Abstracts from the ATRIUM 2014 conference

Richard Heywood, Editor, Cambridge Medicine Journal.
Organisers of the ATRIUM conference

We are pleased to be able to publish the abstracts from the 6th Annual National ATRIUM Conference, which took place on 22nd February 2014 at the Chancellor’s Building, New Royal Infirmary of Edinburgh. This annual conference is organised by ATRIUM, a student-run organisation at the University of Edinburgh which aims to encourage research amongst undergraduate medical students. Their website is http://www.atriumsoc.co.uk/

There were a mixture of oral and poster presentations, which are listed below. The name of the presenting student is in bold.

Oral presentations

Diabetes and its association with self-reported sleep quality and night time awakening: An Understanding Society cohort study.

N Haresceugh, K Lloyd Jones, Emily Moore

University of Leeds Medical School

Background: Recent studies have shown sleep of a poor quality and short duration to be a risk factor in Type 2 diabetes. The current study of the nationally representative Understanding Society (USoc) cohort aims to distinguish an association between four discrete sleep variables and self-reported diabetes.

Methods: Four self-reported sleep measures (sleep duration; sleep onset latency; sleep quality; night time awakening) and self-reported diagnosis of diabetes were analysed from the first wave of USoc using multivariate logistic regression. A directed acyclic graph identified ten covariates (age, sex, ethnicity, BMI, alcohol intake, nutrition, exercise, smoking, highest qualification, profession and technology usage) that were the minimum amount of variables required to adjust for confounding.

Results: Comprehensive data was available for 23,214 participants (mean age=46.4; ♂:♀=45.1:54.9). Following adjustment, no significant association between sleep duration or sleep onset latency and diabetes was identified. However, participants reporting “fairly bad” sleep quality had 1.39 (95%CI:1.13,1.70) the odds of having reported diabetes and those reporting night-time awakening as “more than once most nights” had 1.37 (95%CI:1.12,1.68) the odds of having reported diabetes.

Discussion: Analysis suggests sleep quality and night-time awakening are a more important risk factor for diabetes than sleep duration. The main limitation of the study is that results are based on cross-sectional analysis of self-reported diagnostic data. Further longitudinal analyses need to be conducted using blood glucose and HbA1c data once these have been released in the next wave of data.

Conclusion: Self-reported sleep quality and night time awakening may be better indicators of diabetes risk than sleep duration.

Directed Cord Blood Audit

J. Hayden

University of Glasgow

Background: The Stem Cell Transplant Programme at RHSC Glasgow harvests cord blood from the siblings of patients due to undergo allogeneic haematopoietic stem cell transplantation. The aims are as follows:- 1. Assess the percentage of directed cord blood units which are HLA matched 2. Assess the adequacy of total nucleated cell (TNC) dose and CD34+ cell dose from the collected cord blood 3. Establish if CD34+ and TNC cell count correlates with the volume of cord blood collected

Methods: Patient samples were retrospectively identified over a five year period. Data was collected from patient records and collated onto a spread sheet. Adequacy of cell dose was analysed by comparing to standards set by the European School of Haematology

Results: Percentage of matched sibling cord blood units is higher than expected. The majority of harvested cord blood units met the recommended TNC dose/kg. Most of the harvested cord blood units failed to meet the recommended CD34+ dose/kg . A linear relationship exists between volume of cord blood collected and TNC count The relationship between CD34+ count and volume of cord blood collected is not as clear – it is linear but with outliers

Discussion: Repeat audit should be undertaken in 5 years’ time which also takes into account other variables which have been shown to increase blood volume including parity and delivery method. Look into practical ways of maximising volume of cord blood collected.

Conclusion: The stem cell transplant programme is meeting some but not all of the standards set for allogeneic haematopoietic stem cell transplant.

Can we identify children with high risk of Autism?: Study of the Gilliam Autism Rating Scale

S Kattera, A O’Hare

University of Edinburgh.

Background: Autism spectrum disorder (ASD) is a behaviourally defined pervasive condition. It lacks a universal screening tool, therefore, delaying recognition. The Gilliam Autism Rating Scale (GARS) is one of the few tools that can be completed by nursery staff, making it potentially useful in clinical practise. It was developed as a screening tool for autism across all ages and presentations but evidence of efficacy is weak. We assessed the compliance and screening efficacy of GARS in a group of high risk pre-school children referred for developmental delay.

Methods: A retrospective notes study included 100 participants aged 0-5 years diagnosed with ASD after referral to child development services (2011-2012). Age of diagnosis and parental, nursery GARS scores were recorded. Sensitivity and specificity was calculated through cross tabulation.

Results: Test positivity was a high ASD index GARS score of 84 and above. Combined nursery and parental GARS had a sensitivity of 79% and specificity of 43%. Sensitivity parent scoring was (68%) and nursery (71%). Specificity was parent scoring (78%) and nursery scoring (50%). Compliance for the nursery GARS was 84%.

Discussion: Gathering information on pervasive autistic symptoms for pre-school children presenting with developmental delay is critical to the diagnostic process. Many assessment services rely on direct observation in nursery but this can protract the process. The study showed high nursery staff compliance with providing information by structured GARS questionnaire.

Conclusion: GARS is a useful information gathering instrument for high risk pre-schoolers but not an adequate screening tool and would require further development.

Acknowledgments: I gratefully acknowledge my project supervisor for all her help and guidance. Professor Anne Elizabeth O’Hare Honorary Professor of Child Life and Health, University of Edinburgh Honorary Professor in Paediatrics, Consultant Paediatrician, Community Child Health Vacation Research Scholarship Award 2013 University of Edinburgh. I hereby declare that I do not have any conflict of interest.

Investigating the Presentation and Management of Adult Community Acquired Pneumonia within Two Secondary Care Centres in Edinburgh: The Royal Infirmary and the Western General Hospital

H. Mark, K. Templeton, N. Gadsby

University of Edinburgh.

Background: Community-Acquired-Pneumonia (CAP) results in a significant number of hospital admissions and deaths. The British Thoracic Society provides evidence-based guidelines that outline effective management based on CURB-65 score. Many health boards have adjusted these to create their own recommendations.

Aims: 1) Consider association between clinical features of CAP and outcomes of admission. 2) Evaluate compliance with Local Antimicrobial Guidelines with respect to microbiological sampling and antibiotic prescribing

Methodology: Retrospective analysis of 81 patients admitted with CAP. Clinical information was collected from electronic and paper notes and statistical analysis was performed.

Results: Average age at admission was 63.7 years with 80% being admitted with mild or moderate disease. Higher CURB-65 score at presentation was associated with hospital stay (p=0.039) and increased compliance with respect too antibiotic prescribed (p=0.007) and route of administration (p=0.012). 87% of microbiological samples were taken post-antibiotics with 33.8% isolating a bacteria and 22% a virus. Just 41.8% of patients were treated in complete agreement with guidelines. No connection was seen between compliance and outcome.

Discussion: Compliance with local guidelines is poor. What affect is this having with respect to patient outcomes and how can we attempt to improve compliance?

Conclusion: The small sample size limits applicability of the findings relating to presentation and outcome, however this study does illustrate that CURB-65 is a useful tool in predicting outcome in CAP. Compliance with guidelines is low and time should be spent considering how to improve these levels for patient wellbeing and responsible antimicrobial use.

Acknowledgements: Thanks to Dr Kate Templeton (Consultant Clinical Microbiologist RIE) and Naomi Gadsby (Research Scientist) for input on project design and guidance throughout my research.

Are They Getting Fatter? The Changing Demographics of Total Knee Arthoplasty.

C Robinson, E Goudie, I Brenkel

University of Manchester.

Background: Knee osteoarthritis (OA) is disabling condition of rising prevalence in the UK, due largely to advancing patient age and increasing population obesity. The demand for total knee arthroplasty (TKA) procedures has increased in recent years. Despite this, there is limited research into changing demographic trends for the subgroup of patients undergoing TKA.

Methods: Our objective was to identify changing trends in TKA techniques and patient demographics by retrospective comparison between two TKA patient groups. The first group consisted of 686 patients who underwent operation between Dec. 1994 - Aug. 1998. The second group consisted of 1408 patients who underwent operation between Jan. 2009 - Nov. 2012.

Results & Discussion: Both mean BMI and the proportion of obese (BMI > 30kg/m2) was found to be significantly higher in group two than group one (p<0.01). Mean age at operation was significantly greater in group two (p<0.01). However, significantly greater proportions of both ‘young’ (< 60 years) and ‘old’ (> 80 years) patients were recorded in group two (p<0.01). The mean pain and function components of the American Knee Society Score (AKSS) were worse in group one than group two (p<0.01), indicating that modern patients are being operated upon at a lower threshold for disease severity. The frequency of both bilateral operation and blood transfusion were lower in group two (p<0.01).

Conclusion: These findings substantiate associations between the rising prevalence of knee OA risk factors and increasing demand for TKA. They also emphasise the need for a shifting focus towards preventative measures in the management of knee OA.

Is Self-monitoring of Blood Glucose Levels in Patients with Type 2 Diabetes Mellitus, not Treated with Insulin, Effective at Improving HbA1c Levels?

L Thomas, K Balachadiran, M Blair, R Broome, K Booth, R Longwell

University of Aberdeen.

Background: Self-monitoring of blood glucose (SMBG) is effective in type 1 diabetes and in type 2 diabetes patients on insulin but the effectiveness for patients with type 2 diabetes not on insulin, is uncertain. A systematic review (2012), analysing 12 Randomised Control Trials found benefit at 6 months follow up, but the longer term benefits were unclear. The objective of this review was to assess the effectiveness of SMBG in patients with type 2 diabetes not on insulin.

Methods: A systematic review was carried out. Four electronic bibliographic databases and reference lists of included articles were searched (May 2013). Inclusion criteria were: randomised controlled trials, type 2 diabetes, over 18 years, published since July 2011, glycosylated haemoglobin A1c (HbA1c) results reported, English language. Two authors independently selected studies, extracted data and quality assessed included studies. Outcomes assessed were HbA1c, quality of life, body mass index (BMI) and compliance.

Results: Four trials were included. Follow up ranged from six months to three years. A statistically significant decrease in HbA1c between SMBG and comparator groups was noted in three trials (0.3-0.7%). No statistically significant difference was seen in quality of life. Improvement in BMI ranged from 0.94 to 2.5 kg/m2 however the difference from the comparator group was not statistically significant.

Discussion & Conclusion: SMBG has the potential to improve glycaemic control in type 2 diabetes patients not on insulin. More research on outcomes such as adverse effects and psychological impacts of SMBG is required.

Acknowledgements: This summer student project was undertaken as part of the Aberdeen Summer Research Studentship (ASRS) programme.

POSTER PRESENTATIONS

The management of patients with chronic heart failure at Wychall Lane GP Surgery, Birmingham: a clinical audit.

M Agarwal

University of Birmingham

Introduction: Optimal management of patients with heart failure (HF) is imperative to improve the poor prognosis of this complex condition.

Methods: NICE provides evidence-based guidelines on the management of chronic HF. Three recommendations were chosen to audit the management of patients with HF (audit standards set at 100%) at Wychall Lane GP Surgery, Birmingham. These include (i) offering “both angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers (BB) ...to all patients with HF due to left ventricular systolic dysfunction (LVSD)”, (ii) prescribing aspirin “for patients with the combination of HF and atherosclerotic arterial disease” and (iii) at least six-monthly monitoring of patients including “serum urea, electrolytes, creatinine and eGFR”.

Results: 72 patients (42 female) were on the HF register, of which 56 (78%) had LVSD. 32/56 (57%) were on recommended treatment (ACEI and BB), with valid justification e.g. intolerance, for all but five patients (9%) who were not. 18/25 (72%) of patients with arterial disease and HF were prescribed aspirin. 46/72 (64%) had had the recommended monitoring within the last six months.

Discussion: Wychall Lane Surgery is doing well in initiating ACEI and BB for patients with HF and LVSD, as well as correctly prescribing aspirin for HF patients with co-morbid arterial disease. Regular monitoring is an area requiring improvement.

Conclusion: Monitoring rates may be improved by setting up automated pop-up reminders for blood tests that are due. Medical education (e.g. presentation of this audit at the Surgery) to increase awareness of the guidelines is likely to be beneficial. Improvement should be evaluated by re-auditing.

Measurements of Sleep as Predictors of Stroke: A Nationally Representative Prospective Cohort Study.

A Al-Robeye

University of Leeds.

Introduction: Recent studies have identified a U-shaped association between sleep duration and stroke, yet few studies have examined whether sleep quality predicts stroke.

Methods: This study explored the prognostic value of sleep measurements as predictors of stroke, in n=24,094 "Understanding Society" cohort participants with complete data in both Wave A and B, none of whom had had a stroke at Wave A. The role of self-reported sleep measures as predictors of stroke 18 months later (at Wave B) were examined after adjusting for potential confounders, identified using a directed acyclic graph.

Results: There were strong, statistically significant associations between all sleep measures and subsequent stroke, before and after adjustment for confounders. However, sleep duration was no longer statistically significant when examined separately in the two oldest age groups (aged 40-64yrs and 65+). In contrast, poor sleep quality was a stronger predictor of stroke among 40-64yr olds (OR:17.96; 95%CI:1.89-170.38) while frequent sleep medication use was a stronger predictor of stroke amongst those aged 65+ (OR:9.38, 95%CI:3.25-27.05).

Discussion: Sleep quality measures were stronger predictors of stroke than sleep duration. It remains to be seen whether: (i) there is a direct causal relationship between poor sleep quality and an enhanced risk of stroke; or (ii) other factors affect sleep, for which sleep acted as a proxy in these analyses.

Conclusion: The present study confirms that: self-reported sleep measures are powerful predictors of stroke; and their predictive ability remained statistically significant even after adjustment for confounders.

Acknowledgements: On behalf of the Understanding Society Sleep Project (USocSP) - Temporal Influences on Metabolic Events (TIME) Research Group; Leeds Institute of Genetics; Health and Therapeutics (LIGHT); School of Medicine; University of Leeds; Clarendon Way; Leeds LS2 9JT; www.medhealth.leeds.ac.uk/homepage/136/time

Yersinia pseudotuberculosis, the causative organism of Far East Scarlet-like Fever.

A Amphlett

University of Keele.

Introduction: In Europe, human Yersinia pseudotuberculosis infection typically occurs sporadically, in the form of a self-limiting gastroenteritis. In Russia , outbreaks of infection occur causing severe systemic inflammatory symptoms. This disease variant is called Far East Scarlet-like Fever (FESLF). Geographical heterogeneity exists between virulence factors produced by European and Far Eastern strains, implicating superantigen Y. pseudotuberculosis-dervied mitogen A (YPMa) in the pathogenesis of FESLF. Previous research into FESLF using isogenic mutants in vivo has been limited, with no suitable in vivo model being identified.

Methods: This work addresses these limitations by: Identifying a suitable in vivo model to assess the pathogenicity of FESLF causing strains and assessing the pathogenicity of YPMa in vivo.

Results: This work found that: (i) FESLF causing strains are almost avirulent via the intragastric route of OF1 mice. (ii) The intravenous route is suitable to assess the pathogenicity of FESLF causing strains. (iii) Intravenous challenge with a ΔypmA mutant prolongs mean time to death of OF1 mice and increases LD50, relative to the wildtype.

Discussion: Prior research demonstrated that an isogenic YPMa mutant prolonged time to death but did not affect LD50. In my study YPMa affected both.

Conclusions: My work will enable future researchers to use isogenic mutants in vivo, to differentiate between genomic elements associated with FESLF and those directly involved in the pathogenesis of the disease. Further research is needed into the stability of pVM82 at differing environmental conditions and a new method devised to calculate pVM82 conjugation frequency.

Apamin Block Of rSK2 Potassium Channels

E Antoni

University College London, University of London

Introduction: A plethora of studies established the neurotoxin Apamin as the gold standard inhibitor of small-conductance calcium-activated potassium (SK) channels; however the precise mechanism underlying its blocking action is still not completely understood. Lamy et al. (2010) studies have provided greater insight into this field of investigation proposing that apamin’s pharmacological profile is not consistent with a classical pore blocker like Tetraethylammonium (TEA) but rather suggest that apamin operates with a mechanism consistent with an allosteric-binding model.

Methods: Accordingly, using HEK293 cells as a mammalian expression system for exogenous rSK2 genes, we re-examined the relationship between apamin binding and block of current to elucidate whether these previous published findings can be confirmed. To address this issue herein, we performed electrophysiology experiments under the same conditions as previous apamin binding experiments and compared our findings with the data presented by Lamy et al.

Results/Discussion: Interestingly, when binding was measured using intact cells and same ionic conditions as current inhibition, comparable estimates of KD and IC50 were obtained. Moreover, to determine whether apamin blocks rSK2 channels by binding to a site distinct from the TEA binding site we used rSK2VF, a mutant with an enhanced affinity for TEA (IC50 of 0.3mM). The mutant channel exhibited dramatic reduction in its sensitivity to apamin suggesting that the two binding sites cannot be classified as unrelated.

Conclusion: Even though together these principal findings do not reject the allosteric binding mechanism per se, they do not provide strong evidence to confirm the validity of this model.

A 5 Year Review Study of Grade III Medial Collateral Ligament Injuries of the Knee within the North Bristol Trust.

D Barling, J Robinson

University of Bristol.

Introduction: The Medial Collateral Ligament (MCL) is the most frequently injured ligament in the knee. The increasing popularity of contact sports involving valgus knee loading has led to an increasing prevalence of MCL injury.

Methods: The study included 56 patients with a diagnosis of grade III MCL tear of the knee over a 5-year period between 2008-2013 at Frenchay and Southmead Hospitals, Bristol. Data was retrieved on gender, DOB, the date and mechanism of injury, clinical examination, radiological findings and management.

Results: 73.2% of the patients were male. In 71% of cases there was an associated ligament injury, 42.9% involving the ACL. Diagnosis between radiologist and clinician matched in 43.1% of patients. 27.4% of MRI reports didn't mention the site of MCL damage. The most common site of failure was the superficial MCL. Overall 33.9% of patients required MCL repair (47.1% in patients with rupture of the Posterior Oblique Ligament component)

Discussion: This study demonstrates a lack of consistency between clinical and radiological evaluation of Grade III MCL tears as well as a lack of uniformity in MRI reporting of the exact site of MCL damage. Involvement of the POL was under-reported on MRI but when identified was often an indicator for surgery.

Conclusion: With rupture of the MCL usually accompanied by other knee ligament damage, radiologists may not focus sufficiently on the MCL. There also needs to be a uniform method of clinical assessment for MCL injury. The role of the POL may be underestimated in assessing MCL damage and suitability for surgery.

Can you ever collect too many oocytes?

R Briggs, G. Kovacs

University of Edinburgh

Introduction: The use of stimulated cycles and controlled ovarian hyperstimulation (COH) has become routine in assisted reproductive therapy (ART). Higher doses of hormones can produce higher yields of oocytes but it has been suggested that excessive stimulation may compromise results.

Methods: Our retrospective study looked at 7728 stimulated cycles of IVF and ICSI at Monash IVF over two years, where the patient underwent a fresh embryo transfer. Results - Live birth rate (LBR) per embryo transfer varied from 8.8% following collection of one oocyte to 34.9% following collection of between 31 and 35 oocytes. With regards to both of these outcomes the rates continued to increase linearly as the number of oocytes collected increased.

Results: were then analysed according to patient age and BMI, and both were found to be insignificant as live birth rate continued to increase with number of oocytes collected, across all groups. Again, when results were analysed according to stimulation protocol, there was no difference between cycles involving an antagonist and agonist. Stage of embryo transfer did not affect the outcome, and LBR continued to increase with number of oocytes collected, after both cleavage and blastocyst stage transfers.

Discussion: In contrast to previous studies LBR increased with number of oocytes collected and there is no decline in LBR. Our results were consistent for each subgroup analysed.

Conclusion: The results of this study suggest that you cannot collect too many oocytes as long as the risk of OHSS is considered.

Acute exacerbations of autoimmune neurological conditions – is intensive care access beneficial?

N Caiger

University of Warwick

Introduction: Patients with neurological autoimmune conditions do not always have easy access to ICU. Conditions such as acute disseminated encephalomyelitis (ADEM) and myasthenia gravis (MG) are defined by acute exacerbations, which may require ICU management, and are largely reversible. We sought to identify whether these patients benefited from admission to ICU.

Methods: We hand-searched John Radcliffe (JR) neuro intensive care unit (NICU) admissions for patients with autoimmune neurological disease between 01/01/2010 and 01/08/2013; we identified 15 patients. From patient notes we extracted data including: duration of stay, reason for admission, clinical picture at admission, discharge, 14 day follow up, and the occurrence of complications.

Results: Of the patients included: 8 had MG, 2 ADEM, 3 NMDA receptor antibody mediated encephalitis, 1 progressive encephalomyelitis with stiffness and rigidity (PERM) and 1 anti-synthetase deficiency. The average NICU stay was 17.1 days (over 20 admissions). The main reasons for admission were: respiratory failure (14), and low GCS (2). Complications commonly arose in these patients during their stays, including: lower respiratory tract infection (10) and lung collapse (5). At 14 day follow-up the main outcomes were: deceased (1), discharged/transferred (5), and showing improvement (9).

Discussion and Conclusion: Our data suggested that admission to NICU for these conditions improved outcomes. Only the minority of patients with these conditions will require ICU admission thanks to preventative medicine and rapid management of acute exacerbations; therefore it is difficult for staff to gain expertise with these patients. The difficulty in sharing expertise is being able to define tangible outcomes to follow.

A prospective nested case-control study looking at the effect of domestic violence on women at a high risk of spontaneous preterm birth.

Z Cargill, A Shennan, J Carter, P Seed

King’s College London, University of London

Introduction: During pregnancy domestic violence can affect the mother and unborn child. It has been associated with preterm birth (PTB), reduced birth weight and fetal injury. No studies have investigated whether domestic violence results in poorer outcomes in women already known to be high risk of PTB. This study aims to determine the effect of domestic violence on these women. This is by (i) estimating the prevalence, (ii) assessing the effect before 37 weeks and 34 weeks (iii), assessing the effect on neonatal admissions to the NICU and (iv) assessing neonatal birth weight in this group.

Methods: A prospective nested case-controlled study was carried out in 13 UK hospitals. Demographic information was entered onto a database and outcome data was similarly recorded. Participants (n=216) were then successfully matched and conditional logistic regression used to estimate odds ratios for selected outcome data.

Results: The prevalence of domestic violence in this cohort was 7.3%. The results of the effect of DV on preterm birth before 34 weeks (OR= 1.622, p= 0.311), before 37 weeks (OR=1.072, p= 0.848), on a customised neonatal birth weight centile below 10 (OR= 1.97, p=0.073) or below 5 (OR=2.133, p=0.096) and admission to the SCBU/NICU (OR= 0.978, p=0.961) were not statistically significant.

Conclusions: In pregnant women already at high risk of spontaneous PTB, the additional factor of DV does not appear to significantly increase the risk of poor outcomes. This may show that additional surveillance of women at risk of PTB who also report DV does not appear to be necessary.

Acknowledgements: Professor Andrew Shennan, Jenny Carter and Dr Paul Seed

Current incidence and management of sepsis in the RIE Emergency Department.

GE Clark, AJ Gray

University of Edinburgh

Introduction: Sepsis is a systemic inflammatory disease caused by infection and the Sepsis Six are guidelines to be carried out for all septic patients entering the Emergency Department (ED). The aim of the study was to investigate the incidence of sepsis including severe sepsis and septic shock and compliance with current treatment recommendations in the ED.

Methods: Between the 1st and 28th July, data was gathered for any patient entering the ED of the Royal infirmary of Edinburgh with signs of infection and meeting at least 2 of the NHS Lothian shock chart’s criteria.

Results: Only 5 (3%) out of the 199 patients included in the study had the Sepsis Six completed. Giving IV antibiotics was one of the most adhered to action in the Sepsis Six, but only in 72% of all cases were the antibiotic guidelines followed. The majority of discharge diagnoses were infective (156 infective vs 37 non-infective).

Discussion: Only 0.4% of all attendances and 1.3% of admissions were given a diagnosis of sepsis, below the average number of sepsis admissions, although there could be a seasonal effect. Two of the Sepsis Six were consistently the worst adhered to: giving high flow oxygen and measuring urine output, possibly due to poor documentation.

Conclusion: Completion of the Sepsis Six is poor, but seems to improve slightly in the severe sepsis and septic shock group. Documentation plays a major role in this inadequate compliance with sepsis treatment. Overall patient outcome is satisfactory, but the areas highlighted for improvement will help to reduce sepsis mortality.

Acknowledgements: Funded by University of Edinburgh College of Medicine vacation research scholarship. Supervisor - Dr Alasdair Gray (Research Director EMeRGE, Consultant, Reader & College Professor in Emergency Medicine) EMeRGE research team: Judy Coyle (EMeRGE Research nurse) Rachel O'Brien (EMeRGE Research nurse) Ola Gruszczynska (EMeRGE Research Administrator) Moyra Masson (EMeRGE Research Co-ordinator) Julia Grahamslaw (EMeRGE Research nurse).

Do we need to perform urodynamic studies before surgery for urinary incontinence in women? Cochrane systematic review and meta-analysis

K Clement

University of Aberdeen

Introduction: Urodynamic tests are used to diagnose and guide treatment decisions in patients with incontinence or other urinary symptoms. However, testing is invasive, time-consuming and is generally considered an unpleasant experience for patients. This systematic review aimed to determine if treatment following urodynamics is superior to treatment following any other diagnostic method.

Methods: The Cochrane Incontinence Group Specialised Trials Register was searched (21st November 2012) for randomised and quasi-randomised trials comparing patients treated with urodynamics versus those without. Trials were excluded if they did not report useable data as pre-defined by the reviewers. Two reviewers independently undertook abstract and full-text screening, data extraction, risk of bias assessment, and quality of evidence.

Results: Eight trials met the inclusion criteria. Data was available for 1,036 women from 7 trials, of whom 526 underwent urodynamic testing. Women who underwent urodynamic testing were more likely to have a change in management (n=272, RR 5.07, 95% CI 1.87 to 13.74). However, this did not equate to more women receiving surgery (n=982, RR 0.99, 95% CI 0.88 to 0.11). Lastly, there was no statistically significant difference in the number of people with incontinence after one year (n=802, RR 1.02, 95% CI 0.86 to 1.21).

Discussion: While urodynamics have been shown to alter decision-making in clinicians, this did not equate to more or less women undergoing surgery. Perhaps as a consequence, there was no significant difference in incontinence rates between the groups.

Conclusion: Larger, well-designed controlled trials comparing urodynamics versus other methods of investigation following the recommendations of CONSORT statement are required.

Acknowledgements: The UK National Institute for Health Research as the largest single funder of the Cochrane Incontinence Group.

The use of personal video cameras in assessment of the impact of the Autopulse mechanical CPR device on pre-hospital resuscitation after OHCA

A Crawford, C Crookston, R Lyon, G Clegg

University of Edinburgh

Introduction: Out of hospital cardiac arrest (OHCA) refractory to initial treatment may require life-saving in-hospital intervention. Transporting patients to hospital during OHCA is problematic because CPR during transport is difficult. We employed a novel video recording system to assess the impact of a mechanical CPR device on prehospital OHCA management.

Methods: Since April 2010, a specialist paramedic Resuscitation Rapid Response Unit (3RU) has responded to OHCA in Edinburgh. In our two-phase study we initially examined defibrillator downloads to measure interruption of CPR during extrication. In the second phase, from August 2011, we deployed an Autopulse with a carry-sheet for extrication and wearable video cameras to assess impact on resuscitation quality.

Results: During manual resuscitation, extrication resulted in CPR interruption for a median time of 276s (54s-846s, n=52). In phase 2, deployment of Autopulse occurred rapidly after 3RU arrival. Median time from 3RU arrival to first mechanical compression was 216s (55s-546s, n=56). During deployment the median interruption to CPR was 42s (15s-100s, n=58). Use of the carry-sheet made Autopulse-assisted extrication more rapid than with the scoop 155s (46s-726s, n=35) vs 276s (54s-846s, n=52)(P<0.001) respectively.

Discussion: Pre-hospital video recording demonstrated the length of interruption to CPR during deployment of an Autopulse, and its during extrication and transport. Video also demonstrated the utility of the carry-sheet system for extrication.

Conclusion: Video recording is a feasible and effective method of assessing the impact of equipment change on the effectiveness of OHCA resuscitation. Using Autopulse allows maintenance of high quality CPR with minimal interruption during deployment.

Acknowledgements: The authors would like to thank frontline crews of the Scottish Ambulance Service for their support and facilitation of this study.

Spinal meningioma: the prognostic value of Magnetic resonance imaging in surgical outcome

S Davies

University of Newcastle

Introduction: Spinal meningiomas account for 25 to 46% of spinal tumours. Surgical resection is the standard treatment and is associated with good recovery. Few studies identify prognostic factors; the aim of this study was to identify whether MRI geometrics have prognostic value in patients who undergo spinal meningioma resection.

Methods: We performed a retrospective analysis of patients who underwent resection between August 2005 and December 2012. We analysed pre and postoperative MRIs and functional status (assessed using Nurick Scale). We calculated cord area, the tumour occupancy of canal and cord occupancy of canal at maximum compression. Post-operatively we measured cord area at the same level to assess wastage.

Results: Cord compression was witnessed in all patients and the average cross-sectional area was 60.67%. Average tumour occupancy was 72.11%. Average cord occupancy was 19.69%. When we compared these measurements with the pre and postoperative Nurick score we found no correlation. Postoperatively average cross-sectional area was 84.23%. We found that postoperative expansion was unrelated to preoperative compression.

Discussion: These results suggest the theory of cord wastage may not be relevant in spinal meningiomas. This allows pre-operative compression to be discounted as a prognostic factor. Factors such as length of time with symptoms, tumour position and calcification are more important.

Conclusion: Measurements on MRI scans have no obvious relationship with function before or after surgery. The geometrics of the spinal cord were not found to vary as much as was expected. The theory of cord wastage may not apply to expansion following resection of spinal meningioma.

Acknowledgements: P. Mitchell, consultant neurosurgeon, RVI (supervision). Newcastle University Vacation Scholarship (funding).

The Effects of the PLIN2 Ser251Pro Polymorphism on Plasma Lipid Profiles of 3164 individuals

S Fajutrao Valles

University of St Andrews

Introduction: Hypertriglyceridemia is a prevalent risk factor for cardiovascular diseases, and atherosclerosis is the main underlying cause. Recently, a missense polymorphism Ser251Pro (rs35568725) of the ubiquitously expressed lipid-droplet regulating protein perilipin 2 (PLIN2) has shown to be associated with reduced plasma triglyceride concentration in humans, suggesting an atheroprotective effect. The present study investigates whether BMI modulates the effect of the SNP on plasma lipids.

Methods: Three cohorts (obese, lean and population-based) of in total 3164 individuals were genotyped for the rs35568725 SNP. Genotype-phenotype associations stratified on cohort and sex were executed utilising the PLINK software, to explore whether obesity and gender modulates the SNP’s effect on plasma lipid profiles.

Results: Our results suggest an effect of rs35568725 on plasma lipid profiles in an obese subset and not in lean individuals. Furthermore, we observe an effect of rs35568725 on triglycerides and HDL in men, an effect abolished in women.

Discussion: In this present study, the Ser251Pro polymorphism in perilipin 2 (PLIN2) is associated with triglyceride, glycerol, high density lipoprotein levels in obese individuals. In the obese cohort, rs35568725 has shown to be associated with increased plasma triglycerides levels compared to individuals carrying the major allele (p<0.01), which is opposite to what a previous study has shown. However, similar to the previous study, we observed a trend towards lower levels of glycerol (p=0.093) in the obese population, which may suggest decreased lipolysis.

Conclusion: Our study suggests an effect of rs35568725 on plasma lipid profiles which is modulated by obesity and male sex.

A role of protein phosphatase 1 beta in angiogenesis.

I Garaeva, M Ghorbel, M Caputo, N Singh

University of Bristol

Background: Endothelial cell migration is required in the physiological angiogenic process, but also contributes to various pathological conditions, including tumor vascularization. Protein phosphatase 1 (PP1) is the major serine/threonine specific protein phosphatase and the expression of PP1cB, the beta isoform of the catalytic subunit of PP1, has been shown to be upregulated in chronic hypoxia. Hypoxia is a major regulator of angiogenesis, and the potential role of PP1cB in angiogenesis was investigated in the present study.

Methods: The effect of knocking down and overexpressing PP1cB on endothelial cell migration and endothelial morphogenesis was examined using in vitro wound healing scratch assay and in vitro endothelial tube formation assay respectively.

Results: Our results show that PP1cB knockdown significantly reduces endothelial cell migration, but does not have any significant effect on endothelial tube formation. Endothelial cell migration in the knockdown group is restored to the control level of migration upon consecutive transfection with PP1cB cDNA. PP1cB overexpression does not significantly affect endothelial cell migration.

Discussion: The current study implies that PP1cB is a regulator of endothelial cell migration, which is critical in the process of angiogenesis. PP1cB may affect endothelial cell migration through focal adhesion turnover and actin polymerization pathways. Further investigation regarding the role of PP1cB in the regulation of angiogenesis is required.

Conclusion: This study may contribute to further understanding of endothelial cell migration, specifically in the context of cancer-induced angiogenesis, and highlights PP1cB as a possible promising target for antiangiogenic therapy and inhibition of tumor growth.  

The Breast Cancer Immune Contexture: is it quality or quantity that matters?

S Hessey, S Sethi, M Young, J Owen, J Rosekilly

University of Bristol

Introduction: There is currently no validated method to predict response to treatment or survival in triple negative breast cancers (TNBCs). TNBCs are particularly enriched in tumour infiltrating lymphotcytes (TILs) and recent work has shown that the presence of TILs can predict response to treatment and outcome in TNBCs. We analysed the phenotype of TILs in TNBCs compared with other subtypes of breast cancer to characterise their in situ functional status.

Methods: Primary resected breast cancer tumours were dissociated into single cell suspensions, stained for lymphocyte lineage markers and flow cytometry was used to phenotype the TILs. Functional capacity of the TILs was assessed by ex-vivo stimulation assays and subsequent measurement of IFNγ production.

Results: We found that CD8+ T cells are the major subset of cytotoxic TILs in our cohort of tumours. On gene expression analysis of TNBC from Guy’s Hospital, we found that CD8 gene expression is significantly correlated with improved distant metastases free survival. Although, there was no difference in CD8+ T cell infiltration between TNBC and non-TNBC tumours, there was marked variability in capacity of TILs to produce IFNγ between patients.

Discussion: It is possible that differences in TIL functional capacity could explain the distinct clinical patterns of TNBC. Perhaps it is not the direct cytotoxic action of chemotherapy (or other treatments) on the tumour parenchyma but rather its effects on the tumour immune stroma that determines survival.

Conclusion: Variation in TIL production of IFNγ between patients suggests TNBC outcome might relate to the host capacity to mount an anti-tumour immune response.

Acknowledgements: We thank the NIHR for funding.

Tackling waiting times for clinical neurophysiology

S Irvine

University of Dundee

Introduction: Since the introduction of GP referrals for clinical neurophysiology investigations, waiting times for such tests have increased in Tayside to >6 months. Ideally, this time should be at least <18 weeks. We wanted to investigate the appropriateness of all clinical referrals, compare this and waiting times with those from elsewhere and implement a change to improve the situation.

Method: We analysed all clinical neurophysiology referrals and their reports from 1st Jan-22nd May 2013 (n=657) to assess their appropriateness. In particular, we compared GP and hospital referrals. We also compared our current clinical and referral setup with others published in the literature.

Results: Of all referrals (n=653), 236 came from general practice and 417 were hospital referrals. GP referrals were deemed appropriate in 110 (55.2%) cases. This was significantly less than hospital referrals, which were appropriate in 332 (73.1%) cases (p<0.001; χ2=20.2).

Discussion: There are two main issues associated with this study. Firstly, an increased workload with the introduction of GP referrals and the other the relative inappropriateness of some GP referrals, which may be due to lack of experience in the field. The latter can be solved by a checklist referral system, which the literature has shown to be effective is also recommended by the British neurophysiology society. The former might be tackled by increasing clinic times and staffing to cope with increased demand. We have used this approach and at re-audit waiting times had reduced to <3 months, well within the guidelines.

Macrophages in Liver Disease.

CH Koh, HJ Gale, A Danson, MDY Wood, AJ Baird, A Williams, AM Summers, A Mackinnon

University of Edinburgh

Introduction: Liver disease presents a major, global burden of disease. Current treatments have significant limitations e.g. difficulty in removing disease stimulus; shortage of donated livers. Macrophages play a central role in the fibrogenesis and fibrosis resolution, presenting an attractive therapeutic target. We review how macrophages affect liver pathogenesis, and the evidence available for therapeutic targeting of macrophages.

Methods: We conducted a literature review, gathering evidence from literature indexed on Pubmed and Medline.

Results: There is a significant body of literature available on macrophages and fibrosis. Of the three therapeutic interventions we reviewed, two had entered clinical trials.

Discussion: Mechanisms by which macrophages affect fibrosis include hepatotoxicity, signalling to hepatic stellate cells, secretion of matrix-metalloproteinases. Broadly, macrophages can be divided into M1(/proinflammatory) and M2(/anti-inflammatory) phenotypes. There is conflicting evidence on whether each phenotype is pro- or antifibrotic, complicated by the lack of clear-cut M1/M2 distinction in vivo and the great diversity in role even within each subtype. Targeting of chemokine-receptors showed promise in mice, but caution is advised until human trials are conducted: significant obstacles remain in translating murine models to human pathogenesis. Pioglitazone (PPARγ-agonist which induces M2-phenotype) showed some promise in human trials, although the largest randomized control trial produced statistically insignificant results (p=0.10). Early results of bone-marrow therapy are encouraging- large randomized control trials should now be conducted.

Conclusion: Macrophages affects fibrosis in multiple ways, all of which may be targeted therapeutically. There have been human trials of macrophage targeting, none of which provided a clear evidence for benefit in treatment of liver fibrosis.

Investigating Neuroendocrine Markers of Small Cell Lung Cancer.

T Layton

University of Manchester

Introduction: Small cell lung cancer (SCLC) is a widespread and devastating disease. SCLC tumours contain a neuroendocrine cell population that exhibit ectopic hormone production in a minority of patients. The aim of this study was to investigate a panel of neuroendocrine peptides as potential biomarkers fof SCLC, including pro-opiomelanocortin, neuron specific enolase, chromogranin A and neural-cell adhesion molecule.

Methods: Immunohistochemistry methods were used to examine neuroendocrine peptides in five human lung cancer cell lines (CORL24, CORL47, DMS79, H526, A549) and a novel murine subcutaneous SCLC xenograft tumour. Liver, lung and brain samples were taken from xenograft mice to identify possible metastasis. ELISA measured POMC secretion and expression in cell lines during incubation and a Western Blot quantified chromogranin A levels in all cell lines and xenograft tumours.

Results: Results confirmed a significant neuroendocrine cell population within SCLC xenograft tumours and cell lines. Additionally, POMC secretion proved to be a marker of SCLC growth in vitro in CORL24 and DMS79. H526, CORL47 and A549 did not secrete POMC. Xenograft tumours appeared invasive with infiltration of surrounding connective tissue, but no metastases were present in liver, lung and brain samples.

Discussion and Conclusion: This study validates further investigation into the neuroendocrine phenotype in SCLC, and POMC as a potential biomarker for the disease.

Renal replacement therapy for acute kidney injury associated with fulminant hepatic failure: a cohort study.

L Lecky-Thompson

University of Edinburgh

Introduction: Fulminant hepatic failure (FHF) describes the catastrophic deterioration in liver function, the commonest cause of which in the UK is paracetamol overdose (POD), which can also result in acute kidney injury (AKI). The aim of this study was to determine the utilisation of renal replacement therapy (RRT) in patients with FHF admitted to the NRIE and the relationship between timing of introduction and outcome.

Methods: Notes retrieved from 424 patients admitted with FHF since the NRIE opened (86% of cases) were reviewed specifically in relation to whether RRT was delivered, the timing of initiation and relation with outcome.

Results: RRT was significantly more commonly used in POD FHF (118 of 314 admissions, 38%) compared with non-POD (28 of 110 admissions, 25%, p<0.02). RRT was significantly associated with adverse outcomes: mortality was 52.7% in the RRT cohort compared with those not receiving RRT (11%). Prothrombin time values in the highest quartile (69.2±45.3 vs 44.9±26.9, (mean ± standard deviation, died vs survived), p<0.038) and fluid balance in the highest quartile (2962.9±2201.7 vs 2373.3±1421.4, p<0.001) were significantly associated with mortality. Those who died/were transplanted had significantly shorter time to RRT initiation from POD than survivors (74.1h±43.1 vs 90.3h±27.2, p<0.01).

Discussion and Conclusion: RRT is a frequently used intervention for FHF and is associated with an increased risk of mortality. Patients who receive RRT do worse if synthetic liver function is impaired or fluid balance is very positive. In contrast with other causes of AKI, early initiation of RRT in FHF is associated with adverse outcomes.

Monitoring uterine fibroids: How frequently should patients be receiving ultrasound scans?

N Lee, L Whitaker, J Walker, H Critchley

University of Edinburgh

Introduction: Uterine fibroids are benign tumours of the myometrium, and cause significant morbidity in women with large, or multiple, fibroids. Ultrasound (USS) is used to assess fibroid growth. There is a paucity of clinical guidance on how frequently imaging should be performed. Guidelines issued by the Society of Obstetricians and Gynaecologists of Canada (SOGC) were identified that recommend USS should not be carried out routinely, as the investigation seldom affects clinical management.

Methods: An audit was conducted at the Simpson Centre for Reproductive Health (SCRH), to review current practice and USS findings. 20 patients with fibroids who had attended SCRH for at least 6 months were identified. Data regarding age, race, parity, fibroid size, and on-going management was collated. Changes in diameter of the largest fibroids were utilised to estimate a growth rate for the fibroid .

Results: A median growth rate of -2.2% per 6 months was calculated (range: -59.9% to +24%), with the fibroids remaining unchanged in size, or regressing, in 60% of women.

Discussion: These results show that, for many women, their fibroids are not increasing in size. In this small audit, in these patients, frequent scanning may be unlikely to influence management, and no further USS may be indicated unless there is a change in symptom severity.

Conclusion: For many women, there is no increase in fibroid size over the 6-month period examined. The frequency of USS monitoring for women with fibroids requires review. Further research and expert opinion are needed to inform and guide clinical practice.

Acknowledgements: Grateful thanks go to the College of Medicine and Veterinary Medicine Vacation Scholarship programme, who provided the funding for this research.

Pre-hospital assessment of stroke by paramedics

A Martin

University of Newcastle

Introduction: Stroke is a medical emergency affecting 150,000 people in the UK each year. Thrombolysis is the recommended treatment of suitable cases within 4.5 hours of onset. No system of pre-hospital assessment for thrombolysis eligibility currently exists. However, paramedic reports inform hospital thrombolysis decisions.

Methods: Retrospective case series which collected data from paramedic incident reports and linked it to audit databases for three hospitals. The aim was to describe how pre-hospital assessment of stroke patients and their thrombolysis eligibility could be improved.

Results and Discussion: 460 of 710 confirmed stroke admissions by ambulance were used. Face Arm Speech Test (FAST) was recorded in 63% of cases. FAST sensitivity was 63%. Male gender was associated with not receiving a FAST (P=0.01) or any FAST-like test (P=0.01), possibly because elderly males have more masking comorbidities than elderly females. Glasgow Coma Scale <8 was associated with reduced FAST administration (P<0.001) and reduced identification of stroke (P=0.03). In 22% paramedics failed to report an onset time for witnessed stroke but the hospital identified a time. Where both times were available 82% agreed within 1 hour. Past medical history recording was more successful in conditions checked for in normal paramedic practice. Drug history was documented in 12% with anticoagulant status recorded correctly in only 6/63 anticoagulated patients (9.5%). It did not appear that paramedics actively sought information relevant to thrombolysis.

Conclusion: Paramedics do not routinely gather additional information for thrombolysis decisions. A simple structured approach may improve paramedic assessment for stroke thrombolysis potential.

Acknowledgements: Fundinding from vacation Scholarship grant from Newcastle University.

Cognitive impairment after stroke

H Martin, G Mead

University of Edinburgh

Introduction: Mild cognitive impairment is common in the elderly population. The Department of Health, National Institute of Clinical Excellence and the Royal college of Physicians have all identified cognitive assessment after stroke as an area where improvement is needed given the high prevalence and associated adverse long term sequalae.

Methods: Primary Aims: (1) An audit to assess whether a formal cognitive screen carried out in those who have suffered a stroke? When was this undertaken and which tool was used? The 80 most recent consecutive discharges were identified using Trak from three stroke units in South Edinburgh. Data was extracted from paper case notes and anonymously entered onto a database where basic statistical tests were performed.

Results: 69% of patients received a cognitive assessment as an inpatient. The most commonly used assessment tool was the ACE-R (52%) which was carried out a mean time of 3.9 days after admission. Two patients received a new diagnosis of dementia and one patient a new diagnosis of cognitive impairment.

Discussion: National guidelines all advocate screening for cognitive impairment after stroke. However, currently there is a lack of consensus on screening and follow up procedure. Within this audit, the percentage of patients receiving a cognitive assessment in hospital after stroke (69%) is falling below these guidelines.

Conclusions: A national, clear and standardised pathway of care would reduce the heterogeneity of post- stroke care and increase the efficacy of identifying and managing cognitive impairment after stroke.

Challenges Faced by Parents of Children with Disabilities in Nepal

A McCulloch

University of Leeds

Introduction: This paper looks at the experience of caring for a child with a disability in the low-income country of Nepal. Disability is a hugely under-researched area in Nepal and this paper is the first to look specifically at the challenges faced by parents of children with disabilities in Nepal.

Methods: A qualitative study was carried out comprising of semi-structured interviews with mothers (n=12) of children with disabilities. The study was carried out at Kanti Children's Hospital, which is the only government-run children's hospital in Nepal.

Results: Parents reported a lack of support from their families, negative comments from other people, feelings of guilt, attempts to cure their child through offerings and prayers and disappointment in their child’s lack of improvement. None of the parents could name their child’s condition and only one family had any insight into the prognosis of the condition.

Discussion: It was clear that parents were not well informed about the aetiology and outcome of the child's condition. This uncertainty caused some parents to blame themselves. The lack of prognosis made it impossible for parents to accept the condition and move on. These thoughts not only led to stress for the family, but also a more negative attitude towards caring for the child.

Conclusion Parents need to receive comprehensive and accurate information about their child's condition in order to come to terms with the diagnosis and move away from blaming themselves. Research needs to be carried out into how best to deliver this information to them.

An exploration of medical students’ explanations of behaviour within patient safety and dignity dilemmas

L McDonald, S Wells, H Linford

University of Dundee

Introduction: Medical students often find themselves in the face of professionalism dilemmas yet little has been done to evaluate their behaviours in the face of patient safety and dignity dilemmas. We explore how students act in these dilemmas and how they explain their behaviours.

Methods: 680 medical students from 29/32 UK medical schools provided a written narrative of their ‘most memorable’ professionalism dilemma as part of a questionnaire. Qualitative thematic analyses of narratives were followed by a qualitative and quantitative analysis of students’ explanations of their behaviour.

Results: 275 students provided narratives involving patient safety or dignity dilemmas. 164 (60%) students did something in their dilemmas. Female students were more likely to do something compared with male students (X2=18.987, df=1, p<.001). Action was also related to the age of the student, with students in the 26+ age category more likely to do something than those aged 17-25 years (X2=9.930, df=1, p=.002). Students’ explanations for doing something in their dilemma emphasised the intentionality of their behaviour.

Discussion: Patient safety and dignity dilemmas are common. Although many students do something within these dilemmas, a significant proportion of students do nothing. Within the context of anonymous written narratives of professionalism dilemmas, students seem less motivated by impression management and thus more able to reflect candidly upon their action within their dilemma.

Conclusion: Students need time to recount their experiences of patient safety and dignity dilemmas and to reflect on their actions. We believe better understanding of students’ explanations of their behaviour within professionalism dilemmas will enhance patient care.

Acknowledgements: we would like to thank all participants for giving their time to participate in the research. We also acknowledge institutional heads for allowing us to recruit students at their schools.

Funding: This research was supported by a grant from the Association for the Study of Medical Education in the UK. Laura McDonald was supported by an Education Vacation Scholarship funded by NHS Education for Scotland (NES) Additional Cost of Teaching (ACT) funds.

An Evaluation of the University of Malawi College of Medicine (COM) Elective Programme at the University of Dundee (UoD)

O McIntosh

University of Dundee

Introduction: The University of Malawi and the UoD operate a six-week elective programme in Dundee for medical students studying at the COM. This programme has been running from 2007-2012 with a total of twelve participants. The objective of this pilot study was to evaluate the programme through participants’ perceptions of their experiences.

Methods: Qualitative, grounded theory methodology was adopted. Interviews were conducted with eight COM students/graduates who had completed their elective at the UoD and with four elective coordinators.

Results: Results were examined from several angles: COM students/graduates’ experiences; elective coordinators’ perceived aims and benefits; and programme structure and organisation. Several categories and themes emerged from participants views of their exposure to different diseases, technology and culture.

Conclusions: The COM elective at the UoD provides a valuable opportunity for students to experience healthcare delivery in a high resource setting. Participants perceived it to be a motivating experience, aiding reflection upon domestic healthcare delivery and furthering personal and professional growth. The programme has helped to develop the COM curriculum and has the potential to act as a mechanism for the retention of COM graduates in Malawi. Recommendations for programme development concern structure, organisation, funding and awareness. Collaborative programmes like the UoD-COM exchange are considered fundamental to the progression of global healthcare (Frenk and Chen 2010) and this programme demonstrates one local method of influencing the education of healthcare professionals internationally.

References: Frenk, J. & Chen, L., 2010. Health professionals for a new century: transforming education to strengthen health systems in an interdependent world, Available at: http://healthprofessionals21.org/images/healthprofnewcentreport.pdf.

The role of autophagy in the pathogenesis of Amyotrophic Lateral Sclerosis Type 8

D McMorran, G Pennetta

University of Edinburgh

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition characterised by death of motor neurons leading to paralysis and invariably death. VAPB (VAMP-associated protein B) is a causative gene of ALS8 in humans, however this mechanism remains unclear. Genetic screening using the Drosophila melanogaster model of ALS8, DVAP-P58S, identified genes which interact with mutant DVAP, including autophagy-related genes. Autophagy is an intracellular process which eliminates bulky proteins, and has already been implicated in neurodegeneration. I used systematic genetic analysis approach and the power of Drosophila melanogaster disease modelling to ascertain the effects of DVAP-P58S on autophagy.

Methods: Flies expressing DVAP-P58S were crossed with flies with altered autophagy-related gene expression, and assessment of the resultant progeny's phenotype determined the effects on neurodegeneration. Autophagy was assessed at the cellular level using confocal microscopy, allowing visualisation of autophagosomes.

Results: Reducing the expression of various autophagy-related genes was associated with suppression of the neurodegenerative phenotype, while increasing expression was associated with enhancement. Confocal analysis showed that in flies expressing DVAP-P58S there is altered autophagy and accumulation of autophagosomes prior to fusion with lysosomes.

Discussion: There is a consistent effect, with up-regulation of autophagy associated with enhanced neurodegeneration, while reducing autophagy partially rescues the neurodegenerative phenotype. This appears to be due to autophagy being blocked at a given point pre-autophagolysosome formation, with the resultant accumulation of autophagic intermediates exerting the pathological effect.

Conclusion: Aberrant autophagy is an aspect of ALS8 pathogenesis, and pharmacological reduction of autophagy is a potential therapeutic target for patients which should be explored further.

Acknowledgement: All work was completed at the University of Edinburgh, Centre for Integrative Physiology. Funding for the work of Dr Pennetta is supplied by the Euan MacDonald Centre for Motor Neuron Disease Research.

Diagnosing and Monitoring Multiple Sclerosis Using Optical Coherence Tomography: a review

R Mercer, C Mulholland

University of Edinburgh

Introduction: Visual complications affect around 80% of patients with Multiple Sclerosis (MS), involving an inflammatory reaction that damages ocular tissue. Optical Coherence Tomography (OCT), a method of imaging retinal layers, could potentially detect early pathological changes in MS.

Methods: We reviewed literature on the application of OCT in MS. The data we extracted from the studies focused on the following: 1) The accuracy of various paraclinical tests used to diagnose MS, with specific emphasis placed on OCT. 2) The use of OCT in monitoring MS. In this we specifically looked at the ability of OCT to monitor retinal changes in MS, and to detect any adverse drug reactions to Fingolimod (an immunomodulatory drug).

Results: Patients with MS were found to display greater RNFL thinning than controls on OCT images. OCT can also detect subclinical retinal damage. However OCT is limited to use as a secondary diagnostic aid. Correlations were found between RNFL thinning and disease severity, showing increased visual complications. There was no link with RNFL thinning and disease duration. OCT is able to detect some cases of microcytic macular oedema (MMO), a side effect of Fingolimod and sometimes seen in a small number of high-risk patients with MS.

Conclusion: On the basis of current evidence, OCT remains an unsuitable diagnostic tool on its own. It is also difficult to elucidate the role of OCT in monitoring MS. As treatments such as fingolimod becomes increasingly available, the application of OCT in patients with MS may be seen in a future clinical setting however more research is needed.

Acknowledgements: Professor Baljean Dhillon and Dr. Zuhair Mustafa, Alexandra Eye Pavilion, Edinburgh.

The use of fMRI to study cognitive function in patients with disorders of consciousness

K Nweze

University of Liverpool

Introduction: Evidence has shown that with current behavioural assessments, there is a high rate of misdiagnosis for patients with disorders of consciousness (DOCs). This can lead to unfitting patient management and heavier emotional burdens on close ones. FMRI offers an objective measurement of neural activity and has been manipulated to studying levels of consciousness through task related paradigms. These ‘active paradigms’ involve patients engaging in minimal physical activity (moving fingers) or mental tasks (imagining playing a sport) in the hope that predefined cortical regions will be activated and detected by fMRI. These tests have been trialled on patients with DOCs to gauge levels of retained cognition and awareness when compared to healthy subjects. The aim of this literature review is to examine the design and results of paradigms trialled on patients to test for preserved cognition.

Methods: The literature was searched for articles on fMRI focused evaluations using stringent search criteria. Articles were judged against appraisal standards, namely the CASP diagnostic checklist and the BMJ Evidence-based Toolkit.

Results: From 34 articles, 3 were chosen. These articles had specific study designs, each with the intention of locating regions of conserved function in brain-injured patients.

Discussion: This review found that article 1, a mental imagery-based study, presents the most robust method for determining cerebral function. Although the one positive result for the clinical subject remains ambiguous, the 100% success rate for healthy volunteers is promising.

Conclusion: Further research into replicating results in more clinical subjects and transference of methods to the acute setting is required.

Post-operative outcomes of revascularization procedures for the treatment of Moyamoya Disease

K Nweze

University of Liverpool

Introduction: Moyamoya disease (MMD) is a rare steno-occlusive disease of the terminal internal carotid arteries, with the formation of tiny collateral vessels, described as a ‘puff of smoke’ on angiography. MMD produces a variety of neurological deficits and without treatment, prognosis is dismal. Surgical revascularization has been shown to be the most effective treatment for MMD. Three approaches are used to treat MMD: direct revascularization, indirect revascularization and a combination of the two. Various papers have been published detailing the clinical and angiographic outcomes of the different surgical techniques. The aim of this literature review is to critically appraise the design and findings of studies which report post-operative outcomes for patients with MMD whom had undergone direct, indirect or combined bypass procedures.

Methods: The literature was systematically searched via electronic databases, and recent articles which met inclusion criteria were selected for review. The articles were analysed against criteria from the CASP cohort study checklist and relevant findings were included in the review.

Results: 7 articles were chosen for review. These papers focused on improvements in cerebral haemodynamics, extent of revascularization and patients’ symptoms.

Discussion: From these articles, this review found that direct and combined methods demonstrated better results particularly on angiography than indirect revascularization.

Conclusion: All study designs were flawed and larger prospective studies are required to determine the best surgical procedure for MMD.

Exploring the association between weight change, glycaemic control and cardiovascular morbidity in type 2 diabetic patients: An exploratory study in Tayside.

S Puvaneswaralingam

University of Dundee

Introduction: Two million people in the UK suffer from diabetes mellitus, 90% of which have type 2 (T2DM). Normally, weight increases with age and T2DM is strongly associated with obesity. Weight loss should improve glycaemia and reduce cardiovascular morbidity.

Methods: This study investigated the association between weight change, glycaemic control and cardiovascular morbidity in 611 T2DM patients, aged 35-65 years, diagnosed in 2005 and followed-up until 2010. Correlation and logistic regression determined the odds of experiencing cardiovascular disease (CVD).

Results: Approximately 50% (n=303) lost or maintained their weight at year five; their mean weight change was -6.31kg (SD=5.62kg). Over 25% of patients lost more than 5% of their body weight, meanwhile 46.8% gained weight. Percentage body weight change was inversely correlated with HDL and total cholesterol. Patients who lost weight had a median HbA1c change of -2.00mmol/mol (same as those who did not lose weight). HbA1c and weight change were inversely correlated. HbA1c and CVD were positively correlated at five years.

Discussion: There were no significant differences in CVD risk factors (blood pressure, cholesterol) between those who did and did not lose weight. Weight gain increased risk of CVD at one year. Prevalence of CVD and prescription of cardiovascular drugs increased over the five-year period. Age was the strongest predictor of CVD at all years.

Conclusion: Weight gain improved glycaemic control, possibly due to anti-diabetic drugs. Weight loss was greater in those without CVD at one year than those with CVD. T2DM patients should be encouraged to lose weight to improve glycaemia and reduce CVD.

G’ing in the right direction? Mobile phone use and coverage in rural general practice in the UK

J Reid

University of Edinburgh

Introduction: Poor mobile coverage has a potential impact on health service delivery and provision, and thus patient care. In particular, rural medical professionals face problems of poor coverage despite advances in healthcare technologies.

Aims: The aims of this project were to assess mobile phone use by rural general practitioners (GPs) in the UK.

Methods: A paper questionnaire was given out to all GPs attending the 2nd National Conference on Rural General Practice in Penrith, England, on the 16th March 2013. The questionnaire was also sent out as an online survey to members of the GP rural network.

Results and discussion: The results of the questionnaire provide overwhelming confirmation that poor or no mobile coverage exists in rural general practice in the UK. 75% of GPs who completed the questionnaire felt that poor or no mobile coverage can be detrimental to their work. Nevertheless, technological advances can be useful in the delivery of rural medicine and some potential solutions and opportunities are discussed in relation to future telemedicine.

Post-operative abbreviated mental test score in fractured neck of femur patients

D Roberts

University of Bristol

Introduction: Neck of femur (NOF) fractures are a major public health issue. Cognitive status has a bearing on functional abilities, length of stay and outcome in fractured NOF patients. The Best Practice Tariff introduced by the government for improvement of services requires that abbreviated mental test scores (AMTS) are performed pre- and post-surgery. However, there are no evidence based guidelines as to the timing of post-operative cognitive scoring.

Methods: A prospective study was conducted on all patients presenting to Great Western Hospital with NOF fractures during a 4-week period (24/06/2013 to 19/07/2013). Pre-operative AMTS were recorded at admission; post-operative scores were recorded daily from day 0 (day of surgery) to day 8 or discharge.

Results: 27 patients were identified during this period; all underwent data collection as above. There was no loss of data to follow up. Results showed a decline in AMTS on day 0 and then gradual increase to pre-operative levels at day 3 (no significant difference, p>0.05).

Discussion: Performing the post-operative AMTS too soon after surgery is unlikely to yield useful information about a patients’ recovery. Quite often post-operative delirium would cloud the picture; AMTS could be used as a surrogate marker to assess for this condition. We recommend that fractured NOF patients should have an AMTS recorded on day 4 post-surgery and this should be used towards discharge planning and involvement of social care.

Conclusion: Based on this study, it is recommended that post-operative AMTS measurements should be standardised for the best practice tariff to day 4 post-surgery.

Acknowledgements: Many thanks to Mr Hollinghurst, Mr Mitra, Dr Zaw and Dr Hartley for their help and support over the study period. A special thank you to all the patients who agreed to take part.

PARP1 and RAD51 protein expression as biomarkers of homologous recombination status in ovarian cancers.

S Tomassini

University of Newcastle

Introduction: Homologous recombination (HR) pathway status can predict how ovarian cancers will respond to standard chemotherapy and novel treatments. Currently, it can only be determined from cultured cells derived from ascites, which is rarely feasible in a clinical context. Therefore a clinically feasible test to determine HR status is an important development in the emerging field of stratified medicine. We believe that PARP1 and RAD51 protein expression could reliably determine HR status.

Methods: Protein expression was analysed using immunohistochemical (IHC) labelling of previously assembled tissue microarrays (TMAs) of ovarian cancer. The TMAs were scanned using the Aperio Scanscope System.

Results: We could not identify a correlation between PARP1 /RAD51 expression and HR status. However, a trend between high levels of PARP1 and longer progression free survival (PFS) was identified.

Discussion: Our findings indicate that PARP1 and RAD51 expression either individually or together is not a sufficient biomarker for HR status, but given the multiplicity and interchangeability of DNA-repairing pathways, analysing the expression of an individual protein may be limited as it does not account for possible interactions with other pathways. The correlation with PFS makes PARP1 expression a potential prognostic factor as previously demonstrated in breast cancer (von Minkwitz et al. Journal of Clinical Oncology, 2011).

Conclusion: Whilst not omitting the possibility of PARP1 or RAD51 importance with regard to HR status, further investigation of the expression of more DNA-repair related proteins may prove beneficial in identifying an appropriate biomarker for clinical testing of HR status.

The role of Yes-associated protein (YAP) as an oncogene in Renal Cell Carcinoma: In-vitro and pilot experiments

J Wan [1], A Mathur [2]

[1] University of St Andrews, [2] University of Edinburgh

Introduction: YAP is a transcriptional co-activator in the Hippo signalling pathway that has been shown to have a role as an oncogene in several types of cancers; its role in renal cell carcinoma remains controversial.

Methods: RCC30 cells were transfected with siRNA targeted at YAP. Evidence of reduction of YAP expression was demonstrated using Western blotting. The effects the transfections were assessed using Boyden chamber assay and drug-sensitivity assay using Sunitinib.

esults: There was around a 95% reduction in the expression of cellular YAP in those cells treated with siYAP compared to those treated with siCtrl. On average, this resulted in about a two-fold increase (from 377 to 677) in cellular migration (p< 0.0726, [95% CI= -633.09 to 33.09]) in the Boyden chamber. The decrease in cell numbers after drug treatment in siYAP cells showed a similar trend as siCtrl cells (p< 0.0308,[95% CI= -4955.79 to -474.21); however, these results should be interpreted with caution.

Discussion: Contrary to the original hypothesis that YAP is an oncogene, these experiments suggest that YAP inhibits cell migration. The role of YAP’s interactions with other cell signalling pathways might have influence on the migration of the cells such as the Wnt/ß-catenin pathway (canonical Wnt signalling pathway).

Conclusion: These pilot studies have shown that further experimentation is warranted to accurately elicit the role of YAP in renal cell carcinoma.

Acknowledgements: Funding from Pathological Society of Great Britain and Ireland Undergraduate Bursary 2013. Supervisor: Dr Paul Reynolds, University of St Andrews

The effect of Tartrate-Resistant Acid Phosphatase gene knockout on bone formation in mice.

M Wijeyaratne

University of Bristol

Introduction: TRAP is a group of metalloenzymes associated with osteoclastic action, and is confirmed to participate in bone resorption. Thus, bone resorption is reduced in TRAP gene knockout (-/-) mice models. Bone resorption and formation are biologically interlinked in a dynamic equilibrium in order to maintain bone mass. The aim of this research is to determine the effect of TRAP-/- on bone formation in mice.

Methods: Periodic Calcein injections were given to TRAP-/- and control mice to label newly formed bone in the time between injections. Extent of calcein staining is an index of bone formation rate. Comparison of tibial sections from TRAP-/- and control mice was done using histomorphometry.

Results: Calcein staining was inadequate for accurate measurement of the labelled regions, and so were not utilised. Other parameters, such as perimeter to area ratios, were used to determine effects of TRAP-/- on bone. TRAP-/- bones had significantly more cortical bone and a smaller marrow cavity, compared to controls. TRAP-/- bones displayed a significant increase in bone width on the left (medial) side of the bone only, compared to controls. TRAP-/- did not affect total bone cross-sectional area, compared to control.

Conclusion: TRAP-/- does not significantly affect bone formation rate, but seems to affect location of bone formation. TRAP antagonist drugs could be produced for treatment or prevention of osteoporosis, as they may increase bone mass or prevent bone loss. However, further investigation is required to confirm whether TRAP-/- causes increased bone strength in life, and also rule out any side effects of TRAP antagonism.

Role of TGFβ in the function of tolerogenic dendritic cells for rheumatoid arthritis

OY Wong, C Hilliness, A Anderson

University of Newcastle

Introduction: Tolerogenic dendritic cell (TolDC) therapy is an experimental immunotherapy for rheumatoid arthritis (RA). TolDCs exert their effects by regulating antigen-specific T cells. Previous studies suggest that TolDCs have high expressions of transforming growth factor-beta (TGFβ). Aims: 1) Investigate the role of TGFβ in regulatory mechanism of TolDCs. 2) Assess responsiveness of T cells from RA patients to TGFβ and TolDCs.

Methods: TolDCs, generated by treating monocyte-derived DC with dexamethasone, vitamin D3 and lipopolysaccharide, were co-cultured with allogeneic T cells from healthy or RA donors in the presence of a TGFβ receptor inhibitor. Proliferation rate and cytokine production (IFN-γ and IL-10) of T cells were measured by 3H-thymidine labelling and ELISA. Surface TGFβ receptor II (TGFβRII) and intracellular phosphorylated Smad-2 and Smad-3 were measured in T cells from healthy and RA donors by flow cytometry.

Results: 1) Inhibition of TGFβ signalling reversed regulatory action of TolDCs, demonstrated by reinstatement of IFN-γ in healthy donor CD4+ T cells. 2) T cells from RA patients are similarly responsive to TGFβ at proximal signalling level as healthy controls, indicated by the level of TGFβRII expression and induction of Smads phosphorylation by TGFβ in CD4+ T cells. 3) TolDCs suppressed proliferation and IFN-γ secretion in RA patient synovial T cells.

Conclusions: TGFβ is an important cytokine in the regulation of T cells by TolDCs which may be used as a quality control marker for TolDC-generation for clinical application. This study also further demonstrates the potential of TolDC as a novel therapy for RA.

Clinical audit: The role of genetic analysis in the diagnosis and management of patients with sarcoma

YT Xu

University of Liverpool

Introduction: Sarcomas are rare cancers with limited improvements in survival rates over the past decades. Prompt diagnosis is paramount for minimising recurrence and prolonging long-term survival. The aim of this audit is to investigate the role of genetic analysis in the diagnosis and management of sarcoma patients within Merseyside and Cheshire. This audit is necessary not only due to increasing genetic utilisation in diagnosis, but also because it is the first audit which investigates the efficacy of the regional genetic services. It can provide a baseline of current efficacy of the diagnostic process, as well as a framework for improvements.

Methods: Patients were included by reviewing the regional sarcoma registry data between July 2007 and January 2013. The collected data was analysed by assessing the success rate and factors affecting this rate.

Results: Data on 63 eligible patients was audited. All cases received genetic analysis to confirm initial diagnosis. The types of tests included conventional cytogenetics, fluorescence in situ hybridisation (FISH), and reverse transcription-polymerase chain reaction (PCR). The overall success rate was 71.4% - conventional cytogenetics had a success rate of 60.0%, FISH and PCR 100%.

Discussion and conclusion: The overall success rate was not affected by the time of genetic analysis or the initial diagnosis, but rather by the type of test used. The success rate of conventional cytogenetic analysis needs to be improved by identifying underlying issues. Ideally, multiple types of tests should be used in diagnosis. Additionally, more consistent reporting and documenting of cases will enable regular auditing.