Midlands medicine May 2017 Volume 28 Issue 3

MIDLANDS MEDICINE MAY 2017

VOLUME 28 - ISSUE No 3

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EDITOR’S NOTES

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THE CHANGING FACE OF MEDICAL SCHOOL ADMISSIONS

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HISTORY REPEATS ITSELF

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TISSUE TYPING AND CROSS MATCHING FOR KIDNEY TRANSPLANTATION

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THE INTERNATIONALISATION PROGRAMME AT KUSoM

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AWARD WINNERS

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NEWS

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VASCULAR QUIZ

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REVIEW: SOME WORKS BY OLIVER SACKS

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WORD-FUN FÜNFZEHNTEN

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INTERESTING IMAGES

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QUIZ ANSWERS AND EXPLANATIONS

Midlands Medicine is the journal of the North Staffordshire Medical Institute, whose purpose is to promote postgraduate medical education and research. The journal was first published in 1969 as the North Staffordshire Medical Institute Journal.

COVER IMAGE Keele medical students Bridget Kemball (year 3) and Aliza Hudda (year 4 intercalating student) alongside their colleagues attending the Winter School at UNESP, Botucatu, in August of 2016. (See related article on internationalisation.)

MIDLANDS MEDICINE

CONTENTS

EDITOR Dr D de Takats

EDITORIAL

ASSISTANT EDITOR Mr C Bolger EDITORIAL BOARD Mr D Gough Dr I Smith Mr D Griffiths Helen Inwood Dr B Davies Clive Gibson Professor Bob McKinley Tracy Hall EDITORIAL ASSISTANT Spencer Smith THE NORTH STAFFORDSHIRE MEDICAL INSTITUTE President: Mr B Carnes Chairman: Professor S O’Brien Honorary Secretary: Mr J Kocierz Honorary Treasurer: Mr M Barnish

Please forward any contributions for consideration by the Midlands Medicine Editorial Board to the Editor c/o Spencer Smith, Editorial assistant.

By email: spencer@nsconferencecentre.co.uk Or by post: North Staffs Medical Institute, Hartshill Road, Hartshill, Stoke-on-Trent ST4 7NY Views expressed are solely those of the author(s) and do not reflect the views of the Midlands Medicine Journal.

All material herein copyright reserved, Midlands Medicine ©2017.

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Midlands Medicine

Volume 28, No 3, May 2017

Editor’s notes The Changing Face of Medical School Admissions Gordon Dent, Natalie A Cope & S Andrew Spencer History Repeats Itself Ian Thornflesh

ORIGINALS Tissue Typing and Cross Matching for Kidney Transplantation Manzur Rahman The Internationalisation Programme at KUSoM Andrew Morris, Owen Davis & Divya Maitreyi Chari

REPORTAGE Award Winners News

ENDPIECES Vascular Quiz Jonathan Charles Review: Some Works by Oliver Sacks Paul Laszlo Word-Fun Fünfzehnten Dominic de Takats Interesting Images Quiz Answers and Explanations

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EDITOR’S NOTES Plan-Do-Study-Act, learning from history, trial and error: ways of learning and remembering feature prominently in this smaller, but concentrated spring issue of Midlands Medicine. Learning in medicine without a change in practice is an empty vessel. Failure to learn rapidly in the face of new threats can be fatal.

We start this issue by starting to learn how we might better select those medical students who might learn well in the future. If you look around you and see only the best, the happiest, kindest and most able people practising as doctors, not a flaw amongst them, you may skip the first article. For those who like their tradition and can’t see anything wrong with just carrying on the same, you too may find the contents herein on the irrelevant side. For those of you wondering how you even begin to tackle a question such as how do you look at people with potentially no directly relevant experience and rank their suitability for study and career that may course on through decades, this first one’s for you. Firstly, for potential medical students, we are to take as given their intellectual ability, and we must additionally seek those with people-centric interactive skills, harmony with NHS values (well you might know, but I always need a little help, so here they are: Working together for patients; Respect and dignity; Commitment to quality of care; Compassion; Improving lives; Everyone counts), with a dollop or two of resilience thrown in. And, of course, you can only judge the success of your chosen entry selection method after a decade or two. A doddle then to come up with, trial, develop, hone, implement and prove your selection method works. If you’re interested in finding out how you start to try anything out in this arena, please do read the article by Gordon Dent, Natalie Cope and Andy Spencer.

As if to hammer home just how slow we can be to learn, Ian Thornflesh looks at the human failure to learn from history and some instances of failure to learn, or, perhaps even sadder, a tendency to forget, lessons from adverse incidents and from the history of medicine. He advocates more curiosity which, in his mind, might save the medical cat and her patients.

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Manzur Rahman, a Specialty Doctor in Nephrology, provides us with a review of immunological assessment prior to kidney transplantation. The more technically minded will have an advantage in following this overview, but many of us will take away an appreciation of the technical skills and quick-wittedness, and attention to detail, that are all necessary in order to correctly assess the risk of transplant rejection. The other point is that this is about likelihood and risk, not about certainty of outcome. How well do we convey such uncertainty to our patients?

Internationalisation: what does it mean? In terms of Keele University School of Medicine it appears to be about looking about, globally, and not looking parochially to the Midlands, the UK or Europe. It seems to be about opening the UK health experience to those from very different health settings, and Keele Students going to study in international health settings, and about generating connectedness from Staffordshire to the world. There’s a significant vision going on here which Andrew Morris, Owen Davis and Professor Chari seek to explain to us. It is also work that the North Staffordshire Medical Institute seeks to support.

The Institute continues to be busy doing what it is meant to do and has been actively supporting Medical Research and Education in the last few months. Please check out our Award Winners feature for details.

We are indebted to Jonathan Charles for our themed Quiz which concentrates largely on the human arterial tree. You probably think you know it all already and that you’ll get a high score, but perhaps it contains the odd curved ball. Why not give it a go? Do it properly, look over the answers and follow-up the references when you’re intrigued and you could be into some selfcertified CPD. If this issue is perhaps a little less densely packed than usual this is because it, as all editions always have been, is reliant on contributions received. For all those that have come in, I am very grateful. That said, I feel that quality of what you have here is very well maintained and I would spur you to give it a thorough reading.

Midlands Medicine

THE CHANGING FACE OF MEDICAL SCHOOL ADMISSIONS Gordon Dent, Director of Admissions, Natalie A Cope, Lecturer in Clinical Education (Psychometrics) and S Andrew Spencer, Deputy Director of Admissions, Keele University School of Medicine In recent years, admission to UK medical schools has been based upon academic performance, biographical data in the form of a personal statement, aptitude tests and a panel interview. Considerable variation in the use and weighting of these elements exists between schools, so applicants are well advised to study admissions websites before applying to get the best fit for their profile.

Selection processes are evolving because there are concerns about fairness and transparency, barriers to social mobility1 and recruiting “clever” doctors who may not have the right attitude to patients. Evaluation of admissions methods against performance at medical school and in the profession is difficult, but these are important questions following well-publicised reports of poor patient care.2 So what changes are possible and what might these achieve?

Outstanding academic performance is already a given.

The only question this raises is the degree of latitude to be afforded to those who have attended poorly performing schools, a necessary consideration to overcome one of the barriers to social mobility.1 Consequently, most medical schools will use contextualised academic data3 to prioritise for interview and adjust offers, as well as providing local courses to support disadvantaged students through the admissions process.

The UK Clinical Aptitude Test (UKCAT)4 was specifically developed to provide an assessment of cognitive skills that would be less likely to favour applicants from private and selective schools. In contrast to other admissions tests, UKCAT does not assess science knowledge but rather focuses on application of comprehension and reasoning skills to statements, problems and puzzles. These skills are presumed to be innate and unteachable, and therefore less prone than academic qualifications to schooling and coaching effects. While UKCAT’s ability to predict medical school performance is marginal5 and some evidence suggests that higher UKCAT marks are related to higher socio-economic status,6 it has been argued that it provides a fairer assessment of suitability for medical Volume 28, No 3, May 2017

study than the use of biographical statements alone.7 One recent innovation is the addition of a situational judgement test which aims to select candidates who will make sound choices in a professional environment.

In common with other selection measures it has its own biases, particularly favouring candidates whose first language is English. The objectivity and reliability of aptitude tests do not in themselves make these more valid than other measures of selection for interview.

Assessment of non-academic attributes needs to consider life experiences, hence the emphasis placed on work experience.3 Traditionally this has been assessed using the personal statement, which has sometimes credited students unduly for hospital and GP shadowing placements that are more readily acquired by students with higher socio-economic status. Some medical schools have introduced an alternative to the personal statement where specific questions about caring experiences are asked.8 Students are advised that what they do themselves and what they learn about caring roles is more important than what they observe; moreover, work experience does not need to be undertaken in healthcare environments, which are often seen as inaccessible to disadvantaged students.

Perhaps the most significant recent change to admissions is the move away from panel interviews to multiple miniinterviews (MMIs). MMIs, were developed in Canada for selection to graduate-entry medicine programmes and focused originally on performance in analysis of scenarios presenting ethical dilemmas. They show high levels of test reliability and significant predictive validity for success in medical study9 which goes a long way to reassure candidates about the fairness of the procedure.

Within the UK, MMIs have evolved to cover a varied range of skills and attributes assessed through face-toface discussion, task performance and role-play. This is particularly important because NHS Employers and Health Education England have introduced valuesbased recruitment (VBR) across the NHS:10 a process intended to ensure the student’s or employee’s values and behaviours align with the principles of the NHS constitution.11 113

As the majority of UK medical graduates will work in the NHS, universities are required to implement VBR within medical student selection. MMIs are well suited to the testing of NHS values and qualify as a methodology for introducing VBR.

Keele University. Entry routes and how to apply, The roles and responsibilities form. http://www.keele.ac.uk/medicine/

mbchb5years/entryrouteshowtoapply/

(accessed 03 Aug 2016)

A GMC-commissioned review of selection practices12 recommended the use of objective aptitude tests and multiple mini-interviews to address inequalities inherent in traditional selection methods and to emphasise selection on the basis of appropriate personal characteristics. The aim of admissions is to select future doctors on the basis of their ability to serve the needs of patients in the NHS. For this reason the assessment of aptitude and values will be increasingly important as the methodology evolves to ensure that these are tested as reliably as possible.

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REFERENCES 1

Social Mobility & Child Poverty Commissions.

State of the Nation 2015: Social Mobility and Child Poverty in Great Britain. London: The Stationery Office 2015: pp 83–106

2

Delamonthe T Repeat after me: “Mid Staffordshire” BMJ (2010) ;340:c188.

3.

Medical Schools Council, Selecting for

Excellence Final Report 2014. http://www. medschools.ac.uk/SiteCollectionDocuments/ Selecting-for-Excellence-Final-Report.pdf

(accessed 03 Aug 2016) 4 UK Clinical Aptitude Test. http://www.ukcat.ac.uk (accessed 03 Aug 2016)

5 McManus IC, Dewberry C, Nicholson S,

Dowell JS, Woolf K and Potts HW Construct level predictive validity of educational attainment

and intellectual aptitude tests in medical student

selection: meta-regression of six UK longitudinal studies BMC Medicine (2013) 11 article 243 6

James D, Yates J and Nicholson S Comparison of A level and UKCAT performance in students applying to UK medical and dental schools in 2006: cohort study BMJ (2010) 349:c478

7

Tiffin PA, Dowell JS, McLachlan JC Widening access to UK medical education for underrepresented socioeconomic groups: modelling the impact of the UKCAT in the 2009 cohort BMJ (2012) 344:e1805

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8

Rees EL, Hawarden AW, Dent G, Hays R, Bates L and Hassell A. Evidence regarding the utility of multiple mini-interview (MMI) for selection to undergraduate health programs: a BEME systematic review (BEME Guide No 37) Med Teach 2016 Vol 38 pp443-55

10 Health Education England. Values Based

Recruitment Framework. 2016. https://www. hee.nhs.uk/sites/default/files/documents/ VBR_Framework%20March%202016.pdf

(accessed 09 Jun 2016) 11 Department of Health, The Handbook to

The NHS Constitution 2015. https://www.gov. uk/government/uploads/system/uploads/ attachment_data/file/474450/NHS_ Constitution_Handbook_v2.pdf

(accessed 03 Aug 2016) 12 Cleland J, Dowell J, McLachlan J et al. Identifying

Best Practice in the Selection of

Medical Students (Literature Review and

Interview Survey) 2012 http://www.gmc-uk. org/Identifying_best_practice_in_the_ selection_of_medical_students.pdf_51119804. pdf ADDRESS FOR CORRESPONDENCE

S Andrew Spencer

Keele University School of Medicine

David Weatherall Building

University Drive Keele

ST5 5BG s.a.spencer@keele.ac.uk

Midlands Medicine

HISTORY REPEATS ITSELF Ian Thornflesh, Commentator

History repeats itself.

It has to, no-one listens.

Steve Turner Many young people today have not learned the lessons of the past just as many older people today will not keep up with technological developments in the coming decade.

This year marks 30 years since the King’s Cross underground station fire. In the wake of the fire and the Fennell report1, smoking bans were enforced throughout the London Underground network, and later at all railway stations. If you are less that 30 years of age such things are history to you, if you are a teenager, such national public disasters as the King’s Cross underground station fire and the Bradford City stadium fire (1985) are probably history somebody else knows about; you are likely blissfully ignorant, which is why no sense of guilt, or shame, of danger, or responsibility crowds in on you as you light up a roll-up on platform two.

Doctors may or may not reflect the society they serve.

In many instances they do not: in less developed settings and in hierarchical societies, doctors may reflect privilege and access to education that eludes the many. In moneyed settings, doctors are sometimes seen as technicians, a service to be accessed as convenient.

(See Eyes Wide Shut, 1999, in which Tom Cruise plays William Harford, a doctor in the US working for a very wealthy man. He is used, treated as a flunkey, disregarded in anything other than matters medical, in which he is, instead, compromised, and regarded as humanly inferior — quite the reverse of the power relationships often seen whereby the highly regarded specialist is a least held in high regard, if not virtually deified, and quite enough to put some off the idea of private practice.)

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In the UK, it is hard to say that the doctors in the NHS reflect accurately the society they serve. In social class terms, it is inevitable, given the educational attainment requirements for medical school entry, that they are drawn from the higher achievers. There is a strong class correlation that follows from this because those that do better at school are drawn disproportionately from the middle and upper classes in the UK and in many societies around the world. Though very many, for reasons which could do with explaining, would wish this were not so, it remains the case that this correlation remains stubbornly evident. Furthermore, the high proportion of non-UK graduates working in the UK means that the ethnic mix in the NHS is more evenly distributed than in the UK as a whole: NHS doctors are perhaps more United Nations than United Kingdom.

AN ORGANISATION WITHOUT A MEMORY Though the staff of the NHS may be more international, and better educated, on average than the nation they serve, all are burdened with human limitations which means that the collectively fail to form An organisation with a memory.2 This 2000 report by an expert group made a series of recommendations following an analysis of critical incidents and near misses. These included a reporting system for capturing such incidents. The hope was to have a universal NHS-wide system which would capture and collate incidents and allow learning from a series of near misses to change practice to prevent actual adverse incidents from happening. This would involve in-depth analysis, leading to understanding of systematic problems, solutions would then be devised and disseminated to all concerned, effectively and never-to-be forgotten. In this world view, the memory aspect rises to supreme importance: once the right lesson is learnt right once, by all, the error, or poor practice, would be thenceforth eliminated. Fat chance.

History repeats itself. It has to no-one listens.

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AUDIT IS DEAD, LONG LIVE QIP For the last several years, the Royal College of Physicians, inter alia, has been championing Quality Improvement methodology and getting medical trainees to do Quality Improvement Projects (QIPs).

This is a response to decades in which Clinical Audit was a key requirement of training doctors and as part of CPD for those in established practice. Clinical Audit, however, continually failed to deliver change in practice, betterment, Quality Improvement. It failed, in other words, to make a difference.3 That’s largely because of the Groundhog Day (1993) effect of the rotation of junior doctors needing to do audit and the failure of their senior colleagues to build on good work.

So, far more often than not, audits against standards were conducted, a note made that standards were not met, recommendations for improvement were made and, then … nothing, but the audit could be repeated a year or two later and all the same findings made again.

This served the trainees well, but not patients. History repeats itself. It has to no-one listens.

We can audit for ever but, if we don’t migrate to QIP, little changes, and slowly. Quality Improvement methodology differs in its approach: the assumption is that you already have in mind the improvement a Clinical audit is likely to come up with, or you just have an idea about how things might be done better. Now you need to try to implement the necessary change and do at least one of two things: either study the impact of the change you successfully made, or work out why the change, despite all best efforts, failed to happen in practice. Then either improve more, or have another go.

HISTORY OF MEDICINE Apparently redundant descriptors hold clues to medical history: Has it occurred to you why we state IPPV (intermittent positive pressure ventilation) instead of simply saying just ventilation? The answer is clearly because something needs to be conveyed more accurately than can be managed by a single term. But what is each element about? Starting with the first term,

‘intermittent’ we can see that is held in contradistinction to the ‘continuous’ of CPAP (continuous positive airways pressure). Or if it was felt the initial ‘I’ was for ‘invasive’ then that would be in contrast to NIV (noninvasive ventilation). What, however, is the need for the term ‘positive’? Is it in distinction to ‘negative’?

Well, yes it is! Negative pressure ventilation in ‘iron lungs’ was widespread in the mid-20th Century to help patients with paresis and paralysis of respiratory muscles during large scale polio outbreaks. If you just ask the question “Why is that term there?” and go looking up the answer, you should come across a vast vista of medical history and knowledge you might not otherwise encounter. That negative pressure ventilation was conceived in the 19th Century, that polio occurred in large outbreaks, that public health needs responsive organisation, and has been doing such things for centuries, that polio vaccination has proven the value of the approach, that “those who cannot remember the past are condemned to repeat it”.4 Similarly, the term CVVHF (continuous veno-venous haemofiltration) is long-winded with purpose. The ‘Continuous’ term at the beginning opposes intermittent haemodialysis.

The ‘veno-venous’ term contrasts with arterio-venous and ‘haemofiltration’ with haemodialysis. Of those it is ‘veno-venous’ that is the window into history; the other distinctions are live. Veno-venous is current practice for haemofiltration and haemodialysis, but the simplest circuit achievable, prior to the invention of blood pumps to generate pressure, were reliant on a patient’s own arterial blood pressure to drive the haemofiltration circuit. Back in the day of glass cannulas and Bunsen tubing and arterio-venous shunts. All very different from today’s technology employing blood pumps and specially designed and manufactured central venous dialysis catheters. And the stories of how the tubing, pumps, anti-coagulants and filters were developed by practical QIP (though more likely referred to as ‘trial and error’ in its time.) Nevertheless, all that history lies there in the redundant explicitness of stating the venovenous within CVVHF just waiting to be discovered by those interested enough to delve.

CURIOUS CATS

REFERENCES

It is all too easy to forget many of the lessons that have been learnt along the way as modern Western medical practice has formed into the entity it is now because the five years at medical school pass in a blur. The amount of medical knowledge, attitudes and skills needed to be assimilated in that time is vast and necessary editing of what might be covered takes place. This means that much that should be known by all medical practitioners simply isn’t covered due to practical time constraints.

1 Investigation into the King’s Cross Underground Fire Desmond Fennell, Department of

Transport, Her Majesty’s Stationery Office,

London 1988

If we can’t cover everything as we teach our medical students, perhaps what we do need to do is to encourage their curiosity, their investigative powers, a forensic attitude to learning, foster in them an inquisitive spirit and provide them with skills to go and find out for themselves: they need to be taught research and critical thinking skills in amongst the wealth of other facts and behaviours. The internet is a vast repository of knowledge to be quarried. Students and doctors need to know it’s not the only source available and that it’s not always a safe and reliable source. But they’ll be in far more danger from uncritically accepting what they are taught (spoon fed) or read than from any misinformation they come across when curious and critical, as they try to understand the background and history to what they’re being taught.

2

An organisation with a memory Report of an expert group on learning from adverse events in the NHS chaired by the Chief Medical Officer Department of Health, The Stationery Office, London 2000

3 www.rcplondon.ac.uk/projects/learning-make difference-ltmd 4

George Santayana, Reason in Common Sense, Volume 1 of Life of Reason (1905)

Nature is immense and complex, but it is not impermeable to the intelligence; we must circle around it, pierce and probe it, look for the opening or make it.

Primo Levi in The periodic Table

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TISSUE TYPING AND CROSS MATCHING FOR KIDNEY TRANSPLANTATION Manzur Rahman, Specialty Doctor, Department of Renal Medicine, UHNM INTRODUCTION Successful organ transplantation has revolutionised medical science in terms of acquiring knowledge through research and its bed side application to the benefit of man. This landmark development which has combined the application of laboratory science and clinical science in a unique way has given back quality life to hundreds of thousands of suffering people over the span of half a century.

The concept of transplantation is not new. The ancient Indian plastic surgeon, Sushruta, and his students reconstructed noses, earlobes and so forth, that were amputated accidentally or as a punitive measure as early as 500 years BCE as mentioned in the Sushruta samhita (ca. 500 BC), his medico–surgical compendium.1 The first recorded transplant of modern era was a autograft of skin from her thigh on a woman’s nose performed

by Carl Bunger of Germany in 1823.1 Following these, many unsuccessful allografts were tried over a long period of time and in 1863 Paul Bert of France demonstrated that tissues transplanted from one person to another is rejected.2 To date rejection has remained the most formidable barrier in tissue transplantation between genetically different individuals.

In 1944 Sir Medawar reported that rejection is immunologically mediated host versus graft response.3 The immune system has developed very effective and intricate mechanisms of self-recognition and tolerance as well as non-self recognition to combat foreign antigens, including tissue from genetically disparate individual of the same species.

ABO blood group antigens are immunogenic and transplant across ABO barriers usually leads to irreversible hyper-acute rejection.4 The other most important immunogenic antigens in the context of transplant rejection are the Human Leukocyte antigens (HLA). The encoding genes are located on chromosome 6 and are inherited in a co-dominant fashion i.e. one allele from each parent. Important are the class I HLA

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molecules A, B and C and class II HLA molecules DR, DP and DQ. Class I molecules are expressed on all nucleated cells while class II molecule expression is restricted to cells such as antigen presenting cells. The mismatches between the donor and recipient HLA are understood to generate most rejection episodes, the mismatched antigen serving as the target in the antibody mediated rejection (AMR). Uncommonly non-HLA antigens may generate rejection response.5 HLA alloantigen can induce transplant immunoreactivity at both humoral (antibody) and cellular (T-lymphocyte) level.

Although immunosuppressive medications can reduce but cannot prevent the chances of rejection and for this reason histocompatibility testing before transplantation remains the cornerstone in donor selection.

Serological HLA Typing Typing has traditionally been done by the Complementdependant cytotoxicity (CDC), a serological test, developed by Terasaki and McClelland in 1964 and remained the standard test for about 30 years.3 Sera containing a wide range of known anti HLA antibodies collected usually from multiparous women (HLAspecific alloantisera) or now prepared commercially (monoclonal anti-HLA antibodies) are used.

Lymphocytes from the individual to be typed are incubated with the sera in small flat bottomed wells of a small plastic tray. Rabbit serum is added as a source of complements and finally a vital dye is added. If antibody to the cell surface antigen is present in a well it binds causing complement activation resulting in the formation of membrane attack complexes causing cell lysis. The vital dye then enters the dead cells staining them, thereby rendering them identifiable under phase contras microscopy. The HLA type is allocated from the pattern of HLA specific antigen antibody reactivity with several different known antibodies.4,7,8 CDC HLA typing provides rapid results which is advantageous in case of deceased donor typing by reducing cold ischaemic time8 but has low resolution and low specificity especially in view of the fact that it cannot identify an ever increasing number of HLA alleles.9,10

Molecular HLA Typing These are DNA based typing based on polymerase chain reaction (PCR). More accurate, they are used more commonly now and define alleles that are not recognized by the CDC method.7 Three methods, Sequence-Specific Primer (PCR-SSP), Sequence-specific Oligonucleotide probes (PCR-SSOP) or sequence-based typing (PCRSBT) are in use. Routinely typing is done for HLA-A, B, C, DR and DQ. These advanced typing techniques allow a high level of resolution in donor-recipient matching providing potentially better transplant outcome.8 HLA Antibody Screening Over the past 4-decade evolution of anti HLA antibody detection from traditional CDC based assay to high resolution flow-cytometry and then to solid-phase assays including the Enzyme-linked immunosorbent assay (ELISA) and Luminex has allowed much better pre-transplant graft and recipient outcome stratification.7 Apart from high resolution screening Luminex technology can identify single acceptable or unacceptable antigens by using single antigen beads (SABs).11 HLA: Human Leukocyte Antigen, ELISA: Enzyme Linked Immunosorbant

Tests routinely carried out as part of renal transplant work up and donor selection are: 1. HLA Typing, also known as Tissue Typing.

2. HLA antibody Screening and identification 3. Pre-transplant Cross matching In this review, various specific techniques for tissue typing and cross matching will be described.

HLA TYPING In kidney transplants the mismatched HLA of donor is recognised by the recipient T cell as non-self and this initiates alloimmune response. Thus identifying degree of mismatch between donor and recipient tissues by HLA typing remain one of the most important risk assessment tools in terms of graft survival. Increasing numbers of HLA mismatches at the A, B and DR loci has been associated with poorer graft and patient survival.

Although this association may seem less important with increasing use of potent immunosuppression this remains essential in deceased donor kidney allocation.6

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I love the English language; people can misunderstand each other for ever.

Alan Ayckbourn

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PRE-TRANSPLANT CROSSMATCH CDC Crossmatch (CDC-XM) and additional CDC-XM CDC-XM has been an essential part of pre-transplant work up ever since Terasaki et al proposed it about 4 decades ago.12 This helps donor selection by identifying the presence of significant pre-formed anti-HLA donor specific antibodies (DSAs) in the serum of the recipient potentially causing hyper acute rejection (HAR) and graft loss.

Isolated donor lymphocytes are separated into T and B cells and incubated with the recipient serum in a multi-well tray (Terasaki tray). Rabbit serum added as a source of complement and a vital dye is added.

Complements are activated in those wells in which the serum has pre-formed antibodies against antigens on donor lymphocyte resulting in cell lysis. The vital dye enters the lysed cells and can be detected under phase contrast microscope.13 The result is scored on the basis of percentage of dead cells from 0 denoting no cell lysis to 8 denoting total lysis. A score of 2 representing about 20% cell lysis is generally taken as a cut-off point for a positive result.4 The main advantage of CDC-XM is that it is less time consuming. Shortcomings are the high degree of false negativity and false positivity. Usually a false negative occurs when antibody titre is low or in the presence of non-complement binding antibody.14

Figure 1, Detection of anti-HLA antibodies- difference between cell based and solid phase assays7

PANEL REACTIVE ANTIBODY (PRA): PRA is the percentage of reactive antibody in recipient serum against a panel of random or selected local potential donor T and B cells.8 The panel composition is variable giving rise to inconsistency in PRA reporting.3 To overcome this calculated PRA (cPRA) was introduced based on the detection of unacceptable HLA antigens in a larger panel of actual donors to which the recipient

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is sensitised.11 This is calculated as the proportion of unacceptable mismatches for a recipient against a panel of 10,000 recent actual deceased donors. cPRA gives more consistent information about the level of a recipient’s sensitisation status (cPRA >85%=highly sensitised) and thus reflecting the transplant possibility.11

Midlands Medicine

A false positive CDC-XM is either due to technical error or the presence of IgM autoantibodies. The presence of auto-antibodies can be detected by performing auto crossmatch in which positive results occur when recipient lymphocytes are cross matched with their own serum. The presence of IgM auto-antibody is confirmed by adding Ditheothreitol (DTT) which denatures IgM resulting in negative crossmatch.3 To improve the sensitivity of CDC-XM anti-human immunoglobulin (AHG) is added. These molecules bind to the DSAs already bound to the cell surface antigens increasing the available FC receptors for the complement’s interaction and cell lysis.15

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Fig 2, The CDC Crossmatch4 Flow cytometry Crossmatch (FCXM) In FCXM Donor T or B cells are incubate with recipient serum to allow binding of the alloantibody, if present, to cell surface HLA antigen. Fluorescein labelled AHG is added which binds to the IgG anti HLA antibody bound to HLA- antigen and becomes detectable by flow cytometry. It is either reported simply as ‘positive’ and ‘negative’ or intensity of the fluorescein is measured and reported as ‘channel shifts’ when above control.4 FCXM is more sensitive and unlike CDC can detect low level of DSAs as well as non-complement binding DSAs. Pre-treatment of donor lymphocyte with pronase reduces false positive FCXM by destroying cell surface proteins other than HLA molecules.3 Many centres do not consider FCXM necessary if a CDC XM is negative and prefer ‘virtual cross match’ which saves time.4

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Virtual Crossmatch (VXM): VXM involves comparison of the donor HLA type with the DSA present in the recipient serum as determined

by Luminex test without going through the time consuming CDC or FCXM.16 This method reduces cold ischaemic time which is beneficial to the recipient in terms of graft function and survival.17 Sensitivity and specificity of DSA detection and as such those of VXM has improved significantly with the advent of Luminex single bead antigen assays. VXM should always include a recent recipient serum (<30 days) to detect the latest antibody profile. VXM can be false positive in presence of very low titer or non-complement binding antibody.

On the other hand, an ever expanding HLA antigen repertoire makes it difficult even for the most sensitive assay to detect all antigens giving false negative VXM requiring careful interpretation. Therefore, whenever VXM is used an early post-transplant wet XM is required.

Cellular crossmatch: Cytokines produced by recipient T cells on coming in contact with donor antigen presenting cells (APCs) are measured. This indicates the level of sensitizations of the mainly T cells against the potential donor HLA antigens.18 CLINICAL CASE SCENARIO A 30-year-old male patient with Chronic Kidney Disease Category G5 had been on haemodialysis for the last 5 years, secondary to lupus nephritis.

There was no history of blood transfusion or previous transplantation.

Transplant Status A deceased donor kidney is offered.

Laboratory Tests: • 1-0-0 mismatch.

• CDC crossmatch reported positive for B and T cell, but FCXM was reported negative for both B and T. • Luminex -SAB did not identify any DSA.

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In this case, with these crossmatch results, it is not safe to transplant before further clarification measures.

The possibilities are that the CDC is falsely positive due to technical problems, or this gentleman may have auto-antibodies. In the context of lupus nephritis the second possibility is highly likely. The auto antibodies are usually IgM as compared to the IgG HLA antibodies.

IgM antibodies are considered of no or insignificant pathological consequences in the context of renal transplantation.4 Unfortunately, CDC-XM cannot differentiate HLA and non-HLA antibodies and for further clarification the following tests are required.

The crossmatch repeated with adding Ditheothreitol (DTT). DTT denatures the IgM and the crossmatch becomes negative.

1. The DTT-CDCXM is interpreted by repeating the test by adding a control agent to the well, usually phosphate-buffered saline (PBS) to control the diluting effect of DTT on the antibodies. This should again give a positive result as PBS does not denature the IgM. 2. To establish the presence of auto antibodies an auto crossmatch should be carried out in which recipient’s serum is cross matched against own lymphocyte. A positive test confirms the presence of auto antibodies.

3. It would be safe to proceed for this transplantation if the DTT crossmatch is negative as the additional information from the positive autocrossmatch would reassure that the presence of IgM autoantibody was the cause of initial positive crossmatch.

Continues on P127

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THE INTERNATIONALISATION PROGRAMME AT KUSoM Andrew Morris, Teaching Fellow specialising in Infectious Diseases, Owen Davis, medical student, and Divya Maitreyi Chari, Professor, and Director of Internationalisation, all from Keele University School of Medicine In the autumn of 1999, in a hospital in Flushing, New York a 60 year-old man was seen for a three-day history of fever, weakness and nausea. He went on to develop proximal muscle weakness requiring mechanical ventilation but recovered. Days later an 80 year-old man presented with similar symptoms, but succumbed to his illness. In doing so, he became the first person in the continental United States to die of West Nile Virus (WNV), a mosquito borne flavivirus typically endemic in East Africa and the Middle East. By season’s end, there had been over 8200 infections in New York State. Historically, there had never been a case of WNV contracted within the USA, but by 2002 there were seasonal outbreaks, with associated fatalities, as far as California and other western states. The physicians treating these patients had no previous training in the diagnosis or management of this condition, nor were specific public health measures in place to cope with it. The rapid spread of a severe viral infection, across one of the most developed nations in the world, at the beginning of the 21st Century, was a cause for serious concern. This also gave cause to consider the potentially serious effects that the emergence of a new infectious agent would have on a population with no pre-existing immunity, and its burden on healthcare systems.

Unfortunately the spread of WNV to the USA was only the tip of the iceberg. As we write, five major insectborne viral disease outbreaks have already emerged during the 21st century: dengue fever, West Nile virus, Chikungunya virus, Zika virus and, most recently, a resurgence of Yellow fever.

to South-East England by as early as 2040, with similar estimates for dengue.1 The global rise in antimicrobial resistance has fuelled the concerns. The World Health Organisation estimates that at current trajectories, the 21st Century will see a post-antimicrobial era.2 In 2016 the UK government’s own report into antimicrobial resistance, chaired by renowned economist Jim O’Neill, has highlighted the huge cost to the NHS, both in terms of human morbidity and hard, pound-value, economics.3

As global travel increases and the world becomes an ever smaller place, the prospect of travellers carrying undetected pathogens increases dramatically. The constant, albeit fiercely-debated, issue of global warming has seen the establishment of disease vectors (such as the Aedes mosquito) in regions much farther North than their traditional ranges. This has led to the recent establishment of conditions such as dengue fever in Mediterranean Europe, unthinkable even thirty years ago. Current estimates predict a return for vivax malaria

The Botucatu Medical School looks for a longlasting partnership with Keele School of Medicine an opportunity to prepare our students for a global and intercultural health environment, improving the quality of our education and research.

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The problem is that these issues do not respect international boundaries, treaties or public outrage. As the current mass movement of peoples across Europe caused by the military and political situations in the Middle-East demonstrates, global health issues have arrived and are knocking at the UK’s doors.

Quotes from our international partners “Tongji University School of Medicine and Keele Medical School identified areas of mutual interests in education and research for collaboration and we are looking forward to build strategic partnership with Keele Medical School.” Dr Hao Zheng, Director of Internationalisation, Tongji Medical School

Professor Silke Weber, Director of Internationalisation, Botucatu Medical School.

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It is imperative then for medical schools to futureproof their doctors’ training to handle the new health issues of the 21st Century; Keele is no exception. As the medical school moves towards Curriculum 2018, updating and reviewing the medical course to ensure it is fit for purpose, it is timely to consider our goals regarding internationalisation. Undoubtedly, there is a critical need to establish global-health teaching throughout the medical curriculum, including development of opportunities for international exchange with medical training centres in regions of the world that are most experienced. This process must be reciprocal. As countries such as Brazil, Indonesia, Russia and China (the so-called BRIC nations) develop their healthcare systems their populations encounter issues associated with ‘westernised’ healthcare, such as diabetes, autoimmune disorders and lifestyle-associated cancers. Without the establishment of international partnerships and global health awareness, UK healthcare risks becoming isolated from the inevitable major developing issues in the next fifty years. Indeed, Lord Crisp’s ‘Global Health Partnerships’ - emphasises the importance of “making it easier for students and trainees to gain experience in an international setting at a time when training is becoming more restrictive”.4

Exchange Students from partner medical schools

As a young medical school, we started a programme of internationalisation in 2015 to address some of these challenges. We recently signed a Memorandum of Understanding with Botucatu Medical School, Brasil and Tongji Medical School, Shanghai. A Tongji Medical School delegation visited us April 2016, followed

by Prof Silke Weber from Botucatu in September 2016. They engaged in wide ranging discussions at the medical school and hospital sites, highlighting bilateral exchange opportunities (including teaching and research exchanges), for clinical and non-clinical staff and medical students (Box 1). The medical school has established a three week exchange programme with multiple hospital placements to allow international students to gain an understanding of special aspects of the UK healthcare system, including within the primary care setting and School of Midwifery. Six students from Brasil and Shanghai have now participated in the programme (Box 2) and the enthusiastic feedback we have received confirms the significant benefits to be gained from such exchanges. The Keele Scool of Medicinel also funded two bursaries for medical students to attend the Winter School on Tropical Diseases, Botucatu in July 2016. The course offered a unique experience for the students to gain first-hand knowledge of diseases and conditions rarely experienced in the UK. Our medical students, Bridget Kemball and Aliza Hudda share their exciting experience with us (Box 3). On the research front, Keele’s INSPIRE research programme, supported by the North Staffordshire Medical Institute, Wellcome Trust and Academy of Medical Sciences contributes to our internationalisation agenda, funding two students to undertake research on Dengue and Zika virus in Brasil. One medical student, Owen Davis writes about his experience, as he gained his first taste of laboratory research (Box 4).

we also had the opportunity to see a variety of patients on the infectious diseases ward and attended numerous clinics including hepatitis, HIV and systemic mycoses clinics. This allowed us to get hands on experience; examining patients, seeing about the impact of the diseases on their lives, and understanding more about the Brazilian healthcare system. One of the highlights of the trip was visiting a leprosy hospital in the nearby city of Bauru.

Leprosy was a disease I previously thought of as being confined to the history books. To see patients suffering with it and learning that it is still a big problem worldwide was an eye opening experience.

We also got to learn about venomous animals, saw a patient with a spider bite and went to a research centre to learn more about the animals and how their venom is being used in the creation of new pharmaceuticals. Another fantastic part of this trip was learning about Brazilian culture and traveling to different parts of Brazil. The Winter School was a fantastic opportunity to learn more about global health, infectious diseases and to meet medical students from a variety of countries to learn from their experiences. It would be wonderful if more opportunities like this were available.

Winter School on Tropical Diseases (UNESP, Botucatu): A Keele medical student perspective.

(From L to R) Mrs Julia Molyneux (Assessments Manager, Keele), Dr Angela Nelmes (Clinical Teaching Fellow, Keele) three students from Botucatu Medical School, two students from Shanghai, Prof. Divya Maitreyi Chari (Director of Internationalisation, Keele), Dr Andrew Morris (Teaching Fellow in Infectious Diseases, Keele)

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This summer we spent 3 weeks in Botucatu, Sao Paolo attending their Winter School on Tropical Diseases. This enabled us to learn about diseases that we rarely come into contact with in the UK ranging from Zika virus disease to paracoccididiodomycosis. As well as having lectures on infectious diseases common in Brazil

Midlands Medicine

Keele medical students Bridget Kemball (year 3) and Aliza Hudda (year 4 intercalating student) alongside their colleagues attending the Winter School at UNESP, Botucatu, in August of 2016.

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Whilst such steps are encouraging, we have a long way to go before we embed a comprehensive programme of international activity into the Keele medical programme. Inevitably, this will require a strong vision and the cooperation of many teams. We have a student cohort with an increasing awareness and interest in Global Health. Our vision must expand to the development of worldwide knowledge exchange partnerships including electronic resources, reciprocal opportunities for placements in primary and secondary care systems, training opportunities via short and long taught courses, electives and other short visits. This needs to go hand in hand with reciprocal research visits for laboratory and clinical projects, joint conference presentations/publications and joint funding bids to ensure the sustainability of the programme. A sustainable Global Health agenda will be central in future-proofing the training of our 21st century doctors, with Keele Medical School’s vision highlighting the importance of international cooperation in meeting the challenges we now face. In light of the predicted benefits, the effort seems more than worthwhile.

INSPIRE research project on Dengue virus in UNESP Mrs. M is sat on the end of her bed, eyes ablaze, describing the pain from her Herpes Zoster infection in vivid detail … “It is so bad” she grimaces “that I’ve not slept in 3 days. The painkillers aren’t helping and the insomnia is making my life a misery”…

The blank look on my face is not because I am a robot devoid of empathy, nor even because I‘m not entirely sure what Herpes Zoster is; I simply don’t understand a word of the barrage of heavily accented Portuguese being fired at me at about 100 miles an hour. It is the morning of my first day on the Infectious Disease Ward at the teaching hospital of Sao Paolo State University (UNESP).

The jetlag is kicking in, patients are crying and I am already starting to wish I’d been less of a miser and shelled out the £39.95 that Rosetta Stone were asking for that online language course. Fortunately Helena, a fellow medical student from Brazil, comes to my rescue, explaining (presumably) that I am a useless Gringo who must have missed the seminar on patient communication (and simultaneously checking blood pressure, writing notes, translating the conversation and soothing Mrs. M, who by now looks close to tears.) I am here as an envoy, the first student to test the waters of

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an exchange programme between students and staff from UNESP and Keele Medical Schools. My time will be split between joining UNESP students for their clinical rotation in infectious disease and completing a lab-based research project on Dengue fever, as part of the INSPIRE medical research programme. The research project; charting regional variations in the gut bacteria composition of Aedes Egypti (the mosquito responsible for the transmission of Dengue Fever) is a very small part of a much larger project looking at novel vector control strategies for a condition that is becoming increasingly problematic in the region.

At present this mostly involves trying not trip over my own shoelaces and draw even more attention to the fact that I am significantly taller, pastier and more linguistically challenged than everybody else in the room. Fortunately my colleagues turn out to be some of the most good-natured people I have ever met, and over the following weeks (with endless patience) they explain strange diseases, rescue me from wandering the warren-like corridors looking for ‘Departmento Haematologia’ and mentor me through a series of challenging lunch orders. They even give me a nickname; ‘Palmito’, which I later find out is a large, white, tasteless vegetable… très cool… Much to my amazement, my Portuguese even improves enough to catch the rough drift of consultations, which are later discussed in detail using a mix of English and hand signals, often with hilarious results. Ever find yourself struggling to explain that you saw a patient with a snake bite in a foreign tongue? Easy! Simply wiggle your hand while making ridiculous hissing sounds, bite your teeth together aggressively and wait for the entire staff room to burst into spontaneous, uncontrollable laughter.

Medical charades and vegetable jokes aside, my time in Brazil has been a valuable insight into the study and practice of medicine in a system other than the NHS. Brazil’s socioeconomic and health profiles also differ significantly to the UK’s and present their own unique set of challenges which must be addressed by the country’s healthcare providers. Despite being one of the fastest growing economies in the world, Brazil is still plagued by inequality and this is reflected in the difference in access to good-quality healthcare between rich and poor. While Brazil does have a ‘national health service’, it is chronically overburdened and underresourced. Most of those who can afford to do so pay for private healthcare, which accounts for

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around 70% of the country’s hospitals. While the teaching hospital at UNESP is a state-run facility that delivers a very high standard of care, this is not replicated throughout the country and it is not unheard of for patients to wait days in a corridor for treatment at less well-resourced public hospitals.

This disparity in access to care as well as the general impact of poverty is evident in the differences in mortality and morbidity between socioeconomic groups. The health of the population varies between regions (infant mortality in the economically deprived north is five times higher than in the more affluent south), but also locally (average male life expectancy in Rio de Janiero’s richest areas is 74, whereas those in the poorest areas can only expect to live to 61).

During my time at UNESP I have felt (variously) happy, sad, inspired, frustrated, confused, enlightened, and at times frankly just ridiculous.

But on the whole it has been an immensely positive experience in terms of personal and professional development, and pretty damn good fun to boot.

I would thoroughly recommend it to anyone with a spare month, an open mind and absolutely no sense of embarrassment whatsoever when mimicking venomous reptiles in front of a room full of consultants.

Keele medical student Owen Davis in the dengue research laboratory (Year 4)

REFERENCES

ADDRESS FOR CORRESPONDENCE

1.

Medlock JM and Leach SA Effect of climate change on vector-borne disease risk in the UK Lancet Infectious Diseases (2015) Vol 15 pp721-30

Professor Divya Maitreyi Chari

Keele University School of Medicine

David Weatherall Building

University Drive Keele

ST5 5BG

2.

Antimicrobial Resistance: Global report on surveillance. World Health Organisation (2014)

3.

Tackling drug-resistant infections globally: Final report and recommendations. The review on antimicrobial resistance. O’Neill, J. (2016)

4.

Global health partnerships: The UK contribution

to health in developing countries Crisp N (2007) Continued from P122 CONCLUSION Human effort to replace a diseased, non-functioning organ with a healthy one from a fellow human being, dead or alive has always been challenged by rejection.

The availability of more effective immunosuppressive agents for induction, maintenance as well as rescue therapy has improved one year graft survival to 92% and 96% in deceased and living donor respectively.19 Desensitisation has allowed transplantation across ABO and HLA incompatibility with good short term but poorer long term outcome.20 In spite of all these advancements, careful donor-recipient pairing by high resolution HLA typing, DSA screening and identification and advanced cross matching and their appropriate interpretation and application remain the cornerstone in improved transplant outcome.

REFERENCES 1 History of Renal Medicine: [Internet].

Renalmed.co.uk. 2017

Available from: http://www.renalmed.co.uk/ history-of/renal-transplant 2 Santoni-Rugiu P and Sykes P A history of plastic surgery (2007) 1st ed. Berlin: Springer

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3 Danovitch G Handbook of kidney transplantation (2012) 5th ed. Philadelphia:

Lippincott Williams & Wilkins 4 Mulley W and KanellisJ Understanding

crossmatch testing in organ transplantation:

A case-based guide for the general nephrologist Nephrology (2011) Vol 16 pp125-33 5 Malhotra P Immunology of Transplant Rejection: Overview, History, Types of Grafts

Available from: http://emedicine.medscape. com/article/432209-overview#a2 6

Terasaki P Humoral Theory of Transplantation.

American Journal of Transplantation (2003) Vol 3 pp665-73

7 Nguyen HD, Williams RL, Wong G and Lim WH. The Evolution of HLA-Matching in

Kidney Transplantation (2013) DOI:

10.5772/54747 Chapter 16 in: Current Issues and Future Direction in Kidney Transplantation

ISBN 978-953-51-0985-3 8 MacPhee I and Fronek J

Handbook of renal and pancreatic transplantation (2012)

1st ed. Hoboken: John Wiley & Sons 127

9

Singh A, Sayegh M and Chadraker A Core concepts in renal transplantation (2011) 1st ed, Springer

10

Schreuder G, Hurley C, Marsh S, Lau M, Fernandez-Vina M, Noreen H et al The HLA Dictionary 2004: a summary of HLA-A, -B, -C, -DRB1/3/4/5 and -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens Tissue Antigens (2005) Vol 65 pp1-55

11

Cecka J Calculated PRA (CPRA): The New Measure of Sensitization for Transplant Candidates Am Journal Trans (2009) Vol 10 pp26-9

12

Patel R and Terasaki P Significance of the Positive Crossmatch Test in Kidney Transplantation New England Journal of Medicine (1969) Vol 280 pp735-39

13

Paul W Fundamental immunology (2003) 5th ed. Lippincott Williams & Wilkins

14

Schlaf G, Pollok-Kopp B, Manzke T, Schurat O and Altermann W Novel solid phase-based ELISA assays contribute to an improved detection of antiHLA antibodies and to an increased reliability of pre- and post-transplant crossmatching Clinical Kidney Journal (2010) Vol 3 pp527-38

15

Altermann W, Seliger B, Sel S, Wendt D and Schlaf G Comparison of the established standard complement-dependent cytotoxicity and flow cytometric crossmatch assays with a novel ELISA-based HLA crossmatch procedure Histology and Histopathology (2006) Vol 21 pp1115-24

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16 Bielmann D, Hönger G, Lutz D, Mihatsch M,

Steiger J and Schaub S

Pretransplant Risk Assessment in Renal

Allograft Recipients Using Virtual Crossmatching

American Journal of Transplantation (2007)

Vol 7 pp626-32 17

Taylor C, Kosmoliaptsis V, Sharples L, Prezzi D, Morgan C et al Ten-Year Experience of Selective Omission of the Pretransplant Crossmatch Test in Deceased Donor Kidney Transplantation Transplantation (2010) Vol 89 pp185-93

18 Augustine J, Siu D, Clemente M, Schulak J,

Heeger P and Hricik D

Pre-Transplant IFN-gamma ELISPOTs Are

Associated with Post-Transplant Renal Function

in African American Renal Transplant Recipients

Am J Trans (2005) Vol 5 pp1971-75 19 Ghanta M, Dreier J, Jacob R and Lee I

Overview of Immunosuppression in Renal Transplantation Chapter 10 in: Current Issues

and Future Direction in Kidney Transplantation

ISBN 978-953-51-0985-3 20

Marfo K, Lu A, Ling M and Akalin E Desensitization Protocols and Their Outcome CJASN (2011) Vol 6 pp922-36

AWARD WINNERS The 2016 North Staffordshire Medical Institute grants to support local medical research were given out in a ceremony on 20th October. Research funding totalling approximately £70,000.00 from the North Staffordshire Medical Institute charitable donations and bequests, including a £25,000 donation from the Denise Coates Foundation, was awarded for medical research projects to be undertaken locally by clinical and academic researchers based in UHNM Trust and Keele University. Awards were made for projects as follows:

Prospective study of vascular complications after radial artery catheterisation to improve patient care Dr C S Kwok, Prof Mamas Mamas, Dr A Large, Prof J Nolan, Mr R Butler, Dr E Holroyd and Dr K Ratib

Towards prediction and prevention of preterm birth – what are the mechanical and biochemical differences in fetal membranes from normal and pre-term premature rupture of membranes (PPROM)?

Dr P Wu, Dr Y Yang and Prof P M S O’Brien

Awarded: £19,451

Awarded: £1,995,700

Assessing human brain slices as ‘benchtop’ injury models

Development and evaluation of a clinical laboratory assay to determine the concentration of glycated haemoglobin from dried blood samples

Prof D Chari, Mr N Tzerakis, Dr C Adams and Mr J Sen Awarded: £20,000 Electronic Quantification of Disorders of the Menstrual cycle for Clinical Care: Validation of PreMentrics Smart Phone Application

Dr C Duff, Prof T Fryer, Prof J Sim, Miss K Stokes and Dr F Hanna Awarded: £7515

Dr D Lavu and Prof P M S O’Brien Awarded: £2,750

And as is also now established, those medical students striving and thriving in their studies received support and encouragement in their success by having their efforts rewarded with the North Staffordshire Medical Institute Prizes (Supported by The Bicentenary Fund), as follows:

Midlands Medicine

The Keele University medical student: Best overall performance in Year 2 – 2015/16: Tatiana Christmas

The North Staffordshire Medical Institute and Chamber of Commerce Public Understanding of Science Prize, 2016 Jessica Bratt

The Keele University medical student: Best overall performance in Year 4 OSCE – 2015/16 Joanne Stock

The John Ramage Prize 2016 Sadaf Jafferbhoy

Volume 28, No 3, May 2017

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NEWS

VASCULAR QUIZ

Keele hosts the prestigious Annual Conference of the Association for Medical Humanities

1) According to NICE guidelines, in non-diabetic patients diagnosed with hypertension what is the target blood pressure?

7) In which of the following patients may you not be able to record an accurate Ankle Brachial Pressure Index (ABPI)?

A) Below 120/70 mmHg B) Below 130/80 mmHg C) Below 130/85 mmHg D) Below 140/80 mmHg E) Below 140/90 mmHg

A) Diabetic patients B) Hypertensive patients C) Obese patients D) Patients with a previous DVT E) Unilateral BKA

2) Which of the following are genetic causes of aortic aneurysms?

8) Fibromuscular Dysplasia (FMD) is a vascular disease that commonly affects which arteries?

A) Aneurysm osteoarthritis syndrome B) Arterial tortuosity syndrome C) Ehlers-Danlos syndrome type IV D) Loeys-Dietz syndrome E) Marfan’s syndrome

A) Abdominal aorta and iliac arteries B) Circle of Willis and intracranial branches C) Coronary arteries and thoracic aorta D) Iliac and femoral arteries E) Renal, extracranial carotid and vertebral

3) Are beta-blockers contraindicated in patients with intermittent claudication?

9) In patients with Marfan’s Syndrome that have thoracic aortic aneurysms, on which of the following drugs should the patient be started?

The annual conference of the Association for Medical Humanities 2017 will be held at Keele University, hosted by the Faculty for Humanities and Social Sciences. The overarching theme is that of Critical Stories in the context of both Humanities and Arts research and production. The conference will include three plenary addresses by Dr Mike Shooter, President of the British Association for Counselling and Psychotherapy CBE, and Professor Mark Jackson, Exeter University.

The programme will feature a reception, dinner, tour and poetry reading at the renowned and historic Josiah Wedgwood Museum on the first night and a reception and banquet at Keele Hall on the second night. Artistic research, music, performance and collaboration lie at the heart of this year’s conference. One session will take place at the New Vic theatre, the first purpose-built theatre in the round in Europe where there will be an art exhibition by a local art group, Shires’ Artists. The venue is ideal for showcasing music and performances relating to the themes of the conference. The Emergency Poet will be available to all delegates on the final day in her repurposed ambulance outside Keele Hall and will conclude the conference with some of her own poetry inspired by the conference events and informal conversations with delegates.

The conference sessions will focus on stories about health, illness and disability across the age ranges and from different cultures with the aim of enhancing clinical practice and academic discourse. The conference will bring together people from different disciplines including academics from the humanities, social sciences, health and education as well as a range of healthcare practitioners and service-users. Differences and similarities in the culture and experiences of these disciplines will create challenges and opportunities for learning from one another not just in the formal sessions but, equally important, at the social events.

The conference is being organised by a local committee chaired by Dr Lisetta Lovett and builds on the growing success of Medical Humanities within the Keele Medical School Undergraduate Curriculum.

4) Which of the following antihypertensive drugs should be avoided in patients with bilateral Atherosclerotic Renal Artery Stenosis?

A) ACE inhibitors B) Beta-blockers C) Calcium channel blockers D) Diuretics E) Eplerenone 5) In patients started on lipid modification therapy for primary prevention of Cardiovascular Disease (CVD), what is the target percent reduction in non-high density lipoprotein (non-HDL) cholesterol levels?

A) >10% B) >20% C) >30% D) >40% E) >50% 6) What percentage of strokes is due to Carotid Artery Disease?

A) 10% B) 15% C) 20% D) 25% E) 33%

Full details of the conference with information on how to book a place are available at the conference web site (tinyurl.com/amhconf) or scan the QR code to get direct to the website.

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Yes or No?

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A) Angiotensin II receptor blocker B) ACE inhibitors C) Beta-blockers D) Calcium channel blockers E) Diuretics 10) Which antiplatelet drug is recommended for first line in patients with peripheral arterial disease (PAD) by NICE? A) Aspirin B) Clopidogrel C) Dipyridamole C) Picotamide D) Prasugrel 11) What percentage of Autosomal Dominant Polycystic Kidney Disease (ADPCKD) patients have intracranial aneurysms?

A) 10% B) 20% C) 30% D) 40% E) 50% 12) Which of the following groups is the NHS AAA screening programme offered to?

A) Males ≥60 and Females ≥65 B) Males ≥65 C) Males and Females ≥65 D) Males ≥60 and Females ≥70 E) Males and Females ≥70

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REVIEW: SOME WORKS BY OLIVER SACKS Paul Laszlo, Consultant Physician GRATITUDE

THE MAN WHO MISTOOK HIS WIFE FOR A HAT

Gratitude: The book is a collection of just four short works, a quartet of essays, the musings of a dying man, published two weeks before his death in 2015.

As his preface to The Man Who Mistook His wife for a Hat states, Oliver Sacks was equally interested in diseases and people. This necessarily means that he finds himself interested in people with diseases, appreciating both the pathology that brings about change and difference to their lives and the effects, the practical personal outworkings, of those pathologically explained manifestations in their daily lives. The means he chooses to bring these cases to life, and into our lives, is through a series of personal stories, recognisable to a medical reader as case histories. As he states, this has been a natural means of medical communication since Hippocrates, and as such he flows in a long and noble tradition.

This is a little book. Short and quick to read, but there is some gravitas too it; it does matter whose words and observations these are, as they mark the passing of one of the great 20th Century characters in English speaking medicine. A man who studied, cared for and cared about his patients, and people, and the human condition. He was also a living contradiction in a number of ways: born and brought up British but he practised his Neurology in the US; steeped in orthodox Judaism, he was secular; he was a physician and a drug addict; he was private but out of the closet; he was conflicted all the while, but ever so grateful for the life he had. This emotion is what he chose to be the title of the book written at the end of his life If you already know Oliver Sacks’ work but know little of the man then this is a book you should read so you can appreciate something of the man who brought us Awakenings and The Man Who Mistook His wife for a Hat; if you are not familiar with these works, then before you watch Awakenings or read The Man Who Mistook His wife for a Hat maybe this book will serve you as a quick introduction to the author and his style and draw you in to enjoy those works more deeply and emphatically.

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AWAKENINGS In charades this would be a book and a film. Awakenings the book was first published in 1973 (and has been reprinted many times since). It took the form of an introduction to Parkinson’s disease, Parkinsonism, and Encephalitis Lethargica, some personal biography and then a case series in the form of a series of case histories, but written from such a human perspective that these were a series of life stories. The effect of levodopa on their Parkinsonian state was described and the dramatic physical expressive awakenings that resulted, sadly to prove ephemeral in many cases due to the development of drug tolerance. The stories were told with such passion and evoked such pathos that an inspired play and a film version followed. The book is characteristically littered with detail, explanations and footnotes, yet has won plaudits for its narrative literary style.

version of himself, Malcolm Sayer, and was played brilliantly by Robin Williams (who, later also brilliantly played a psychiatrist in Good Will Hunting (1997) with Matt Damon as the eponymous troubled youthful savant, and who so tragically suffered mental ill health struggling and failing to deal with a diagnosis of Lewy body dementia.) Robert de Niro also put in one of his best acting performances as a patient, to be considered alongside Jack Nicholson’s performance in One Flew Over the Cuckoo’s Nest (1975).

The 1990 film of the same name was based on the book, but written as a film, doing to the original what that normally means, so Oliver Sacks became a fictionalised

MORE FILMS

Sacks is concerned with humanising the experience of neurology for the reader. This may be particularly important for a neurologist who finds himself interested in cognitive function and inevitably thereby has a glimpse into the psyche, contrasted in his mind with the laboratory scientist or the vet who can equally well analyse the pathology before them but can have no concept of the mind of their subject. Sacks is drawn equally to the mechanical dysfunctions of the brains of his subjects and to the adaptive responses and complex rationalisations of their minds. He paints 25 pictures covering 25 subjects and colours them with wit and passion, a sense of anecdote, compassion and polymathery, littering the book with further explanations, diagrams, references and quotes. For the interested reader, this book lays out a fascinating journey into the human brain and 26 minds, counting the author. For Neurologists, psychologists and psychiatrists, this should be mandatory homework.

Midlands Medicine

If ever any neuroscientist were feeling keen, there is much to read here; should she be feeling lazy, there’s a bunch of neuro-psychiatry films mentioned above that might count as CPD. But mainly they’re just rather good films.

Girl, Interrupted (1999) A Beautiful Mind (2001)

If you don’t mind, it doesn’t matter Jack Benny

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WORD-FUN FÜNFZEHNTEN

left and right, in terms of up and down or fore and aft.

One can have thoughts of some use on themes such as these, no ifs, ands or buts. Guts, brains, bones, heart: all lie in the scope of words of but one part.

Dominic de Takats, Consultant Nephrologist You can see the commonality between English and German in the rendering of 15. Both start with [a contracted derivation of] their five and then run into a reference to ten. In English, ten has become elongated to ‘teen’, perhaps to avoid confusion with ten minutes past five of the clock.

‘Fifteen’ and ‘50’ may be readily confused by a hearer, particularly an audio typist, if great care is not taken by the dictator to annunciate clearly through slowing and syllable stress, or through explanation when dictating (“fifteen – one, five” or “50 – five, O”).

MORE TLAs & FLAs Most three letter abbreviations (TLAs) are acronyms, or initialisms. Pharmaceutically produced erythropoietin drops an ‘i’ and becomes epoietin which, in a nonanacronymistic way enters popular, or at least competitive cycling, culture as Epo (a TLA with a difference). But then an FLA (four letter abbreviation) comes along – CERA (continuous erythropoiesis receptor activator) – which is a different type of drug doing the same job, and a class-by-action needs to be conjured up, hence, ESA (Erythropoiesis Stimulating Agent).

Some of our dearly loved TLAs become ingrained in our psyche and then shared across specialties, and some have a secular life outside medicine. Sometimes the boundaries blur. From a hospital near you: “As a Trust we take the health and wellbeing of our staff very seriously. We are committed to supporting you so that you feel happy and safe at work. It is for this reason that I am pleased to announce the re-launch of our Employee Support Advisors (ESAs). ESAs are just one the support options available to you and are trained volunteers who offer a completely confidential service to staff wishing to discuss a concern. An ESA can listen to any problem, whether it’s in the workplace or at home, and talk you through the support that is available. This can be done either face-to-face or over the phone.” But that wasn’t a particularly original use as it seems likely to have risen from the ashes of the Educational Support Allowance.

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When you see SLE written down, what do you think of? Or is it context driven? For many years it was only possible to think of SLE as Systemic Lupus Erythematosus, a term which merits some explanation.

In three parts, it is perhaps somewhat odd, clunky and difficult to say. For that reason it is either referred to as its TLA, SLE, or as simply Lupus. Lupus is Latin for wolf. Why the disease is named after wolves is far from clear. There are several accounts lying around. One suggesting the disease is metaphorically voraciously destructive like a wolf, much feared in medieval times, another suggesting that the characteristic butterfly pattern facial rash makes the sufferer look as if they had survived a wolf attack, another that it makes the person look like a wolf. Systemic is an easier term to get, because it’s plain English and means what it says: the disease is systemic, by which is meant humeral in mechanism and generalised and widely distributed in its effects. Erythematosus refers to the tendency to develop erythematous (or reddened) rashes. Such a familiar term is the initialism SLE to doctors that they have recycled it for use in medical education and training jargon as Supervised Learning Event. For many younger physicians the chances are that this newer use will become more daily relevant to them than the original sense of the TLA SLE. Rather similarly MRCP (Member of the Royal College of Physicians) stood in splendid isolation until magnetic resonance imaging, fellows of the Royal College of Radiologists, or FRCRs, lighting on something familiar, but not directly affecting them, added Magnetic Resonance Cholangio-Pancreatogram to the medical lexicon.

MONOSYLLABIC MISCHIEF MARCHES ON Last time out, this piece fell short and in it there was a word in two parts. Next comes a form in which that has been fixed*: It is on the cards to write text in which all words have just one part, where not one of them spans two or more parts. And it can all make good sense and not seem too forced; it can be read quite well. Give it some time and you will see that there are ways round some of the hard parts where you think it might not be on to say just what you want to say. Think in terms of Midlands Medicine

To make my point, I could go on and on, but that would be to write for the sake of it. But the truth is that at this point my job is done!

AMBIDEXTROUS, NOT In Latin it’s dexter and sinister for right and left. Due to unevenhandedness and majority rule we see that that these so-called opposites carry very different connotations: dextrous describes those with (literally) good manipulative skills; sinister suggests subjects are … sinister.

Sometimes it is possible to get a little confused between left and right. Apparently more so than East and West and certainly more so than in front or behind, or up or down.

Stage left, right? When looking at radiographs we routinely reverse our reality and place the patient at the centre, referring to the right of the screen as we look at it as the left [of the patient]. This originated as a consequence of technology, a forced fact of the imaging technique, easily coped with, being not at all out with the human experience after millennia of managing the transformation meted by mirrors. But many people are not good at this. And modern digital image manipulation makes so very possible such inversions and rotations that mean it’s always better to check for left/right markers lest the unwary, but silhouette aware, diagnoses dextrocardia or situs invertus unwittingly and erroneously. If unmarked, it is reasonable to assume that the image has been produced in accordance with what is now convention and no longer constraint with the left of the patient to the right of the screen and the right of the patient to the left of the screen, from your perspective as you view it. After all, conventions count for a great deal so we all drive on the left in England whilst they all drive on the right in France. I presume the risk of misdiagnosing dextrocardia as a result of assuming conventional orientation of an unlabelled image is less than doing so on a left-right inverted image labelled as such but disregarded.

At a stroke: more fertile territory for confusion. I get confused, befuddled and consequently distressed when a colleague tells me about a patient’s left sided (or right-sided) stroke because of decussation I have no understanding, when they say that, what they mean, lateralisationally. My clear preference is for a statement from the patient’s perspective of which functions and which sides are affected: “She’s got dysphasia and left arm weakness.” conveys much more. My second preference would be to be told the anatomical territory of the stroke, e.g. “She has a stroke affecting the distribution of the right middle cerebral artery.” Less patient-centric, but still very informative. But tell me a patient has a left sided stroke and at a stroke I’m lost.

Try as I might, I cannot find a medical term for the condition of not being easily, or at all, able to tell one’s left from one’s right. It is a common enough phenomenon, but lacks a specific medical designation, unlike difficulties with mathematics (dyscalculia), with reading (dyslexia), with co-ordinated movements (dyspraxia), or the ability to recognise faces (prosopagnosia).

Are you left any clearer right after this exchange?

“The kidney you had removed was on the left?”

“Right.”

“So the right kidney was taken?”

“Left.”

“The left kidney was taken and the right kidney was left?”

“Left out, right left. Right mate?

“Right left… Right. Got it. Do you mind if I examine your abdomen?

“Your left with a scar on the left. So I was right.”

ADDRESS FOR CORRESPONDENCE

Dr D de Takats

Consultant Nephrologist

The Kidney Unit

Royal Stoke University Hospital

Newcastle Road Stoke-on-Trent

ST4 6QG FURTHER INFORMATION

Volume 28, No 3, May 2017

* www.Howmanysyllables.com/words/fixed

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INTERESTING IMAGES This elderly lady presented to clinic for assessment at an interval of some weeks after the onset of a rash. By the time of her clinic visit, the rash had resolved leaving no clue as to its prior state. At the time the rash was most florid she had blood and protein on dipstick testing of her urine and fleeting AKI Stage 1. By the time of her clinic visit she had ostensibly normal renal excretory function and just non-visible haematuria on dipstick testing of her urine. Her son had these images on his mobile phone, and they were reviewed at the consultation.

Blurred as these images are, they allow the confident diagnosis of the presence of a purpuric rash which, in this clinical context, suggests a working diagnosis of Henoch SchĂśnlein Purpura.

This is an example of telemedicine across time, as well as space, and democratisation of the process as the pictures were taken at the initiative of the patientâ&#x20AC;&#x2122;s family for documentary purposes, in case that should be useful. With ever more sophisticated cameras now incorporated into mobile phones, pictures are more frequently being taken of injuries, wounds or ulcers to document improvement, deterioration or otherwise. This approach is also much more convenient to use than a mirror and a craned neck to show patients their own lesions sited in places inaccessible to their direct gaze.

Pictures supplied by patientâ&#x20AC;&#x2122;s son and used with her permission.

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QUIZ ANSWERS AND EXPLANATIONS 1) E Below 140/90 mmHg According to NICE Hypertension guidelines, you should aim for a target clinic blood pressure below 140/90 mmHg in people with treated hypertension.

This is for patients under 80 years old. Patients who are older than 80 the target changes to 150/90 mmHg.1 2) All of the syndromes listed can cause aortic aneurysms. In the literature, these have been described as syndromic causes of aortic aneurysms and are associated with abnormalities of other organ systems.

These are often diagnosed by gene testing or their dysmorphic characteristics.2 3) No Contrary to received wisdom, beta blockers are not contraindicated in patients with intermittent claudication. The latest Cochrane systematic review concluded that there is currently no evidence to suggest that beta blockers significantly worsen walking time to claudication, walking distance, calf blood flow, calf vascular resistance or skin temperature in patients with intermittent claudication, when compared to placebo.3 4) A ACE inhibitors In patients with bilateral ARAS, starting them on ACE inhibitor risks significant AKI. The presence of renal impairment after induction of ACE inhibitors is a highly sensitive test for the presence of bilateral ARAS.4 5) D >40% NICE guidance suggests measuring non-HDL cholesterol levels after 3 months of initiating statin therapy for primary prevention. The aim of treatment is to achieve a greater than 40% reduction in baseline non-HDL cholesterol levels.5 6) C 20% The British Heart Foundation states that Carotid Artery Disease is a major cause of stroke, accounting for 20 in every 100 cases.6

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7) A Diabetic patients Although a reliable test, there are some limitations when using the ABPI. Falsely raised values may be associated with arterial incompressibility at the ankle, secondary to calcification of the arterial wall. This is often seen in patients with diabetes but may also affect renal patients and the elderly.7,8 8) E Renal, extracranial carotid and vertebral arteries FMD is an uncommon, vascular disease which can affect arteries of all sizes and affect multiple anatomical territories. However, it most commonly affects the renal, extracranial carotid and vertebral arteries.9 9) C Beta-blockers Studies have shown that the majority of patients with Marfanâ&#x20AC;&#x2122;s syndrome will benefit from initiating a beta blocker. The latest reviews of the literature suggest that beta blockers are the gold standard therapy in these patients.9,10,11 10) B Clopidogrel NICE guidelines suggest that people with PAD should be prescribed antiplatelet treatment for the secondary prevention of cardiovascular events. Clopidogrel 75mg daily is their preferred antiplatelet.12 11) D 40% There are many extra-renal vascular findings in patients with Autosomal Dominant PKD, including cardiac valvular disease and thoracic/abdominal aortic aneurysms. However, the most lethal manifestation is intracranial aneurysms, which can rupture causing intracranial haemorrhage. These have been found in up to 40% of patients.9,11

REFERENCES 1 NICE (2011) Hypertension in adults: diagnosis

and management https://www.nice.org.uk/ guidance/cg127/resources/hypertension-in adults-diagnosis-and-management 35109454941637 2 Pomianowski P and Elefteriades J

The Genetics and Genomics of Thoracic Aortic Disease Annals of Cardiothoracic Surgery

(2013) Vol 2 pp 271-9 3 Paravastu S, Mendonca D and Silva A Beta

Blockers for Peripheral Arterial Disease

Cochrane Database of Systematic Reviews (2013) 4 Main J Atherosclerotic renal artery stenosis,

ACE inhibitors, and avoiding cardiovascular death Heart (2005) Vol 91 pp 548-52 5 Clinical Knowledge Summaries (2015) Lipid

Modification - CVD Prevention https://cks.nice.org.uk/lipid-modification-cvd prevention#!scenario 6 British Heart Foundation Focus On: Stroke and

Carotid Artery Disease https://www.bhf.org. uk/heart-matters-magazine/medical/stroke and-carotid-artery-disease 7

8

American Diabetes Association Peripheral Arterial Disease in People With Diabetes Diabetes Care (2003) Vol 26 pp3333-41

9 Shivapour D, Erwin P and Kim E Epidemiology

of Fibromuscular Dysplasia: A Review of the Literature Vascular Medicine

(2016) Vol 21 pp376-81 10 Pepe G, Giusti B, Sticchi E, Abbate R, Gensini

G and Nistri S Marfan Syndrome: Current Perspectives The Application Of Clinical

Genetics (2016) Vol 9 pp55-65 11

Attenhofer Jost CH, Greutmann M, Connolly H, Weber R, Rohrbach M et al Medical Treatment of Aortic Aneurysms in Marfan Syndrome and other Heritable Conditions Current Cardiology Reviews (2014) Vol 10 pp161-71

12 NICE (2015) Antiplatelet treatment https://cks. nice.org.uk/antiplatelet-treatment#!scenario:1 13 Public Health England Abdominal aortic

aneurysm screening: programme overview

(2015) Available at: https://www.gov.uk/ guidance/abdominal-aortic-aneurysm screening-programme-overview

Al-Qaisi M, Nott D, King D. and Kaddoura S Ankle Brachial Pressure Index (ABPI): An Update for Practitioners Vascular Health And Risk Management (2009) Vol 5 pp833-41

12) B Males 65 and older The NHS offer AAA screening to all men aged 65 and over in England.13

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