Publications
309 results found
Appleby R, Moghul I, Khan S, et al., 2019, Non-alcoholic fatty liver disease is associated with dysregulated bile acid synthesis and diarrhea: a prospective observational study, PLoS ONE, Vol: 14, ISSN: 1932-6203
BackgroundNon-alcoholic fatty liver disease (NAFLD) may be associated with changes in bile acid (BA) metabolism. Hepatic BA production, measured by serum levels of the precursor 7α-hydroxy-4-cholesten-3-one (C4), is regulated by the farnesoid-X-receptor (FXR)-dependent ileal hormone fibroblast growth factor 19 (FGF19). Low FGF19 and high C4 are features of chronic BA diarrhea. Obeticholic acid, an FXR agonist, stimulates FGF19 and has shown therapeutic potential in both BA diarrhea and in NAFLD. We hypothesized there are associations of FGF19, C4 and BA diarrhea with NAFLD.Methods and findings127 patients with known NAFLD were recruited prospectively. Clinical features, including metformin use, markers of NAFLD severity and BA synthesis were analyzed. The overall incidence of chronic diarrhea was 25%, with features of BA diarrhea in 12%. FGF19 negatively correlated with C4 (rs = -0.43, p = 0.001) and with alanine aminotransferase (rs = -0.22, p = 0.03), but not with either NAFLD fibrosis or Fibroscan scores. High C4 was associated with a higher NAFLD fibrosis score (p < 0.05), and with diarrhea (p = 0.001). The median NAFLD fibrosis score was higher in those with diarrhea (p = 0.002). Metformin use, in 44% overall, was particularly associated with diarrhea (in 36% vs 17%, p = 0.02), and a lower median FGF19 (74 vs 105 pg/mL, p < 0.05).ConclusionsIncreased hepatic BA production and diarrhea, but not low FGF19, were associated with increased NAFLD fibrosis score, indicating dysregulation of the FXR-FGF19 axis and suggesting hepatic FGF19 resistance. Metformin use was an important factor in a subgroup, lowering FGF19, and resulting in bile acid diarrhea.
Pattni SS, Walters JRF, 2019, Bile Acid Diarrhea, Encyclopedia of Gastroenterology, Second Edition, Pages: 279-286, ISBN: 9780128124604
Bile acid diarrhea, or bile acid malabsorption, is a syndrome of chronic watery diarrhea. It can be diagnosed by measuring fecal bile acids or by the SeHCAT (selenium-homocholic acid taurine) test. Symptoms usually respond to bile acid sequestrants. Bile acid diarrhea may be secondary to ileal resection or Crohn's disease, affecting the enterohepatic circulation of bile acids, and is often recognized after cholecystectomy. Primary bile acid diarrhea (PBAD) is a common condition affecting approximately 1% of the population and has no definitive cause. PBAD is under-diagnosed, but accounts for around 30% of IBS-diarrhea, with a large associated burden of disease.
Walters JRF, 2018, Letter: long-term treatment of severe bile acid diarrhoea-obeticholic acid can normalise SeHCAT retention, Alimentary Pharmacology and Therapeutics, Vol: 48, Pages: 1032-1034, ISSN: 0269-2813
Hegyi P, Maléth J, Walters JR, et al., 2018, Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease, Physiological Reviews, Vol: 98, Pages: 1983-2023, ISSN: 1522-1210
Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.
Arasaradnam RP, Brown S, Forbes A, et al., 2018, Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition, Gut, Vol: 67, Pages: 1380-1399, ISSN: 0017-5749
Chronic diarrhoea is a common problem, hence clear guidance on investigations is required. This is an updated guideline from 2003 for the investigations of chronic diarrhoea commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). This document has undergone significant revision in content through input by 13 members of the Guideline Development Group (GDG) representing various institutions. The GRADE system was used to appraise the quality of evidence and grading of recommendations.
Best D, Kelman L, Walters JR, 2018, PROBLEMS EXPERIENCED BY PATIENTS WITH BILE ACID DIARRHEA: A CONTENT ANALYSIS OF POSTINGS ON A FACEBOOK SUPPORT GROUP, Annual Meeting of the American-Society-for-Gastrointestinal-Endoscopy / Digestive Disease Week, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S912-S912, ISSN: 0016-5085
Lee JM, Ong JR, Vergnes L, et al., 2018, Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants, Journal of Lipid Research, Vol: 59, Pages: 429-438, ISSN: 0022-2275
Diet1 modulates intestinal production of the hormone fibroblast growth factor 15 (FGF15), which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1 null mutation are resistant to hypercholesterolemia compared to wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL6/J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant (rs12256835) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions.
Appleby RN, Nolan JD, Johnston ID, et al., 2017, Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis., BMJ Open Gastroenterology, Vol: 4, ISSN: 2054-4774
Background Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD.Methods A cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea.Findings Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (rs=−0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis.Interpretation The diagnosis of BAD is associated with fatty liver disease and with galls
Walters JRF, 2017, Editorial: diagnosing bile acid diarrhoea with blood tests, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 46, Pages: 699-700, ISSN: 0269-2813
Ong S, Rodriguez-Garcia C, Grabczynska S, et al., 2017, Alopecia areata incognita in Cronkhite-Canada syndrome, British Journal of Dermatology, Vol: 177, Pages: 531-534, ISSN: 1365-2133
Cronkhite-Canada syndrome is an acquired inflammatory polyposis syndrome in which alopecia, onychomadesis and hyperpigmentation occur concurrently with gastrointestinal symptoms. The pathophysiology of alopecia in Cronkhite-Canada syndrome has not been definitively elucidated. We present evidence for alopecia areata incognita as a possible mechanism of hair loss.
Turner J, Walters JR, 2017, RESPONSE OF COELIAC PATIENTS TO A LONG-TERM GLUTEN-FREE DIET, Annual General Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A195-A196, ISSN: 0017-5749
Introduction Most complications in coeliac disease appear to be secondary to small intestinal disease, and assessment of this is therefore essential in monitoring coeliac disease status. Recent studies have suggested that tissue transglutaminase (tTG) autoantibodies are insufficient for this, highlighting the need for follow-up biopsy. The aims of this study were to evaluate the criteria for assessing coeliac disease status and suitability for discharge in long-term coeliac patients and to examine factors associated with risk of morbidity.Method An prospective analysis was made of coeliac patients who reported being compliant with a gluten-free diet for more than two years. They were seen by a single consultant and had attended a follow-up appointment during a 15 month period. Patients were recommended to have a repeat duodenal biopsy and other evaluations, including tissue tTG serology, other blood tests and bone densitometry.Results 81 patients were reviewed, with 22% not receiving scheduled biopsies, and 2% being unsuitable. Of the 61 patients who had follow-up biopsies, 46 (75%) demonstrated mucosal healing (Marsh grade 0–1). Paired biopsy and IgA serology results were available for 54 patients. Negative tTG IgA antibodies were a poor marker of mucosal healing, with a sensitivity for detecting villous atrophy of 29% and a negative predictive value of 79%. Long-term complication rates, especially low haemoglobin, folate or vitamin D, and reduced bone mineral density, were frequent regardless of mucosal healing. Complication rates were lower in those with mucosal healing (75%) compared to those without (86%), but this was not significant (p=0.50).Conclusion We confirm that tTG serology is poor at predicting mucosal healing, supporting the use of follow-up biopsy. Decisions regarding healing are difficult to make in patients not wishing to receive follow-up biopsy. Other factors apart from mucosal healing also have importance in the development of comp
Turner J, Pattni SS, Appleby RN, et al., 2017, IN PATIENTS WITH CHRONIC DIARRHOEA, DIAGNOSING BILE ACID DIARRHOEA WITH A POSITIVE SEHCAT TEST RESULTS IN FEWER SUBSEQUENT INVESTIGATIONS, Annual General Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A267-A268, ISSN: 0017-5749
Turner JM, Pattni SS, Appleby RN, et al., 2017, A positive SeHCAT test results in fewer subsequent investigations in patients with chronic diarrhoea., Frontline Gastroenterology, Vol: 8, Pages: 279-283, ISSN: 2041-4137
Chronic diarrhoea is a common condition, resulting from a number of different disorders. Bile acid diarrhoea, occurring in about a third of these patients, is often undiagnosed. We hypothesised that a positive diagnosis of bile acid diarrhoea would reduce the need for subsequent investigations for alternative diagnoses. METHODS: Patients previously recruited to a study of chronic diarrhoea who had selenium homocholic acid taurine (SeHCAT) testing and subsequent follow-up at our institution were identified. In a retrospective analysis, the numbers of defined investigations undertaken from the first 3 months after SeHCAT in the following 5 years were compared. RESULTS: 90 patients were identified with primary bile acid diarrhoea (SeHCAT retention <15%, n=36) or idiopathic diarrhoea (SeHCAT retention >15%, n=54). Follow-up had been performed on 29 and 39 subjects, respectively, with no differences in previous investigations or the last contact date. In the follow-up period, the proportions of these patients who had undergone endoscopic procedures (gastroscopy, colonoscopy and sigmoidoscopy) were the same. However, there was a higher proportion of patients in the SeHCAT-negative group who had other investigations, including imaging, physiological tests and blood tests (p=0.037). The use of cross-sectional imaging was significantly higher in this group (p=0.015) with greater proportions having CT (0.44 vs 0.10) and MRI (0.26 vs 0.07). Ultrasound use and the number of blood tests were higher in the SeHCAT-negative group whereas the SeHCAT-positive group attended more clinic appointments (p=0.013). CONCLUSION: A positive diagnosis of bile acid diarrhoea, made by a SeHCAT test, resulted in reduced use of diagnostic investigations over the subsequent 5 years.
Walters JRF, 2017, Editorial: developing a stimulation test to identify FGF19 deficiency in bile acid diarrhoea, Alimentary Pharmacology and Therapeutics, Vol: 46, Pages: 69-70, ISSN: 0269-2813
Walters JRF, 2017, A Twist in the Tale of a Pig Model of Short-Bowel Syndrome, CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, Vol: 4, Pages: 201-202, ISSN: 2352-345X
Walters JR, Bannaga A, O'Connor M, et al., 2017, BILE ACID DIARRHEA: PATIENT-REPORTED SYMPTOMS AND OUTCOMES, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S1-S2, ISSN: 0016-5085
Ovadia C, Chambers J, Martineau M, et al., 2017, Cholestatic pregnancy is associated with dynamic changes in total bile acids secondary to dietary intake - relevance for clinical diagnosis, management and underlying pathology, British Maternal & Fetal Medicine Society (BMFMS) 19th Annual Conference 2017., Publisher: Wiley, Pages: 117-117, ISSN: 1470-0328
Bannaga A, Kelman L, O'Connor M, et al., 2017, How bad is bile acid diarrhoea: an online survey of patient-reported symptoms and outcomes., BMJ Open Gastroenterology, Vol: 4, ISSN: 2054-4774
OBJECTIVES: Bile acid diarrhoea (BAD) is an underdiagnosed condition producing diarrhoea, urgency and fear of faecal incontinence. How patients experience these symptoms has not previously been studied. Bile Acid Malabsorption (BAM) Support UK was established in 2015 as a national charity with objectives including to provide details regarding how BAD affects patients, to improve earlier recognition and clinical management. DESIGN SETTING AND MAIN OUTCOME: A questionnaire was collected anonymously by BAM Support UK and the Bile Salt Malabsorption Facebook group over 4 weeks at the end of 2015. It comprised 56 questions and aimed to inform patients and clinicians about how BAD affects the respondents. RESULTS: The first 100 responses were analysed. 91% of the respondents reported a diagnosis of BAD. 58% of total respondents diagnosed following a Selenium-homocholic acid taurine scan, 69% were diagnosed by a gastroenterologist, with type 2 and 3 BAD comprising 38% and 37%, respectively, of total respondents. Symptoms had been experienced for more than 5 years before diagnosis in 44% of respondents. Following treatment, usually with bile acid sequestrants, 60% of participants reported improvement of diarrhoea and most reported their mental health has been positively impacted. Just over half of the cohort felt as though their symptoms had been dismissed during clinical consultations and 28% felt their GPs were unaware of BAD. CONCLUSIONS: BAD requires more recognition by clinicians to address the current delays in diagnosis. Treatment improves physical and mental symptoms in the majority of participants.
Keely SJ, Walters JRF, 2016, The farnesoid X receptor: good for BAD., Cellular and Molecular Gastroenterology and Hepatology, Vol: 2, Pages: 725-732, ISSN: 2352-345X
Diarrhea is a feature of several chronic intestinal disorders that are associated with increased delivery of bile acids into the colon. Although the prevalence of bile acid diarrhea is high, affecting approximately 1% of the adult population, current therapies often are unsatisfactory. By virtue of its capacity to inhibit colonic epithelial fluid secretion and to down-regulate hepatic bile acid synthesis through induction of the ileal fibroblast growth factor 19 release, the nuclear bile acid receptor, farnesoid X receptor, represents a promising target for the development of new therapeutic approaches. Here, we review our current understanding of the pathophysiology of bile acid diarrhea and the current evidence supporting a role for farnesoid X receptor agonists in treatment of the disease.
Appleby RN, Bajor A, Gillberg P-G, et al., 2016, Effects of conventional and a novel colonic-release bile acid sequestrant, A3384, on fibroblast growth factor 19 and bile acid metabolism in healthy volunteers and patients with bile acid diarrhoea, UNITED EUROPEAN GASTROENTEROLOGY JOURNAL, Vol: 5, Pages: 380-388, ISSN: 2050-6406
Background:Primary bile acid diarrhoea (BAD) is associated with increased bile acid synthesis and low fibroblast growth factor 19 (FGF19). Bile acid sequestrants are used as therapy, but are poorly tolerated and may exacerbate FGF19 deficiency.Aim:The purpose of this study was to evaluate the pharmacological effects of conventional sequestrants and a colonic-release formulation preparation of colestyramine (A3384) on bile acid metabolism and bowel function in patients with BAD.Methods:Patients with seven-day 75selenium-homocholic acid taurine (SeHCAT) scan retention <10% were randomised in a double-blind protocol to two weeks treatment with twice-daily A3384 250 mg (n = 6), 1 g (n = 7) or placebo (n = 6). Thirteen patients were taking conventional sequestrants at the start of the study. Symptoms were recorded and serum FGF19 and 7α-hydroxy-4-cholesten-3-one (C4) measured.Results:Median serum FGF19 on conventional sequestrant treatment was 28% lower than baseline values in BAD (p < 0.05). C4 on conventional sequestrant treatment was 58% higher in BAD (p < 0.001). No changes were seen on starting or withdrawing A3384. A3384 improved diarrhoeal symptoms, with a median reduction of 2.2 points on a 0–10 Likert scale compared to placebo, p < 0.05.Conclusions:Serum FGF19 was suppressed and bile acid production up-regulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD.
Brydon WG, Walters JR, Ghosh S, et al., 2016, Letter: hydroxypropyl cellulose as therapy for chronic diarrhoea in patients with bile acid malabsorption - possible mechanisms, Alimentary Pharmacology & Therapeutics, Vol: 44, Pages: 306-307, ISSN: 1365-2036
Moghul I, Appleby RN, Khan S, et al., 2016, Bile Acid Diarrhea and Low Fibroblast Growth Factor 19 (FGF19) Are Associated With Non-Alcoholic Fatty Liver Disease (NAFLD) and Metformin Use, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S125-S126, ISSN: 0016-5085
Nolan JD, Appleby RN, Zhang JH, et al., 2016, Stimulation of Expression of Ileal Fibroblast Growth Factor 19 (FGF19) by Bile Acids Is Reduced in Patients With Crohn's Disease, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S126-S126, ISSN: 0016-5085
Moghul I, Appleby RN, Khan S, et al., 2016, Diarrhea and High 7-Hydroxy-4-Cholesten-3-One (C4), But Not Low Fibroblast Growth Factor 19 (FGF19) Are Predictors of High Non-Alcoholic Fatty Liver Disease (NAFLD) Fibrosis Score, 57th Annual Meeting and Residents Fellow Conference of the Society-for-Surgery-of-the-Alimentary-Tract (SSAT) / 52nd Annual Meeting on Digestive Disease Week (DDW) / Meeting of the American-Gastroenterological-Association (AGA), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S717-S717, ISSN: 0016-5085
Johnston IM, Nolan JD, Pattni SS, et al., 2016, Characterizing Factors Associated With Differences in FGF19 Blood Levels and Synthesis in Patients With Primary Bile Acid Diarrhea, American Journal of Gastroenterology, Vol: 111, Pages: 423-432, ISSN: 1572-0241
OBJECTIVES: Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD.METHODS: Patients with PBAD, defined by reduced 75Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR.RESULTS: FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01).CONCLUSIONS: These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.
Jameie-Oskooei S, Appleby R, Geers J, et al., 2016, CAFESTOL BUT NOT RESVERATROL IS A PARTIAL AGONIST OF FARNESOIDX RECEPTOR AND STIMULATES FGF19 IN HUMAN ILEAL EXPLANTS, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S684-S684, ISSN: 0168-8278
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Geers J, Appleby R, Walters J, 2016, URSODEOXYCHOLIC ACID INCREASES OBETICHOLIC ACID STIMULATION OF FGF19 IN HUMAN ILEAL EXPLANTS, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S440-S440, ISSN: 0168-8278
Appleby RN, Nolan JD, Johnston IM, et al., 2015, Bile acid diarrhoea is associated with gallstones, 2nd Digestive-Disorders-Federation Conference, Publisher: BMJ Publishing Group, Pages: A521-A521, ISSN: 0017-5749
Appleby RN, Dinh TAB, Walters JJRF, 2015, A positive faecal calprotectin does not predict bile acid diarrhoea, 2nd Digestive-Disorders-Federation Conference, Publisher: BMJ Publishing Group, Pages: A205-A205, ISSN: 0017-5749
Nolan JD, Appleby RN, Madhan GK, et al., 2015, Stimulated expression of ileal fibroblast growth factor 19 by bile acids is impaired in patients with primary and secondary bile acid diarrhoea, 2nd Digestive-Disorders-Federation Conference, Publisher: BMJ Publishing Group, Pages: A19-A19, ISSN: 0017-5749
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