

faster when various psychosocial interventions were used as

adjuncts to pharmacotherapy, in comparison to minimal use of

psychosocial treatment.26 Such psychosocial therapies include

psychoanalytic psychotherapy, psychodynamic psychotherapy, and

psychoeducation.26

CBT is also a useful adjuvant in the prevention of mood episode

relapse.26 Randomised controlled trials (RCTs) have shown lower rates

of relapse in both adolescents and adults with a diagnosis of BD

receiving CBT.26 Furthermore, studies of CBT showed that its

therapeutic use resulted in a 50% reduction in the number of days

with depressed mood or antidepressant dose alterations, overall

resulting in positive outcomes for BD patients.26

Lithium

Mood stabilisers such as lithium have been the foundation of BD

treatment for over 60 years due to their serotonergic effects, with a

recorded six-fold reduction in suicide rates compared to no

treatment.3,11,27 RCTs between 1970 and 2006 have shown lithium to

be efficacious in the prevention of relapses.2,28 Lithium remains the

only agent to reduce the risk of suicide by more than 50%.2,29,30 As

such, lithium must not be discontinued abruptly due to its

promotion of rapid relapse, placing patients at increased risk of

suicide attempts.29,31

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Lithium induces multiple biochemical and molecular effects on

neurotransmitter and receptor-mediated signalling, signal

transduction cascades, circadian and hormonal regulation, gene

expression, and ion transport.11 Based on a 40-year review, lithium

dosage should be between 600 and 2,400mg/day to give an ideal

serum level between 0.8 and 1.2µg/mL.4 Side effects of lithium

treatment include polyuria, polydipsia, weight gain, gastrointestinal

(GI) upset, acne, hypothyroidism and/or hyperthyroidism.4,30 Due to

its narrow therapeutic index, patients require regular monitoring of

serum hormone and electrolyte levels, along with serum drug

concentration.2,30

Anticonvulsants

Initial research that led to the use of anticonvulsants as first-line BD

treatment was concentrated on lithium-resistant patients suffering

from rapid cycling mixed states, with or without additional

substance abuse.3 Sodium valproate is a popular antiepileptic mood

stabiliser used in combination with lithium for symptomatic

improvement and maintenance from the time of first mood

episode.2 However, lithium still remains more effective than

valproate alone.2,32 Interestingly, through observational studies,

patients on valproate were found to have a higher rate of requiring

additional medications and therapy switching in comparison to

patients receiving lithium.2,33

Valproate has been approved for mania as well as mixed or irritable

mania and rapid cycling; however, further studies are required to

clarify valproate’s long-term usage.4,26 The general dose for its

immediate-release preparations ranges from 500-3,500mg/day in

two divided doses, whereas extended-release products are once

daily at similar doses, with a plasma level between 75 and

1,252µg/mL.4 Side effects include sedation, diarrhoea, weight gain,

alopecia, tremor, and elevated liver enzymes.4 However, more

serious side effects such as thrombocytopenia, leukopenia,

pancreatitis, and hepatotoxicity should also be closely monitored

for.2,4 In addition, both lithium and valproate are known teratogens,

making prescribing difficult in young women of child-bearing age;

this led to a re-issued FDA ‘black box’ warning in 2016, as well as

renewed warnings via the Health Products Regulatory Authority

(HPRA).2,4,34

The antiepileptic lamotrigine is a mood stabiliser with the most

evidence for prevention of BD.2,35 Its use in acute mania shows

inconsistent data; however, this has been superseded through a

meta-analysis showing efficacy at doses higher than 200mg/day.35,36

Side effects of lamotrigine include a rash and Stevens-Johnson-type

syndromes, which may be fatal.2,37-39

Atypical antipsychotics

Atypical antipsychotics have an established role for the treatment of

acute mania, assisting with psychosis and insomnia.2,4,25 However,

monotherapy with these agents is not supported, apart from

quetiapine, which is often prescribed on its own.25 Quetiapine has

also been shown to reduce the symptoms associated with depression

in acute mixed episodes of BD.40 The side effect profile of

antipsychotics is well characterised, specifically weight gain with

olanzapine, risperidone, and quetiapine, and weight loss with

ziprasidone or topiramate (20-400mg).2,4,41 They also pose risks to

patients’ metabolic function, specifically glucose regulation.4,42

Antidepressants

The use of antidepressants in BD is controversial.2,43 A random-effect

meta-analysis showed that there was no significant difference

between their use in unipolar depression and BD.44 Notably,

antidepressant use was associated with a 2.5% weekly risk rate of

conversion to mania.2,44 Interestingly, the FDA has not approved

antidepressants for use in BD, apart from fluoxetine when in

combination with olanzapine.2 SSRIs, except paroxetine and

bupropion, may be used as first-line therapy in patients with no

previous history of rapid cycling and with absence of manic

symptoms.2 However, SSRIs should always be used in conjunction

with either a mood stabiliser or atypical antipsychotic.2

Since patients with BD are more conscious of depressive episodes and their associated symptoms, compared to mania

or hypomania, treatment often requires antidepressants

in all cycles.

Since patients with BD are more conscious of depressive episodes and their

associated symptoms, compared to mania or hypomania, treatment often

requires antidepressants in all cycles.3 This creates clinical concern, as

studies have shown that patients treated with concurrent antidepressants

and lithium are twice as likely to experience manic episodes than those

treated for mania with lithium alone.45-47 Bupropion and paroxetine are

two antidepressants shown to have a lower risk of provoking manic

episodes when in combination with lithium, in comparison to tricyclic

antidepressants such as amitriptyline.3,48 However, even with such benefits

they still appear to have long-term risks of inducing rapid cycling, and thus

caution must be exercised when prescribing these agents.3

staff reviewRCSIsmj


staff review

References

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Available from: http://www.who.int/mental_health/media/investing_mnh.pdf.

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4. Hilty DM, Brady KT, Hales RE. A review of bipolar disorder among adults.

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RCSIsmj

A global call for renewed action

With a population of approximately 450 million people suffering

from mental or behavioural disorders, it is clear that further work is

required to improve mental health across the globe.1

The WHO has published ‘Investing in Mental Health: Evidence

for Action’, which identifies new areas of interest and strategies

for improving psychological well-being on an international

scale.49

The WHO has also emphasised that this global disease burden is

further accentuated by poor service availability and access,

highlighting the issues of economic development and social welfare

as additional areas in dire need of intervention.

This report has called on governments worldwide to address these

and other barriers, and to ensure that multidisciplinary mental

health initiatives are made an investment and health sector

priority.49

Conclusion

Unfortunately, lifetime management of BD is extremely challenging due to

its dynamic and fluctuating course. It is crucial for healthcare providers to

help limit the burdens of BD for both patients and their caregivers. While

pharmacological methods are currently the mainstay of treatment, it is

essential to consider drug efficacy and associated risk profiles when

initiating treatment, so as to prevent further complications or declines in

mental state. Most recently, a global renewed interest in research for

mental health conditions in terms of diagnosis and management is poised

to help alleviate the stigma of mental illness, expand care access, and

improve patient outcomes. Through multidimensional efforts, a hopeful

future is in sight for patients afflicted with mental health disorders. Bipolar

disorder remains a topic of interest for many healthcare providers and

communities alike, and will continue to demand collaborative,

compassionate, evidence-based strategies until suitable patient outcomes

have been achieved.

RCSIsmj


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Psychiatry. 1981;38(8):902-7.

48. Sachs GS, Lafer B, Stoll AL et al. A double-blind trial of bupropion versus

desipramine for bipolar depression. J Clin Psychiatry. 1994;55(9):391-3.

49. World Health Organisation. Investing in Mental Health: Evidence for

Action. 2013. [Internet]. Available from:

http://apps.who.int/iris/bitstream/handle/

10665/87232/9789241564618_eng.pdf?sequence=1.

staff review


Abstract

Depression is a complex illness that significantly contributes to the global burden of disease. The two main

symptoms are depressed mood and anhedonia; however, depression can manifest with a wide range of

psychological, behavioural, and physical symptoms. This diversity of symptoms, as well as the reluctance

of many patients to reveal their depressed feelings, can make it difficult for healthcare practitioners to

diagnose. Depression is especially common in patients with chronic physical illnesses, such as diabetes

mellitus (DM), as the management regimen for DM is complex and usually involves significant lifestyle

changes. Having one or more chronic illnesses is the greatest risk factor for depression, and having

depression is also a major risk factor for developing those physical illnesses. Importantly, depression is

largely treatable as there are many management options available to patients, including psychotherapy,

pharmacological treatments, electroconvulsive therapy, and community support groups. However, despite

the wide range of treatments, increasing awareness of the prevalence of depression and how it can

negatively impact patient health when comorbid with other illnesses increases the efficacy of primary care

interactions and allows healthcare organisations and policies to better address the issue. This can increase

diagnostic rates and ultimately strengthen the amount of support provided to such patients.

Ola M. Michalec


The intersection of depressionand chronic illness


staff reviewRCSIsmj


Introduction

Depression is a complex and medically relevant illness. According to

the Global Health Estimates made by the World Health Organisation

(WHO) in 2015, depression affects 4.4% of the global population.1

That amounts to a total of 322 million people living with depression,

and the numbers are increasing.1 In a span of ten years, from 2005 to

2015, the prevalence of depression increased by approximately

19%.1-4 Globally, depression contributed 7.5% to all years lived with

disability (YLDs) in 2015, making it the greatest contributor to

non-fatal disease burden.1 Additionally, depression contributes to

approximately 800,000 suicides annually.1 The increasing prevalence

and morbidity of depression highlights the need for both current and

future healthcare practitioners (HCPs) to thoroughly understand the

effect that depression has on a patient’s quality of life. As Harvey

Cushing (1869-1939) said: “A physician is obligated to consider more

than a diseased organ, more even than the whole man – he must view

the man in his world”. It is the responsibility of HCPs to take the time

to gain a thorough understanding of the realities faced by patients,

mentally and physically, in order to optimise and strengthen the care

and support provided. It is essential to realise that patients coping

with depression often face new limits regarding their capabilities and

well-being, which can prove difficult and may impact on other

illnesses.

Depression is highly prevalent among patients with chronic illnesses,

such as diabetes mellitus (DM), with 9-23% of patients presenting

with comorbid depression, depending on the illness.5 However,

depression is left undiagnosed in approximately 42-48% of patients

who have a chronic physical illness.6-8 This review aims to emphasise

that increasing awareness of the signs and symptoms of depression,

as well as its classification as a mental illness, optimises the support

that patients with chronic physical illness receive at both an

individualised and community-wide level. It is through this

understanding and effort that HCPs can strive to improve the mental

health of patients worldwide.

The stigma associated with depression, as well as how it varies cross culturally, are important factors to consider, as theymay impair the willingness of patients

to admit they are experiencing emotional distress.

Depression: clinical signs and symptoms

Depression most commonly presents with two main symptoms: a

deep feeling of sadness (depressed mood) and a loss of interest or

pleasure in regular activities (anhedonia).9 However, depression can

manifest itself in a variety of ways, including through psychological,

behavioural, and physical symptoms (Table 1). If untreated,

depression carries a higher risk of suicide.10 The duration and severity

of symptoms, which can persist from weeks to years, determine the

difference between major depressive disorder (MDD) and dysthymia.

MDD is defined by the Diagnostic and Statistical Manual of Mental

Disorders – 5th Edition (DSM-5) as having five or more of the nine

outlined symptoms (Table 2) nearly every day in the same two-week

period, at least one of which must be depressed mood or

anhedonia.9,10 Dysthymia, or chronic depression, is defined as the

persistence of the outlined symptoms of MDD for over two years,

even though patients often present less severely.9,10

Even when aware of the psychological, behavioural, and physical

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Table 1: Common psychological, behavioural, and physical symptoms associated with depression.10

Psychological symptoms

Depressed mood

Irritability/anxiety/nervousness

Difficulty concentrating

Lack of motivation

Anhedonia: lack of pleasure in doing things

Indecisiveness

Feelings of helplessness

Reduced libido

Sensitive to rejection and criticism

Perfectionism/obsessiveness

Behavioural symptoms

Crying spells

Interpersonal friction/confrontation

Anger outbursts

Avoiding situations that may cause anxiety

Decreased productivity

Social withdrawal

Substance use/abuse

Avoiding emotional and sexual intimacy

Workaholic tendencies

Physical symptoms

Fatigue

Dull, heavy or slow feelings in arms or legs

Insomnia or hypersomnia

Change in appetite

Significant weight gain or loss

Erectile dysfunction

Difficulties with sexual arousal

Pains and aches

Muscle tension

Gastrointestinal upset

Heart palpitations


staff reviewRCSIsmj

symptoms, diagnosing depression remains challenging. The stigma

associated with depression, as well as how it varies cross culturally, are

important factors to consider, as they may impair the willingness of

patients to admit they are experiencing emotional distress.10,11 Since

patients are often reluctant to come forward regarding their

depressed emotions, offering the opportunity for a patient to raise

concerns, and referring them to a psychologist if necessary, is

effective.12-14 By enhancing the quality of communication with

patients who are depressed, HCP–patient interactions can become

more meaningful.13 In addition to the wide range of symptoms,

associated stigma, and reluctance of patients to come forward,

diagnosing depression can be further complicated by its association

with other conditions, in particular chronic physical illnesses that can

manifest with similar symptoms.

Depression, chronic illness, or both?

Chronic physical illnesses, also known as non-communicable diseases,

are not transmitted from person to person, tend to be of long

duration, and usually progress slowly.1 On a global scale, chronic

physical illnesses are responsible for 71% of deaths worldwide, or 41

million deaths annually.1 Based on the World Health Survey (WHS)

conducted by the WHO, which surveyed 250,000 participants from

60 countries, 9-18% of those with one or more chronic physical

illnesses also had depression (Table 3).5 Depression is significantly

more prevalent in patients with a chronic physical illness compared to

those without, and the greatest risk factor for depression is having

multiple comorbid diagnoses.5,15,16 Additionally, comorbidity

decreases health status in elderly, female, less educated, low-income,

and unemployed patient groups.5 Therefore, the comorbidity of

depression and common chronic physical illnesses, like cardiovascular

disease, cancer, respiratory diseases, arthritis, and diabetes, is an

important issue for HCPs to consider when managing patients with

these conditions.10,17

Moreover, depression itself is a risk factor for physical illness.12 Having

depression either on its own or in conjunction with another condition

is significantly associated with poorer health status.12 This is of

particular importance as patients who have depression together with

a chronic physical illness are often left undiagnosed by physicians,

which can lead to worse health outcomes.5,18,19

Diabetes mellitus as a comorbid condition of depression

DM is a chronic physical illness commonly associated with

depression.20-22 In the long term, if not well controlled, DM may lead

to complications that can be a source of significant distress for many

patients.23 The majority of patients with DM have type 2 DM, which

more frequently occurs in overweight or obese patients.24,25

Additionally, the management regimen for diabetes is complex, time

intensive, and can prove emotionally distressing for patients, as many

elements of the treatment are often carried out by the patient

themselves.26 When diagnosed with DM, an individual will be

counselled to adopt significant lifestyle changes including a healthier

diet, engaging in a regular exercise regimen, and counting and

regulating carbohydrates. The comorbidity between diabetes and

depression can often impair adherence to treatment regimens and

compromise glycaemic control, leading to further complications and

poor health outcomes.20,21,27

The prevalence of depression in people with diabetes is three times as

high for patients with type 1 diabetes and twice as high for patients

with type 2 diabetes compared to those without.21,28 This is a major

concern given that depression significantly increases the risk of

Major depressive disorder

Having five or more out of the following nine symptoms

nearly every day in the same two-week period:

Note: Must include at least one of depressed mood or anhedonia.

1. Depressed mood (subjective OR observed)

2. Anhedonia: loss of interest or pleasure in all, or almost all,

activities, most of the day

3. Change in appetite or significant weight loss or gain

4. Insomnia or hypersomnia

5. Observed psychomotor agitation or retardation

6. Fatigue/loss of energy

7. Feelings of worthlessness or excessive guilt

8. Impaired concentration

9. Thoughts of death or suicidal ideation or attempt

Table 2: DSM-5 diagnostic criteria for major depressive

disorder (MDD).

Disease Prevalence of having Prevalence of having

the disease on the disease comorbid

on its own with depression

Depression 3.2% –

Diabetes 2.0% 9.3%

Asthma 3.3% 18.1%

Arthritis 4.1% 10.7%

Angina 4.5% 15%

Table 3: The prevalence of a particular illness concurrent

with depression was higher compared to prevalence of

the disease on its own.5


staff review

References

1. World Health Organisation. Depression and Other Common Mental

Disorders: Global Health Estimates. Geneva: World Health Organisation.

2017. [Internet]. Available from: https://www.who.int/mental_health/

management/depression/prevalence_global_health_estimates/en/.

2. Ustun TN, Ayuso-Mateos JL, Chatterji S, Mathers C, Murray CJL. Global

burden of depressive disorders in the year 2000. Br J Psychiatry.

2000;184:386-92.

3. Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ et al.

Burden of depressive disorders by country, sex, age and year: findings from

the global burden of disease study 2010. PLoS Med. 2013;10(11):e1001547.

4. Ferrari A, Somerville AJ, Baxter A, Normal R, Patten S, Vos T et al. Global

variation in the prevalence and incidence of major depressive disorder: a

mortality in patients with diabetes.22 Furthermore, patients with

diabetes under the age of 65, of female gender, and those not married

are more likely to become depressed.21,28 Since patients with diabetes

often present to a large team of HCPs multiple times a year, or at the

very least for an annual review, there are many opportunities for

engagement, education, and supportive healthcare interactions.

Improving mental health: current treatments and increasing

awareness

Recovery takes time, but depression is often a treatable illness. The

management options are highly individualised, and vary based on

symptom severity. Patients with depression can receive support at the

primary care level, as well as from support groups in the community.

Cognitive behavioural therapy (CBT), a type of psychotherapy, is a

treatment option that focuses on changing patients’ thoughts and

behaviours to help manage depression.29 CBT is a highly effective

treatment modality and significantly reduces relapse rates in comparison

to pharmacological treatments such as selective serotonin reuptake

inhibitors (SSRIs).29 Most patients with depression are managed with a

combination of therapies that involve both psychotherapy and

pharmacological treatment.29 In severe cases of depression, or in patients

with treatment-resistant depression, electroconvulsive therapy (ECT) may

be offered.30,31 ECT involves passing small electric currents through the

brain to induce brief seizures. While controversial, ECT is thought to be

one of the most effective treatments for depression.30,31 Additional

management options for depression exist beyond those mentioned here,

including a spectrum of individualised and community-based support

programmes.

In addition to the variety of treatment options available, increasing

mental health awareness is particularly important due to the increased

likelihood of depression in patients with a chronic physical illness.5,15,16

Ultimately, the delivery of mental health interventions should be

integrated into all levels of healthcare provision: on a small scale, with

every primary patient–HCP interaction, as well as on a larger scale,

through health systems policy changes.32,33 Currently, global models such

as the Chronic Care Model (CCM), implemented by the WHO, aim to

decrease the global burden of disease for chronic illness by improving the

delivery of healthcare to patients with chronic conditions on many

levels.34 Such an approach would prove valuable in improving patient

access to mental health support. It is by increasing awareness of the

negative effects that depression can have on patient health, especially

when comorbid with other chronic illnesses, that strides can be made to

improve multidisciplinary psychological support at the individual,

healthcare organisational, and policy-making level.

Depression can be difficult to diagnose, as it is often comorbid with chronicphysical illnesses that may present

with similar symptoms.

Conclusion

Depression is both a serious illness and an important public health

concern. It is crucial that HCPs are aware of the psychological,

behavioural, and physical symptoms of depression so that they use each

patient interaction to observe for symptoms. Depression can be difficult

to diagnose, as it is often comorbid with chronic physical illnesses that

may present with similar symptoms. DM is one chronic illness commonly

associated with depression, and the complex interplay between these

two illnesses can have lasting psychological and physical implications.

Therefore, it is important that patients with chronic physical illnesses

receive optimal emotional and psychosocial support to address

depression, and prevent it from resulting in poorer health outcomes.

Finally, advancements in individualised treatment options are needed to

decrease the prevalence and impact of depression. Through improved

awareness of the association between depression and chronic physical

illness, and enhanced mental health support for patients at every level of

care, steps can be taken to decrease the global burden of depression

complicating chronic physical illness.

RCSIsmj


staff review

systematic review of the epidemiological literature. Psychol Med.

2013;43(3);471-81.

5. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression,

chronic diseases, and decrements in health: results from the World Health

Surveys. Lancet. 2007;370:851-8.

6. Li C, Ford E, Zhao G, Ahluwalia I, Pearson W, Mokdad A. Prevalence and

correlates of undiagnosed depression among US adults with diabetes: The

Behavioural Risk Factor Surveillance System, 2006. Diabetes Res Clin Pract.

2009;83(2):268-79.

7. Lecrubier Y. Widespread underrecognition and undertreatment of anxiety

and mood disorders: results from 3 European studies. J Clin Psychiatry.

2007;68(Suppl. 2):36-41.

8. Katon WJ, Simon G, Russo J, Von KM, Lin EH, Ludman E. Quality of

depression care in a population based sample of patients with diabetes

and major depression. Med Care. 2004;42:1222-9.

9. American Psychiatric Association. Diagnostic and Statistical Manual of

Mental Disorders, Fifth Edition (DSM-5). American Psychiatric Association;

Washington, DC, 2013.

10. Cassano P, Fava M. Depression and public health: An overview. J

Psychosom Res. 2002;53(4):849-57.

11. Chowdhury AN, Sanyal D, Bhattacharya A, Dutta SK, De R, Banerjee S et

al. Prominence of symptoms and level of stigma among depressed

patients in Calcutta. J Indian Med Assoc. 2001;99(1):20-3.

12. Pollock K. Maintaining face in the presentation of depression: constraining

the therapeutic potential of the consultation. Health (London). 2007;11:163-80.

13. Gask L, Rogers A, Oliver D, May C, Roland M. Qualitative study of patients’

perceptions of the quality of care for depression in general practice. Br J

Gen Pract. 2003;53:278-83.

14. Beverly E, Ganda O, Ritholz M, Lee Y, Brooks K, Lewis-Schroeder N et al.

Look who’s (not) talking: diabetic patients’ willingness to discuss self-care

with physicians. Diabetes Care. 2012;35(7):1466-72.

15. Katon W, Schulberg H. Epidemiology of depression in primary care. Gen

Hosp Psychiatry. 1992;14(4):237-47.

16. Harpole LH, Williams JW Jr, Olsen MK et al. Improving depression

outcomes in older adults with comorbid medical illness. Gen Hosp

Psychiatry. 2005;27(1):4-12.

17. Chapman DP, Perry GS, Strine TW. The vital link between chronic disease

and depressive disorders. Prev Chronic Dis. 2005;2(1):A14.

18. Andrews G. Should depression be managed as a chronic disease? BMJ.

2001;322(7283):419-21.

19. Luber MP, Hollenberg JP, Williams-Russo P et al. Diagnosis, treatment,

co-morbidity, and resource utilization of depressed patients in general

medical practice. Int J Psych Med. 2000;30(1):1-13.

20. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of

depressive symptoms on adherence, function and costs. Arch Intern Med.

2000;160(21):3278-85.

21. Egede LE, Zheng D, Simpson K. Comorbid depression is associated with

increased health care use and expenditures in individuals with diabetes.

Diabetes Care. 2002;25(3):464-70.

22. Park M, Katon WJ, Wolf FM. Depression and risk of mortality in individuals

with diabetes: a meta-analysis and systematic review. Gen Hosp Psychiatry.

2013;35(3):217-25.

23. Ismail K, Moulton C, Winkley K, Pickup J, Thomas S, Sherwood R et al. The

association of depressive symptoms and diabetes distress with glycaemic

control and diabetes complications over 2 years in newly diagnosed type 2

diabetes: a prospective cohort study. Diabetologia. 2017;60(10):2092-102.

24. Liu N, Brown A, Folias A, Younge M, Guzman S, Close K et al. Stigma in

people with type 1 or type 2 diabetes. Clin Diabetes. 2017;35(1):27-34.

25. Browne J, Ventura A, Mosely K, Speight J. ‘I call it the blame and shame

disease’: a qualitative study about perceptions of social stigma surrounding

type 2 diabetes. BMJ Open. 2013;3(11):e003384.

26. Tanenbaum ML, Kane NS, Kenowitz J, Gonzalez JS. Diabetes distress from

the patient’s perspective: Qualitative themes and treatment regimen

differences among adults with type 2 diabetes. J Diabetes Complications.

2016;30(6):1060-8.

27. Van Bastelaar K, Pouwer F, Geelhoed-Duijvestijn P, Tack C, Bazelmans E,

Beekman A et al. Diabetes-specific emotional distress mediates the

association between depressive symptoms and glycaemic control in type 1

and type 2 diabetes. Diabet Med. 2010;27(7):798-803.

28. Roy T, Lloyd CE. Epidemiology of depression and diabetes: a systematic

review. J Affect Disord. 2012;142(Suppl.):S8-21.

29. Sudak DM. Cognitive behavioural therapy for depression. Psychiatr Clin

North Am. 2012;35(1):99-110.

30. Oremus C, Oremus M, McNeely H et al. Effects of electroconvulsive

therapy on cognitive functioning in patients with depression: protocol for

a systematic review and meta-analysis. BMJ Open. 2015;5(3):e006966.

31. Antunes PB, Rosa MA, Belmonte-de-Abreu PS et al. Electroconvulsive

therapy in major depression: current aspects. Braz J Psychiatr.

2009;31(Suppl. 1):S26-33.

32. Katon W, Guico-Pabia CJ. Improving quality of depression care using

organized systems of care: a review of the literature. Prim Care

Companion CNS Disord. 2011;13(1):pii: PCC. 10r01019blu.

33. Von Korff M, Gruman J, Schaefer J et al. Collaborative management of

chronic illness. Ann Intern Med. 1997;127(12):1097-102.

34. Epping-Jordan JE, Pruitt SD, Bengoa R, Wagner EH. Improving the quality of

health care for chronic conditions. Qual Saf Health Care. 2004;13:299-305.

RCSIsmj


staff review

Abstract

Chronic kidney disease (CKD) is an indolent yet unrelenting condition that affects 10% of the global

population. CKD often progresses to end-stage renal disease (ESRD), and resulted in 1.2 million deaths in

2017. The prevalence of CKD continues to rise, with increasingly stark health and economic consequences.

Current treatment seeks to delay the onset of ESRD, with kidney transplantation representing the only

potentially curative option. However, donor organ supplies are unpredictable, and as demand continues to

increase, waiting list times are increasingly untenable for late-stage patients. Transplantation is also

associated with complications, immunosuppression, and unending expense. Therefore, alternatives or

adjuncts are desperately needed. One particularly attractive option is the rejuvenation of a patient’s own

failing organs via whole tissue bioengineering. Utilising the techniques of decellularisation, wherein a

surgically excised organ is stripped of its dysfunctional cells into an extracellular matrix scaffold ex vivo, and

recellularisation, where the organ is repopulated with the patient’s own in vitro-derived stem cells prior to

re-implantation, whole tissue bioengineering may improve patient outcomes. However, it remains an

iterative practice that has yet to achieve translational relevance. This is primarily due to the problems

associated with applying animal-derived research findings to human clinical practice. In general, scaling

established protocols from animal to human kidneys remains challenging and elusive. Due to the

compartmentalised structure of the kidneys, methods of establishing viable cellular growth remain to be

refined to the extent necessary for clinical trials. This review will explore the remaining challenges facing

whole-organ tissue bioengineering in the context of CKD.

Vladimir Djedovic


Bioengineered transplants:stem cell reversal of chronickidney disease


RCSIsmj


Introduction to CKD

Chronic kidney disease (CKD) is a complex condition defined by

progressive loss of kidney function over months to years.1 Initially, patients

are asymptomatic or may present with non-specific clinical symptoms

such as fatigue, loss of appetite, or confusion.1 Diagnosis relies on clinical

parameters such as creatinine clearance, reduced estimated glomerular

filtration rate, and altered urinary albumin excretion rate.2 The prime risk

factors for CKD include type 1 or 2 diabetes, a family history of kidney

disease, and hypertension.3 However, it ultimately arises from a complex

interplay of genetic, lifestyle, and environmental factors.3

At present, CKD affects 750 million people worldwide, with a mortality

rate of 1.2 million in 2017.4,5 As prevalence continues to rise on an

unabated upward trajectory, the economic implications for international

health systems are stark.6,7 For example, CKD costs the British National

Health Service (NHS) £1.5bn, the American Government $48bn US, and

the Irish Government €120m annually, representing 6-7% of total

healthcare expenditure.6-8

Current treatments

Initial treatment of CKD consists of adjusting lifestyle habits to manage risk

factors, and focused interventions to preserve nephron function.9 As 80%

of CKD patients have hypertension, this involves limiting sodium and

alcohol intake, increasing exercise, and smoking cessation.10 Further, for

patients with comorbidities such as hyperlipidaemia and type 1 or 2

diabetes mellitus, managing these conditions is a paramount goal of early

therapy.10 When lifestyle modifications are insufficient, pharmacological

intervention commences with angiotensin-converting enzyme (ACE)

inhibitors or angiotensin II receptor blockers, and progresses to

beta-adrenergic receptor blockers, calcium channel blockers, diuretics,

and vasodilators.11 However, these efforts are not curative, and the stated

objective is merely to delay the often inevitable onset of end-stage renal

disease (ESRD).11

ESRD is temporarily treated by replacing renal function through

haemodialysis or peritoneal dialysis.12 The management of water and

electrolyte balance, and removal of blood-borne waste products such as

creatinine and urea, is well established through these methods, allowing

patients to survive near indefinitely.12 However, the immunomodulatory

and endocrine functions of the kidney are absent and unrestored by

dialysis.13 Quality of life is also diminished due to the frequency of

treatment, as it is generally performed 156 times per annum.12 As a result,

associated costs for haemodialysis and peritoneal dialysis reach up to

$90,000 US or €60,000 annually, per patient, as treatment typically

occurs in an outpatient setting requiring specialised equipment and

personnel.5,6,13,14 Successful haemodialysis also frequently requires the

surgical formation of arteriovenous shunts (sites of unimpeded blood flow

between arteries and veins), which serve as access points to the patient’s

circulation.15 Complications of shunt formation include thrombosis,

ischaemic neuropathy, infection, aneurysm, and lymphoedema, which

further obscure the clinical picture of CKD sufferers.15 Haemodialysis and

peritoneal dialysis are undoubtedly useful tools for preserving the patient’s life

while they await a donor kidney, but this expensive and complication-prone

procedure does not represent a long-term solution; every year spent on

dialysis increases relative risk of all-cause mortality by 7%.16,17

Kidney transplantation

The only potentially curative treatment for CKD is a kidney transplant.18

Ireland performed a record number of organ transplants in 2018.19

However, this occurred in the midst of an increasing patient backlog due

to organ shortages.19 Globally, the supply of donor kidneys is

unpredictable, and patients typically wait over three years to receive an

organ.19 Moreover, once the kidney is transplanted there are considerable

risks and considerations. The immunosuppressive drugs required to keep

organ-damaging antibody titres within acceptable ranges to prevent

organ rejection increase the predilection for post-transplant infection and

carcinogenesis. Concurrently, these medications impose a financial

expenditure of up to €10,000 annually per patient in Ireland and $15,000

in the United States.8,19 While a successful transplant yields an improved

quality of life, most healthcare systems are unable to meet the demand for

organs due to the increasing prevalence of CKD.19 Indeed, 13 patients die

awaiting a donor, while 110 patients are added to transplant lists, each day.19

In this climate, it is clear that the capacity of transplantation and dialysis

procedures alone is insufficient to deal with the growing issue of CKD.

Innovative or supplementary methods of replacing native kidney function

are urgently needed. One promising method may be through

rejuvenating organs using a process called whole organ tissue

bioengineering.20 Whole organ tissue bioengineering – a process by which

a patient’s or donor’s organs are stripped of defective cells and then

repopulated with host-derived stem cells, to restore function – holds the

promise of maximising the potential of transplant surgery by reducing

organ shortages, and by providing a potentially life-saving resource bereft

of the complications and associated costs that currently plague organ

transplantation in general.20 Fortunately, the means to actualise this

technology are drawing closer.6

Whole organ tissue bioengineering

Whole organ tissue bioengineering is the process of using chemical,

biological, and physical means to regenerate biological tissues.20 Broadly, the

method consists of several steps: the damaged organ is removed from a

patient, stripped of its dysfunctional cells, repopulated with the patient’s own

stem cells, and implanted back into the original patient (Figure 1).20,21

staff reviewRCSIsmj


Regenerating organs in this manner begins by first creating a tissue

scaffold.20,21 Tissue scaffolds are three-dimensional (3D) extracellular

matrix (ECM) structures containing the complete anatomy, cues, and

homeostatic signals necessary for cellular function, proliferation, and

organ ultrastructure.22 Scaffolds are generated by the process of organ

decellularisation.22 Decellularisation is the gradual removal of cells from an

organ’s ECM backbone with gentle detergents, enzymes, and other stimuli

such as physical agitation.22 The purpose of this process is to generate a

biological ‘blank slate’, which can theoretically support new, healthy cell

growth.22,23 In the decellularised state, organ scaffolds appear as hollow or

translucent versions of the original organ itself.22,23 The methodological

challenges of decellularisation have been surmounted, as various

organ-specific scaffold-generating protocols exist.23 For example, initial

studies in rat kidney decellularisation guided the way to the recent

achievements in viable human kidney scaffold production.24 Recently, even

entire human limbs have been successfully decellularised, leaving the ECM

and anatomical features intact.25

Once a scaffold is cleared of defective cells, the methodological challenge

of re-establishing functional cell growth on the organ begins. Effective

recellularisation is currently the bottleneck for development of

bioengineered organs.26 The process broadly consists of perfusing stem

cells through the acellular scaffold by slowly propelling them through the

preserved vestiges of the vascular framework, or other channels such as

the ureters.26 This is currently accomplished using tissue bioreactors,

devices that both preserve and mature scaffolds, and provide the chemical

and physical regulatory signals required to induce appropriate stem cell

differentiation therein.26 At present, recellularisation faces several key

challenges that present a roadblock to clinical application.

Today’s hurdle – challenges in whole organ tissue bioengineering

Challenges to recellularising the human kidney result from: (1) its

complex structure; and (2) its large size relative to experimental

models.13 The primary difficulties researchers face at present include:

identifying appropriate cells for recellularisation; establishing suitable

blood flow to allow cell growth; and identifying reproducible means of

seeding cells throughout scaffolds.13

The functional unit of the kidney is the nephron. Anatomically, each

nephron contains a proximal and distal tubule, loop of Henle, and

collecting ducts. These components are each lined by regionally

specialised epithelial cells with unique functional properties, a

basement membrane composed of endothelial cells enclosed by

podocytes, and mesangial cells, which exhibit both immune and

structural activities.13 As such, these crucial cell types must be either

produced ex vivo through cell culture methods, or in vivo via the

differentiation of pluripotent stem cells.13

Currently, induced pluripotent stem cells are the most heavily studied

option since, in contrast to differentiated cell lines, they can expand

readily in vivo, do not require costly continual cell culture growth

methods, and have been demonstrated to develop into renal cells in

animal models.13 Importantly, they can be procured autologously from

the patient, bypassing the need for immunosuppression.13 Indeed,

nearly 160 bioengineered tracheas, blood vessels, and bladders have

been successfully transplanted into humans without need for

immunosuppressive medication.28,29 However, these organs all bypass

the need for establishing vascular access within the patient since they

are able to meet cellular metabolic requirements through diffusion due

to their thin-walled structures.28,29

staff review

FIGURE 1: Process of whole-organ tissue bioengineering using de- and recellularisation in a tissue bioreactor. First, the native human kidney is removed from the patient;functionally deficient cells are then removed to generate a tissue scaffold, using chemical reagents, ionic detergents, and physical agitation; next, cells grown in vitro or invivo are seeded into the scaffold using a tissue bioreactor; finally, the recellularised organ is ready for transplantation.27

RCSIsmj

Sourcen Goatn Humann Mousen Porcinen Ratn Monkey

Native kidney

Implantation

Decellularising agents

t

t

t

t

ECM scaffold

Seeding cells

Recellularisation assess

Cell lines:n iPSCsn BM-MSCn Pluripotent ES cellsn ES cellsn NKCsn HUVECsn RCTE

t

Chemical reagents:NaOH/Triton X-100/SDS/NaDOC/PAA/NH4OH/Trypsin/EDTA/EGTA

GAGs + fibrous proteins(collagen, elastin, fibronectin,laminin, etc.)

Other ECM proteins like growthfactors, etc.

Minimal residual DNA


In contrast, tissue bioengineering in the human kidney primarily hinges

on establishing sufficient blood perfusion to the organ’s various

structural compartments.30-32 As oxygen diffuses only up to 100-200µM

through tissues, sustainable 3D cell growth is limited to within this

proximity of the capillaries.20 In smaller bioengineered tissues, such as

the trachea, oxygen can diffuse sufficiently throughout the entire

structure, permitting cell growth and in vivo viability.13 In others, such

as bioengineered skin grafts, vascular access can be achieved through

anastomosis with native vasculature due to the sheet-like structure of

the graft itself.13,20 However, for more complex viscera, the presence of

an oxygen saturation gradient that decreases further away from the

capillaries leads to phenotypic differences in cell number, spatial

viability, and maturation.20 For example, as kidneys have a convoluted

and compartmentalised structure with differences in regional blood

flow, less vascularised areas of the organ will have less robust cell growth

and may consequently necrose.13,20 Rat kidney scaffold recellularisation

trials have recently achieved nearly 100% viable cell coverage, leading

to the production of rudimentary urine.33 Yet, human scaffold

repopulation currently remains difficult, partly due to avascular cellular

necrosis resulting from ischaemia and hypoxia.33 However,

recellularisation of kidney scaffolds has been recently scaled up to rhesus

monkeys, representing a major milestone in primate tissue

bioengineering.34 Recent work has also identified the paramount need

to first seed endothelial cells into the scaffolds, as endothelial cells

undergo angiogenesis and generate the capillaries necessary to support

colonisation of further cellular subtypes.13 Recent studies are currently

refining these protocols, but preliminary results indicate that, following

endothelial cell perfusion, admixtures of stem cells are more likely to

implant successfully.35

As the kidney relies on vascular access for both its glomerular filtration

function and its endocrine role, it is imperative to achieve sufficient cellular

viability through adequate blood flow.13 Prior to the first human trials,

complete recellularisation must also be achieved to minimise the presence

of free ECM subunits.13 Uncovered ECM components, such as collagen,

can activate the coagulation cascade, leading to thrombosis and

tissue damage.13 Therefore, prior to human bioengineered organ

transplantation, it is necessary to achieve 100% recellularisation to limit

the risk of thrombogenic events, especially when treating vulnerable

patient populations.13,20 While animal models can currently survive

indefinitely with anti-coagulation therapy, it is essential to limit this risk in

patients with comorbidities that may predispose to vascular events;

indeed, this is a feature of the majority of individuals with CKD.13,20

Consequently, a major challenge in the development of bioengineered

kidneys is identifying appropriate routes for cell perfusion.36 The kidney has

tripartite access for recellularisation due to its complete venous, arterial,

and ureteric architecture. As a result, multiple routes and strategies for

seeding cells currently exist.36 The most commonly used method relies on

impelling cells solely through the renal artery.33,36 This technique has been

used to recellularise rat kidneys sufficiently to produce rudimentary

urine.33,36 At present, this is the subject of much active research.

The growing burden of CKD is drivingdemand for dialysis and renal

transplantation to unprecedented levels and overwhelming current capacities.

Conclusions

The growing burden of CKD is driving demand for dialysis and renal

transplantation to unprecedented levels and overwhelming current

capacities. Whole organ tissue bioengineering offers an attractive,

cutting-edge alternative to conventional treatments, and seeks to

overcome the pitfalls of inherent organ shortages, mounting costs, and

unavoidable complications. Indeed, optimism is called for, as a majority of

the main technological hurdles – developing scaffolds, recellularising

animal organs, and demonstrating functionality in vivo – have been

successfully surmounted. It is true that organ engineering remains largely

an iterative practice, requiring continual refinement and troubleshooting,

but that will no doubt remain true long beyond the first human trials.

While three key challenges remain – namely, full organ recellularisation,

codifying seeding methods, and establishing in vivo vascular access –

recent successes portend the proximity of future clinical trials, which may

revolutionise how we treat CKD.

staff review

References

1. Centers for Disease Control and Prevention. National Chronic Kidney Disease

Fact Sheet. 2017. [Internet]. [Accessed 2017 June 7]. Available from:

https://www.cdc.gov/diabetes/pubs/pdf/kidney_factsheet.pdf.

2. Wouters OJ, O’Donoghue DJ, Ritchie J, Kanavos PG, Narva AS. Early chronic

kidney disease: diagnosis, management and models of care. Nat Rev

Nephrol. 2015;11(8):491-502.

3. Kazancioglu R. Risk factors for chronic kidney disease: an update. Kidney Int

Suppl. 2011;3(4):368-71.

RCSIsmj


4. World Health Organization. Preventing chronic diseases: a vital investment.


http://www.who.int/chp/chronic_disease_report/full_report.pdf.

5. Kerr M, Bray B, Medcalf J, O’Donoghue D, Matthews B. Estimating the

financial cost of chronic kidney disease to the NHS in England. Nephrol Dial

Transpl. 2012;27(3):73-80.

6. Honeycutt AA, Segel JE, Zhuo X, Hoerger TJ, Imai K, Williams D. Medical costs

of CKD in the Medicare population. J Am Soc Nephrol. 2013;24(9):1478-83.

7. Houston M. Number of people needing kidney dialysis rises by 50%. The

Irish Times. 2009. [Internet]. Available from: https://www.irishtimes.com/

news/health/number-of-people-needing-kidney-dialysis-rises-by-50-1.719332.

8. Gordon EJ, Prohaska TR, Sehgal AR. The financial impact of

immunosuppressant expenses on new kidney transplant recipients. Clin

Transplant. 2008;22(5):738-48.

9. Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, How W et al. Renin-angiotensin

system inhibitors and kidney and cardiovascular outcomes in patients with

CKD: a Bayesian network meta-analysis of randomized clinical trials. Am J

Kidney Dis. 2015;67(5):728-41.

10. Levey AS, Schoolwerth AC, Burrows NR, Williams DE, Stith KR, McClellan W.

Comprehensive public health strategies for preventing the development,

progression, and complications of CKD: report of an expert panel convened by

the centres for disease control and prevention. Am J Kidney Dis. 2009;53(3):522-35.

11. Toto RD. Treatment of hypertension in chronic kidney disease. Semin

Nephrol. 2005;25(6):435-9.

12. Rocco MV. More frequent hemodialysis: back to the future? Adv Chronic

Kidney Dis. 2007;14(3):e1-9.

13. Madariaga MLL, Ott HC. Bioengineering kidneys for transplantation. Semin

Nephrol. 2014;34(4):384-93.

14. National Kidney Foundation. Dialysis. 2015. [Internet]. Available from:

https://www.kidney.org/atoz/content/dialysisinfo.

15. Stolic R. Most important chronic complications of arteriovenous fistulas for

hemodialysis. Med Princ Pract. 2013;22(3):220-8.

16. Chertow GM, Johansen KL, Lew N, Lazarus JM, Lowrie EG. Vintage, nutritional

status, and survival in hemodialysis patients. Kidney Int. 2000;57(3):1176-81.

17. Braun L, Sood V, Hogue S, Lieberman B, Copley-Merriman C. High burden

and unmet patient needs in chronic kidney disease. Int J Nephrol Renovasc

Dis. 2012;5:151-63.

18. Organization for Economic Co-operation and Development. OECD health

statistics 2018. 2018. [Internet]. Available from:

http://www.oecd.org/els/health-systems/health-data.htm.

19. National Kidney Foundation. Organ donation and transplantation statistics.

2014. [Internet]. Available from: https://www.kidney.org/news/newsroom/

factsheets/Organ-Donation-and-Transplantation-Stats.

20. Lovett M, Lee K, Edwards A, Kaplan DL. Vascularization strategies for tissue

engineering. Tissue Eng Part B Rev. 2009;15(3):353-70.

21. Caralt M, Uzarski JS, Iacob S, Obergfell KP, Berg N, Bijonowski BM et al.

Optimization and critical evaluation of decellularization strategies to develop

renal extracellular matrix scaffolds as biological templates for organ

engineering and transplantation. Am J Transplant. 2015;15(1):64-75.

22. Jain A, Bansal R. Applications of regenerative medicine in organ

transplantation. J Pharm Bioallied Sci. 2015;7(3);188-94.

23. Gilbert TW. Strategies for tissue and organ decellularization. J Cell Biochem.

2012;113(7):2217-22.

24. Ott HC. Perfusion decellularization of discarded human kidneys: a valuable

platform for organ regeneration. Transplantation. 2015;99(9):1753.

25. Gerli MFM, Guyette JP, Evangelista-Leite D, Ghoshhajra BB, Ott HC. Perfusion

decellularization of a human limb: a novel platform for composite tissue

engineering and reconstructive surgery. PLoS One. 2018;13(1):e0191497.

26. Scarritt ME, Pashos NC, Bunnell BA. A review of cellularization strategies for

tissue engineering of whole organs. Front Bioeng Biotechnol. 2015;3:43.

27. Destefani AC, Sirtoli GM, Nogueira BV. Advances in the knowledge about

kidney decellularization and repopulation. Front Bioeng Biotechnol. 2017;5:34.

28. Orlando G, Soker S, Stratta RJ. Organ bioengineering and regeneration as

the new Holy Grail for organ transplantation. Ann Surg. 2013;258(2):221-32.

29. Orlando G, Di Cocco P, D’Angelo M, Clemente K, Famulari A, Pisani F.

Regenerative medicine applied to solid organ transplantation: where do we

stand? Transplant Proc. 2010;42(4):1011-3.

30. Folkman J, Hochberg M. Self-regulation of growth in three dimensions.

Journal Exp Med. 1973;138(4):745-53.

31. DesRochers TM, Palma E, Kaplan DL. Tissue-engineered kidney disease

models. Adv Drug Deliv Rev. 2014;0:67-80 [published online].

32. Rosines E, Johkura K, Zhang X et al. Constructing kidney-like tissues from

cells based on programs for organ development: toward a method of in vitro

tissue engineering of the kidney. Tissue Eng Part A. 2010;16(8):2441-55.

33. Song JJ, Guyette J, Gilpin G, Gonzalez G, Vacanti JP, Ott HC. Regeneration

and experimental orthotopic transplantation of a bioengineered kidney.

Nature Med. 2013;19(5):646-51.

34. Nakayama KH, Batchelder CA, Lee CI, Tarantal AF. Decellularized rhesus

monkey kidney as a three-dimensional scaffold for renal tissue engineering.

Tissue Eng Part A. 2009;16(7):2207-16.

35. Xu Y, Yan M, Gong Y, Chen L, Zhao F, Zhang Z. Response of endothelial cells

to decellularized extracellular matrix deposited by bone marrow

mesenchymal stem cells. Int J Clin Exp Med. 2014;7(12):4997-5003.

36. Remuzzi A, Figliuzzi M, Bonadrini B, Silvani S, Azzollini N, Nossa R et al.

Experimental evaluation of kidney regeneration by organ scaffold

recellularization. Sci Rep. 2017;7:43502.

staff reviewRCSIsmj


staff review

Abstract

Life-threatening cardiac arrhythmias are rare yet perilous conditions that affect children and adults alike.

Implantable cardioverter-defibrillators (ICDs) have been proven as effective means of preventing sudden

cardiac death (SCD) secondary to arrhythmias, but studies regarding their use in children remain limited.

There are many considerations surrounding paediatric ICD use that may significantly impact on quality of

life. Physical complications manifest in numerous forms, including inappropriate shocks, infections, and

higher frequency of device replacement. Psychosocial effects, such as depression and anxiety, and financial

repercussions may be overlooked, but are essential concerns. Potential solutions have been proposed and

developed to reduce the burden of ICDs in paediatric patients, ranging from conservative to invasive

procedures. Further studies must be conducted to clarify the effectiveness and potential negative effects of

such interventions when compared to the current risk–benefit profile of paediatric ICDs.

Jeffrey Lam



Introduction

Palpitations are one of the most common

presenting complaints for patients in hospitals,

outpatient clinics, and specialist care centres.1,2

Forming the primary symptomatology of roughly

16% of presenting patients, palpitations arise from a

wide range of underlying aetiologies.2 Common

causes include cardiac arrhythmias, psychosomatic

disorders such as anxiety, medication use, caffeine

consumption, and illicit substance use, among

many others.1,2 While palpitations are often benign,

they may be due to an underlying life-threatening

condition, such as an arrhythmia that could result in

debilitating palpitations, syncope, or even death.3

Cardiac arrhythmia severity and risk of adverse

health effects range from mild, benign, and

RCSIsmj

The big and the small of it:paediatric implantablecardioverter-defibrillators


occasional discomfort to significant risk of sudden cardiac death (SCD).3

Technological advances have led to the development of numerous

strategies to combat these life-threatening conditions.

An implantable cardioverter-defibrillator (ICD) is a small battery-powered

medical device that is typically implanted subcutaneously on the anterior

chest wall below the left clavicle. First developed for clinical use in 1980,

ICDs are considered the standard first-line management for primary

prevention of SCD in at-risk patients, and secondary prevention of SCD in

patients with a history of ventricular fibrillation (VF) or ventricular

tachycardia (VT).4-9 SCD is mainly caused by sustained VF or VT, as such

arrhythmias may result in sudden cessation of cardiac activity.10

SCD secondary to cardiac arrest is the most common cause of death

worldwide and accounts for over 50% of all cardiovascular deaths.11-13

Cardiac arrests that occur outside of the healthcare setting have an

estimated overall survival rate of only 10%.12 VF accounts for most

sudden cardiac arrest episodes and SCD, with survival declining by

nearly 10% for every minute the patient is in VF.11,13,14 Survivors of a VF

episode have a recurrence rate of up to 30%, and thus ICDs may have

an important role in secondary prevention of SCD.14,15 A meta-analysis of

three randomised trials found that ICDs led to a 50% reduction in

relative risk of arrhythmic death.16

However, existing paediatric studies havefound ICDs to have significant physical,psychosocial, and financial impacts on a

child’s quality of life.

While the uses, effectiveness, indications, and complications of adult ICDs

have been investigated extensively, studies on paediatric ICDs remain

limited.17,18 Existing paediatric studies have found ICDs to have significant

physical, psychosocial, and financial impacts on a child’s quality of life.

Alternatives to paediatric ICDs have been proposed, but further

comparative studies are required.

What is an ICD?

An ICD is composed of a pulse generator and one to three leads for

electrodes that regulate pacing and defibrillation.5,6 The pulse generator

contains a battery, capacitors for charge storage, microprocessors for

rhythm analysis, and memory chips for data storage.5 Pacing and

defibrillation electrodes are typically located on a single lead, with

transvenous leads as the present standard.5,6 Defibrillation leads contain

coils for heat dissipation during discharges to the myocardium, as well

as bipolar electrodes for ventricular pacing and sensing.5,6

While an ICD may look similar to an artificial cardiac pacemaker, there

are key differences. Artificial pacemakers are implantable medical

devices that automatically regulate heart rate, especially in patients with

bradycardia.19 Bradycardia is defined as a resting heart rate of less than

60 beats per minute.20 In contrast, ICDs act as safeguards against

potential cardiac arrest by delivering high-energy shocks when

arrhythmias such as VF or VT are detected.21 Contemporary ICDs often

have the functional capabilities of both pacemakers and defibrillators.6,22

ICD indications in children

A study in the United States found the estimated annual incidence of

SCD in children to be roughly one in 100,000.23,24 As a result, children

and patients with congenital heart disease constitute fewer than 1% of

all ICD recipients.9,25,26 The low volume of paediatric ICD implants

results in minimal available data regarding benefits following ICD

placement, as most paediatric ICD studies are retrospective, with small

sample sizes, and conducted at individual hospitals.25,27 However,

studies show that ICD use in children is increasing.23,25,27 The average

age of children who receive ICDs varies, but typically ranges from 12 to

14 years of age.23,27-29 Indications for ICDs in children include a variety

of pathologies and conditions; one study found that 46% of paediatric

ICD patients had congenital heart disease, 23% had cardiomyopathy,

and 31% had primary electrical diseases, such as congenital long QT

syndrome.26 Idiopathic VF and a family history of SCD were also found

to be indications for ICDs in children.17,27

Physical complications of paediatric ICDs

In paediatric medicine, anatomical differences prevent the effective use

of transvenous ICD technology designed for adults.27,30 Studies have

found that there are greater instances of inappropriate shock therapy

and lead-related complications within the paediatric population, with

lead failure being a significant cause of complications and

staff reviewRCSIsmj

Implantable cardioverter defibrillator (ICD)

ICD

Leads

Heart

Pulsegenerator

t

tt

t

t


malfunction.17,26,27,31-33 Infections and higher ICD replacement frequency

are also important complications to consider.

Treadmill exercise testing after ICDimplantation may be an effective means ofidentifying the appropriate high heart rate

zone within a controlled setting.

Inappropriate shocks

Supraventricular tachycardia and sinus tachycardia during physical activity

have been found to be the primary causes of inappropriate shock

delivery.34,35 To avoid inappropriate shock discharge, it is crucial for ICDs to

be able to differentiate between supraventricular tachycardia,

physiological sinus tachycardia (e.g., normal exercise), and life-threatening

VT. Treadmill exercise testing after ICD implantation may be an effective

means of identifying the appropriate high heart rate zone within a

controlled setting.18 It is suggested that the higher incidence of paediatric

ICD complications may be due to increased physical activity alongside

significant physiological growth occurring throughout childhood.9,36

Interestingly, growth as measured by height and weight changes is a

strong predictor of lead failure.31 Children will also live with their ICD for

longer periods of time compared to adults, inherently giving rise to an

increased likelihood of complications, such as lead failure and infection.

Infections

In addition to accidental inappropriate shocks, one study found paediatric

ICD infection rates to be higher compared to adults despite undergoing

implantation by the same surgeons, in the same facility and time period.18

Overall infection rates following ICD implantation range from 1-8%.37

Infections may occur during the implantation procedure, during

subsequent surgical procedures involving the ICD, or if parts of the ICD

erode through the skin over time.37 Infection of the ICD leads can also

occur via haematogenous spread of a distant infection.37 Paediatric ICD

infections were found to be more common in patients with a congenital

heart disease or defect.37 The majority of infections are superficial and thus

are successfully treated with antibiotics, but more severe infections require

device removal.37,38 It is thought that the higher infection rates may be

associated with suboptimal wound care and an insufficient rest period

prior to returning to physical activity.26,37

Higher frequency of ICD replacement

Paediatric ICDs are associated with a higher frequency of ICD

replacement.17,26,31 Dislodgment, haemothorax, pneumonia, and superior

vena cava syndrome are additional acute complications that contribute to

paediatric morbidity.31 One study found that 26% of paediatric ICD

patients required reintervention in the form of ICD extraction or

replacement as a result of an underlying issue.39 In contrast, another study

found that 18.3% of adult ICD patients required replacement due to

device fault.40 Ultimately, small patient body size and rapid somatic growth

pose unique challenges for ICD placement in children; further work to

develop strategies to minimise these complications in children is required.

Psychosocial effects in children

Although paediatric ICDs are effective life-saving devices, the

psychological implications must be considered during patient

management. In the setting of SCD primary prevention, asymptomatic

patients and their families may find the diagnosis of a potentially

life-threatening condition to be particularly distressing, especially in

children who have a poor understanding of the overarching situation.41

Likewise, secondary prevention of VT or VF recurrence is undoubtedly

stressful following a recent traumatic episode.41 Some children and

adolescents report a feeling of helplessness and loss of control during ICD

placement, as the decision to have an ICD is essentially non-negotiable –

it is a matter of life or death.42

Delivery of an ICD shock can be adistressing and physically painful

experience that leaves patients feelingfrightened and anxious. As a result, many

children with ICDs develop anxiety.

The fear of unpredictable inappropriate shock episodes may have a

significant psychological impact. A study that interviewed adolescents

with ICDs found that following ICD placement, their concept of

normalcy had changed; they subsequently always felt “slightly short of

normal”.42 Delivery of an ICD shock can be a distressing and physically

painful experience that leaves patients feeling frightened and anxious.42

As a result, many children with ICDs develop anxiety, with one study

reporting the development of school phobias and post-traumatic stress

disorder requiring administration of antidepressant and anxiolytic

medications.17,18,33 Some paediatric patients develop transient

depression, especially shortly following the ICD placement

procedure.41,42 Social isolation, learning difficulties, and sleep

disturbances are also prevalent in this patient demographic.33,41,43

Professional psychological support should be considered for paediatric

ICD patients, both before and after implantation, as part of the

long-term multidisciplinary management plan.17,43

In addition, paediatric ICD patients often report changes to quality of life.

As a physically active demographic, many patients stated that they were

required to immediately cease participation in nearly all competitive

staff reviewRCSIsmj


sports.42 Athletic sports involving physical contact are typically

discouraged.44 Sports have innumerable positive effects on child social

development, health, and even cognitive development; abstaining from

such activities may yield unintentional social isolation.41,45-47 There are

reports of harassment and bullying from peers as a result of the ICD,

further pushing paediatric ICD patients to social isolation.42 Furthermore,

many paediatric ICD patients state that they feel overprotected due to

consistent monitoring by family, friends, and teachers.42 It is evident that

the psychosocial implications of paediatric ICDs are significant and

numerous, and must challenge healthcare providers to seek solutions to

these complex consequences.

The burden of cost

In addition to the physical and psychosocial effects, the significant financial

implications of paediatric ICDs must also be considered. One American

study found the total ICD cost per patient to be $433,000 US in 2006,

which included the costs of implantation, management, and issues such

as device malfunction.48 When adjusted for inflation, this would add up to

more than $540,500 US in 2017. Furthermore, it must be considered that

the process of ICD implantation may reduce the patient’s quality of life.49

In Ireland and the UK, many insurance companies provide coverage for

ICD and pacemaker implantation.50 While insurance companies cover

specific cases of paediatric ICD implantation deemed medically necessary,

some situations are considered investigational and thus costs may not be

covered.51-54 Variances are present when comparing insurance coverage in

the United States, UK, Ireland, and Canada, and further discrepancies arise

in the setting of paediatric ICDs as they are far less common than adult

ICDs. With the high costs and precarious nature of some insurance

schemes, a paediatric ICD may be an unaffordable luxury for some families.

Looking to the future – potential alternatives to ICDs

In light of these considerable and varied challenges, many families may

seek alternatives to ICDs. ICD implantation in children is more complex

than in adults, often owing to children’s smaller venous vessels, which put

them at risk for occlusion.55 The subcutaneous ICD (SICD) is a recent

development that may be used as an alternative to traditional ICDs.56 This

is a particularly attractive option for children because SICDs do not require

a transvenous approach during lead implantation, nor do they require a

sternotomy.27,57 The avoidance of a transvenous approach obviates the

need for attempting to implant ICD leads within the child’s smaller venous

vessels. Adult studies have found SICDs to be equally effective in

defibrillation compared to ICDs.58 However, the SICD is larger than

conventional ICDs and thus may be less comfortable when implanted in

children with smaller body sizes.27 Despite this, SICDs remain a viable

alternative for children in comparison to traditional ICDs.

Alternatives to ICDs include anti-arrhythmic medications, ablation surgery,

and cardiac transplantation.6 Compared to treatment with anti-arrhythmic

medications, quality of life in adults remains unchanged or is improved

with ICD treatment.59 However, no such research on paediatric ICD

patients is currently available.59 Unfortunately, there is limited data that

focuses on alternatives to paediatric ICDs; it remains a niche area in

desperate need of further research and innovation.

Conclusion

Ultimately, the decision to undergo ICD implantation is complicated and

the risks of SCD, implant complications, comorbidities, and decreased life

expectancy must be considered.8 While an ICD can prevent SCD caused

by VF or VT, its drawbacks must be thoroughly assessed prior to

implantation, especially in children. Children must live with the ICD for

longer, and will undergo significant growth that may increase the risk of

lead-related complications. Anxiety and depression are common in

paediatric ICD patients, and must be considered as part of the

management process. The costs of ICD implantation and maintenance are

substantial, and may place families in difficult financial situations. However,

the effectiveness of ICDs in preventing SCD is well established, and for

many patients the decision to implant an ICD is not negotiable. While

some alternatives to paediatric ICDs exist, further research and developments

are needed to reduce complications and improve quality of life.

staff review

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AB et al. 2017 AHA/ACC/HRS guidelines for management of patients with

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al. Implantable cardioverter defibrillator (ICD) in children. Int J Cardiol.

2006;107(1):30-5.

18. Stefanelli CB, Bradley DJ, Leroy S, Dick II M, Serwer GA, Fischbach PS.

Implantable cardioverter defibrillator therapy for life-threatening arrhythmias

in young patients. J Interv Card Electrophysiol. 2002;6:235-44.

19. Das G, Carlblom D. Artificial cardiac pacemakers. Int J Clin Pharmacol Ther

Toxicol. 1990;28(5):177-89.

20. Olshansky B, Gopinathannair R. Bradycardia. BMJ Best Practice. [Internet].

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21. Pinski SL, Fahey GJ. Implantable cardioverter-defibrillators. Am J Med.

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22. Kang S, Snyder M. Overview of pacemakers and implantable cardioverter

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=85&contentid=p00234.

23. Jin BK, Bang JS, Choi EY, Kim GB, Kwon BS, Bae EJ et al. Implantable

cardioverter defibrillator therapy in pediatric and congenital heart disease

patients: a single tertiary center experience in Korea. Korean J Pediatr.

2013;56(3):125-9.

24. Cross BJ, Estes NA, Link MS. Sudden cardiac death in young athletes and

nonathletes. Curr Opin Crit Care. 2011;17(4):328-34.

25. Burns KM, Evans F, Kaltman J. Pediatric ICD utilization in the United States

from 1997-2006. Heart Rhythm. 2011;8(1):23-8.

26. Berul CI, Van Hare GF, Kertesz NJ, Dubin AM, Cecchin F, Collins KK et al.

Results of a multicenter retrospective implantable cardioverter-defibrillator

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Cardiol. 2008;51(17):1685-91.

27. Griksaitis MJ, Rosengarten JA, Gnanapragasam JP, Haw MP, Morgan JM.

Implantable cardioverter defibrillator therapy in paediatric practice: a

single-centre UK experience with focus on subcutaneous defibrillation.

Europace. 2013;15:523-30.

28. Wilson WR, Greer GE, Grubb BP. Implantable cardioverter-defibrillators in

children: a single-institutional experience. Ann Thorac Surg.

1998;65:775-8.

29. Corcia MCG, Sieira J, Pappaert G, de Asmundis C, Chierchia GB, La Meir

M et al. Implantable cardioverter-defibrillators in children and adolescents

with Brugada syndrome. J Am Coll Cardiol. 2018;71(2):148-57.

30. Stephenson EA, Batra AS, Knilans TK, Gow RM, Gradaus R, Balaji S et al. A

multicenter experience with novel implantable cardioverter defibrillator

configurations in the pediatric and congenital heart disease population. J

Cardiovasc Electrophysiol. 2006;17(1):41-6.

31. Alexander ME, Cecchin F, Walsh EP, Triedman JK, Bevilacqua LM, Berul CI.

Implications of implantable cardioverter defibrillator therapy in congenital

heart disease and pediatrics. J Cardiovasc Electrophysiol. 2004;15(1):72-6.

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32. McLeod KA. Cardiac pacing in infants and children. Heart. 2010;96:1502-8.

33. Harkel ADJT, Blom NA, Reimer AG, Tukkie R, Sreeram N, Bink-Boelkens

MTE. Implantable cardioverter defibrillator implantation in children in The

Netherlands. Eur J Pediatr. 2005;164(7):436-41.

34. Korte T, Köditz H, Niehaus M, Paul T, Tebbenjohanns J. High incidence of

appropriate and inappropriate ICD therapies in children and adolescents

with implantable cardioverter defibrillator. Pacing Clin Electrophysiol.

2004;27(7):924-32.

35. Gradaus R, Wollmann C, Köbe J, Hammel D, Kotthoff S, Block M et al.

Potential benefit from implantable cardioverter-defibrillator therapy in

children and young adolescents. Heart. 2004;90:328-9.

36. Sanatani S, Cunningham T, Khairy P, Cohen MI, Hamilton RM, Ackerman

MJ. The current state and future potential of pediatric and congenital

electrophysiology. J Am Coll Cardiol. 2017;3(3):195-206.

37. Baddour LM, Epstein AE, Erickson CC, Knight BP, Levison ME, Lockhart PB

et al. Update on cardiovascular implantable electronic device infections

and their management. Circulation. 2010;121:458-77.

38. Cohen MI, Bush DM, Gaynor JW, Vetter VL, Tanel RE, Rhodes LA. Pediatric

pacemaker infections: twenty years of experience. J Thorac Cardiovasc

Surg. 2002;124:821-7.

39. DeWitt ES, Triedman JK, Cecchin F, Mah DY, Abrams DJ, Walsh EP et al.

Time dependence of risks and benefits in pediatric primary prevention

implantable cardioverter-defibrillator therapy. Circ Arrhythm Electrophysiol.

2014;7:1057-63.

40. Gould PA, Krahn AD. Complications associated with implantable

cardioverter-defibrillator replacement in response to device advisories.

JAMA. 2006;295(16):1907-11.

41. Dunbar SB, Dougherty CM, Sears SF, Carroll DL, Goldstein NE, Mark DB et

al. Educational and psychological interventions to improve outcomes for

recipients of implantable cardioverter defibrillators and their families.

Circulation. 2012;126:2146-72.

42. Ziegler VL, Nelms T. Almost normal: experiences of adolescents with

implantable cardioverter defibrillators. J Spec Pediatr Nurs.

2009;14(2):143-51.

43. Koopman HM, Vrijmoet-Wiersma CMJ, Langius JND, van den Heuvel F,

Clur SA, Blank CA et al. Psychological functioning and disease-related

quality of life in pediatric patients with an implantable cardioverter

defibrillator. Pediatr Cardiol. 2012;33:569-75.

44. Dimsdale C, Dimsdale A, Ford J, Shea JB, Sears SF. My child needs or has

an implantable cardioverter-defibrillator; what should I do? Circulation.

2012;126:e244-7.

45. Felfe C, Lechner M, Steinmayr A. Sports and child development. PLoS

One. 2016;11(5):e0151729.

46. Light RL. Children’s social and personal development through sport: a case

study of an Australian swimming club. J Sport Soc Issues.

2010:34(4);379-95.

47. Bailey R. Physical education and sport in schools: a review of benefits and

outcomes. J Sch Health. 2006;76(8):397-401.

48. Feingold B, Arora G, Webber SA, Smith KJ. Cost-effectiveness of

implantable cardioverter-defibrillators in children with dilated

cardiomyopathy. J Card Fail. 2010;16(9):734-41.

49. Sanders GD, Hlatky MA, Owens DK. Cost-effectiveness of implantable

cardioverter defibrillators. N Engl J Med. 2005;353:1471-80.

50. GloHealth. List of Cardiac Procedures. 2012. [Internet]. Available from:

https://www.123.ie/health-insurance-quote/cardiac-procedures.pdf.

51. Blue Cross Blue Shield of Massachusetts Association. Medical Policy –

Implantable Cardioverter Defibrillator. [Internet]. Available from:

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52. EmblemHealth. Implantable Cardioverter Defibrillators. 2018. [Internet].

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53. PriorityHealth. Cardioverter Defibrillators. 2017. [Internet]. Available from:

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-policies/91410.pdf?la=en.

54. Gateway Health Plan. Subcutaneous Implantable Cardioverter Defibrillator.


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H_Subcutaneous%20ICD.pdf.

55. Bové T, François K, Caluwe WD, Suys B, De Wolf D. Effective cardioverter

defibrillator implantation in children without thoracotomy: a valid

alternative. Ann Thorac Surg. 2010;89:1307-9.

56. Adragão P, Agarwal S, Barr C, Boersma L, Brock-Johanssen J, Butter C et al.

Worldwide experience with a totally subcutaneous implantable

defibrillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J.

2014;35(25):1657-65.

57. Jarman JWE, Lascelles K, Wong T, Markides V, Clague JR, Till J. Clinical

experience of entirely subcutaneous implantable cardioverter-defibrillators

in children and adults: cause for caution. Eur Heart J. 2012;33(11):1351-9.

58. Bardy GH, Smith WM, Hood MA, Crozier IG, Melton IC, Jordaens L et al.

An entirely subcutaneous implantable cardioverter defibrillator. N Engl J

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59. Sears SF, Conti JB. Implantable cardioverter-defibrillators for children and

young adolescents: mortality benefit confirmed – what’s next? Heart.

2004;90(3):241-2.

staff review

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide. Advances in interventional

cardiology and cardiothoracic surgery, coinciding with an increasing number of patients with complex

comorbidities, have led to new hybrid treatments for cardiovascular disease. These hybrid procedures can

be used to treat coronary artery disease (CAD), arrhythmias, and valvular heart disease. The approaches aim

to utilise minimally invasive procedures with reduced complications, while maximising improved patient

outcomes. Hybrid coronary revascularisation (HCR) involves performing both coronary artery bypass

grafting (CABG) and percutaneous coronary intervention (PCI), or stenting of the coronary vessels, to treat

multi-vessel coronary disease. Patients with concomitant valvular and coronary artery disease can be treated

with a hybrid valve and PCI via minimally invasive procedures. Advantages include lower rates of cardiac

and cerebrovascular events, shortened hospital stays, and reduced blood transfusion rates. The hybrid maze

procedure combines epicardial thoracoscopic ablation surgery and endocardial catheter ablation.

Advantages of this hybrid maze procedure include improved patient recovery times, reduced mortality, and

increased success rates compared to either cardiology interventions or cardiothoracic surgery alone.

However, hybrid cardiovascular procedures are performed in only a limited number of facilities, and no

standardised methods exist at present to determine which patients will most benefit from these procedures.

Randomised controlled trials need to be performed to maximise patient benefit. While challenges remain,

these pioneering hybrid procedures offer a remarkable combination of the most effective, lowest risk, and

highest quality technologies and techniques from interventional cardiology and cardiothoracic surgery

alike. Such hybrid interventions deliver improved patient outcomes and success rates, particularly for

high-risk patients with comorbidities.

Laura Staunton


An evolving strategy forcardiovascular intervention: a hybrid approach


RCSIsmj


Introduction

Cardiovascular disease (CVD) is the leading cause of mortality worldwide

and is responsible for 17.7 million deaths per annum.1 CVD includes

coronary artery disease (CAD), valvular heart disease, arrhythmias, and

congenital heart conditions.1 With the increasing prevalence of CVD, great

advances have evolved in the fields of interventional cardiology and

cardiothoracic surgery. As interventional cardiology strives to become

more invasive, cardiothoracic surgery becomes less so.2-5

Invasive cardiology procedures, including cardiac catheterisation and

angioplasty, have revolutionised the treatment of CVD.6 Since the first

percutaneous coronary intervention (PCI) in humans in 1977,

technology and expertise have continuously improved.6 In 2018,

60% of patients presenting with acute coronary syndrome (ACS)

underwent a PCI procedure.6

From the development of the cardiopulmonary bypass (CPB) in 1953,

to the advancement of minimally invasive robotic-assisted techniques,

cardiac surgery has undergone a revolution of its own.4,5 With the use

of the da VinciTM Surgical System to perform totally endoscopic

robotic coronary artery bypass grafting (TECAB), as well as atrial

fibrillation ablation, the specialty has been transformed.4

Subsequent to the significant advances in each of these two fields,

hybrid approaches to patient cardiac care have emerged, combining

the technology and skills from the catheterisation lab with the

expertise of the operating theatre.2,7-10 Hybrid procedures were

initially performed in the 1990s to accommodate the increasing

number of patients with CVD presenting with complex

comorbidities.2,7-10 Such strategies include hybrid coronary

revascularisation, hybrid valve/PCI intervention, and hybrid maze for

treating atrial fibrillation.2,7-10 These techniques allow use of minimally

invasive surgery and stent technology to effectively treat patients with

CAD or valvular disease. Therefore, high-risk patients with comorbid

conditions can be treated successfully in a minimally invasive way.

These procedures have varying success rates, but continue to

challenge boundaries and advance the fields of cardiology and

cardiothoracic surgery.

Hybrid coronary revascularisation

PCI is the standard of care for unstable angina, non-ST elevated

myocardial infarction (NSTEMI), and ST-elevated myocardial

infarction (STEMI) when performed between 90 and 120 minutes

post STEMI.6,11 However, CAD is often multi vessel, and frequently

occurs with comorbidities. Coronary artery bypass grafting (CABG) is

the gold standard for treating multi-vessel CAD, due to increased

survival rates, lower risk of MI, and improved angina relief. CABG also

reduces the need for repeat revascularisation compared to

PCI.2,3,5,7,8,12 Typically, the CABG technique involves grafting of the left

internal mammary artery (LIMA) to the left anterior descending (LAD)

artery, using either on-pump or off-pump techniques.13 The on-pump

CABG procedure involves median sternotomy with CPB and aortic

clamping of an arrested heart.14,15 A newer technique, performed

without the use of CPB, is the off-pump CABG, which utilises

specialised instruments to stabilise the beating heart.14,15 On-pump

CABG is more widely used, as the off-pump procedure is highly

specialised, more technically challenging, and can lead to incomplete

revascularisation, which would require a repeat procedure.15,16 Many

other risks are associated with CABG, including increased incidence of

atrial fibrillation and stroke.2,17

Over time, stenting has progressed from utilising bare metal stents toinserting drug-eluting stents (DES),showing reduced complications,

morbidity, and mortality.

PCI has been shown to be superior for non-LAD revascularisation.

Over time, stenting has progressed from utilising bare metal stents to

inserting drug-eluting stents (DES), showing reduced complications,

morbidity, and mortality.3,6 More recently, some studies have reported

that the use of second-generation DES can be as effective as CABG for

multi-vessel coronary disease.2,12 At present, however, CABG remains

the gold standard procedure for multi-vessel revascularisation.14,15

With improved minimally invasive CABG and stent technology, hybrid

coronary revascularisation (HCR), combining LIMA-LAD grafting with

DES for non-LAD vessels, is shown to be extremely effective, especially

for high-risk patients with comorbidities.2,5,7,8,12,17

Staging

All hybrid procedures involving cardiothoracic surgery and

interventional cardiology must be staged. Staging refers to the

procedures occurring either on the same day in a hybrid suite, or

separated by time (days or weeks) and space (i.e., in the operating

theatre and catheterisation lab).2,5,7,8,12,17 A one-stage HCR approach

involves a hybrid suite with an operating team and cardiology team

performing the revascularisation on the same day.2,5,7,8,12,17

Advantages of a one-stage HCR procedure include reduced resources,

procedure time, and length of patient hospital stay, and fewer

postoperative complications.2,5,7,8,12,17 However, it is not without its

limitations. Dual anti-platelet therapy is required during a HCR

procedure, which can increase bleeding risk.2,5,7,8,12,17

Hypercoagulability has been associated with minimally invasive

staff reviewRCSIsmj


CABG; therefore, stent thrombosis is a risk when PCI is performed at

the same time in a one-stage HCR procedure.2,5,7,8,12,17 The optimal

formula for performing a one-stage HCR, including timing, dosage of

dual anti-platelet drugs, and heparin reversal is still under

consideration.2,5,7,8,12,17

A two-stage hybrid approach for coronary revascularisation involves

performing PCI first, followed by the LIMA-LAD procedure, or vice

versa, on different days.2,5,7,8,12,17 Due to risk of bleeding from

anti-platelet therapy used in PCI, and the increased risk of

cardiovascular events, PCI followed by LIMA-LAD is rarely

performed.2,5,7,8,12,17 The majority of HCR procedures employ a

two-stage approach, with the LIMA-LAD procedure performed first in

the operating theatre, followed by PCI in the catheterisation lab days

or weeks later.2,5,7,8,12,17 Advantages include a reduction in bleeding

risk, and visualisation of the LIMA-LAD graft during angiography,

which can confirm patency.2,5,7,8,12,17

Outcomes of HCR

Current analysis of HCR procedures reveals conflicting evidence, with

some research reporting a lower rate of cardiac and cerebrovascular

events compared to CABG alone, while other studies report a similar

rate.5,12,17 Confirmed advantages include shortened hospital stays and

ventilator times, and decreased blood transfusion rates, thereby

shortening the overall recovery period.5,12,17 Disadvantages include

higher costs and longer operation times.5,12,17 As HCR has been

performed on a limited number of patients to date, and there is a

shortage of randomised controlled trials, additional evidence is

required to determine whether HCR can become the mainstay of

multi-vessel coronary disease management.5,12,17

Hybrid valve/PCI intervention

Valve surgery

Valvular heart disease is highly prevalent worldwide, and can arise via

damage following rheumatic fever, congenital cardiac defects, infection,

or valvular calcification.18 Most commonly affected are the mitral and

aortic valves.18 Mitral regurgitation occurs in approximately 19% of the

population, but typically does not have a significant impact on patient

mortality rates.18 Mitral regurgitation can occur due to cardiomyopathy or

heart failure.18 Aortic valve calcification has a significant impact on patient

mortality, and in high-income countries, its incidence is increasing due to

the ageing population.18 Calcified aortic valves occur in 40% of the

population over 75 years of age, and can lead to aortic stenosis requiring

valve replacement surgery.18

Cardiac valve surgery can be performed either using minimally invasive

techniques, or via median sternotomy, which requires CPB.2,19-22 Aortic and

mitral valve disease are treated surgically with either replacement or

repair.2,19-22 Upper hemi-sternotomy is performed for aortic valve surgery,

while right mini-thoracotomy or lower hemi-sternotomy are the minimally

invasive techniques used for mitral valve surgery.2,19 There are numerous

advantages to minimally invasive valve surgery, including shorter hospital

stays, faster recovery times, and improved patient outcomes.2,19

Concomitant valve and coronary artery disease

Up to 50% of patients undergoing valve surgery also present with severe

CAD.10,19-21 Currently, the surgical treatment of choice is an open

procedure employing median sternotomy, in which the CABG and valve

replacement are performed at the same time.10,19 This high-risk

procedure involves CPB and aortic clamping, the timing of which is

crucial to prevent cardiac ischaemia.10,19,22 This procedure is associated

with high mortality rates and long hospital stays.10,19,22 If valve surgery is

required post CABG in a separate procedure, morbidity and mortality

significantly increase due to a number of complications including

adhesions, scarring, and vascular or graft injury.10,19,22

Hybrid procedure

An alternative to the surgical procedures of CABG and valve repair or

replacement is to perform a hybrid procedure in which the CABG is

replaced with PCI; this would be performed prior to the valve

surgery.2,9,19-22 This hybrid valve/PCI procedure uses minimally invasive

surgical techniques to transform a high-risk operation into two

lower-risk procedures.10,19-22 Protection of the myocardium from

ischaemia is achieved by performing PCI prior to valve surgery, which

restores blood flow to the heart.21 Encouragingly, this intervention

results in lower rates of morbidity and mortality for patients who have

had previous cardiac surgery.10,19-22

staff reviewRCSIsmj


Staging

In line with HCR, staged approaches are also used for the hybrid valve/PCI

intervention. A one-stage procedure involves performing PCI prior to valve

surgery in a hybrid suite on the same day.20 Advantages include reduced

resources, time, length of stay, and postoperative complications.23 Studies

have shown a higher risk of acute kidney injury (AKI) when these

procedures are performed in the same admission, however.10,19 Other

limitations include staff and hybrid suite availability.20 In addition, PCI

procedures require anti-platelet therapy to reduce the risk of stent

thrombosis.2,5,7,8,12 It has been hypothesised that performing the valve

surgery within six hours of PCI will reduce bleeding risk, as the anti-platelet

agent will not have taken full effect; this highlights the importance of a

hybrid suite to carry out the procedure.2

A two-stage procedure involves performing PCI days or weeks prior to

valve surgery.20 Advantages include a reduced risk of AKI, no anti-platelet

requirements on the day of surgery, and reduced postoperative

complications.10,19 To decrease the risk of AKI, an interval of three weeks

has been suggested between procedures.10,19 Currently, the hybrid

approach of valve surgery/PCI would only be beneficial in those patients

who do not have significant LAD disease.10,19 The two-stage approach is

the preferred hybrid procedure, due to the lower risk of AKI and the fact

that a hybrid suite is not required.2,9,10,19

Research shows that hybrid valve/PCIprocedures have considerable advantagesfor both first-time cardiac operations

and patients who have had previous cardiac surgery.

Outcomes of hybrid valve/PCI

Research shows that hybrid valve/PCI procedures have considerable

advantages for both first-time cardiac operations and patients who have

had previous cardiac surgery.10,19-22 Advantages of the hybrid approach

to valve/PCI include reduced operation times, decreased need for blood

transfusions, fewer cardiac and cerebrovascular adverse events, and

improved mortality rates.10,19-22 As with other hybrid procedures,

randomised controlled trials remain limited and will be required to

determine the optimal approach to hybrid valve/PCI intervention and its

potential for widespread application.10,19-22

Hybrid maze

Atrial fibrillation

Atrial fibrillation (AF) occurs when the cardiac atria beat in an

irregularly irregular pattern, causing unsynchronised contraction; it

carries a high risk of stroke.10,24 Patients diagnosed with AF who are

resistant to anti-arrhythmic drugs (AADs) are recommended for

pulmonary vein isolation catheter ablation or surgical

procedures.25-27 Atrial fibrillation can occur as: paroxysmal AF

(poAF), which is intermittent and usually resolves in 48 hours;

persistent AF (pAF), which persists >48 hours; or longstanding

persistent AF (LSpAF), which lasts ≥1 year.24 A successful endpoint

for either surgical or catheter-based treatment is achievement of

bidirectionally blocked signal conduction into the pulmonary veins,

or termination of AF.25-27

Endovascular catheter ablation

Endovascular catheter ablation for AF is performed by an

electrophysiologist, and has varying degrees of success due to the

use of different procedures to isolate the pulmonary veins from the

left atrium.26,27 Once isolated via a catheter inserted through the

femoral vein, radiofrequency is applied at the pulmonary vein

ostium.26,27 A linear lesion is created in hopes that the irregular

signal conduction will be blocked, thus terminating the AF.25-27

Paroxysmal AF can be effectively treated using this technique, with

an 80% success rate.28 However, for pAF, endovascular ablation has

much lower success rates as it involves a more challenging

procedure.28 Long-term linear lesions are more difficult to achieve,

and irregular conduction outside of the pulmonary veins can lead to

failure of endovascular treatment.27,28

Surgical management of AF

Surgical procedures have high success rates for poAF.29 Current

procedures include Cox Maze IV, thoracoscopic ablation, and the da

VinciTM robotic surgical system, which combines mitral valve

repair with cryomaze.11,24,26,30 Cox Maze IV is the gold standard

surgical procedure for AF, and combines surgical ablation and

incisional techniques, either via median sternotomy or right

mini-thoracotomy.30 However, Cox Maze IV is a complex procedure

with varying long-term success rates (66-96% of patients remain free

of atrial fibrillation after five years), and it is heavily dependent on

surgical skill.29,30 It is performed with CPB and has moderate

effectiveness for treating pAF and LSpAF.24,29,30 Thoracoscopic surgical

ablation eliminates the need for CPB, has improved morbidity and

mortality rates, and is successful in 70-87% of patients with poAF.29

The ability of surgical ablation to create transmural lesions is

limited.28,29 Linear lesions, especially at the mitral isthmus, are a

challenge, which can be crucial to achieving bidirectional block.26,28

These factors attribute to surgical ablation’s low success rates in

treating pAF and LSpAF.24,28,29

staff reviewRCSIsmj


Hybrid maze

The hybrid maze procedure, which combines epicardial

thoracoscopic ablation surgery and endocardial catheter ablation,

is an effective alternative to the current gold standard for AF.29

The advantage of combining endocardial catheter ablation with

surgical ablation is that surgically inaccessible lesions can be

created.29 Delivering currents via catheter is also more effective for

transmural lesions in thicker tissue areas compared to surgical

ablation alone.29

Staging

A one-stage or two-stage approach can be adopted. The one-stage

approach involves surgical ablation followed by catheter ablation on

the same day.10,24,29 A one-stage procedure allows shorter patient

stays, and permits assessment of conduction gaps during the same

admission.10,24,29 A two-stage procedure involves performing catheter

ablation weeks to months after the surgical ablation.29 In this case,

stabilisation of the epicardial lesions can occur prior to catheter

ablation; therefore, success rates for the two-stage procedure are

higher, suggesting that this is the optimal hybrid procedure going

forward.10,29

Outcomes of hybrid maze

The fundamental basis of the hybrid maze procedure is its efficacious

ability to generate transmural lesions through epicardial and

endocardial approaches.2,10,26,28 Hybrid maze procedures result in

increased rhythm control for both poAF and pAF compared to

individual surgical or catheter-based approaches.10,29 Combining

endocardial and epicardial strategies allows bidirectional blockage

and AF termination, with similar results achieved for paroxysmal AF

and pAF.10,26,28 The risk of short-term severe complications is low and

comparable to thoracoscopic surgical ablation alone.10 As this

procedure is relatively new, there are limited long-term follow-up

studies. Short-term studies report a 78-100% success rate for pAF and

LSpAF without anti-arrhythmic drugs.10,28 After a three-year follow-up,

Maesen et al. reported success rates of 80% without AADs for poAF

and LSpAF, and a 95% return to sinus rhythm with repeat catheter

ablation and AADs.26 Randomised case-control studies are currently

unavailable for the hybrid maze procedure, and comparative studies

will also be required to determine whether this might present a new

gold standard treatment option for drug-resistant AF.10

Techniques such as hybrid coronary revascularisation, hybridvalve/PCI intervention, and the hybrid maze procedure have shown increased safety and

efficacy, especially in high-risk individuals.

Conclusion

Hybrid approaches to cardiovascular intervention include many novel

techniques, with the scope of clinical relevance ranging from

arrhythmias to coronary revascularisation. These techniques have

evolved due to the increasing number of high-risk patients presenting

with comorbid conditions. Techniques such as hybrid coronary

revascularisation, hybrid valve/PCI intervention, and the hybrid maze

procedure have shown increased safety and efficacy, especially in

high-risk individuals. Due to increasing rates of success that have been

demonstrated using such hybrid cardiovascular interventions, it is not

surprising that physicians and surgeons are beginning to adopt these

approaches.

However, many challenges persist, including the need for operator

training and optimal staging, access to technology, high costs, and

uncertain availability of appropriate facilities and hybrid

suites.2,6,8,10,12,20,26 At present, no standardised methods

exist to determine which patients will most benefit from these

procedures, and few, if any, randomised controlled trials have been

performed. A hybrid approach relies heavily on interdisciplinary

teamwork.2,8 Effective collaboration and ingenuity between

interventional cardiologists and cardiac surgeons is necessary for

these hybrid procedures to become successful and conventional.

Is hybrid cardiovascular intervention the way forward? Only time

will tell.

References

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[Internet]. [cited 2018 Sep 10]. Available

from:http://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-dis

eases-(cvds).

staff reviewRCSIsmj


2. Byrne JG, Leacche M, Vaughan DE, Zhao DX. Hybrid cardiovascular

procedures. JACC 2008;1(5):459-68.

3. Papadopoulos K, Lekakis I, Nicolaides E. Outcomes of coronary artery

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second-generation drug-eluting stents for patients with multivessel and

unprotected left main coronary artery disease. SAGE Open Med.

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4. Bush B, Nifong LW, Chitwood WRJ. Robotics in cardiac surgery: past,

present, and future. Rambam Maimonides Med J. 2013;4(3):e0017.

5. Sardar P, Kundu A, Bischoff M, Chatterjee S, Owan T, Nairooz R et al.

Hybrid coronary revascularization versus coronary artery bypass grafting in

patients with multivessel coronary artery disease: a meta-analysis. Catheter

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6. Bhatt DL. Percutaneous coronary intervention in 2018. JAMA.

2018;319(2):2127-8.

7. Misumida N, Moliterno DJ. Hybrid coronary revascularization: time for a

new comparator? Catheter Cardiovasc Interv. 2018;91(2):213-4.

8. Papakonstantinou NA, Baikoussis NG, Dedeilias P, Argiriou M, Charitos C.

Cardiac surgery or interventional cardiology? Why not both? Let’s go

hybrid. J Cardiol. 2017;1(69):46-56.

9. Santana O, Xydas S, Williams RF, LaPietra A, Mawad M, Rosen GP et al.

Outcomes of a hybrid approach of percutaneous coronary intervention

followed by minimally invasive aortic valve replacement. J Thorac Dis.

2017;9(7):569-74.

10. Jiang YQ, Tian Y, Zeng LJ, He SN, Zheng ZT, Shi L et al. The safety and

efficacy of hybrid ablation for the treatment of atrial fibrillation: a

meta-analysis. PLoS One. 2018;13(1):e0190170.

11. Mancone M, van Mieghem NM, Zijlstra F, Diletti R. Current and novel

approaches to treat patients presenting with ST elevation myocardial

infarction. Expert Rev Cardiovasc Ther. 2016;14(8):895-904.

12. Harskamp RE, Zheng Z, Alexander JH, Williams JB, Xian Y, Halkos ME et al.

Status quo of hybrid coronary revascularization for multi-vessel coronary

artery disease. Ann Thorac Surg. 2013;96(6):2268-77.

13. Karthik S, Fabri BM. Left internal mammary artery usage in coronary artery

bypass grafting: a measure of quality control. Ann R Coll Surg Engl.

2006;88:367-9.

14. Shekar PS. On-pump and off-pump coronary artery bypass grafting.

Circulation. 2006;113(4):51-2.

15. Blackstone EH, Sabik JF III. Changing the discussion about on-pump versus

off-pump CABG. N Engl J Med. 2017;377:692-3.

16. Dieberg G, Smart NA, King N. On- vs. off-pump coronary artery bypass

grafting: a systematic review and meta-analysis. Int J Cardiol.

2016;233:201-11.

17. Dong Li, Kang Y-K, Xiang-guang A. Short-term and mid-term clinical outcomes

following hybrid coronary revascularization versus off-pump coronary artery

bypass: a meta-analysis. Arg Bras Cardiol. 2018;110(4):321-30.

18. Coffey S, Cairns BJ, Lung B. The modern epidemiology of heart valve

disease. Heart. 2015;102(1):1-2.

19. Santana O, Funk M, Zamora C, Escolar E, Lamas GA, Lamelas J. Staged

percutaneous coronary intervention and minimally invasive valve surgery:

results of a hybrid approach to concomitant coronary and valvular disease.

Thorac Cardiovasc Surg. 2012;144(3):634-9.

20. George I, Nazif TM, Kalesan B, Kriegal J, Yerebakan H, Kirtane A et al.

Feasibility and early safety of single-stage hybrid coronary intervention and

valvular cardiac surgery. Anne Thorac Surg. 2015;99(6):2032-7.

21. Lu JC, Shaw M, Grayson AD, Poullis M, Pullan M, Fabri BM. Do beating

heart techniques applied to combined valve or graft operations reduce

myocardial damage? Interact Cardiovasc Thorac Surg. 2018;7(11):111-5.

22. Byrne JG, Leacche M, Unic D, Rawn JD, Simon DI, Campbell D et al.

Staged initial percutaneous coronary intervention followed by valve

surgery (hybrid approach) for patients with complex coronary and valve

disease. J Am Coll Cardiol. 2005;45(1):14-8.

23. Bundhun PK, Sookharee Y, Bholee A, Huang F. Application of the SYNTAX

score in interventional cardiology: a systematic review and meta-analysis.

Medicine (Baltimore). 2017;96(28):e7410.

24. Pinho-Gomes AC, Amorim MJ, Oliveira SM, Leite-Moreira AF. Surgical

treatment of atrial fibrillation: an updated review. Eur J Cardiothorac Surg.

2014;46(2):167-78.

25. Kim J, Desai S, Jadonath R, Beldner SJ. The importance of bidirectional

block during pulmonary vein isolation. Pacing Clin Electrophysiol.

2013;36(5):143-5.

26. Maesen B, Pison L, Vroomen M, Luermans JG, Vernooy K, Maessen JG et

al. Three-year follow-up of hybrid ablation for atrial fibrillation. Eur J

Cardiothorac Surg. 2018;53(1):26-32.

27. Oral H, Knight BP, Tada H, Özaydin M, Chugh A, Hassan S et al.

Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation.

Circulation. 2002;105:1077-81.

28. Pison L, La Meir M, Van Opstal J, Baauw Y, Maessen J, Crijns HJ. Hybrid

thoracoscopic surgical and transvenous catheter ablation of atrial

fibrillation. J Am Coll Cardiol. 2012;60(1):54-61.

29. Wang PJ. Hybrid epicardial and endocardial ablation of atrial fibrillation: is

ablation on two sides of the atrial wall better than one? J Am Heart Assoc.

2015;4(3):e001893.

30. Ruaengsri C, Schill MR, Khiabani AJ, Schuessler RB, Melby SJ, Damiano RJ.

The Cox-Maze IV procedure in its second decade: still the gold standard?

Eur J Cardiothorac Surg. 2018;53(1):19-25.

staff reviewRCSIsmj


staff review

Abstract

Human sequencing tools and population genomics are becoming increasingly available commercially.

Advertised as fun and informative direct-to-consumer genomic kits, this commercial enterprise has become

commonplace in households across the world, and has helped to educate populations that were previously

unaware of genetic testing. Analysis of an individual’s genome can be an intriguing experiment for some,

or medically necessary for others; in either case, genetic testing is no longer confined to medical

laboratories. The expansion of commercial genetic sequencing companies pushes boundaries, posing many

questions and risks. Commercial accessibility can mean that the process of informed consent is not

rigorously upheld and patient understanding may not be uniform, resulting in potential confusion and

upset. Without stringent safeguarding, information security could pose another risk for users whose genetic

sequence may be stored in databases and sold to third-party companies in the name of profit. While it is

clear that strict regulations need to be placed on this growing field to protect patient identity and medical

information, the expansion of this scientific discipline has therapeutic potential. Improved genetic data

mining and family pedigree genealogy research is helping to identify new therapeutic targets for many

diseases, and holds promise for identifying new drug targets. If the human genome represents the

fundamental unit of ‘who we are’, should it be allowed to become a commercial enterprise, or must an

individual’s genetics be safeguarded?

Katie Nolan



RCSIsmj

Introduction

The Human Genome Project and the rapidly

advancing ability to sequence individual human

genomes have opened the floodgates for commercial

utilisation of genetic home testing kits. Genetic

testing, which was once a medical and scientific

diagnostic tool, is now advertised and sold

commercially online through private companies.

While there is inherent benefit to advancing

technology and expanding the reaches of healthcare,

direct-to-consumer (DTC) genetic testing has yet to

overcome some very real and potentially devastating

pitfalls before it can be seen as sound medical and

legal practice. For a generation that uploads a vast

Six degrees of geneticidentification


amount of personal and private information to the internet through apps

and online profiles, is uploading one’s genetic code for public consumption

merely the next step in digitising the human existence? While DTC genetic

testing allows everyone to explore their genetic history, increases genetic

awareness, and encourages people to take a proactive role in their own

healthcare decisions, it is also a new health promotion frontier, the

potential drawbacks of which have yet to be fully identified.1 Rapid

advancements in DTC genetic testing make it easier than ever to discover

information about ourselves and our ancestors – those that are known to

us, and those as yet unknown. However, the increasing amount of

information provided by genetic profiling and DNA mining raises

considerable personal and social implications, including ancestry inference,

discovery of misattributed paternity, and potential genetic discrimination.2,3

A study published in 2018 by Ambry Genetics identified a 40% false

positive rate among the results of DTC genetic tests analysed in their labs.4

Results such as these indicate the importance of confirmatory testing and

interpretation by medical professionals following DTC genetic testing.

While the possibility of identifying ‘risk genes’ holds promise for future

targeted therapies and a better understanding of disease mechanisms

through population genetics, the lack of confidentiality surrounding these

results necessitates attention toward ethical considerations such as

genomic discrimination and social stigmatisation.

Informed consent and the consumer

The broad consent obtained when an individual donates blood, saliva, or

urine to biobanks often means that users consent to their samples being

stored and used in genetic research. However, the range of uses covered

under this broad consent is vast, and people may be unaware of the full

scope of possibilities. Firstly, the understanding and recall of consent by

research participants has been shown to vary, and participants’ perceptions

of the harms or risks involved is also varied, with many studies using different

consent models for biobanking samples.5 A Canadian study examining

informed consent for online sexually transmitted infection (STI) screening

identified that participants had differing understandings of the various

components of informed consent, but that patients with prior testing

experience had a greater understanding of informed consent.6 The study

also identified the importance of webpage design in informing patients, and

the need to highlight consent pages to prevent users from clicking onto the

next webpage too quickly.6 Another study, which stratified participants

based on race and previous biobank participation, found that the broad

consent model was the most preferred model, followed closely by a

“study-specific” research model where consent is required for each

subsequent research project that utilises a patient’s sample.7 Participants

highlighted receiving sufficient information, being asked for permission

regarding the use of their samples, and provision of general and specific

information on secondary research as important factors for their consent

model preference.7 It is still unclear whether broad consent or a

study-specific model is advantageous, both for participants and for ethics

committees that must approve the work.8 Indeed, researchers have

examined the use of online dynamic consent models that allow ongoing

communication between researchers and research participants; however,

this model may require researchers to re-examine their relationship with

participants.9,10 There is evidence that patients are happy to give broad

consent for sample biobanking, in part due to a subjective understanding of

the samples’ potential use, and also for prosocial reasons such as altruism

and gratitude.11 Analysis of the ethics surrounding biospecimens has

endorsed the broad consent model as being adequate.12,13

There is evidence that patients are happy to give broad consent for sample biobanking,in part due to a subjective understanding

of the samples’ potential use.

One of the most famous examples of the importance of informed consent

in research is that of Henrietta Lacks. Henrietta Lacks was diagnosed with

cervical cancer in the United States in 1951, and her aggressive cancerous

cells were grown in culture by researchers hoping to use the thriving cell

line for research.14 The cells, termed HeLa cells after their owner, are

commonplace in labs all over the world; many companies and institutions

have profited from Ms Lacks’s contribution. While informed consent was

not required for research in the 1950s, this story has demonstrated the

importance of ownership and consent surrounding biospecimens, and the

associated implications for generations of family members into the

future.14 In 2013, Landry et al. published the entire genome sequence of

Henrietta Lacks, taken from her cells, without the consent of her family.15

While not illegal, this action had huge implications for members of her

family and exposed them on a level most would deem unimaginable.16

When family or distant relatives use DTC genetic testing and have their

genome sequenced, the story of Henrietta Lacks is a reminder that this can

have far-reaching implications for other members of that family.

Another area of concern is the possibility of minors using these ancestry

services and discovering misattributed paternity.17 In an era when

knowledge of family medical history is of great personal benefit, disclosure

of misattributed paternity is not necessarily a negative aspect of DTC

genetic testing, but it does have far-reaching social and psychological

implications. In addition to the personal implications for the minor, it also

affects the privacy of other individuals and their extended families. In an

analysis of 43 DTC genetic testing companies, one study found no specific

guidelines relating to participation by minors and, furthermore, the

companies were found not to address sensitive information, such as

staff reviewRCSIsmj


misattribution of paternity, in their polices or terms of service.18 Situations

such as these make it clear that, in certain instances, a broad consent

model may not provide all the relevant information to a participant,

especially a minor. This is one area where biobanking regulation may

require further scrutiny, and the implementation of additional safeguards

to ensure protection for all participants and consumers.

Information safety and security

Security concerns about genetic testing arise when DNA samples volunteered

for one purpose are used without explicit consent for other purposes. For

example, police have recently used DNA samples submitted for ancestry or

genealogy purposes to identify DNA collected from a series of linked crimes

involving rape and murder.19 The previously unidentified Golden State killer

was identified when DNA submitted by relatives was partially matched to

DNA collected from the crime scenes.19 This use of online DNA and ancestry

databases by police calls into question the accessibility and indeed linkability

of genetic information, and how vulnerable society is to a new form of online

scrutiny, without knowledge or explicit consent.

For example, MyHeritage, a family tree and genealogy platform from

Israel, recently reported a data breach experienced in October 2017.20

Researchers were alerted that email and password data of 92 million of its

users had been hacked. While the only stolen information was log-in

details, and the company assured users that no family tree or DNA data

was accessed, the event does raise concerns over the security and usability

of this personal genetic information.20 Informed consent is an individual

task, but when informed consent involves the use of DNA and genetic

information, there is perhaps cause to include broader family members

and biological relatives in the consent process. A system of generational

consent may be required to ensure ethical practice when isolating and

analysing genetic samples, in order to prevent inadvertent privacy issues.21

With recreational genetics becoming commonplace across the world, it is

important that companies have safeguards and policies in place for dealing

with sensitive information that may be derived from their products.

The Ethical, Legal, and Social Implication (ELSI) research programme, set

up at the dawn of the human genome project to protect genetic

information, may not be followed or adequately upheld by privately

owned genetics companies.22,23 The question is whether newer personal

genetics companies have the potential to abuse the genetic information

they become privy to in the future. The rapidly expanding opportunities

in personal genetics necessitate a review and revision of regulatory

guidelines to ensure that these newer commercial entities uphold the

confidentiality of this sensitive information.

Contributions to science and research

Genealogy databases are also an extremely useful tool for scientific

research. Access to worldwide genealogical information can allow

researchers to perform familial aggregation studies to look for genetic

linkages in particular diseases, or assess geographical shifts in disease in

relation to population dynamics. Genealogical inference is a tool used by

researchers to establish patterns of gene inheritance and genotype

profiling across populations. Data mining and computational tools can

assist in this analysis of both genetic information and familial pedigree

data. Analysis of familial clustering patterns for specific diseases can help

researchers to confirm familial inheritance patterns, and high-risk pedigrees

can be further analysed for genes of interest and genetic pathways.24 A

major problem with the accuracy of this research is genetic recombination

or single nucleotide polymorphisms, which can impair researchers’ ability to

analyse the genetic polymorphisms at a particular locus.25

Research using companies such as Ancestry.com has used genealogical

data to investigate large-scale population dynamics and migration

patterns among US populations.26 This work looks at identity-by-descent

inference, which can combine inheritance patterns with demographic

data to reveal common ancestry. While this work is ongoing, it has allowed

researchers to identify clusters with disease-risk variants.26 On large-scale

analysis, these genome-wide association studies (GWAS) allow researchers

to identify multiple loci that correspond to disease phenotypes, which

could introduce new research targets for treatments.27,28 This emerging

facet of research can identify relatedness in diseases where a familial

component may not have been previously identified. Analysis of the Utah

Population Database genealogical data has identified high-risk familial

clusters with a predisposition to developing spinal cord tumours.29

Identifying high-risk pedigrees is the first step in identifying novel gene

variants that may contribute to tumour development.29 This research is

also very important for establishing new treatment targets in rare diseases

that are not yet fully understood. Amyotrophic lateral sclerosis (ALS) is a

fatal neurodegenerative disease with no successful treatment options and

little understanding of its pathological mechanisms. Project MinE is an

international research collaboration that includes ALS researchers in

staff reviewRCSIsmj


Ireland, which aims to identify and characterise ALS using large-scale

GWAS data from thousands of ALS patients.30 While large-scale studies like

this may take time to yield results, they involve a wealth of genetic

information and allow researchers to examine population disease

dynamics as a whole rather than in parts.

Warning! The need for regulation

The simplicity of DTC genetic tests lies in the fact that they do not require

a medical professional to perform the test or deliver the results. In Ireland,

which has no defined legislation for DTC genetic testing, this alone

presents many ethical, legal, and regulatory issues. Furthermore, this

format does not provide any advice or direct counselling for the patient

who may receive test results they do not fully understand, or may

misinterpret, results which often have weighty medical and psychosocial

consequences.31 New studies are examining the importance of

concomitant genetic counselling for patients receiving genomic risk

assessment results online. These studies have shown that genetic

counselling is important for a patient’s understanding of their disease risk

and genetic susceptibility, as well as to help patients gain personal utility

from the results.32,33 In the United States, the Food and Drug

Administration (FDA) has repeatedly placed restrictions on DTC home

testing kits and the companies that provide them, in an effort to prevent

unnecessary medical decisions being made by uninformed or panicked

members of the public.34,35 Ethical analysis of commercial genetic testing

websites and marketing strategies demonstrates that companies use

medical language to establish trust in the product; they foster a sense of

personal empowerment in the individual through the use of their

products, and they appeal to a consumer’s sense of personal

responsibility.36 Furthermore, third-party interpretation websites, which

seek to help consumers to understand the results of their DTC genetic

testing, add another level of complexity to the ethical and privacy issues

surrounding DTC genetic testing.37

Finally, additional concern lies in the transparency (or lack thereof) of

personal genetics companies’ research activities. Some companies have

been shown to store consumer data for unspecified future research, or for

shared research with third-party companies. While all data is anonymised,

there is little information regarding the ability to re-identify or trace an

individual’s samples, and the possible implications of such events. Without

proper legislation and monitoring of such systems, the process of informed

consent cannot be validated, as neither consumers nor the companies

involved have complete control of the future fate of the data.38

Conclusion

Whether one considers DTC genetic testing to be a novel birthday gift

idea, or a way to explore heritage and health, it is clear that the scope and

reach of this platform is ever expanding. As a research tool, it holds

promise to provide a deeper understanding of genetic linkages within

populations and across generations. Therapeutically, DTC genetic testing

could yield further insight into disease mechanisms and genetic

inheritance, and could pave the way for developing novel disease

therapies. As a commercial medical platform, it offers the public a learning

resource and an appealing introduction to genetics and health promotion.

However, as DTC genetic testing evolves, it will require an expanding set

of ethical and legal legislation to ensure the safety and privacy of its

customers. Furthermore, more stringent genetic counselling and

education is required to provide consumers with up-to-date and accurate

methods to interpret their results and guide their subsequent healthcare.

With all great advances come great responsibility; with proper scrutiny and

oversight, DTC genetic testing could revolutionise how the medical

community promotes, distributes, and advances healthcare.

staff review

References

1. Khoury MJ. Centers for Disease Control and Prevention. Direct to consumer

genetic testing: think before you spit. 2017. [Internet]. Available from:

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2. Allyse MA, Robinson DH, Ferber MJ, Sharp RR. Direct-to-consumer testing 2.0:

emerging models of direct-to-consumer genetic testing. Mayo Clin Proc.

2018;93(1):113-20.

3. Puryear L, Downs N, Nevedal A, Lewis ET, Ormond KE, Bregendahl M et al.

Patient and provider perspectives on the development of personalized

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4. Tandy-Connor S, Guiltinan J, Krempely K, LaDuca H, Reineke P, Gutierrez S et

al. False-positive results released by direct-to-consumer genetic tests

highlight the importance of clinical confirmation testing for appropriate

patient care. Genet Med. 2018. [Epub ahead of print].

5. D’Abramo F, Schildmann J, Vollmann J. Research participants’ perceptions

and views on consent for biobank research: a review of empirical data and

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6. Gilbert M, Bonnell A, Farrell J, Haag D, Bondyra M, Unger D et al. Click yes

to consent: acceptability of incorporating informed consent into an

internet-based testing program for sexually transmitted and blood-borne

infections. Int J Med Inform. 2017;105:38-48.

RCSIsmj


7. Brown KM, Drake BF, Gehlert S, Wolf LE, DuBois J, Seo J et al. Differences in

preferences for models of consent for biobanks between black and white

women. J Community Genet. 2016;7(1):41-9.

8. Chin WW, Wieschowski S, Prokein J, Illig T, Strech D. Ethics reporting in

biospecimen and genetic research: current practice and suggestions for

changes. PLoS Biol. 2016;14(8):e1002521.

9. Budin-Ljosne I, Teare HJ, Kaye J, Beck S, Bentzen HB, Caenazzo L et al.

Dynamic consent: a potential solution to some of the challenges of modern

biomedical research. BMC Med Ethics. 2017;18(1):4.

10. Thiel DB, Platt J, Platt T, King SB, Fisher N, Shelton R et al. Testing an online,

dynamic consent portal for large population biobank research. Public Health

Genomics. 2015;18(1):26-39.

11. Richter G, Krawczak M, Lieb W, Wolff L, Schreiber S, Buyx A. Broad consent

for health care-embedded biobanking: understanding and reasons to donate

in a large patient sample. Genet Med. 2018;20(1):76-82.

12. Warner TD, Weil CJ, Andry C, Degenholtz HB, Parker L, Carithers LJ et al.

Broad consent for research on biospecimens: the views of actual donors at

four U.S. medical centers. J Empir Res Hum Res Ethics. 2018;13(2):115-24.

13. Grady C, Eckstein L, Berkman B, Brock D, Cook-Deegan R, Fullerton SM et al.

Broad consent for research with biological samples: workshop conclusions.

Am J Bioeth. 2015;15(9):34-42.

14. Beskow LM. Lessons from HeLa cells: the ethics and policy of biospecimens.

Annu Rev Genomics Hum Genet. 2016;17:395-417.

15. Landry JJ, Pyl PT, Rausch T, Zichner T, Tekkedil MM, Stutz AM et al. The

genomic and transcriptomic landscape of a HeLa cell line. G3 (Bethesda).

2013;3(8):1213-24.

16. Skloot R. The immortal life of Henrietta Lacks, the sequel. The New York Times.

2013. [Internet]. Available from: https://www.nytimes.com/2013/03/24/

opinion/sunday/the-immortal-life-of-henrietta-lacks-the-sequel.html.

17. Hercher L, Jamal L. An old problem in a new age: revisiting the clinical

dilemma of misattributed paternity. Appl Transl Genom. 2016;8:36-9.

18. Moray N, Pink KE, Borry P, Larmuseau MH. Paternity testing under the cloak

of recreational genetics. Eur J Hum Genet. 2017;25(6):768-70.

19. Ducharme J. A DNA site helped authorities crack the golden state killer case.

Here’s what you should know about your genetic data privacy. Time. 2018.


http://time.com/5257474/golden-state-killer-genetic-privacy-concerns/.

20. Reuters. Security breach at MyHeritage website leaks details of over 92

million users. Reuters: Thomson Reuters. 2018. [Internet]. Available from:

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heritage-website-leaks-details-of-over-92-million-users-idUSKCN1J1308.

21. Wallace SE, Gourna EG, Nikolova V, Sheehan NA. Family tree and ancestry

inference: is there a need for a ‘generational’ consent? BMC Med Ethics.

2015;16(1):87.

22. Caulfield T, Chandrasekharan S, Joly Y, Cook-Deegan R. Harm, hype and

evidence: ELSI research and policy guidance. Genome Med. 2013;5(3):21.

23. Pullman D, Etchegary H. Clinical genetic research 3: Genetics ELSI (ethical,

legal, and social issues) research. Methods Mol Biol. 2015;1281:369-82.

24. Scholand MB, Coon H, Wolff R, Cannon-Albright L. Use of a genealogical database

demonstrates heritability of pulmonary fibrosis. Lung. 2013;191(5):475-81.

25. Mirzaei S, Wu Y. RENT+: an improved method for inferring local genealogical

trees from haplotypes with recombination. Bioinformatics. 2017;33(7):1021-30.

26. Han E, Carbonetto P, Curtis RE, Wang Y, Granka JM, Byrnes J et al. Clustering

of 770,000 genomes reveals post-colonial population structure of North

America. Nat Commun. 2017;8:14238.

27. Pickrell JK, Berisa T, Liu JZ, Segurel L, Tung JY, Hinds DA. Detection and

interpretation of shared genetic influences on 42 human traits. Nat Genet.

2016;48(7):709-17.

28. Szulc P, Bogdan M, Frommlet F, Tang H. Joint genotype- and ancestry-based

genome-wide association studies in admixed populations. Genet Epidemiol.

2017;41(6):555-66.

29. Spiker WR, Brodke DS, Goz V, Lawrence B, Teerlink CC, Cannon-Albright LA.

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J. 2018;8(4):340-4.

30. Project MinE ALS Sequence Consortium. Project MinE: study design and pilot

analyses of a large-scale whole-genome sequencing study in amyotrophic

lateral sclerosis. Eur J Hum Genet. 2018;26(10):1537-46.

31. de Paor A. Direct to consumer genetic testing – law and policy concerns in

Ireland. Ir J Med Sci. 2017;187(3):575-84.

32. Sweet K, Sturm AC, Schmidlen T, McElroy J, Scheinfeldt L, Manickam K et al.

Outcomes of a randomized controlled trial of genomic counseling for

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33. Chung MW, Ng JC. Personal utility is inherent to direct-to-consumer

genomic testing. J Med Ethics. 2016;42(10):649-52.

34. Baird S. Don’t try this at home: the FDA’s restrictive regulation of home

testing devices. Duke Law J. 2017;67(2):383-426.

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36. Schaper M, Schicktanz S. Medicine, market and communication: ethical

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staff reviewRCSIsmj



staff review

Abstract

Recent advances in neonatal and perinatal medicine (NPM) enable greater chances of survival for

premature infants. Due to the advent of neonatal intensive care units (NICU), infants born today at 24-25

weeks of gestation have an increased chance of survival. Over the past few years, the limits of viability have

been further challenged, aiming to push the boundary of survivability down to 22-23 weeks of gestation.

These advances come with controversies and concerns regarding long-term neurodevelopmental and

learning disabilities. The decision to stop intensive support in futile circumstances requires the involvement

of family members and a multidisciplinary team of healthcare providers who may not share the same views,

therefore necessitating a collaborative, interdisciplinary care framework to promote communication and

transparency in healthcare decision-making. This balanced approach requires consideration of clinical

evidence while respecting the personal, cultural, and religious views of the family. Additionally, the growing

influence of social media has a profound impact on healthcare information, public perception, and care

expectations. The cost of supporting premature infants and caring for prematurity-related morbidities with

unique developmental needs can carry a substantial financial burden. In high-income countries, these costs

undergo constant contemplation due to financial pressures entangled with questions about quality of life,

pain, and suffering. In contrast, restricted resources in low-income countries mean that care is largely

limited to treating full-term infants and providing only essential care to support a healthy pregnancy. The

incidence of preterm birth in low-income countries can be reduced through better maternal education,

family planning, extended breastfeeding, more optimal birth spacing, preventive health measures, and

hygiene strategies.

Monika Cieslak


Against all odds: ethicaldilemmas in modern peri- and neonatal medicine


RCSIsmj


Introduction

Dedicated to the care of the most vulnerable newborns, neonatology

has emerged as one of the newest branches of medicine. Historically,

only the fittest and full-term infants had a chance to survive.1 The first

basic incubators were installed at the Paris Maternity Hospital in 1880.2

In the 1950s, Dr Virginia Apgar created the eponymous newborn

assessment score, which is still used worldwide today.3 In the following

years, better understanding of neonatal pathophysiology led to the

development of interventions aimed at reducing morbidity.3 This

included the use of oxygen to care for hypoxic neonates and the

introduction of ventilators generating positive pressure for infants in

respiratory distress.4,5 In 1975, the first American neonatologists were

certified to provide specialised care to the infant, especially to those

born prematurely at less than 37 weeks of gestation.6

In recent years, emerging technologies and innovative therapies have

led to remarkable advances in neonatal and perinatal medicine

(NPM). Healthcare professionals are increasingly able to provide

effective care to prematurely born infants, as well as term infants born

under unfavourable circumstances or with complex conditions.

Advances in respiratory therapy, such as high-frequency ventilators,

positive pressure breathing-assisting machines, laboratory

micro-methods, imaging techniques, and real-time monitoring of

relevant physiological parameters, have all reduced infant morbidity

and mortality.7,8 In addition, better hygiene, parenteral nutrition, and

effective infection control methods have allowed for the achievement

of outcomes that were far from possible merely a decade ago.9 And

yet, it remains that not all battles to support the life and health of

prematurely born infants can be won.

Redefining the limits of viability

Infants born at less than 28 weeks of gestation are described as

“extremely low gestational age” (ELGA).7 The dramatic progress in

NPM now enables physicians to effectively support ELGA infants born

at 24-25 weeks of gestation.10 Over the past few years, the boundaries

of viability have been further challenged by outcome reports from

centres with sophisticated neonatal intensive care programmes.11 This

includes promising results from Japan and Germany, where infants

born at 22-23 weeks were provided life-saving care; this gestational

age was previously considered “periviable”.11 However, prior to

altering existing guidelines and recommendations, clinicians must

take into consideration the long list of clinical, ethical, cultural, and

religious variables that play a significant role when it comes to

performing medical interventions for these vulnerable patients.12,13

Infants born at the borders of viability typically endure highly

dynamic, rapidly changing clinical circumstances and numerous

complications, requiring the utilisation of an array of medical

resources. The full implications of these intensive supportive measures

may not be known for days, weeks, or perhaps longer.9 In some

circumstances, medical interventions may only temporarily postpone

death, at the consequence of severe suffering; at other times, they

may lead to survival with life-long morbidity and tribulation for the

patient and their family.14 The lack of ability to accurately predict

long-term complications in individual ELGA survivors increases

prognostic uncertainty and therefore the moral distress involved in

making life or death decisions for ELGA infants.15 For this reason,

determining the best course of action while achieving consensus

regarding treatment, at times when outcomes are uncertain, poses

major ethical dilemmas.16 If available medical interventions fail, the

decision to withdraw care can be very complex, multidimensional,

and fraught with ethical turmoil.17

Despite the statistics available addressing prematurely born infants as a population, outcomes for each

specific infant are unknown. Frequently, the most controversial decision to be made is whether or not to initiate resuscitation efforts

or withdraw care.

Decision-making: the role of the healthcare team

In many modern neonatal programmes, these exceedingly difficult

situations tend to be approached on a case-by-case basis, using an

individualised prognostic strategy.18 A team approach is utilised to

steer the direction of medical and nursing care offered to support

premature infants. Those involved in the decision-making process

include parents, family members, physicians, nurses, allied

professionals, and often hospital ethics committees.12 The inherent

difficulty with team-based decision-making comes from the fact that

survival and disability are often viewed very differently among

healthcare providers, and even families.19 At times, physicians and

nurses may have contrasting views regarding how and by whom

end-of-life decisions should be made.12 The key difference between

both groups seems to be a function of the professional role played by

each, rather than differences in ethical reasoning or moral

motivation.20 In general, physicians bear the weight of clinical

decision making.20 Nurses frequently experience conflict regarding

healthcare decisions, and may implement actions that they perceive

as morally wrong.20

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Despite the statistics available addressing prematurely born infants as a

population, outcomes for each specific infant are unknown. Frequently,

the most controversial decision to be made is whether or not to initiate

resuscitation efforts or withdraw care.14 Furthermore, decisions are not

only based on acute care, but require the additional consideration of

other factors such as neurodevelopmental sequelae.10 Structural

abnormalities of the brain can persist into childhood, adolescence, and

adulthood.9 Advanced brain imaging has therefore become a standard

of care to predict prognosis and unify a treatment plan by the

healthcare team.9 Decision-making in NPM continues to be an area of

ethical debate and clinical complexity, and a better collaborative

interdisciplinary care framework is required to promote ongoing

discourse in order to reduce moral distress.21

Decision-making: the role of parents and society

In addition to helping to guide NPM interventions and management,

a team-based approach to decision-making is also required upon

recognising the futility of care. Such circumstances occur when the

outlook for an infant’s survival is extremely grim, or invariably carries

devastating disability or poor quality of life burdened by significant

physical discomfort and suffering.9 Typically, the NPM team takes into

account existing clinical evidence, but must balance this with the

wishes of the family, respecting their personal, cultural and religious

values.16 The decision to limit or withdraw life support is very difficult

for all involved; it is thus essential for healthcare professionals and

families to engage in effective, mutually respectful communication

during this highly emotional time.22,23

In cases of disagreement about the direction of care and support for the

infant, it has been suggested that there should be an option in place

for a family to appeal the clinical decision.24 This is exemplified by

recent controversies, such as the case of Liverpool’s Alfie Evans in early

2018.24 Alfie had a severe undiagnosed neurodegenerative disorder

and had been ventilated in intensive care for 16 months before his

physicians determined that continuing treatment would be futile and

would only prolong his suffering.24 Although his parents wanted life

support to continue, a judge ruled that further medical treatment failed

to respect Alfie’s autonomy.24 His case brought to light the ever-present

debates regarding the value of life, the rights of parents versus the

state, and in what circumstances discontinuing life support could be

interpreted as terminating innocent life. While the ethical principles are

guiding pillars that healthcare providers frequently turn to when faced

with difficult decisions, these tenets do not always align: how does one

weigh autonomy against beneficence, or non-maleficence?

Conflicting views on what is deemed a reasonable level of care and

intervention for prematurely born infants is often deeply influenced

by cultural beliefs and differences in society. This is further

complicated by a new influence that did not exist even a generation

ago: social media. Social media enables easy access to medical

literature, communication with healthcare providers, interprofessional

co-operation in clinical management, and promotion of public

health.25 People commonly use social media and web searches to

explore health-related issues.26 Nevertheless, internet data may

contain incorrect information that contradicts present-day,

established medical understanding.27 The media is also capable of

spreading sensational stories, often conveyed without trusted

background information or objectivity. This may fuel unreasonable

healthcare expectations and demands, and play a role in the push for

intensifying life-sustaining supports or extending futile treatments

and care.26,28 Such ‘public pressure’ may place physicians and other

allied professionals in an unnecessarily difficult position. In contrast, few

examples exist where extremely premature infants have been

resuscitated against parental wishes and survived with severe

neurological abnormalities.18 Finding a balance between these two

extremes, and navigating the ever-expanding social media landscape

and its associated pressures, will continue to be a challenge in the future.

Neonatal medicine in developed countries: societal

priorities and costs

In most high-income countries, there is an understandable

expectation for governments and regulatory bodies to ensure a

caring, compassionate approach to the weak and vulnerable

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members of society. This includes not only seniors and those living

with disability, but infants as well. In most cases, financial cost is

considered secondary to other values.16 It is inherent within most

societies to consider the health and well-being of children as a

necessary and worthy expense, a form of investment into the future

of the country.

A specialised neonatal intensive care unit (NICU) has become the

standard in many hospitals, offering a level of support unheard of

20-30 years ago.

Nevertheless, the cost of caring for premature infants is substantial,

especially for those born below 28 weeks of gestation, or born

weighing less than 500g.7 A specialised neonatal intensive care unit

(NICU) has become the standard in many hospitals, offering a level of

support unheard of 20-30 years ago. All of this comes at a

considerable expense to taxpayers. In Canada, preterm births

accounted for approximately 8% of pregnancies between 2009 and

2010, with CAN $8bn in associated costs.29 Expenditures associated

with prematurity-associated morbidities and interventions contribute

to an annual average hospitalisation cost of CAN $201,250 per

infant.30,31 Additionally, these expenses often amplify with increased

resource utilisation as patients grow into adulthood.32 Long-term

impairment, particularly neurological or cognitive, is a concern for

many healthcare providers and families of prematurely born infants.19

The association of prematurity with learning and motor disabilities,

and visual and hearing impairments, means that these infants require

specialised neurodevelopmental follow-up for years to come.9 Beyond

impacting on the lives of these infants, these cases often create a

burden for the family, as they are associated with significant

caregiving responsibilities that are often lifelong.32 Families often

require substantial support for many years, either through financial

aid from the government or through services already in high demand.

As a result, intensive neonatal interventions must be balanced by an

informed consideration of the long-term individual, familial, and

societal costs of such efforts.

Neonatal medicine in developing countries: financial

burden and logistical barriers

In low-income countries, childhood mortality has fallen dramatically

over the past few decades, but neonatal death rates are still

disproportionately high, accounting for 40% of total mortality in

children less than five years of age.33 Infants born at 28 weeks of

gestation in low-income countries have a 90% mortality rate within

the first few days of life, in contrast to 10% mortality in high-income

countries.34 In these resource-poor areas, 50% of all infants born at or

below 32 weeks of gestation die due to lack of basic cost-effective

care.34 Preventable maternal infections, such as malaria or syphilis,

have now been linked to higher rates of stillbirths.1 Low-income

countries still have limited means to support full-term infants who

require specialised care involving costly equipment, medications, or

procedures. A large portion of neonatal deaths result from birth

asphyxia, with an estimated 10 million newborns requiring some level

of intervention to establish breathing and circulation at the time of

death.35 Unfortunately, the ability to support newborns, especially

those born at extremely low gestational ages, is not universal, due to

lack of finances, resources, facilities, and trained personnel.

One of the initiatives aimed at reducing neonatal mortality associated

with asphyxia and respiratory complications in low-income countries

has been to improve neonatal resuscitation knowledge and skills

among providers.36 A low-cost and low-tech simulation-based

educational resuscitation programme, known as Helping Babies

Breathe (HBB), was developed to support this strategy.36 After a

successful pilot study, a large-scale implementation of HBB in

Tanzania over a period of three years was reported in 2017.36 This

noteworthy initiative provided healthcare policy makers with valuable

information and a wealth of data, but the impact of improving

knowledge and skills on health outcomes, most notably mortality, still

requires further evaluation.36

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In the meantime, the reality in many low-income countries is that

scarce resources must be prudently allocated to areas of healthcare

benefiting term, or near-term, newborns. Currently, the primary focus

is on lowering maternal deaths associated with childbearing,

preventing infections, and providing basic nutrition, clean water, and

vaccinations.1 In the current climate, with limited or non-existent

options to offer modern life-saving support for premature infants, the

best strategy is to prevent or minimise the incidence of premature

deliveries.34 An interesting statistical observation noted that for

neonatal and infant mortality, the risk of death decreases with

increasing birth interval lengths up to 36 months, at which point the

risk plateaus.37 Additionally, as there is a clear risk pattern of childhood

malnutrition with short birth intervals, there are recommendations for

counselling women on optimal birth spacing, which is currently

understood to be between 36 and 59 months.37 Better maternal

education, family planning, healthcare access, proper use of

contraceptives, and extended breastfeeding leading to lactation

amenorrhoea (temporary postnatal infertility) can increase the

inter-pregnancy interval.38 Factors contributing to decreased

inter-pregnancy spacing include poverty, cultural and religious

attitudes towards sex, and lack of contraceptive use.39

Specific risk factors associated with preterm delivery include

primiparity, single marital status, low frequency of antenatal visits,

antenatal infection, previous child death, and poor maternal

education.40 To address this, the WHO’s antenatal guidelines to

prevent preterm birth include counselling on healthy diet,

counselling on tobacco and substance use, and management of key

risk factors such as infection.34 It is estimated that by implementing

fundamental cost-effective care, more than three-quarters of

preterm infant lives could be saved in low-income countries.34 Given

the circumstances, is it more ethical to direct finances towards

improving survival among term and near-term infants in

low-income countries? Determining whether international financial

support should be directed to these infants versus the extremely

preterm infants with uncertain outcomes in high-income countries

is an ongoing global ethical dilemma.

Conclusion

It is inevitable that healthcare professionals face ethical challenges

almost daily in their practice. In contrast to paediatric or adult

medicine, the principles of biomedical ethics are not as easily

applied in neonatal and perinatal medicine. Autonomy bears

significant weight in medical decision-making. However, an infant is

unable to voice an opinion, and beneficence and non-maleficence

are often impossible to reconcile at the time of intensive

neonatal decision-making. Collaborative and integrative measures

in neonatology have resulted in a nearly 50% decline in morbidity

in infants less than 29 weeks of gestation,41 but even the

most cutting-edge clinical advances are unable to resolve the

weighty ethical dilemmas and disparities surrounding neonatal life

saving across the globe. Future healthcare providers must approach

these quandaries by remaining unbiased, clinically astute and,

above all, respectful of parental wishes, culture, religion, and spiritual

needs.

References

1. Global Burden of Disease Child Mortality Collaborators. Global, regional,

national, and selected subnational levels of stillbirths, neonatal, and

under-5 mortality, 1980-2015: a systematic analysis for the Global Burden

of Disease Study 2015. Lancet. 2016;388(10053):1725-74.

2. Baker JP. The incubator and the medical discovery of the premature infant.

J Perinatol. 2000;20(5):321-8.

3. Apgar V. A proposal for a new method of evaluation of the newborn

infant. Originally published in July 1953, volume 32, pages 250-259.

Anesth Analg. 2015;120(5):1056-9.

4. Silverman WA. Prematurity and retrolental fibroplasia. Sight Sav Rev.

1969;39(1):42-6.

5. Delivoria-Papadopoulos M, Swyer PR. Assisted ventilation in terminal

hyaline membrane disease. Arch Dis Child. 1964;39:481-4.

6. Fanaroff A, Martin R, Walsh M. Fanaroff and Martin’s Neonatal-Perinatal

Medicine. (10th ed.). Elsevier Saunders, 2015.

7. Berrington J, Ward Platt M. Recent advances in the management of infants

born <1,000g. Arch Dis Child. 2016;101(11):1053-6.

8. Papa F, Rongioletti M, Ventura MD, Di Turi F, Cortesi M, Pasqualetti P et al.

Blood cell counting in neonates: a comparison between a low volume

micromethod and the standard laboratory method. Blood Transfus.

2011;9(4):400-6.

9. Glass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes

for extremely premature infants. Anesth Analg. 2015;120(6):1337-51.

10. Ceriani Cernadas JM. The limits of viability in preterm infants, a growing

ethical dilemma. Arch Argent Pediatr. 2018;116(3):170-1.

11. Patel RM, Rysavy MA, Bell EF, Tyson JE. Survival of infants born at

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periviable gestational ages. Clin Perinatol. 2017;44(2):287-303.

12. Bucher HU, Klein SD, Hendriks MJ, Baumann-Holzle R, Berger TM, Streuli JC et

al. Decision-making at the limit of viability: differing perceptions and opinions

between neonatal physicians and nurses. BMC Pediatr. 2018;18(1):81.

13. Lorch SA, Enlow E. The role of social determinants in explaining

racial/ethnic disparities in perinatal outcomes. Pediatr Res.

2016;79(1-2):141-7.

14. Liu J, Chen XX, Wang XL. Ethical issues in neonatal intensive care units.

J Matern Fetal Neonatal Med. 2016;29(14):2322-6.

15. Coughlin KW, Hernandez L, Richardson BS, da Silva OP. Life and death

decisions in the extremely preterm infant: What happens in a level III

perinatal centre? Paediatr Child Health. 2007;12(7):557-62.

16. Einaudi MA, Gire C, Auquier P, Le Coz P. How do physicians perceive

quality of life? Ethical questioning in neonatology. BMC Med Ethics.

2015;16:50.

17. Mahgoub L, van Manen M, Byrne P, Tyebkhan JM. Policy change for

infants born at the “cusp of viability”: a Canadian NICU experience.

Pediatrics. 2014;134(5):e1405-10.

18. Nadroo AM. Ethical dilemmas in decision making at limits of neonatal

viability. J IMA. 2011;43(3):188-92.

19. Dupont-Thibodeau A, Barrington KJ, Farlow B, Janvier A. End-of-life

decisions for extremely low-gestational-age infants: why simple rules for

complicated decisions should be avoided. Semin Perinatol.

2014;38(1):31-7.

20. Oberle K, Hughes D. Doctors’ and nurses’ perceptions of ethical problems

in end-of-life decisions. J Adv Nurs. 2001;33(6):707-15.

21. Browning DM, Solomon MZ, Initiative for Pediatric Palliative Care (IPPC)

Investigator Team. The Initiative for Pediatric Palliative Care: an

interdisciplinary educational approach for healthcare professionals. J

Pediatr Nurs. 2005;20(5):326-34.

22. Abe N, Catlin A, Mihara D. End of life in the NICU. A study of ventilator

withdrawal. MCN Am J Matern Child Nurs. 2001;26(3):141-6.

23. Burt RA. Resolving disputes between clinicians and family about “futility”

of treatment. Semin Perinatol. 2003;27(6):495-502.

24. Wilkinson D, Savulescu J. Alfie Evans and Charlie Gard – should the law

change? BMJ. 2018;361:k1891.

25. Levac J, O’Sullivan T. Social media and its use in health promotion. Revue

interdisciplinaire des sciences et de la santé – Interdisciplinary Journal of

Health Sciences. 2016. [Internet]. [cited 2018 July 23]. Available from:

https://uottawa.scholarsportal.info/ojs/index.php/RISS-IJHS/article/view/1534.

26. de Martino I, D’Apolito R, McLawhorn AS, Fehring KA, Sculco PK,

Gasparini G. Social media for patients: benefits and drawbacks. Curr Rev

Musculoskeletal Med. 2017;10(1):141-5.

27. Ghenai A. DH’17: Proceedings of the 2017 International Conference on

Digital Health. New York, USA; Association for Computing Machinery, 2017.

28. Heath S. How healthcare bias affects patient-provider

relationships. 2017. [Internet]. [cited 2018 July 24]. Available from:

https://patientengagementhit.com/news/how-healthcare-bias-affects-p

atient-provider-relationships.

29. Lim G, Tracey J, Boom N, Karmakar S, Wang J, Berthelot JM et al. CIHI

survey: hospital costs for preterm and small-for-gestational age babies in

Canada. Healthc Q. 2009;12(4):20-4.

30. Johnson TJ, Patel AL, Jegier BJ, Engstrom JL, Meier PP. Cost of morbidities

in very low birth weight infants. J Pediatr. 2013;162(2):243-49.e1.

31. Muraskas J, Parsi K. The cost of saving the tiniest lives: NICUs versus

prevention. Virtual Mentor. 2008;10(10):655-8.

32. Johnston KM, Gooch K, Korol E, Vo P, Eyawo O, Bradt P et al. The

economic burden of prematurity in Canada. BMC Pediatr. 2014;14:93.

33. Global Health Observatory. Global Health Observatory (GHO) data. 2016.

[Internet]. [cited 2018 August 1]. Available from: http://www.who.int/ gho/en.

34. World Health Organisation. Preterm birth. 2018. [Internet]. [cited 2018

June 18]. Available from:

http://www.who.int/news-room/fact-sheets/detail/ preterm-birth.

35. Wall SN, Lee SE, Niermeyer S, English M, Keenan WJ, Carlo W et al. Neonatal

resuscitation in low-resource settings: what, who, and how to overcome

challenges to scale up? Int J Gynaecol Obstet. 2009;107(Suppl. 1):S47-62, S3-4.

36. Arlington L, Kairuki AK, Isangula KG, Meda RS, Thomas E, Temu A et al.

Implementation of “Helping Babies Breathe”: a 3-year experience in

Tanzania. Pediatrics. 2017;139(5):pii. E20162132.

37. Rutstein SO. Effects of preceding birth intervals on neonatal, infant and

under-five years mortality and nutritional status in developing countries:

evidence from the demographic and health surveys. Int J Gynaecol Obstet.

2005;89(Suppl. 1):S7-24.

38. Ganatra B, Faundes A. Role of birth spacing, family planning services, safe

abortion services and post-abortion care in reducing maternal mortality.

Best Pract Res Clin Obstet Gynaecol. 2016;36:145-55.

39. Conde-Agudelo A, Belizan JM. Maternal morbidity and mortality associated

with interpregnancy interval: cross sectional study. BMJ.

2000;321(7271):1255-9.

40. Prazuck T, Tall F, Roisin AJ, Konfe S, Cot M, Lafaix C. Risk factors for

preterm delivery in Burkina Faso (west Africa). Int J Epidemiol.

1993;22(3):489-94.

41. Shah PS, McDonald SD, Barrett J, Synnes A, Robson K, Foster J et al. The

Canadian Preterm Birth Network: a study protocol for improving

outcomes for preterm infants and their families. CMAJ Open.

2018;6(1):E44-E9.

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perspective

Introduction

Regular engagement in physical exercise has been shown to vastly

improve both mental and physical health. Exercise is used as a form

of therapy in many disorders due to its ability to regulate mood and

sleep patterns, improve cognitive function, reduce neurocognitive

and metabolic diseases, and increase overall well-being.1 By

increasing serotonin, brain-derived neurotrophic factor (BDNF),

dopamine, and other hormones such as adrenaline and

noradrenaline, exercise improves the brain’s ability to regulate mood

and sleep patterns.1 It has been shown that those who participate

regularly in exercise tend to sleep better at night and feel more

energetic throughout the day.1 Unfortunately, most young adults do

not engage in the level of exercise recommended for their age

group, contributing to increased levels of obesity in children and

young adults.2

Physical health is of particular importance for medical students, as the

positive effects of exercise are seen to directly correlate with academic

output. As such, the benefits of exercise, its influence on brain

neurotransmitters, and its impact on cognitive function in medical

students and young adults warrant discussion.

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HARVEEN HAYER and SUKHMANI BENIPAL discuss the neurocognitive

benefits of exercise, particularly for medical students.

How fitness can fuel the brain


perspective

Modulation of neurotransmitters through exercise

Adrenaline and noradrenaline are the hormones whose concentrations

have been shown to increase the most dramatically in response to

exercise (1.5 to >20 times resting concentrations).3 After being released

from neurons into the synaptic cleft, noradrenaline and adrenaline bind

to appropriate α- and β-adrenergic receptors to mediate their effects.

High levels of noradrenaline released into the synaptic cleft have a

positive effect on attention, while low levels are strongly associated

with depression.4 Additionally, noradrenaline is responsible for memory

retrieval and stress resistance due to enhanced neuronal adaptation,

while adrenaline can mediate similar effects on stress adaption and

memory consolidation via β-adrenergic receptors.3,5 Lastly, the increase

in adrenaline and noradrenaline during exercise results in

cardiovascular and respiratory adjustments, such as an increased heart

rate. This positive chronotropic effect supplies more oxygen to working

muscles and promotes energy release from cells. This prompts

psychological changes as well, explaining why exercise of low to

moderate intensity lasting more than 20 minutes can decrease fatigue.6

Exercise has been shown toimprove cognitive performance due to the downregulation of 5-HT1A

receptors and upregulation of 5-HT2Areceptors in cognition-related

areas of the brain.

The neuronal circuitry within the brain plays a critical role in

controlling cognitive function. Catecholamines such as dopamine and

BDNF are released during exercise, resulting in improved verbal

memory.7 The interaction of dopamine with its receptors activates the

reward system via the nucleus accumbens and the amygdala,

resulting in pleasure sensations, and via the dorsolateral prefrontal

cortex, resulting in enhanced working memory.8,9 Working memory

processes visual and auditory stimuli until they are translated from

short-term memory into long-term memory. As previously

mentioned, adrenaline also enhances long-term memory storage

through the activation of peripheral β receptors.5 Neurogenesis, or

the creation of new neurons, is carried out by the protein fibronectin

type III domain-containing protein 5 (FNDC5).5 During exercise and

sweat production, FNDC5 is released into the bloodstream, where it

stimulates the production of BDNF, which in turn triggers the growth

of neurons and their associated circuitry, resulting in improved

cognitive function.10

Additionally, serotonin (5-HT) has been proven to play important roles

in cognitive function. While serotonin is typically known for its

antidepressant and anxiolytic properties, it plays a supplementary role

in learning and memory.11 Exercise has been shown to improve

cognitive performance due to the downregulation of 5-HT1A receptors

and upregulation of 5-HT2A receptors in cognition-related areas of the

brain.11 Serotonin also collaborates with the BDNF pathway to regulate

and improve neurogenesis, neuronal plasticity, and neural survival.8,9

Neurocognition, mood disorders, and addiction:

the benefits of exercise

Depression and anxiety

Exercise has been successfully utilised as a form of therapy for many

illnesses such as anxiety, depression, Parkinson’s disease (PD), and

dementia. On the contrary, sedentary behaviour has been directly

linked to an increase in anxiety disorders.12 Some researchers have

shown that exercise is just as effective as antidepressants when treating

mild to moderate depression.13 Exercise can also prevent individuals

from relapsing into depressive and/or anxious states by serving as a

form of distraction. In the distraction hypothesis, exercise allows

individuals to reserve time for themselves during which they can be free

from negative thoughts.14 In addition to distraction, exercise is also

involved in the release of the neurotransmitter β-endorphin.

β-endorphin is released primarily from the anterior pituitary gland as

the precursor molecule pro-opiomelanocortin (POMC).15 During

exercise of sufficient capacity, the circulating levels of β-endorphin

increase, resulting in a marked increase in energy and mood.15 Through

both distraction and the release of endorphins, exercise can help to

relieve stress, reduce its impact, and enhance overall well-being,

thereby easing the symptoms of depression. Specifically in anxiety

disorders, exercise has been linked to increasing alpha wave brain

activity, resulting in reflexive relaxation and reduction of anxiety.3,15

Neurocognitive disorders

In addition to mood disorders, regular physical activity is associated

with a reduced risk of neurocognitive diseases such as PD and

dementia.15 Physical exercise, through the neurotransmitters

mentioned above, enhances cognitive processes controlled by the

prefrontal cortex such as scheduling, planning, and working

memory.15 The prefrontal cortex is particularly susceptible in

neurocognitive diseases. Furthermore, the use of physical exercise in

patients with PD has been studied as a non-pharmaceutical

therapeutic approach to avoid the high side effect profile that is

associated with pharmaceutical treatment.11 Overall, studies have

shown that exercise has the capability to improve executive function

in patients with mild to moderate PD.11

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perspective

Substance abuse

Physical activity is inversely correlated with substance use disorders,

and is increasingly used as a form of adjunctive therapy in these

situations.16,17 All drugs of abuse activate the mesolimbic dopamine

system, and either directly or indirectly increase dopamine

transmission in the nucleus accumbens.18 In prolonged drug use,

there is a build-up of dopamine, due to drug interactions with

dopamine transporters and receptors, which ultimately diminishes

the natural release of dopamine. Exercise can effectively restore

changes in the neuroplasticity of the brain, acting on the mesolimbic

reward pathway through normalised dopamine release.19 Similar to its

use in mood disorders, a secondary benefit of the use of exercise in

substance abuse disorders is the introduction of exercise as a

distraction from cravings to prevent relapse.

Physical exercise in young adults

With clear evidence of the impact of exercise on mood regulation and

chronic disease prevention, young adults, and particularly medical

students, should engage in regular physical activity to avoid the

detrimental effects of stress on the mind. Many risk factors contribute to a

decreased quality of life in medical students, including increased workload,

long shifts in the hospital, and recurrent stressful exam preparation.20

However, due to high stress levels, lack of time, and lack of motivation,

medical students often find it hard to adopt healthy exercise habits.21

Colleges, universities, and medical schools play a tremendous role in

promoting physical health in students. Increasing awareness about the

beneficial impacts of exercise, and making workout classes and gym

hours easily accessible to students, are valuable and effective ways to

improve exercise adherence. Beyond student well-being, it is essential

that future physicians understand and adopt healthy lifestyles in order

to promote good health practices for their patients.21

According to World Health Organisation (WHO) recommendations,

young adults should partake in moderate physical activity for at least

150 minutes per week.22 This is an average of 20-25 minutes per day;

however, students may find it difficult to allot even this amount of

time within their busy schedules. But in comparison to those who lack

engagement in physical activity, regular participants are more likely to

appropriately respond to and cope with high levels of stress.22

Exercise has also been proven to increase levels of REM sleep.1 The

role of exercise in the sleep-wake cycle is paramount, as a lack of

quality sleep is linked to poor academic performance and excessive

daytime sleepiness.1,20 Therefore, exercise is a tool that can be used by

young adults, specifically medical students, to supplement their

productivity and alleviate stressors.

Recommendations for fellow students

Medical students are recommended to engage in exercise as part of

preventive health behaviour. If young adults fall into a sedentary

pattern and practise an unhealthy lifestyle, including smoking or

excessive drinking, this behaviour can continue into middle or late

adulthood.23 Although it may be difficult to adhere to an active

lifestyle amid the demanding schedule of medical school, the

cognitive benefits of exercise should be discussed and promoted as an

additional incentive for students, beyond just the physical benefits.

Finding a balance between studying and keeping physically active

is crucial to avoid problems such as burnout and fatigue. Minor

changes in day-to-day activity, such as walking or biking instead of

motor transport, can make a significant difference. Consistent effort

to engage in physical activity can increase adherence until exercise

eventually becomes a routine part of daily life. This increase in

physical activity is proven to increase cognition, induce changes in

working memory, and increase the brain’s processing capacity, all

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perspective

of which directly correlate with the amount of energy and focus

students have for their academic work.20

Conclusion

With a growing body of literature addressing the effects of exercise

on mental health, the myriad positive effects of exercise are

undeniable. Predominantly, exercise is immensely beneficial for an

individual’s overall cognitive functioning, mood, and sleep cycles.

Through its impact on neurotransmitters such as dopamine,

serotonin, and noradrenaline, exercise is able to modulate brain

function and improve cognitive performance. Exercise can also serve

as a form of preventive therapy for neurocognitive disorders; those

who regularly participate in physical activity have a reduced risk of

developing diseases such as Parkinson’s and dementia. As an outlet

from negative thoughts and stressful environments, exercise can

greatly assist medical students in clearing their heads and

replenishing their mental energy. As research continues to enhance

our knowledge, the roles and benefits of exercise will continue to

expand within the realm of medicine as a form of both preventive

and maintenance therapy.

References

1. Gerber M, Brand S, Herrmann C, Colledge F, Holsboer-Trachsler E, Pühse

U. Increased objectively assessed vigorous-intensity exercise is associated

with reduced stress, increased mental health and good objective and

subjective sleep in young adults. Physiol Behav. 2014;135:17-24.

2. Daugherty PL. The effects of three exercise intensities on the alpha brain

wave activity of adult males. Dissertation. 1986. [Internet]. Available from:

https://commons.lib.niu.edu/handle/10843/16167.

3. Zouhal H, Jacob C, Delamarche P, Gratas-Delamarche A. Catecholamines and

the effects of exercise, training and gender. Sports Med. 2008;38(5):401-23.

4. Norepinephrine. Caam.rice.edu. 2019. [Internet]. [cited 2019 January 15].

Available from: https://www.caam.rice.edu/~cox/wrap/norepinephrine.pdf.

5. Roozendaal B, McGaugh JL. Memory modulation. Behav Neurosci.

2011;125(6):797-824.

6. Loy BD, O’Connor PJ, Dishman RK. The effect of a single bout of exercise

on energy and fatigue states: a systematic review and meta-analysis.

Fatigue: Biomedicine, Health & Behavior. 2013;1(4):223-42.

7. Winter B, Breitenstein C, Mooren FC, Voelker K, Fobker M, Lechtermann A

et al. High impact running improves learning. Neurobiol Learn Mem.

2007;87(4):597-609.

8. Tanaka S. Dopaminergic control of working memory and its relevance to

schizophrenia: a circuit dynamics perspective. Neuroscience.

2006;139(1):153-71.

9. Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron.

2015;86(3):646-64.

10. Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Haidar EA, Stringer T et al.

Exercise promotes the expression of brain derived neurotrophic factor

(BDNF) through the action of the ketone body β-hydroxybutyrate. eLife.

2016;5:e15092.

11. Lin T-W, Kuo Y-M. Exercise benefits brain function: the monoamine

connection. Brain Sci. 2013;3(1):39-53.

12. Allen MS, Walter EE, Swann C. Sedentary behaviour and risk of anxiety: a

systematic review and meta-analysis. J Affect Disord. 2019;242:5-13.

13. Blumenthal JA, Babyak MA, Doraiswamy PM, Watkins L, Hoffman BM,

Barbour KA et al. Exercise and pharmacotherapy in the treatment of major

depressive disorder. Psychosom Med. 2007;69(7):587-96.

14. Mikkelsen K, Stojanovska L, Polenakovic M, Bosevski M, Apostolopoulos V.

Exercise and mental health. Maturitas. 2017;106:48-56.

15. Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise

effects on brain and cognition. Nat Rev Neurosci. 2008;9(1):58-65.

16. Taylor CB, Sallis JF, Needle R. The relation of physical activity and exercise

to mental health. Public Health Rep. 1985;100(2):195-202.

17. Linke SE, Ussher M. Exercise-based treatments for substance use disorders:

evidence, theory, and practicality. Am J Drug Alcohol Abuse. 2015;41(1):7-15.

18. Annett S. Drugs of Abuse [unpublished lecture notes]. Royal College of

Surgeons in Ireland; notes provided at lecture given on October 1, 2018.

19. Zhou Y, Zhao M, Zhou C, Li R. Sex differences in drug addiction and

response to exercise intervention: From human to animal studies. Front

Neuroendocrinol. 2016;40:24-41.

20. El Hangouche AJ, Jniene A, Aboudrar S, Errguig L, Rkain H, Cherti M et al.

Relationship between poor quality sleep, excessive daytime sleepiness and

low academic performance in medical students. Adv Med Educ Pract.

2018;9:631-8.

21. Rao CR, Darshan B, Das N, Rajan V, Bhogun M, Gupta A. Practice of

physical activity among future doctors: A cross sectional analysis. Int J Prev

Med. 2012;3(5):365-9.

22. World Health Organisation. Prevalence of insufficient physical activity.

2018. [Internet]. [Accessed 2018 October 16]. Available at:

http://www.who.int/gho/ncd/risk_factors/physical_activity_text/en/.

23. Lau JS, Adams SH, Irwin Jr CE, Ozer EM. Receipt of preventive health

services in young adults. J Adolesc Health. 2013;52(1):42-9.

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Donateor do not?

MATTHEW PATEL looks at evidence-based strategies

to increase rates of organ donation.


Introduction

Organ transplantation is the standard of care for patients with

end-of-life organ failure.1 A rapid increase in the number of patients

requiring organ transplantation, without an increase in the number of

organ donors, has resulted in long transplant waiting lists and a

scenario where patients often die before receiving a transplant.2

Organ donation rates remain frustratingly low, despite

encouragement for donation from governments, the public, and

healthcare professionals.3

Efforts to increase organ donation have largely failed, due to a lack of

theoretical framework and standardisation.4 Expanding the scope of

organ donation requires a multidisciplinary approach, grounded in

ethics, considering the multitude of factors and stakeholders

involved.4,5 Evidence-based strategies involving legislation, education,

donation co-ordinators, hospital committees, and population-based

donor programmes have the potential to increase organ donation rates

and eliminate the disconnect between organ supply and demand.

Legislative strategies

Changing legislation from an opt-in system, where citizens must

register to donate their organs, to an opt-out system, where

individuals are automatically regarded as a donor and must convey

their objection to donating, has been shown to successfully increase

organ donation rates.6-8 An opt-out donor strategy can also be

justified using tacit and normative consent.9

By default, opt-out legislation registers individuals without a

preference regarding donation as organ donors, and has been shown

to increase family consent rates when an individual’s donation wishes

are unknown.9 This strategy also increases donation among the

young, by enabling the procurement of organs from those who had

not registered to donate prior to an untimely death.8 Opt-out

legislation leads to the belief that the government recommends that

its citizens become donors, altering public opinion and influencing

decision-making.6 Perhaps most effectively, opt-out legislation

removes the barrier between an intention to become an organ donor

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and the act of legally doing so, providing significant support for this

model.4,6

Opt-out legislation is supported by medical professionals, who believe

it is the most effective method of increasing donation rates, as well as

the majority of the public, who support the policy if it is ethically

implemented.4,8 Furthermore, a ‘soft opt-out’ system, present in most

countries with this legislation, allows family wishes to override the

legislation, eliminating potential legal or ethical issues.4,6,7 The effect

of opt-out legislation is modulated by the public’s awareness of the

legislation, their knowledge surrounding organ donation, and their

level of trust in the healthcare system, thus making public education

and action plans crucial in order to ensure optimal impact.6

Consequently, opt-out legislation can only be effective in increasing

organ donation rates if a platform of social support for this change in

legislation is established, through developing strong public trust in

the healthcare system and implementing widespread public

awareness campaigns.8

Ireland stands as one of the few countries in the European Union that

does not currently have opt-out legislation. However, this could

change in 2019 as the Irish cabinet will consider the Human Tissue

Bill, proposing opt-out legislation.10 If the Bill is passed, the deceased’s

family will still be involved in the decision and their wishes will be

respected.10

Healthcare staff at transplant centres have specialised training and play critical roles in identifying potential

donors and determining their donation preferences.

The role of education

Knowledge about organ donation and the donation process is a

strong predictor of willingness to be a donor.11 Predictably, a lack of

knowledge about organ donation results in decreased donation

rates.1 Education is a proven strategy, and increases family consent

rates and donor conversion rates by 75%.2,7,12-14 If skilfully

implemented, education compares favourably to other strategies, is

cost-effective, and can be easily implemented.15

Knowledge about donation lessens the fear and sense of uncertainty

surrounding donation, while also dispelling myths and clarifying

misconceptions.2 Education should also focus on the positive impacts

of donation, such as saving a life and immeasurably aiding a family.16

Successful programmes must cover a wide variety of topics and

should be longitudinal, since organ donation is time sensitive and

potential donors are more likely to consent if they have seen

information recently and repeatedly.7 Examples of effective education

methods include home-based video programmes and outreach

efforts involving the mass media, schools, places of religious worship,

and hospitals.2,7,12-14

Informative outreach campaigns have a major impact on minority

and religious populations, where there is a need for cultural, religious,

language, and communication sensitivity. One strategy to educate

minority groups is to collaborate with donation co-ordinators of

specific ethnic backgrounds who can target certain populations using

programmes in multiple languages.17 As all major religions accept

organ donation and leave this decision to the individual, religious

leaders, using a faith-based approach, can inform individuals and

communities on the religious views of donation to help quell

misconceptions.12,13

Healthcare staff at transplant centres have specialised training and

play critical roles in identifying potential donors and determining their

donation preferences.5 While healthcare providers are involved in

various processes of organ donation and believe it is within their duty

of care, many are uncomfortable performing tasks related to

donation.2,14 It is therefore vital to educate healthcare professionals

regarding strategies for initiating donation conversations; by

enhancing their readiness to identify potential donors and provide

information related to consent, rates of organ donation will

rise.3,15,18,19 Increasing healthcare professionals’ confidence in

completing tasks associated with the donation process will strengthen

patient trust and help to overcome donation barriers.2,16 There are no

reports of reduced patient satisfaction when healthcare providers

initiate educational discussions about organ donation, thus

eliminating the worry that informing patients about donation could

lead to dissatisfaction.2

Healthcare staff education should begin in training programmes and

continue throughout practice, where it has the greatest impact.16

Staff with key roles in the donation process should receive mandatory

specialised training to ensure that they can provide information on all

aspects of donation.20

Population-based strategies

Increasing donor registration increases organ donation rates by

enlarging the donor pool.7 Low donor registration rates are attributed

to non-cognitive factors, which are intricately linked to an individual’s

willingness to donate organs.13 Non-modifiable, non-cognitive factors

include age, ethnicity, gender, and religion, with low organ donation

rates seen in older, minority, and highly religious popuations.1,11,16,21

Modifiable non-cognitive factors include medical mistrust, a sense of

fear and anxiety about organ donation, and a reluctance to

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contemplate one’s own death or discuss one’s wishes after death with

relatives.13 Non-cognitive organ donation perceptions can be

positively influenced through education and awareness campaigns.

Cognitive factors include donor socioeconomic status, organ

donation perceptions, and financial incentives for donors.16 Financial

incentives to increase donor registration include direct payment for

organs, reimbursement for lost income, and payment of donor

funeral expenses.7,16,22 However, introducing financial incentives for

organ donation can create ethical dilemmas, despite well-established

direct payment for plasma donations in the USA.23 In countries with

opt-in legislation, the challenges of registration are often cited as a

disincentive.6 Thus, a simplified registration process is needed to

increase donor registration rates.7

The majority of organ donors are cadaveric or living brain dead

donors.24 Broadening the donor pool through the introduction of

different donor types, such as living donors and non heart-beating

donors, has increased donation rates.1,3 These donor eligibility

amendments have been publicly well received, with greater

willingness for donation after cardiac death.3 The non-medical public

generally understands cardiac death better than brain death,

explaining increased willingness to donate a family member’s organs

after cardiac death.3 The use of living donors also has many

advantages, including shorter wait times and hospital stays, and

improved post-transplant outcomes.18

Donation co-ordinators

Donation co-ordinators also play a crucial role in increasing donation

rates.1 They ensure that all potential donors are identified and

monitored, and provide education sessions and family support

throughout the donation process.4,20 Donation co-ordinators

synchronise tasks and aid communication between the emergency,

intensive care unit (ICU), and surgical transplant teams.20

Organ donation rates are greater when co-ordinators, rather than the

healthcare provider, connect with families regarding donation. This is

explained by the separation between the notification of brain death

(relayed by the healthcare practitioner) and request for donation,

carried out by the co-ordinator.11,18,20 Donation co-ordinators from a

variety of backgrounds can conduct culturally sensitive discussions with

families and patients, further increasing donation rates.21 Co-ordinators

act as a neutral third party to provide family support and education,

and have a unique role in the effort to increase organ donation rates.20

Hospital-based strategies

Hospitals play a vital role in the donation process during the organ

procurement stage.22 For hospitals to have a positive impact on

donation, there must be a formal organ procurement programme

that supports staff and donors, and promotes a positive attitude

towards organ donation.25

Hospitals specialising in transplant services with neurosurgical and

emergency departments see a greater number of potential donors,

leading to a higher organ procurement rate compared to general

hospitals.5,22 Resource limitations necessitate that organ donor

programmes be allocated at regional transplant centres and large

centres with neurosurgical programmes, matching resources to

potential donors.22 However, general hospitals can increase their organ

donation rates by providing staff training and implementing best

practices for donation.5,25 Increasing ICU bed capacity positively affects

a hospital’s donation rate by expanding facilities to prolong donors’ lives

and ensure that their organs remain viable for transplant.14

Administrative barriers, such as poor communication between healthcare

teams involved in donor management or improper identification of

potential donors, negatively affect organ donation rates.19 However,

sharing donor management techniques and creating additional transplant

centres with specialised units can help to overcome this.

Conclusion

Increasing organ donation rates is critical to saving the lives of

patients with end-stage organ failure. Intensified attention to this

issue has increased the number of potential donors who ‘convert’ and

become true registered donors, and has increased the number of

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organs procured per donor.12 Evidence-based approaches to increase

organ donation include legislative change to an opt-out system,

liberalising eligibility criteria, and increasing the population of

potential donors.4,6-8 Education regarding organ donation fosters

discussion, dispels myths, enhances public trust, and promotes the

benefits of donation.2 Working to change non-cognitive donor

factors, such as mistrust in the healthcare system and a sense of

anxiety regarding donation, can further increase recruitment of

potential donors. Hospitals can work towards increasing donation

rates by sharing donation best practices, providing training,

promoting a positive attitude towards donation among staff, and

hiring donation co-ordinators.5,25 For maximal effect, efforts to

overcome barriers to organ donation should combine the multitude

of evidence-based approaches.

perspective

References

1. Brown CV, Foulkrod KH, Dworaczyk S, Thompson K, Elliot E, Cooper H et

al. Barriers to obtaining family consent for potential organ donors. J

Trauma. 2010;68(2):447-51.

2. Thornton JD, Sullivan C, Albert JM, Cedeno M, Patrick B, Pencak J et al.

Effects of a video on organ donation consent among primary care patients:

a randomized controlled trial. J Gen Intern Med. 2016;31(8):832-9.

3. Bastami S, Matthes O, Krones T, Biller-Andorno N. Systematic review of

attitudes toward donation after cardiac death among healthcare providers

and the general public. Crit Care Med. 2013;41(3):897-905.

4. Rudge CJ, Buggins E. How to increase organ donation: does opting out

have a role? Transplantation. 2012;93(2):141-4.

5. Redelmeier DA, Markel F, Scales DC. Organ donation after death in

Ontario: a population-based cohort study. CMAJ. 2013;185(8):E337-44.

6. Shepherd L, O’Carroll RE. Awareness of legislation moderates the effect of

opt-out consent on organ donation intentions. Transplantation.

2013;95(8):1058-63.

7. Salim A, Malinoski D, Schulman D, Desai C, Navarro S, Ley EJ. The

combination of an online organ and tissue registry with a public education

campaign can increase the number of organs available for transplantation. J

Trauma. 2010;69(2):451-4.

8. Ugur ZB. Does presumed consent save lives? Evidence from Europe. Health

Econ. 2015;24(12):1560-72.

9. Saunders B. Normative consent and opt-out organ donation. J Med Ethics.

2010;36(2):84-7.

10. McGee H. Cabinet to finally consider ‘opt-out’ organ donation law. The

Irish Times. 2019. [Internet]. [cited 2019 January 3]. Available from:

https://www.irishtimes.com/news/health/cabinet-to-finally-consider-opt-out

-organ-donation-law-1.3746347.

11. Wakefield CE, Reid J, Homewood J. Religious and ethnic influences on

willingness to donate organs and donor behavior: an Australian

perspective. Prog Transplant. 2011;21(2):161-8.

12. Davis BD, Norton HJ, Jacobs DG. The Organ Donation Breakthrough

Collaborative: has it made a difference? Am J Surg. 2013;205(4):381-6.

13. O’Carroll RE, Foster C, McGeechan G, Sandford K, Ferguson E. The “ick”

factor, anticipated regret, and willingness to become an organ donor.

Health Psychol. 2011;30(2):236-45.

14. Cohen B, Wight C. A European perspective on organ procurement: breaking

down the barriers to organ donation. Transplantation. 1999;68(7):985-90.

15. Whiting JF, Kiberd B, Kalo Z, Keown P, Roels L, Kjerulf M. Cost-effectiveness

of organ donation: evaluating investment into donor action and other

donor initiatives. Am J Transplant. 2004;4(4):569-73.

16. Rasiah R, Manikam R, Chandrasekaran SK, Naghavi N, Mubarik S, Mustafa

R et al. Deceased donor organs: what can be done to raise donation rates

using evidence from Malaysia? Am J Transplant. 2016;16(5):1540-7.

17. Biehl M, Kashyap R, McCormick JB. Education of minorities to increase

organ donation consent rate. Crit Care Med. 2013;41(10):e298-9.

18. Roels L, Smits J, Cohen B. Potential for deceased donation not optimally

exploited: donor action data from six countries. Transplantation.

2012;94(11):1167-71.

19. Shaheen FA, Souqiyyeh MZ. Increasing organ donation rates from Muslim

donors: lessons from a successful model. Transplant Proc. 2004;36(7):1878-80.

20. Friele RD, Coppen R, Marquet RL, Gevers JK. Explaining differences

between hospitals in number of organ donors. Am J Transplant.

2006;6(3):539-43.

21. Tong A, Chapman JR, Wong G, Josephson MA, Craig JC. Public awareness

and attitudes to living organ donation: systematic review and integrative

synthesis. Transplantation. 2013;96(5):429-37.

22. Howard DH, Siminoff LA, McBride V, Lin M. Does quality improvement

work? Evaluation of the Organ Donation Breakthrough Collaborative.

Health Serv Res. 2007;42(6Pt1):2160-73; discussion 2294-323.

23. Wigmore SJ, Forsythe JL. Incentives to promote organ donation.

Transplantation. 2004;77(1):159-61.

24. Domen R. Paid-versus-volunteer blood donation in the United States: a

historical review. Transfus Med Rev. 1995;9(1):53-9.

25. Dalley K. Improving organ donation rates – what can be done? Nurs Crit

Care. 2008;13(5):221-2.

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Introduction

Cigarette smoking is the leading cause of preventable death and

disability worldwide.1 Electronic nicotine delivery systems (ENDS),

also known as e-cigarettes or ‘vapes’, have been gaining significant

traction and momentum in two main populations: adults attempting

smoking cessation, and adolescents experimenting with nicotine

products.1,2 ENDS are battery-operated devices, which form a vapour

– by heating liquids containing nicotine, flavouring, and other

chemicals – which is then inhaled by the user.3 This led to the term

‘vaping’ to describe the act of using an ENDS. There are three

generations of ENDS, with each improving on its predecessor by

offering the user new and enticing features such as rechargeability,

compact size, and personalised touches.3

While ENDS are less harmful than combustible cigarettes (CCs), which

contribute to the deaths of two in three long-term users, this does not

mean that ENDS are safe.4 Inaccurate perceptions of ENDS can lead to

harmful behaviour in those attempting to quit smoking and may even

encourage non-smokers to use them.2 ENDS entered the market without

government regulation as they were produced by small companies, and

they are currently not approved by the United States (US) Food and Drug

Administration (FDA) for smoking cessation.5

Since ENDS entered the market in the US and Europe in 2006,

their surging popularity raises questions regarding long-term safety

compared to CCs.4,6 As future healthcare workers, it is vital to be informed

about the risks associated with e-cigarettes in order to appropriately

counsel and care for patients seeking advice regarding these devices.

Adverse effects of ENDS

While there have been no studies or data showing the long-term effects of

vaping, it is generally accepted that ENDS are less harmful than traditional

smoking.7 Propylene glycol/glycerol are commonly used ingredients in

ENDS liquid. A recent study stated that glycol compounds formed during

ENDS liquid vapourisation generate pulmonary irritants; however, there

has been little research into the safety or carcinogenic effects of these

ingredients when heated and aerosolised, as they may form propylene

oxide, a potential carcinogen.8,9 The levels of toxic and probable

carcinogens vary depending on which ENDS device and liquid are used.10

As a result, there is significant unpredictability regarding potential side

effects associated with various ENDS products. This further highlights the

need to standardise the ingredients included in these products in order to

protect user health and safety. Of note, the Centers for Disease Control

and Prevention (CDC) website clearly states that “E-Cigarettes are not

safe for youth, young adults, pregnant woman or adults who do not

currently use tobacco products”,11 and the American Academy of

perspective

E-cigarettes: a new age of smoking

LAN-LINH TRUONG and SRI SANNIHITA

VATTURI discuss the recent surge in popularity

of ‘vaping’, amid concerns about e-cigarette

use, particularly among young people.

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Pediatrics states that “nicotine may disrupt the formation of circuits in the

brain that control attention and learning”.12

ENDS also carry a risk of burns or other injuries due to device malfunction.

This is owing to the combustible nature of the device, which may result

in burns to the thigh, inner groin, or hand during use or incorrect storage

of the product in users’ pockets.13 On occasion, routes other than

inhalation, such as oral, parenteral, or skin contact, have been known to

cause seizures, anoxic brain injury, lactic acidosis, and even death.13

Cross-sectional and longitudinal analyses have shown that symptoms

of depression were associated with ENDS use.14 One study explored a

dose-dependent relationship between ENDS use and depression, and

revealed that increasing nicotine concentrations within the product

were positively associated with depressive symptoms.14 This is

especially concerning given that many ENDS users are teenagers, and

this sudden increase in ENDS use may lead to an increased incidence

of depression in this population. Low self-esteem is one of the factors

associated with increased vulnerability to depression.15 This is of

particular concern in adolescents, who often become more

self-conscious of their image and perception by peers.

One study found that although 63% of individuals have accurate harm

perceptions about ENDS use relative to CCs, only 9% were accurately

able to identify nicotine as one of the less harmful chemicals found in

cigarettes.2 A separate study reported that a number of the compounds

used in ENDS liquid had various warning codes classified according to

the Danger Globally Harmonized System (GHS) of Classification and

Labelling of Chemicals.16 Forty-one of the most common compounds

used had warning codes, while 11 had danger codes, which further

demonstrates the harmful nature of compounds used in ENDS.16

Additionally, non-smokers exposed to second-hand vapour from

ENDS were found to have tobacco-specific nitrosamine in their

urine.17 This highlights that e-cigarettes affect not only the user, but

indeed those around them as well, similar to CCs. Furthermore, the

effect of flavourings on respiratory function is still unknown.18

One study found that users who previouslyused nicotine-free or low-dose nicotineENDS fluid were now using higher dosesof nicotine, suggesting that they may beon a path towards nicotine dependence.

What are ENDS used for?

Smoking cessation

ENDS have the ability to replicate the pharmacological and

sensorimotor aspects of CCs.4 As a result, one of the most commonly

reported reasons for using ENDS is to aid smoking cessation.1,4 The

majority of studies analysing ENDS use for smoking cessation have no

evidence to confirm or deny its effectiveness; therefore, it cannot be

recommended as a tool to aid those attempting to quit.1

Two separate studies have shown that ENDS users were twice as likely

to still be smoking at the time of follow-up compared to

non-users.19,20 Patients report using ENDS to manage nicotine

cravings and withdrawal; however, the majority of individuals

continue to use both products. The study suggested that ENDS users

were more nicotine dependent than non-users;21 this may be

explained, in part, by the variable nicotine content in ENDS products

and users’ belief that ENDS are less harmful than CCs, leading to

increased ENDS use. Despite decreased CC use, low levels of cigarette

smoking are still associated with significant health risk.21 In addition,

the nicotine contained in ENDS is vaporised and thus absorbed by the

body within seconds, similar to CCs and significantly faster than

nicotine replacement products intended to aid smoking cessation

such as chewing gum or patches.3,4 As a result, ENDS have potent

addictive properties, which are most pronounced in teenagers.3,5

Weight loss

Nicotine, as found in both CC and ENDS products, has

appetite-suppressant effects and can help curb cravings for sweet

foods.22 Smoking has been shown to increase resting energy

expenditure and induce an acute anorexic effect, with increasing doses

of nicotine being positively associated with satiety.23,24 In addition, the

behaviour of smoking e-cigarettes, like traditional cigarettes, can be

used as a distraction from or as a substitute for eating.22

Unique to ENDS is a wide array of flavoured vaping liquids, some of

which mimic high-calorie or high-fat foods and beverages that an

individual may crave; this may help those attempting to lose weight to

comply with a restricted diet.25 Some companies specifically market

ENDS for weight loss. For example, Vapor Diet is “USA’s hottest diet,”

enticing customers to purchase ENDS liquid in indulgent flavours such

as pizza, cupcakes, and cocktails, alongside phrases such as “zero

calories, zero guilt, tastes like you are eating your favourite foods”.25

Vaportrim encourages users to “inhale flavour, curb cravings, lose

weight”.25 These novel and unique features may be enticing to those

looking for an alternative to the traditional methods of weight loss.

The influence of e-cigarettes on young people

Pepper et al. reported that the most common reasons adolescents

experimented with ENDS were curiosity (54.4%), appealing flavours

(43.8%), and the influence of family or friends (31.6%).26 Peers are

the major source for ENDS procurement in teenagers.27 By design,

ENDS are easier to use and share among friends compared to CCs,

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further contributing to their rising popularity.28 In fact, teenagers

account for over 70% of ENDS sales in the US.29

In particular, the willingness of middle school and high school

students to experiment with ENDS was aided by the product’s easy

availability at malls and convenience stores.26 Adolescents are

increasingly exposed to ENDS in various locations including petrol

stations, shopping centres, magazines, and online resources.28 ENDS

companies have also commenced aggressive marketing campaigns

on popular websites such as Facebook, Instagram, and YouTube.30

This highlights the importance of closely monitoring how marketing

affects ENDS use, and the influence of social media on young people.

Other factors that drive vaping include ENDS being perceived as

“cool” and being associated with a positive social image through

experimenting with flavours or performing “smoke tricks”.26

Younger individuals are also at higher risk of being misinformed about

the harms associated with nicotine and ENDS. Indeed, young people

believe ENDS are less harmful, cheaper, and better smelling than

CCs.26 There are no ashes or ash trays to clean up, and because the

odour does not linger, a vaping habit can easily be hidden from

parents and teachers.26 While family use of ENDS is associated with

more accurate harm perceptions, it is also associated with increased

likelihood of ENDS use among young people.2

Young people believe ENDS are less harmful, cheaper, and better

smelling than CCs.

Krishnan-Sarin et al. discovered that many adolescents reported ENDS use

as their first tobacco product.28 ENDS are the leading tobacco product

used by young people in the US, with over 80% of these users claiming

they were initially drawn to the product by the wide variety of liquid

flavours.25,27 However, ENDS are perceived as being less satisfying than

CCs.26 Alarmingly, one study found that, upon follow-up, users who

previously used nicotine-free or low-dose nicotine ENDS fluid were now

using higher doses of nicotine, suggesting that they may be on a path

towards nicotine dependence.28,31 This further perpetuates the concern

that ENDS may be a gateway to traditional smoking.

Current guidelines and safeguards

At present, one must be at least 18 years of age to legally purchase ENDS

cartridges in the UK.32 The European Union (EU) limits the amount of

nicotine contained in each ENDS device, but the US does not, meaning

that a varying amount of nicotine may be contained in each device.33

However, following pressure from the FDA, Juul Labs (the company that

manufactures the popular Juul e-cigarettes) announced that it would

stop its social media promotions and suspend sales of certain flavours.34

In addition, the EU and Canada restrict ENDS advertising to young

people; the EU requires graphic health warnings, while Canada bans

confectionary ENDS flavours in an attempt to deter adolescents.35

Conclusion

Nearly everywhere you look, whether an ad on your phone or at the bus

stop, or a newspaper headline, the subject of ENDS will appear.

E-cigarettes are undeniably popular, as both a topic for debate and a

gadget for smoking, and there is a growing divide between ENDS

supporters and critics. Federal and local policies addressing adolescents’

access to ENDS, as well as programmes to prevent an exponential rise

in ENDS use among young people, are urgently needed.28 The rapid

emergence of the ENDS industry must be met with an informed public

health response. Research on product design, exposure to toxins and

carcinogens, metabolic effects, initiation of young people, and the role

of ENDS in smoking cessation is needed to counteract deceptive

marketing and inform regulatory changes.30

Concurrently, medical education should be updated to reflect and

accommodate the ever-changing trends in society and healthcare. As new

products and habits gain popularity, there must be concomitant

amendments to the medical curriculum to prepare future healthcare

professionals for scenarios they may encounter in everyday clinical practice.

perspective

References

1. Unger M, Unger DW. E-cigarettes/electronic nicotine delivery systems: a word

of caution on health and new product development. J Thorac Dis.

2018;10(Suppl. 22):S2588-s92.

2. East K, Brose LS, McNeill A, Cheeseman H, Arnott D, Hitchman SC. Harm

perceptions of electronic cigarettes and nicotine: A nationally representative

cross-sectional survey of young people in Great Britain. Drug Alcohol Depend.

2018;192:257-63.

3. Grana R, Benowitz N, Glantz SA. E-cigarettes: a scientific review. Circulation.

2014;129(19):1972-86.

4. Cahn Z, Siegel M. Electronic cigarettes as a harm reduction strategy for

tobacco control: a step forward or a repeat of past mistakes? J Public Health

Policy. 2011;32(1):16-31.

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perspective

5. Ebbert JO, Agunwamba AA, Rutten LJ. Counseling patients on the use of

electronic cigarettes. Mayo Clin Proc. 2015;90(1):128-34.

6. Hajek P, Etter JF, Benowitz N, Eissenberg T, McRobbie H. Electronic cigarettes:

review of use, content, safety, effects on smokers and potential for harm and

benefit. Addiction. 2014;109(11):1801-10.

7. Britton J, Arnott D, McNeill A, Hopkinson N. Nicotine without smoke –

putting electronic cigarettes in context. BMJ. 2016;353:i1745.

8. Erythropel HC, Jabba SV, DeWinter TM, Mendizabal M, Anastas PT, Jordt SE et

al. Formation of flavorant-propylene glycol adducts with novel toxicological

properties in chemically unstable e-cigarette liquids. Nicotine Tob Res. 2018;Oct 18.

9. Laino T, Tuma C, Moor P, Martin E, Stolz S, Curioni A. Mechanisms of propylene

glycol and triacetin pyrolysis. Journal Phys Chem A. 2012;116(18):4602-9.

10. Kosmider L, Sobczak A, Fik M, Knysak J, Zaciera M, Kurek J et al. Carbonyl

compounds in electronic cigarette vapors: effects of nicotine solvent and

battery output voltage. Nicotine Tob Research. 2014;16(10):1319-26.

11. Centers for Disease Control and Prevention. About Electronic Cigarettes

(E-Cigarettes). 2018. [Internet]. [updated 2018 October 23]. Available from:

https://www.cdc.gov/tobacco/basic_information/e-cigarettes/

about-e-cigarettes.html.

12. American Academy of Pediatrics. Section on Tobacco Control [press release].

Itasca, Illinois, 2018.

13. National Academies of Sciences. Public Health Consequences of E-Cigarettes.

Stratton K, Kwan LY, Eaton DL (eds.). Washington, DC; The National

Academies Press, 2018: 774p.

14. Wiernik E, Airagnes G, Lequy E, Gomajee R, Melchior M, Le Faou AL et al.

Electronic cigarette use is associated with depressive symptoms among

smokers and former smokers: Cross-sectional and longitudinal findings from

the Constances cohort. Addict Beh. 2018;90:85-91.

15. Masselink M, Van Roekel E, Oldehinkel AJ. Self-esteem in early adolescence as

predictor of depressive symptoms in late adolescence and early adulthood:

the mediating role of motivational and social factors. J Youth Adolesc.

2018;47(5):932-46.

16. Girvalaki C, Tzatzarakis M, Kyriakos CN, Vardavas AI, Stivaktakis PD, Kavvalakis

M et al. Composition and chemical health hazards of the most common

electronic cigarette liquids in nine European countries. Inhal Toxicol. 2018:1-9.

17. Martinez-Sanchez JM, Ballbe M, Perez-Ortuno R, Fu M, Sureda X, Pascual JA

et al. Secondhand exposure to aerosol from electronic cigarettes: pilot study

of assessment of tobacco-specific nitrosamine (NNAL) in urine. Gac Sanit. 2018.

18. Barrington-Trimis JL, Samet JM, McConnell R. Flavorings in electronic

cigarettes: an unrecognized respiratory health hazard? JAMA.

2014;312(23):2493-4.

19. QuickStats: Cigarette Smoking Status Among Current Adult E-cigarette Users,

by Age Group – National Health Interview Survey, United States, 2015. 2015.

Morb Mortal Wkly Rep. 2018;65(42):1177.

20. Borderud SP, Li Y, Burkhalter JE, Sheffer CE, Ostroff JS. Electronic cigarette use

among patients with cancer: characteristics of electronic cigarette users and

their smoking cessation outcomes. Cancer. 2014;120(22):3527-35.

21. Inoue-Choi M, Liao LM, Reyes-Guzman C, Hartge P, Caporaso N, Freedman

ND. Association of long-term, low-intensity smoking with all-cause and

cause-specific mortality in the National Institutes of Health-AARP Diet and

Health Study. JAMA Intern Med. 2017;177(1):87-95.

22. Kovacs MA, Correa JB, Brandon TH. Smoking as alternative to eating among

restrained eaters: effect of food prime on young adult female smokers. Health

Psychol. 2014;33(10):1174-84.

23. Hofstetter A, Schutz Y, Jequier E, Wahren J. Increased 24-hour energy

expenditure in cigarette smokers. N Engl J Med. 1986;314(2):79-82.

24. Jessen A, Buemann B, Toubro S, Skovgaard IM, Astrup A. The

appetite-suppressant effect of nicotine is enhanced by caffeine. Diabetes Obes

Metab. 2005;7(4):327-33.

25. Kong G, Morean ME, Cavallo DA, Camenga DR, Krishnan-Sarin S. Reasons for

electronic cigarette experimentation and discontinuation among adolescents

and young adults. Nicotine Tob Res. 2015;17(7):847-54.

26. Pepper JK, Ribisl KM, Emery SL, Brewer NT. Reasons for starting and stopping

electronic cigarette use. Int J Environ Res Public Health. 2014;11(10):10345-61.

27. Jamal A, Gentzke A, Hu SS, Cullen KA, Apelberg BJ, Homa DM et al. Tobacco

use among middle and high school students – United States, 2011-2016.

MMWR Morb Mortal Wkly Rep. 2017;66(23):597-603.

28. Krishnan-Sarin S, Morean ME, Camenga DR, Cavallo DA, Kong G. E-cigarette

use among high school and middle school adolescents in Connecticut.

Nicotine Tob Research. 2015;17(7):810-8.

29. Bright J. The price of cool: a teenager, a Juul and nicotine addiction. The New

York Times, November 16, 2018.

30. Noel JK, Rees VW, Connolly GN. Electronic cigarettes: a new ‘tobacco’

industry? Tob Control. 2011;20(1):81.

31. Siqueira LM. Nicotine and tobacco as substances of abuse in children and

adolescents. Pediatrics. 2017;139(1).

32. Rough E, Barber S. The regulation of e-cigarettes. House of Commons Library.

2017:4.

33. European Commission. Revision of the Tobacco Products Directive. 2016.


http://ec.europa.eu/health/tobacco/products/revision/index_en.htm.

34. Kaplan S, Hoffman J. Juul suspends selling most e-cigarette flavors in stores.

The New York Times, November 13, 2018.

35. Prochaska JJ. The public health consequences of e-cigarettes: a review by the

National Academies of Sciences. A call for more research, a need for

regulatory action. Addiction. 2018; Oct 22.


Introduction

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that initiates

catabolism of the essential amino acid tryptophan. Early research on

IDO has focused on its role in preventing maternal T cell rejection of

the foetus in pregnancy by inducing T cell tolerance of the allogeneic

foetus.1 When applied to the study of immuno-oncology, it has been

observed that IDO is overexpressed in multiple tumour groups,

including ovarian cancer, colon cancer, and melanoma. Effectively,

cancer cells can manipulate IDO activity to promote local tolerance

and enable immune evasion.2 A limited number of IDO inhibitors

have been discovered. One IDO-1 inhibitor (epacadostat) is currently

in phase III trials for malignant melanoma.2 In research preceding this

study, novel compounds possessing IDO inhibition ability were

discovered, as depicted in Figure 1. Moieties of R1 and R2 were

explored chemically and a number of analogues prepared. The aim

of this study was to assess the inhibition rates of these compounds

on the IDO enzyme and their anti-proliferative effects on cancer cell

lines.

Methods

Enzymatic assays were performed to establish the inhibition rates of

the compounds on IDO during in vitro tryptophan metabolism. For

the cell-based analysis, epidermoid carcinoma cells were first

cultured and then treated with the test inhibitors. Following

treatment, cell viability assays were performed to determine the

cytotoxic and anti-proliferative effects of each compound on the

cancer cell lines.3

Results

The enzymatic assays demonstrated satisfactory IDO inhibition rates

in three of the new compounds tested. It was hypothesised that the

cell-based assays would demonstrate corresponding anti-proliferative

effects on the cell lines; however, the IC50 was not reached in the

cell-based assays for the inhibitors tested. Since IDO inhibition was

achieved with three different compounds in the enzymatic assays, it

is presumed that the viability of the cell cultures was suboptimal, thus

accounting for the inconsistent findings in the cell-based studies.

Conclusion

Three novel IDO enzyme inhibiting compounds were discovered,

with a proven satisfactory inhibition rate on the metabolism of

tryptophan in vitro. Further cell-based studies are needed in order to

ascertain the anti-proliferative effects of these compounds and to

expand upon the role of IDO inhibition therapy in immuno-oncology.

Acknowledgements

The author wishes to acknowledge the RCSI Research Summer School

for the funding provided to undertake this research.

abstract

Novel developments in cancer immunotherapy:an analysis of compounds that inhibitindoleamine 2,3-dioxygenaseClaire Conlon,1 Xu Lumei,2 Prof. Chunhua Qiao2

1RCSI medical student, 2College of Pharmaceuticals, Soochow University, China

FIGURE 1: Replica of IDO inhibitor under investigation.

References

1. Munn DH, Zhou M, Attwood JT, Bonarev I, Conway SJ, Marshall B et al.

Prevention of allogeneic fetal rejection by tryptophan catabolism. Science.

1998;281(5380):1191-3.

2. Yue EW, Sparks R, Polam P, Modi D, Douty B, Wayland B et al. INCB24360

(epacadostat), a highly potent and selective indoleamine-2,3-dioxygenase

1 (IDO1) inhibitor for immuno-oncology. ACS Med Chem Lett.

2017;8:486-91.

3. Van Meerloo J, Kaspers GJ, Cloos J. Cell sensitivity assays: the MTT assay.

Methods Mol Biol. 2011;731:237-45.

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O

R1N

NH

R2

X


abstract

Volume 12: Number 1. 2019 | Page 137

Introduction

Chronic wound infections fail to proceed through the normal phases

of healing in an orderly and timely manner. Evidence suggests that

chronic wound infections often involve biofilms produced by

Staphylococcus aureus and Pseudomonas aeruginosa.1 Bacterial biofilms

are innately resistant to many host immune responses and various

antibiotics. Cold air plasma (CAP) may be an effective therapeutic

alternative to eradicate biofilms within chronic wounds and accelerate

the tissue repair process.2 This study aimed to investigate the efficacy

of CAP for eradicating bacterial biofilms grown under simulated

wound conditions.

Methods

Biofilms of methicillin-sensitive S. aureus (MSSA) strain SH1000,

methicillin-resistant S. aureus (MRSA) strain USA300, and a P. aeruginosa

(PA) strain were grown in simulated wound fluid composed of 50%

foetal calf serum and 50% physiological NaCl in 0.1% peptone water.

The strains were grown in a 96-well microtire plate at 37ºC for either 24

or 48 hours. Each test well was preconditioned with collagen prior to

inoculation. Polymicrobial biofilms composed of MSSA plus PA, or MRSA

plus PA, were grown under the same conditions. Biofilms were stained

with crystal violet, and the absorbance of stained adhered cells was

measured at 492nm. Biofilms were either left untreated (control) or

treated with CAP for 90 seconds, ciprofloxacin (2mg/ml) for 24 hours,

or 30% ethanol (positive control) for 24 hours. Following treatments, a

Resazurin assay was used to determine biofilm viability.

Results

All bacterial strains were biofilm positive under these growth

conditions. However, polymicrobial biofilms required longer growth

incubation. CAP treatment for 90 seconds resulted in a 70% and 53%

reduction in MSSA and MRSA biofilm viability, respectively. In

comparison, a 23% and 33% reduction in MSSA and MRSA biofilm

viability, respectively, was seen following treatment with

ciprofloxacin. PA biofilms, mixed biofilms of MSSA plus PA, and

biofilms of MRSA plus PA were more susceptible to treatment with

ciprofloxacin than CAP.

Conclusion

CAP may be an effective alternative in the treatment of chronic

wound infections when MSSA or MRSA is the causative pathogen.

Ciprofloxacin appears to be more effective when P. aeruginosa

biofilms are involved. However, further investigations are required to

determine the benefits of using CAP to treat chronic wound infections

over routinely used antibiotics.

Eradicating bacterial biofilms with cold airplasma under simulated wound conditions

Elaine Tan,1 Dr Stephen Daniels,2 Prof. Hilary Humphreys,1,3 Dr Niall Stevens1

1Department of Clinical Microbiology, RCSI Education & Research Centre, Beaumont Hospital, Dublin

2National Centre for Plasma Science and Technology, Dublin City University

3Department of Microbiology, Beaumont Hospital, Dublin

References

1. Serra R, Grande R, Butrico L, Rossi A, Settimio UF, Caroleo B et al. Chronic

wound infections: the role of Pseudomonas aeruginosa and Staphylococcus

aureus. Expert Rev Anti Infect Ther. 2015;13(5):605-13.

2. Tanaka H, Nakamura K, Mizuno M, Ishikawa K, Takeda K, Kajiyama H et

al. Non-thermal atmospheric pressure plasma activates lactate in Ringer’s

solution for anti-tumor effects. Sci Rep. 2016;6:36282.

RCSIsmj


abstract

Introduction

Cystic fibrosis (CF) is characterised by recurring pulmonary microbial

colonisation and neutrophil-mediated inflammation. This results in

formation of thick dehydrated mucus secretions, which impair mucociliary

clearance and obstruct airways, forming a breeding ground for

pathogens, namely Pseudomonas aeruginosa and Staphylococcus aureus.

However, the neutrophil-mediated inflammation fails to effectively

eradicate these microbes from the CF lung.1 It is hypothesised that this is

due to abnormal pH regulation within phagosomes in CF, causing

sustained alkalinisation following phagocytosis, which impairs bactericidal

activity.2 The aim of this study was to investigate the impact of this

environment on the antimicrobial activity of primary granule proteins,

α-defensin and neutrophil elastase (NE), against P. aeruginosa and S. aureus.

Methods

The effect of pH on α-defensin and NE activity was assessed usingbactericidal assays at various pH levels. P. aeruginosa (PAO1) was treated

with 2.5µg/ml or 10µg/ml of α-defensin, or 10µg/ml of NE, for 20minutes at 37°C. S. aureus (8325-4) was treated with α-defensin under thesame conditions. As NE is only effective against gram-negative bacteria, S.

aureus was not treated with NE.3 Serial dilutions were carried out before

plating the samples in triplicate onto lysogeny broth (LB) agar and

incubated overnight. Colony-forming units (CFUs) were counted and

percentage survival was calculated relative to controls at each pH tested. The

effect of pH on NE activity was determined using a fluorescence resonance

energy transfer (FRET) assay. Statistical significance was determined using a

one-way ANOVA and Bonferroni's post-test in Graph Pad Prism, version 5.0.

Results

The antimicrobial effect of α-defensin is optimal at a low pH (5.5) (n=3,p<0.0023). α-defensin was more effective against P. aeruginosa than

against S. aureus (Figures 1 and 2). Interestingly, NE showed significant

activity at a more alkaline pH, between 8.0 and 6.5 (n=3, p=0.0001), but

had no antimicrobial effect on P. aeruginosa.

Discussion

This study found α-defensin to be highly effective against P. aeruginosa atan acidic pH of 5.5. However, the alkaline pH of the CF phagosome does

not support α-defensin antimicrobial activity. S. aureus remains resistant toα-defensin even at increased dosage. While NE is most active at thepresent CF phagosome pH, it had no bactericidal effect on P. aeruginosa.

These findings demonstrate the significance of CF phagosomal pH on

bactericidal activity; future therapeutic strategies should consider

optimising neutrophil pH for enhanced antimicrobial activity.

An aberrant phagosomal pH impairs neutrophilmicrobial killing in cystic fibrosisSaw Le Er (Stephanie), Karen McQuillan, Dr Emer Reeves

Royal College of Surgeons in Ireland

References

1. Rada B. Interactions between neutrophils and Pseudomonas aeruginosa in

cystic fibrosis. Pathogens. 2017;6(1):10.

2. Browne N, White MM, Milner M et al. Reduced HVCN1 in neutrophils of

individuals with cystic fibrosis alters phagosomal pH and degranulation.

Am J Resp Crit Care Med. 2017;195:A1272.

3. Moore G, Knight G, Blann A. Haematology. New York; United States, 2010.

RCSIsmj

FIGURE 1: Survival of Pseudomonas aeruginosa (PAO1) treated with α-defensin(2.5µg/ml) at varying pH levels.

FIGURE 2: Survival of Staphylococcus aureus (8325-4) treated with α-defensin(10µg/ml) at varying pH levels.

100

80

60

40

20

0 Ctrl 5.5 6.0 6.5 7.5 8.0

PH

% survival of P. aerug

inos

a

*

100

80

60

40

20

0 Ctrl 5.5 6.0 6.5 7.5 8.0

PH

% survival of S. aureu

s

*


abstract

Introduction

Over-encapsulation is a technique used to conceal the identity of a

tablet for blinding in randomised controlled trials. It involves inserting

the tablet into an opaque capsule shell along with a backfill excipient

to prevent rattling.1 Clinical investigators must provide evidence that

over-encapsulation does not alter stability for the duration of the

product’s shelf life.2 This study assessed the effect of

over-encapsulation on long-term product storage and active

medication release from modified penicillin V tablets.

Methods

Penicillin V tablets were over-encapsulated in hard gelatin capsules

with a set quantity of backfill talc powder. Batches of unmodified

tablets (positive control) and over-encapsulated tablets (OETs,

modified tablets) were stored for 0, 1, 2, 3, and 6 months (Time 0, 1,

2, 3, 6) at accelerated storage conditions (40 ± 2°C, relative humidity:

75 ± 5%), or for 0 and 12 months in ambient storage conditions.3

Disintegration and dissolution testing was performed according to

the European Pharmacopoeia. OETs modified with hydroxypropyl

methylcellulose (HPMC) backfill were used as a negative control.

Results

There was 60-90% release of penicillin V during dissolution testing

between 5 and 15 minutes from Time 0, 1, and 2 unmodified tablets

stored under accelerated conditions. There was a lag in release

between unmodified tablets and OETs. Release from the Time 0, 1,

and 2 OETs was nominal at 0 and 5 minutes, 30-50% at 15 minutes,

and >90% at 30 minutes. There was complete release of penicillin V

from both unmodified tablets and OETs stored for 12 months.

Interestingly, penicillin release was slower from unmodified tablets

compared to OETs at 15 minutes. Disintegration times for both

unmodified tablets and OETs were acceptable for compendial

standards at 5 and 11 minutes, respectively.

Discussion

Penicillin V release from unmodified tablets and OETs under

accelerated storage conditions was not significantly affected

according to regulatory specification. Release was more gradual from

the Time 0, 1, and 2 OETs compared to OETs stored for 12 months.

However, compendial release specification was met for both

formulations. It is possible that, under certain conditions, the slight

difference in release results in a lag time to onset of action. This study

shows, for the first time, that inappropriate selection of high-viscosity

backfill impedes optimal release of penicillin V from an

over-encapsulated formulation, highlighting the importance of

backfill selection as a critical pharmacologic parameter.

Effect of long-term storage on disintegrationand dissolution of over-encapsulated penicillin V tabletsJoseph Saleh,1 Dr Sam Maher,2 Dr Abel Wakai,3 Mr John C. Hayden2

1RCSI pharmacy student

2Department of Pharmacy, Royal College of Surgeons in Ireland

3Beaumont Hospital, Dublin

References

1. Wan M, Orlu-Gul M, Legay H, Tuleu C. Blinding in pharmacological trials:

the devil is in the details. Arch Dis Child. 2013;98:656-9.

2. Huynh-Ba K, Aubry A. Analytical development strategies for comparator

products. Am Pharm Rev. 2003;6(2):92-7.

3. Boland F, Quirke M, Gannon B et al. The Penicillin for the Emergency

Department Outpatient treatment of CELLulitis (PEDOCELL) trial: update

to the study protocol and detailed statistical analysis plan (SAP). Trials.

2017;18(1):391.

RCSIsmj

[email protected]@rcsi.iewww.rcsismj.com.

RCSIRoyal College of Surgeons in IrelandStudent Medical Journal

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