Scientific Business Abstracts of the 112th Annual Meeting of the Association of Physicians of Great Britain and Ireland

Biography Dr Chauhan graduated from University of Birmingham with his primary medical and BSc degree in 2006. He started higher specialty trainee in gastroenterology and hepatology in 2010. After being awarded a Wellcome trust clinical research training fellowship in 2013 Abhishek completed his doctoral research on the role of platelets activation in acute live failure working Adams and Watson lab(s) at the University of Birmingham. Currently, a clinical lecturer in Gastroenterology and Hepatology, Dr Chauhan's research is now focussed on the role platelets play in liver disease and is interested specifically in designing anti-platelet interventions for fulminant hepatic failure. Dr Chauhan serves on the editorial board of Frontline Gastroenterology. Introduction: Paracetamol (APAP) overdose is the leading cause of ALF in the West; the mechanisms that lead to ALF in APAP overdose remain poorly understood. We hypothesized that platelets could be important players in this process. The platelet receptor CLEC-2 mediates powerful platelet activation independently of haemostasis through its ligand podoplanin (PDPN). We sought to investigate the role of CLEC-2-dependent platelet activation in ALF. Methods: (APAP) was used to induce acute liver damage in mice with conditional deletions for either the platelet CLEC-2 receptor (PF4creClec1bfl/fl), or its activating ligand podoplanin (Vav1− iCre+PDPNfl/fl) or in mice treated with function blocking antibodies. Liver damage was assessed by measuring serum ALT, histology and quantifying the hepatic infiltrate/cytokine production. Results: CLEC-2-deficient mice healed much quicker after a toxic hepatic insult compared with WT mice (APAP ALT: WT 6768 IU/l vs. CLEC1bfl/flPf4Cre 317.0 IU/l; CCl4 ALT: WT 4451 IU/l vs. CLEC1bfl/flPf4Cre 810.2 IU/l). Targeting this pathway therapeutically using a specific PDPN function blocking antibody in WT mice also enhanced healing compared with control mice (IMC treated ALT—6768 IU/l vs. AB treated 238.0 IU/l). CLEC-2-deficient platelets interact with Kupffer cells to enhance TNF production which then increased hepatic neutrophil accumulation. Blocking TNF using an antibody (etanercept) or depleting neutrophils removed the protective effect of a CLEC-2 deficiency. We confirmed the relevance of this pathway in human ALF using PCR and immunohistochemistry. Conclusion: Blocking CLEC-2-mediated platelet activation enhances neutrophil-driven hepatic recovery without causing bleeding; this may represent a completely novel treatment for human ALF. Biography Dr Tariq Farrah MBChB Hons, BSc, MRCP Renal Specialist Registrar Clinical Research Fellow and Mackenzie Lecturer Background: Chronic kidney disease (CKD) is strongly associated with incident cardiovascular disease (CVD) that is partly explained by conventional CVD risk factors. Despite statin use, many CKD patients continue to have elevated lipids and persisting CVD risk. Endothelin-A (ETA) receptor antagonism is currently being investigated as a novel therapeutic approach to improve outcomes in CKD. Aim: We investigated the effects of selective ETA receptor antagonism on circulating lipids and PCSK9, whose inhibition offers a novel mechanism to reduce lipids. Design and methods: We performed a post hoc analysis of a randomized, double blind, three-way crossover study in 27 patients with varying degrees of CKD.1 On top of standard care, subjects received 6 weeks of sitaxentan, an ETA antagonist, matched placebo or nifedipine. Six weeks of sitaxentan and nifedipine reduced blood pressure (BP) and arterial stiffness similarly whereas only sitaxentan reduced proteinuria. Placebo did not affect these parameters. Results: Eighteen (67%) subjects were prescribed statins. Baseline lipids were similar between the three phases of the study (total cholesterol: 4.9±0.1mmol/l; HDL: 0.9±0.1mmol/l; LDL: 2.8±0.2mmol/l; triglycerides: 1.7±0.3mmol/l). Whereas placebo and nifedipine did not affect these, sitaxentan reduced cholesterol (−11±1%), LDL (−20±3%) and triglycerides (−20±4%), and increased HDL (+14±2%) (all Ps<0.001). These effects were independent of reductions in proteinuria, BP and arterial stiffness. Interestingly, sitaxentan treatment also led to an 18±2% fall in circulating PCSK9 (P<0.05). Conclusion: ETA antagonism offers a potentially novel strategy to reduce CVD risk in optimally managed patients with CKD. On-going larger and longer-term studies will explore these observations further. Biography Rahul Kalla is a Gastroenterology Registrar (ST6) in the Northwest Deanery and has an interest in Inflammatory Bowel Diseases (IBD). He has recently undertaken a PhD at the University of Edinburgh under Professor J. Satsangi investigating the clinical utility of epigenetic mechanisms in Inflammatory Bowel Disease. He is a co-investigator on two Crohn’s and Colitis grant applications investigating the role epigenetic biomarkers in IBD. He has recently been involved in setting up a research network in the Northwest (GastTRIN NoW) which aims to perform collaborative trainee led research initiatives across multiple sites in the Northwest deanery. Introduction: Biomarker discovery to predict disease outcomes is a key focus in Inflammatory Bowel Disease (IBD). We have characterized disease-associated methylation changes in newly diagnosed IBD, defined the relationship to genetic variation (meQTL) and assessed its prognostic utility in IBD. Methods: Genome-wide methylation and genotyping were performed in 641 peripheral blood DNA samples from new IBD cases across Europe (298 controls, 150 CD, 167 UC, 26 IBDU) using the Illumina 450k and HumanOmniExpressExome-8 BeadChips, respectively. Covariates included age, sex and cell counts, deconvoluted by the Houseman method. Treatment escalation in IBD was defined as the need for surgery and/or biologic therapies after initial induction of disease remission. Results: Totally, 1261 probes exhibited Holm significant IBD-associated methylation differences, including MIR21 (P = 2.8 × 10−20), RPS6KA2 (5.5 × 10−26) and PHOSPHO1 (8.3 × 10−15) and were consistent within the European cohort. Paired genetic and methylation data showed 4517 significant meQTLs on several key loci: RPS6KA2 (holm P = 1.4 × 10−20), ITGB2 (P = 3.3 × 10−38) and MIR21 (P = 3.5 × 10−19). Follow-up data were available for 296 patients with IBD and 68 patients required treatment escalation. Forty DMPs predicted treatment escalation (top probe holm P = 7.49 × 10−6). Unsupervised linear discriminant consensus clustering were performed using three top probes, identifying two patient subgroups with significantly different disease courses (HR 6.95, 95% CI: 2.6–18.3; P = 2.5 × 10−18), outperforming conventional biomarkers such as Albumin (HR 2.6 (1.4–4.9); P = 0.0001). Conclusion: These data show novel associations and important unequivocal replication of recent discoveries and provide insight into germline variation of epigenetic mechanisms in IBD. As biomarkers, the methylome shows promise in predicting disease course in IBD. Biography Rick Body is a Professor of Emergency Medicine. His main research interest is in improving the early diagnosis of acute coronary syndromes and he is a member of the International Federation of Clinical Chemistry Task Force on Cardiac Biomarkers. Prof. Body has over 100 publications, has given more than 80 invited presentations and his clinical studies have recruited >10 000 patients. Prof. Body pioneered the ‘single test rule out’ strategy using the limit of detection of the high sensitivity cardiac troponin T assay, and the Manchester Acute Coronary Syndromes (MACS) decision aid. Background: The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) computer decision aid can ‘rule in’ and ‘rule out’ acute myocardial infarction (AMI) with one blood test at the time of arrival in the Emergency Department (ED). Successful validation with a near-patient cardiac troponin (cTn) assay would reduce turnaround time, helping to unburden crowded EDs. We aimed to prospectively validate T-MACS with a contemporary near-patient cTn assay. Methods: In this multi-centre prospective diagnostic accuracy study nested within the Bedside Evaluation of Sensitive Troponin (BEST) programme, we recruited patients with suspected cardiac chest pain presenting to nine EDs. Patients with another medical condition requiring hospital admission and those whose symptoms peaked >12 h ago were excluded. Blood samples drawn on arrival were analysed for cTnI using the POC i-Stat assay (Abbott Point of Care). The primary outcome was a diagnosis of AMI, adjudicated based on serial central laboratory cTn analysis over at least 3 h. Results: Of 622 included patients, 78 (12.5%) had AMI. With one near-patient test, T-MACS would have ‘ruled out’ 41.6% (n = 259) patients with 97.4% sensitivity (95% CI 91.0–99.7%) and 99.2% negative predictive value (95% CI 97.0–99.8%). T-MACS would have ‘ruled in’ 7.1% (n = 44) patients with 99.2% specificity (95% CI 98.0–99.8%) and 90.9% (95% CI 78.5–96.5%) positive predictive value. Conclusions: To our knowledge this is the first successful validation of a single test ‘rule out strategy’ using a POC cTn assay. Its use could enable almost immediate reassurance and discharge for >40% of patients with suspected cardiac chest pain. Biography Peter N. Taylor BSc, MBChB, MSc is a Clinical lecturer specializing in diabetes and endocrinology at Cardiff University and the University Hospital of Wales. He received his undergraduate and medical degrees from the St. Andrews University and the University of Manchester. He undertook his core medical training at the two teaching hospitals in Edinburgh, before commencing specialist training in diabetes and endocrinology in Bristol and Bath and received a prestigious MRC scholarship to undertake a masters’ degree in epidemiology at the London School of Hygiene and Tropical Medicine. He is now finalizing his PhD in thyroid epidemiology under Professor Colin Dayan. His research has focused on the effects of common variation in thyroid status as well as thyroid hormone prescribing. In this work, he has also published the first whole genome sequence study to identify rarer variants associated with thyroid function and published the first Mendelian Randomization in thyroidology to better clarify the relationship between thyroid hormone and body composition. He has received awards at both national and international conferences for his work. Aims: Low thyroid function in pregnancy is associated with adverse obstetric outcomes. We investigated whether screening and treating subclinical hypothyroidism and isolated hypothyroxinemia during pregnancy improves obstetric outcomes. Methods: Analysis of UK participants in the Controlled Antenatal Thyroid Screening study a randomized controlled trial. Thyroid function was measured in 16 346 pregnant women between 11 and 16 weeks gestation. Women with thyroid stimulating hormone in the highest 2.5% (>3.16 mU/l) or free thyroxine in the lowest 2.5% (<10.9 pmol/l) were randomized to receive levothyroxine. In the original study IQ of offspring was assessed (Lazarus et al. NEJM 2012). In this study we analysed foetal loss after recruitment, gestational age at delivery, birthweight, delivery method and APGAR score using data-linkage from the Secure Anonymised Information Linkage databank. Results: Data were obtained on all individuals with low thyroid function (N = 753) and 13 651 (86.7%) of those with normal thyroid function. Untreated women (N = 371) had higher odds of fetal loss than both those with normal thyroid function OR = 8.76 (95% CI 3.64, 16.5) P < 0.0001 and those who received levothyroxine (N = 382) OR = 4.07 (95% CI 1.14, 14.5) P = 0.03. Treatment benefits were less clear for other outcomes although there was a higher rate of premature delivery in untreated women compared with those with normal thyroid function OR = 1.45 (95% CI 1.00, 2.12) P = 0.05. Conclusion: Screening and treating women with low thyroid function at 12 − 16 weeks gestation reduces the risk of foetal loss. Effects are substantial; up to 20% of foetal losses occurring after 16 weeks could be prevented with this safe and inexpensive treatment. Biography Dr Corcoran is a Cardiology Registrar in the West of Scotland deanery. Dr Corcoran recently completed a 3-year British Heart Foundation Clinical PhD Fellowship at the University of Glasgow's Institute of Cardiovascular and Medical Sciences. Dr Corcoran holds an Honorary Clinical Lectureship at the University of Glasgow and has an interest in coronary microvascular dysfunction. Aims: Remote ischaemic preconditioning (RIPC) is a cardioprotective intervention invoking intermittent periods of ischaemia in a tissue or organ remote from the heart. The mechanisms of this effect are incompletely understood. We hypothesized that RIPC might enhance coronary vasodilatation by an endothelium-dependent mechanism. Methods: We performed a prospective, randomized, sham-controlled, blinded clinical trial. Patients with stable coronary artery disease (CAD) undergoing elective invasive management were prospectively enrolled, and randomized to RIPC or sham (1:1) prior to angiography. Endothelial-dependent vasodilator function was assessed in a non-target coronary artery with intracoronary infusion of incremental acetylcholine doses (10–6, 10–5, 10–4 mol/l). Venous blood was sampled pre- and post-RIPC or sham, and analysed for markers of endothelial function. Coronary luminal diameter was assessed by quantitative coronary angiography. The primary outcome was the between-group difference in the mean percentage change in coronary luminal diameter following the maximal acetylcholine dose (Clinicaltrials.gov identifier: NCT02666235). Results: Seventy-five patients were enrolled. Following angiography, 60 patients (mean±SD age 57.5 ± 8.5 years; 80% male) were eligible and completed the protocol (n = 30 RIPC, n = 30 sham). The mean percentage change in coronary luminal diameter was −13.3 ± 22.3% and −2.0 ± 17.2% in the sham and RIPC groups, respectively (difference 11.32%, 95% CI: 1.2–21.4, P = 0.032). This remained significant when age and sex were included as covariates (difference 11.01%, 95% CI: 1.01–21.0, P = 0.035). There were no between-group differences in endothelial-independent vasodilation, ECG parameters or markers of endothelial function. Conclusions: RIPC attenuates the extent of vasoconstriction induced by intracoronary acetylcholine infusion. This endothelium-dependent mechanism may contribute to the cardioprotective effects of RIPC. Biography Tom Parks is an academic clinician based in the UK training in infectious diseases and general internal medicine. His doctoral studies were based at the Wellcome Trust Centre for Human Genetics in Oxford as a Medical Research Council Clinical Research Training Fellow. There he held grants from the British Heart Foundation and others. At the World Congress of Cardiology in 2016, he was awarded the World Heart Federation Young Investigator Award for his work on genetic susceptibility to rheumatic heart disease. He has recently taken up a postdoctoral Academic Clinical Fellowship at the London School of Hygiene and Tropical Medicine. Objective: Rheumatic heart disease is an important but neglected cause of morbidity and premature mortality in developing countries. Considered heritable for more than a century, we sought to investigate genetic susceptibility by using the latest approaches. Methods: We undertook case–control genome-wide studies of susceptibility in individuals of recruited across and individuals of recruited in and We obtained using a of and After by we used linear to the and data before using Results: We and a novel susceptibility in the across we the to a of variants in the to the odds P = we a more in the human This was in the the peaked in the = P = two independent the and our study insight into the of this disease with for This the value of such diseases using these into the role of which have been neglected in common disease Biography Professor at the University of Glasgow and graduated with in He then a PhD in in his he to the and in the Department of at the University of at he held the of this he was awarded a Research Institute a Blood Foundation and received several awards including the Blood Foundation for Research in and an Foundation Investigator In he was awarded a prestigious Research UK Fellowship and to work in the UK at the Institute of and in the University of Professor research is currently focused on of disease and this knowledge into therapeutic for patients. In is the of the Centre and also a programme, which the between clinical and Professor has published in the of and He was a of the of in and is a Research Fellow at the University of University of and the University of the West of Objective: There is a need in to identify biomarkers that can patients into to rheumatic We sought to identify the of and to whether such could predict to Methods: blood samples at 6 and 12 were from participants in a nested within patients recruited to the newly diagnosed patients commencing We performed and to Patients were to to Results: We circulating in patient in were in early compared to In we a significant (P < in conventional cells in to of the activation of 3 and and activation of in the there was significant of and in but not To these we performed linear analysis to a and markers that at from Conclusions: The of this study provide the first that in that are in peripheral these to and could treatment Biography Dr is a in Manchester and an lecturer with the University of Manchester. He was an MRC clinical research and an clinical Aims: in of in liver human of during as a to predict risk of Methods: was in in mice during and treatment patients were assessed for on liver was used for and with was into those who had and those who did in were assessed and a defined to predict disease. Results: In is associated with of and in hepatic cells and induced by CCl4 and with significantly reduced and a more in from patients, was increased with The in the initial with of = In an elevated significantly predicted risk of = The predictive was independent of age and and to risk factors. Conclusion: These data provide the first in that is a key of liver The role in human the for and its as new prognostic and therapeutic in liver Biography Dr from medical in and in and then Clinical undertook a Trust Clinical Research Fellowship genetic disease at The University of Manchester. then as an Clinical currently work as an Research Fellow at The University of Manchester and in the Department at Manchester Foundation research interest is Aim: To study the relationship between and in with Diseases Methods: Following clinical and was performed in with The and and and The was based on data from human or studies function with was assessed by quantitative PCR and was by in all Results: To at least with enhanced and have been studies in these has led to significant in the of in with in of with including such as and was in of the and showed significant with the assay = in in of inhibition and receptor work that through of patients with a that is not to a single diagnostic can be in would be of value. Biography Dr is an Clinical Lecturer at the University of Manchester. Aims: of to in liver Methods: cells from or control mice were in and analysed for markers by and and analysis used the Liver was induced in by or CCl4 in or control and and were assessed for by and assay. Results: were less by reduced and analysis of involved in and of all using liver in In as the production from human from mice were less and mice were liver We have that through in liver the of its clinical analysis we the as we that attenuates liver in and is a novel therapeutic available have specific are in clinical both may be for as

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