Impact of obesity and metabolic health status in the development of non-alcoholic fatty liver disease (NAFLD): A United Kingdom population-based cohort study using the health improvement network (THIN).

BACKGROUND: With the obesity epidemic reaching crisis levels, there has been attention around those who may be resilient to the effects of obesity, termed metabolically healthy obesity (MHO), who initially present without associated metabolic abnormalities. Few longitudinal studies have explored the relationship between MHO and non-alcoholic fatty liver disease (NAFLD), which we address using over 4 million primary care patient records. METHODS: A retrospective population-based longitudinal cohort was conducted using The Health Improvement Network (THIN) database incorporating adults with no history of NAFLD or alcohol excess at baseline. Individuals were classified according to BMI category and metabolic abnormalities (diabetes, hypertension and dyslipidaemia). Diagnosis of NAFLD during follow-up was the primary outcome measure. NAFLD was identified by Read codes. RESULTS: During a median follow-up period of 4.7 years, 12,867 (0.3%) incident cases of NAFLD were recorded in the cohort of 4,121,049 individuals. Compared to individuals with normal weight and no metabolic abnormalities, equivalent individuals who were overweight, or obese were at significantly greater risk of incident NAFLD (Adjusted HR 3.32 (95%CI 2.98-3.49), and 6.92 (6.40-7.48, respectively). Metabolic risk factors further increased risk, including in those with normal weight and 1 (2.27, 1.97-2.61) or = < 2 (2.39, 1.99-2.87) metabolic abnormalities. CONCLUSIONS: MHO individuals are at greater risk of developing NAFLD compared to those with normal weight. This finding supports that the MHO phenotype is a temporary state, and weight must be considered a risk factor even before other risk factors develop. Being normal weight with metabolic abnormalities was also associated with risk of NAFLD.

Faecal transplantation for IBD management-pitfalls and promises.

BACKGROUND: Faecal microbiota transplantation (FMT) as a potential treatment for inflammatory bowel disease (IBD) is an area of active current research, having been stimulated by the remarkable efficacy of FMT in treatment of Clostridium difficile-associated colitis. SOURCES OF DATA: This review is based on data from numerous case series on FMT in IBD since 1989 and results of four RCTs in ulcerative colitis (UC); three fully published. AREAS OF AGREEMENT: Early signals of short to medium-term efficacy of FMT for UC are promising. AREAS OF CONTROVERSY: Methodology, underlying mechanisms and questions regarding safety of FMT remain controversial. GROWING POINTS: Many trials of FMT in adults and children are currently recruiting. AREAS TIMELY FOR DEVELOPING RESEARCH: Future trials of FMT will likely revisit Crohn's disease and patients undergoing pouch surgery. Advances in microbial culture complementing genetic sequencing and investigations into the virome and mycobiome in IBD will be of great future interest.

Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection.

BACKGROUND: Clostridium difficile infection (CDI) is the commonest nosocomial cause of diarrhoea. Faecal microbiota transplantation (FMT) is an approved treatment for recurrent or refractory CDI but there is uncertainty about its use. AIM: To evaluate the efficacy of FMT in treating recurrent and refractory CDI and investigate outcomes from modes of delivery and preparation. METHODS: A systematic review and meta-analysis was performed. MEDLINE, EMBASE, CINAHL, Cochrane Library, trial registers and conference proceedings were searched. Studies on FMT in recurrent and refractory CDI were included. The primary outcome was clinical resolution with subgroup analyses of modes of delivery and preparation. Random effects meta-analyses were used to combine data. RESULTS: Thirty seven studies were included; seven randomised controlled trials and 30 case series. FMT was more effective than vancomycin (RR: 0.23 95%CI 0.07-0.80) in resolving recurrent and refractory CDI. Clinical resolution across all studies was 92% (95%CI 89%-94%). A significant difference was observed between lower GI and upper GI delivery of FMT 95% (95%CI 92%-97%) vs 88% (95%CI 82%-94%) respectively (P=.02). There was no difference between fresh and frozen FMT 92% (95%CI 89%-95%) vs 93% (95%CI 87%-97%) respectively (P=.84). Administering consecutive courses of FMT following failure of first FMT resulted in an incremental effect. Donor screening was consistent but variability existed in recipient preparation and volume of FMT. Serious adverse events were uncommon. CONCLUSION: Faecal microbiota transplantation is an effective treatment for recurrent and refractory Clostridium difficile infection, independent of preparation and route of delivery.

Management of acute upper gastrointestinal bleeding: an update for the general physician.

Acute upper gastrointestinal bleed (AUGIB) is one of the most common medical emergencies in the UK, with roughly one presentation every 6 min. Despite advances in therapeutics and endoscopy provision, mortality following AUGIB over the last two decades has remained high, with over 9,000 deaths annually in the UK; consequently, several national bodies have published UK-relevant guidelines. Despite this, the 2015 UK National Confidential Enquiry into Patient Outcome and Death in AUGIB highlighted variations in practice, raised concerns regarding suboptimal patient care and released a series of recommendations. This review paper incorporates the latest available evidence and UK-relevant guidelines to summarise the optimal pre-endoscopic, endoscopic, and post-endoscopic approach to and management of non-variceal and variceal AUGIB that will be of practical value to both general physicians and gastroenterologists.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Organising a World Congress of Epidemiology (WCE): reflections and lessons from the XIX WCE, Scotland.

The 3-yearly World Congress of Epidemiology is the premier, international, scientific conference organised under the auspices of the International Epidemiological Association (in open competition). This paper explores the justification for seeking to host the Congress and reflects on the structures and processes adopted in making the XIXth Congress in Scotland happen. Preparing the bid was invaluable for forming collaborations, generating scientific ideas, and garnering opinion. After the bid was accepted, we formed a local organising committee, named the Management Executive Committee to signal its decision making authority; and scientific, fundraising, marketing, international and social subcommittees. There was uncertainty about critical matters such as delegate numbers, costs and the total budget. Early decisions had to be made on, for example, the fee and fundraising target (£250,000), despite financial risks. Development of the scientific programme was a critical step that underpinned fundraising and marketing and permitted involvement of the international committee. Overall the 2011 WCE succeeded. The key ingredients to success were: a large collaboration of institutions and individuals; early pledges of financial support mostly from the UK; the valuable and relevant experience of the professional conference organisers; unstinting support and advice from IEA; and the effectiveness of the committee structure. The educational and professional development benefits of this WCE will reach a worldwide community and not just delegates, because of video, PowerPoint and textual accounts being open access on the Internet. This reach is unprecedented for IEA's World Congresses. We anticipate that the Congress will translate into better public health practice, better future Congresses, advances in epidemiology and improved population health.

Epidemiology Congresses XIX, XX and beyond: back to the future of population health.

The XIX World Congress of Epidemiology discussed 'Changing populations, changing diseases: epidemiology for tomorrow's world' and was able to set a benchmark for the current state for the science of population health. However, 'changing populations and changing diseases' mean that robust epidemiological enquiry is, and will continue to be, required, but most importantly, it must remain objective and relevant to the public it serves. We look forward to further discussion on population health science in tomorrow's world in three years time at the XX World Congress of Epidemiology in Anchorage, Alaska.

Changing trends of diseases in Eastern Europe: closing the gap.

One of the greatest challenges in Europe at the beginning of the 21st Century is the wide east-west health gap. In 2008, the difference in life expectancy between men in some Western European countries and Russia was 20 years. Whilst trends for life expectancy at birth have improved in many areas around the world, those for Russia, as well as those for some other former Soviet Union countries, have fluctuated greatly and have not shown signs of growth since the middle of the 20th Century. This problem is most acute in Russia and former Soviet Union countries, but is also far from being solved in the states that have made significant progress since 1990 and joined the European Union in the 21st Century. One of the priorities of the Polish presidency of the European Union, which began in July 2011, is the call for a European solidarity for health that could help to close the health gap dividing Europe.

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.

BACKGROUND: Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. METHODS: We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. FINDINGS: In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations. INTERPRETATION: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%. FUNDING: UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort.

BACKGROUND AND AIMS: Fatigue is the commonest symptom described by patients in most populations with the autoimmune liver disease primary biliary cirrhosis (PBC), and appears to be unrelated to liver disease severity. At present, it is unclear how the fatigue experienced by patients (only characterised to date in cross sectional studies) evolves over time. In this study, we set out to address how fatigue had changed over four years of follow up in a geographically defined cohort of PBC patients who participated in an earlier cross sectional study of fatigue impact. METHODS: Participants in the original 2000 study who were still alive in 2004 were asked to complete the same fatigue assessment tool (fatigue impact score, FIS). In those who had died between 2000 and 2004, medical notes, death certificates, and primary care records were reviewed. RESULTS: A total of 108 of the original cohort of 136 patients were alive at the time of the follow up study, 99 of whom (92%) participated in the follow up study. With the exception of four patients who underwent transplantation between 2000 and 2004, all of whom showed significant improvement in fatigue severity as assessed by FIS, fatigue severity was unchanged over four years of follow up. Among the 28 patients who died during the follow up period, survival was significantly lower in patients who were fatigued at the 2000 baseline (FIS above the median for the whole PBC population (40/160); log rank test, p = 0.006 v non-fatigued patients at baseline). Increased fatigue severity was independently associated with decreased survival on multivariate analysis. Fatigued PBC subjects were significantly more likely to have suffered a cardiac death than non-fatigued patients. CONCLUSIONS: The fatigue phenotype appears to be highly stable in PBC. The presence of fatigue in PBC is independently associated with a significantly increased risk of death in general, and cardiac death in particular. Factors underpinning fatigue in PBC, and the mechanisms whereby fatigue is associated with increased mortality, warrant further study.

Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis.

BACKGROUND AND AIMS: Study of health related quality of life (HRQOL) and the factors responsible for its impairment in primary biliary cirrhosis (PBC) has, to date, been limited. There is increasing need for a HRQOL questionnaire which is specific to PBC. The aim of this study was to develop, validate, and evaluate a patient based PBC specific HRQOL measure. SUBJECTS AND METHODS: A pool of potential questions was derived from thematic analysis of indepth interviews carried out with 30 PBC patients selected to represent demographically the PBC patient population as a whole. This pool was systematically reduced, pretested, and cross validated with other HRQOL measures in national surveys involving a total of 900 PBC patients, to produce a quality of life profile measure, the PBC-40, consisting of 40 questions distributed across six domains. The PBC-40 was then evaluated in a blinded comparison with other HRQOL measures in a further cohort of 40 PBC patients. RESULTS: The six domains of PBC-40 relate to fatigue, emotional, social, and cognitive function, general symptoms, and itch. The highest mean domain score was seen for fatigue and the lowest for itch. The measure has been fully validated for use in PBC and shown to be scientifically sound. PBC patient satisfaction, measured in terms of the extent to which a questionnaire addresses the problems that they experience, was significantly higher for the PBC-40 than for other HRQOL measures. CONCLUSION: The PBC-40 is a short easy to complete measure which is acceptable to PBC patients and has significantly greater relevance to their problems than other frequently used HRQOL measures. Its scientific soundness, shown in extensive testing, makes it a valuable instrument for future use in clinical and research settings.

The management and survival of patients with advanced germ-cell tumours: improving outcome in intermediate and poor prognosis patients.

AIMS: The survival of germ-cell tumours (GCT) was transformed after the introduction of cisplatin-based therapy. Previous trials have indicated BEP (bleomycin, etoposide and cisplatin) as the optimum treatment, although some centres including our own advocate the use of the alternating regimen POMB-ACE (cisplatin, vincristine, methotrexate, bleomycin and dactinomycin, cyclophosphamide and etoposide) for men with intermediate or poor prognosis disease. We analysed the survival and management of GCT patients treated at a specialist cancer centre in relation to internationally recognised prognostic groupings. MATERIALS AND METHODS: We retrieved patient information using the Trent Testicular Tumour Registry and supplemented it with information from patient notes. This included all patients with Royal Marsden Hospital Stage II, III and IV disease and patients with stage I disease at diagnosis with raised markers or subsequent relapse. We compared the efficacy and toxicity of the BEP and POMB-ACE chemotherapy regimens, and assessed relapse-free and overall survival. RESULTS: We identified 178 non-seminomatous germ cell tumours (NSGCT) and 71 seminoma patients. Overall survival was similar to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification for the good (95% vs 92%) and intermediate groups (82% vs 80%). The outcome for the poor prognosis group was better than expected in our series (57% vs 48%). There was a higher proportion of both immediate and late side-effects with POMB-ACE. CONCLUSION: Survival and disease progression rates at this single institution were at least as good as reported by the IGCCCG and somewhat better for the poor-prognosis group. This may reflect use of the POMB-ACE chemotherapy regimen as opposed to standard BEP regimen. However, a randomised comparison of BEP and POMB-ACE would be required to validate this.