Sandwell General Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents.In contrast, information regarding the roles of this hormone in humans is limited.Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia.Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development.Leptin deficiency was associated with reduced numbers of circulating CD4 + T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration.The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency.

BACKGROUND: IBS affects 5-11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. AIM: To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. METHODS: Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. RESULTS: Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients' concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT(3) antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT(4) agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. CONCLUSIONS: Better ways of identifying which patients will respond to specific treatments are urgently needed.

INTRODUCTION: Alcoholic hepatitis is associated with a high short term mortality. We aimed to identify those factors associated with mortality and define a simple score which would predict outcome in our population. METHODS: We identified 241 patients with alcoholic hepatitis. Clinical and laboratory data were recorded on the day of admission (day 1) and on days 6-9. Stepwise logistic regression was used to identify variables related to outcome at 28 days and 84 days after admission. These variables were included in the Glasgow alcoholic hepatitis score (GAHS) and its ability to predict outcome assessed. The GAHS was validated in a separate dataset of 195 patients. RESULTS: The GAHS was derived from five variables independently associated with outcome: age (p = 0.001) and, from day 1 results, serum bilirubin (p<0.001), blood urea (p = 0.019) and, from day 6-9 results, serum bilirubin (p<0.001), prothrombin time (p = 0.002), and peripheral blood white blood cell count (p = 0.001). The GAHS on day 1 had an overall accuracy of 81% when predicting 28 day outcome. In contrast, the modified discriminant function had an overall accuracy of 49%. Similar results were found using information at 6-9 days and when predicting 84 day outcome. The accuracy of the GAHS was confirmed by the validation study of 195 patients The GAHS was equally accurate irrespective of the use of the international normalised ratio or prothrombin time ratio, or if the diagnosis of alcoholic hepatitis was biopsy proven or on the basis of clinical assessment. CONCLUSIONS: Using variables associated with mortality we have derived and validated an accurate scoring system to assess outcome in alcoholic hepatitis. This score was able to identify patients at greatest risk of death throughout their admission.

BACKGROUND: The duration of follow up to assess the risk of long term renal impairment in Henoch-Schönlein purpura (HSP) without nephritic or nephrotic syndrome or renal failure on diagnosis remains undetermined. AIMS: To undertake a systematic review of the literature to assess whether the risk of long term renal impairment without renal involvement on diagnosis could be estimated and to determine the time period when renal involvement is very unlikely after the diagnosis of HSP. METHODS: Search of studies of unselected children with HSP, and available information on urinary findings, renal involvement, and long term renal function follow up. Studies of selected children with HSP nephropathy at diagnosis were excluded. RESULTS: Twelve studies of 1133 children were reviewed. The follow up period ranged from 6 weeks to 36 years. Proteinuria and/or haematuria, which occurred in 34.2%, of which only one fifth were in association with nephritic or nephrotic syndrome, developed in 85% of cases within 4 weeks of the diagnosis of HSP, in 91% within 6 weeks, and in 97% within 6 months. Permanent renal impairment never developed after normal urinalysis; it occurred in 1.6% of those with isolated urinary abnormalities, and in 19.5% of those who developed nephritic or nephrotic syndrome. CONCLUSION: No long term renal impairment occurred after normal urinalysis. Even if urinalysis is normal at presentation, the testing should be continued for six months. There is no need to follow up after the first six months those whose urinalysis remains normal.

This document represents the first position statement produced by the British Society of Gastroenterology and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, setting out the minimum expected standards in diagnostic upper gastrointestinal endoscopy. The need for this statement has arisen from the recognition that while technical competence can be rapidly acquired, in practice the performance of a high-quality examination is variable, with an unacceptably high rate of failure to diagnose cancer at endoscopy. The importance of detecting early neoplasia has taken on greater significance in this era of minimally invasive, organ-preserving endoscopic therapy. In this position statement we describe 38 recommendations to improve diagnostic endoscopy quality. Our goal is to emphasise practices that encourage mucosal inspection and lesion recognition, with the aim of optimising the early diagnosis of upper gastrointestinal disease and improving patient outcomes.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

BACKGROUND AND STUDY AIMS: Upper gastrointestinal (UGI) cancer in the Western world usually presents at an advanced stage, when opportunities for curative therapy are limited. The failure to detect subtle, early-stage UGI cancer at endoscopy may contribute to a poor prognosis. We undertook a meta-analysis of studies of endoscopic miss rates for UGI cancer to quantify how often opportunities to diagnose cancer at an earlier stage are missed. PATIENTS AND METHODS: A MEDLINE search was conducted to identify relevant studies, and a meta-analysis was conducted. "Missed" UGI cancer was defined as cancer that had not been diagnosed by UGI endoscopy performed within 3 years before the diagnosis. Random effects meta-analysis was used to determine the event rate of missed UGI cancer. RESULTS: Ten studies were identified that included 3,787 patients with UGI cancer. Four hundred eighty-seven UGI cancers were missed at endoscopy within 3 years before diagnosis. Marked heterogeneity was observed between studies (I (2), 94.4 %; P < 0.001). On random effects meta-analysis, the pooled miss rates were 6.4 % (95 % confidence interval [CI], 4.3 % - 9.5 %) within 1 year and 11.3 % (95 % CI, 7.5 % - 16.6 %) within 3 years before diagnosis. There appeared to be no difference between the miss rates of oesophageal (44 %) and gastric (51 %) cancer (P = 0.42). Conclusion It appears that 11.3 % of UGI cancers are missed at endoscopy up to 3 years before diagnosis. To ameliorate the poor prognosis of patients with UGI cancer in the Western world, efforts should be made to improve the quality of UGI endoscopy and create opportunities for earlier diagnosis.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

BACKGROUND: A number of families have been described which include multiple members with symptomatic, endoscopic, or complicated gastro-oesophageal reflux disease (GORD). First degree relatives of patients with GORD are more likely to suffer with GORD symptoms. These observations raise the possibility of a genetic contribution to the aetiology of GORD. AIMS: To determine the relative contribution of genetic factors to GORD by evaluating GORD symptoms in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A total of 4480 unselected twin pairs, identified from a national volunteer twin register, were asked to complete a validated symptom questionnaire. GORD was defined as symptoms of heartburn or acid regurgitation at least weekly during the past year. RESULTS: Replies were obtained from 5032 subjects (56% response rate). A total of 1960 twin pairs were evaluable: 928 MZ pairs (86 male pairs, mean (SD) age 52 (13) (range 19-81) years) and 1032 DZ pairs (71 male pairs, mean age 52 (13) (20-82) years). The prevalence of GORD among both groups of twins was 18%. Casewise concordance rates were significantly higher for MZ than DZ twins (42% v 26%; p<0.001). Multifactorial liability threshold modelling suggests that additive genetic effects combined with unique environmental factors provide the best model for GORD. Heritability estimates suggest that 43% (95% confidence interval 32-55%) of the variance in liability to GORD is due to additive genetic factors. CONCLUSIONS: There is a substantial genetic contribution to the aetiology of GORD.

BACKGROUND: The 'three delays model' attempts to explain delays in women accessing emergency obstetric care as the result of: 1) decision-making, 2) accessing services and 3) receipt of appropriate care once a health facility is reached. The third delay, although under-researched, is likely to be a source of considerable inequity in access to emergency obstetric care in developing countries. The aim of this systematic review was to identify and categorise specific facility-level barriers to the provision of evidence-based maternal health care in developing countries. METHODS AND FINDINGS: Five electronic databases were systematically searched using a 4-way strategy that combined search terms related to: 1) maternal health care; 2) maternity units; 3) barriers, and 4) developing countries. Forty-three original research articles were eligible to be included in the review. Thirty-two barriers to the receipt of timely and appropriate obstetric care at the facility level were identified and categorised into six emerging themes (Drugs and equipment; Policy and guidelines; Human resources; Facility infrastructure; Patient-related and Referral-related). Two investigators independently recorded the frequency with which barriers relating to the third delay were reported in the literature. The most commonly cited barriers were inadequate training/skills mix (86%); drug procurement/logistics problems (65%); staff shortages (60%); lack of equipment (51%) and low staff motivation (44%). CONCLUSIONS: This review highlights how a focus on patient-side delays in the decision to seek care can conceal the fact that many health facilities in the developing world are still chronically under-resourced and unable to cope effectively with serious obstetric complications. We stress the importance of addressing supply-side barriers alongside demand-side factors if further reductions in maternal mortality are to be achieved.

BACKGROUND: Endometriosis is found in 0.5-5% of fertile women and 25-40% of infertile women. It is known that endometriosis is associated with infertility, but there is uncertainty whether women with endometriosis have adverse pregnancy outcomes in in vitro fertilisation (IVF) treatment. OBJECTIVES: To explore the association between endometriosis and IVF outcome. SEARCH STRATEGY: Searches were conducted on MEDLINE, EMBASE, Cochrane Library and Web of Science (inception, December 2012) in all languages, together with reference lists of retrieved papers. SELECTION CRITERIA: Studies comparing IVF outcome in women with endometriosis with women without endometriosis. Patients were classified by stage of endometriosis. The outcomes were fertilisation, implantation, clinical pregnancy and live birth rates. Study selection was conducted independently by two reviewers. The Newcastle-Ottawa Quality Assessment Scale was used for quality assessment. DATA COLLECTION AND ANALYSIS: Data extraction was conducted independently by two reviewers. Relative risks from individual studies were meta-analysed. MAIN RESULTS: Twenty-seven observational studies were included, comprising 8984 women. Meta-analysis of these studies showed that fertilisation rates were reduced in stage I/II of endometriosis (relative risk [RR] = 0.93, 95% confidence interval [95% CI] 0.87-0.99, P = 0.03). There was a decrease in the implantation rate (RR = 0.79, 95% CI 0.67-0.93, P = 0.006) and clinical pregnancy rate (RR = 0.79, 95% CI 0.69-0.91, P = 0.0008) in women with stage III/IV endometriosis undergoing IVF treatment. CONCLUSION: The presence of severe endometriosis (stage III/IV) is associated with poor implantation and clinical pregnancy rates in women undergoing IVF treatment.

BACKGROUND: Eosinophilic oesophagitis (EoE) is an increasingly common cause of dysphagia in both children and adults, as well as one of the most prevalent oesophageal diseases with a significant impact on physical health and quality of life. We have provided a single comprehensive guideline for both paediatric and adult gastroenterologists on current best practice for the evaluation and management of EoE. METHODS: The Oesophageal Section of the British Society of Gastroenterology was commissioned by the Clinical Standards Service Committee to develop these guidelines. The Guideline Development Group included adult and paediatric gastroenterologists, surgeons, dietitians, allergists, pathologists and patient representatives. The Population, Intervention, Comparator and Outcomes process was used to generate questions for a systematic review of the evidence. Published evidence was reviewed and updated to June 2021. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to assess the evidence and make recommendations. Two rounds of voting were held to assess the level of agreement and the strength of recommendations, with 80% consensus required for acceptance. RESULTS: Fifty-seven statements on EoE presentation, diagnosis, investigation, management and complications were produced with further statements created on areas for future research. CONCLUSIONS: These comprehensive adult and paediatric guidelines of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition are based on evidence and expert consensus from a multidisciplinary group of healthcare professionals, including patient advocates and patient support groups, to help clinicians with the management patients with EoE and its complications.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

Cascade testing using DNA-mutation information is now recommended in the UK for patients with familial hypercholesterolaemia (FH). We compared the detection rate and mutation spectrum in FH patients with a clinical diagnosis of definite (DFH) and possible (PFH) FH. Six hundred and thirty-five probands from six UK centres were tested for 18 low-density lipoprotein receptor gene (LDLR) mutations, APOB p.Arg3527Gln and PCSK9 p.Asp374Tyr using a commercial amplification refractory mutation system (ARMS) kit. Samples with no mutation detected were screened in all exons by single strand conformation polymorphism analysis (SSCP)/denaturing high performance liquid chromatography electrophoresis (dHPLC)/direct-sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications in LDLR.The detection rate was significantly higher in the 190 DFH patients compared to the 394 PFH patients (56.3% and 28.4%, p > 0.00001). Fifty-one patients had inadequate information to determine PFH/DFH status, and in this group the detection rate was similar to the PFH group (25.5%, p = 0.63 vs PFH). Overall, 232 patients had detected mutations (107 different; 6.9% not previously reported). The ARMS kit detected 100 (44%) and the MLPA kit 11 (4.7%). Twenty-eight (12%) of the patients had the APOB p.Arg3527Gln and four (1.7%) had the PCSK9 p.Asp374Tyr mutation. Of the 296 relatives tested from 100 families, a mutation was identified in 56.1%. In 31 patients of Indian/Asian origin 10 mutations (two previously unreported) were identified. The utility of the ARMS kit was confirmed, but sequencing is still required in a comprehensive diagnostic service for FH. Even in subjects with a low clinical suspicion of FH, and in those of Indian origin, mutation testing has an acceptable detection rate.

The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents. In contrast, information regarding the roles of this hormone in humans is limited. Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia. Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development. Leptin deficiency was associated with reduced numbers of circulating CD4(+) T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency.

AIMS: Fractional flow reserve (FFRCT) using computed tomography coronary angiography (CTCA) determines both the presence of coronary artery disease and vessel-specific ischaemia. We tested whether an evaluation strategy based on FFRCT would improve economic and clinical outcomes compared with standard care. METHODS AND RESULTS: Overall, 1400 patients with stable chest pain in 11 centres were randomized to initial testing with CTCA with selective FFRCT (experimental group) or standard clinical care pathways (standard group). The primary endpoint was total cardiac costs at 9 months. Secondary endpoints were angina status, quality of life, major adverse cardiac and cerebrovascular events, and use of invasive coronary angiography. Randomized groups were similar at baseline. Most patients had an initial CTCA: 439 (63%) in the standard group vs. 674 (96%) in the experimental group, 254 of whom (38%) underwent FFRCT. Mean total cardiac costs were higher by £114 (+8%) in the experimental group, with a 95% confidence interval from -£112 (-8%) to +£337 (+23%), though the difference was not significant (P = 0.10). Major adverse cardiac and cerebrovascular events did not differ significantly (10.2% in the experimental group vs. 10.6% in the standard group) and angina and quality of life improved to a similar degree over follow-up in both randomized groups. Invasive angiography was reduced significantly in the experimental group (19% vs. 25%, P = 0.01). CONCLUSION: A strategy of CTCA with selective FFRCT in patients with stable angina did not differ significantly from standard clinical care pathways in cost or clinical outcomes, but did reduce the use of invasive coronary angiography.

How to cite this article: McKenzie Y.A., Alder A., Anderson W., Wills A., Goddard L., Gulia P., Jankovich E., Mutch P., Reeves L.B., Singer A. &amp; Lomer M.C.E. on behalf of Gastroenterology Specialist Group of the British Dietetic Association. (2012) British Dietetic Association evidence‐based practice guidelines for the dietary management of irritable bowel syndrome in adults. J Hum Nutr Diet . 25 , 260–274 Abstract Background: Irritable bowel syndrome (IBS) is a chronic debilitating functional gastrointestinal disorder. Diet and lifestyle changes are important management strategies. The aim of these guidelines is to systematically review key aspects of the dietary management of IBS, with the aim of providing evidence‐based guidelines for use by registered dietitians. Methods: Questions relating to diet and IBS symptom management were developed by a guideline development group. These included the role of milk and lactose, nonstarch polysaccharides (NSP), fermentable carbohydrates in abdominal bloating, probiotics and empirical or elimination diets. A comprehensive literature search was conducted and relevant studies from January 1985 to November 2009 were identified using the electronic database search engines: Cinahl, Cochrane Library, Embase, Medline, Scopus and Web of Science. Evidence statements, recommendations, good practice points and research recommendations were developed. Results: Thirty studies were critically appraised. A dietetic care pathway was produced following a logical sequence of treatment and formed the basis of these guidelines. Three lines of dietary management were identified. First line: Clinical and dietary assessment, healthy eating and lifestyle management with some general advice on lactose and NSP. Second line: Advanced dietary interventions to improve symptoms based on NSP, fermentable carbohydrates and probiotics. Third line: Elimination and empirical diets. Research recommendations were also identified relating to the need for adequately powered and well designed randomised controlled trials. Conclusions: These guidelines provide evidence‐based details of how to achieve the successful dietary management of IBS.

AIM: To examine the prevalence of gastro-oesophageal reflux disease symptoms and potential risk factors among community subjects. METHODS: A questionnaire was sent to 4000 subjects, stratified by age, gender and ethnicity to be representative of the local population. Gastro-oesophageal reflux disease symptoms were defined as at least weekly heartburn or acid regurgitation. RESULTS: 2231 responded (59%), 691 refused to participate and seven were incomplete. 1533 (41%) were evaluable (637 male, mean age 51 years, range: 20-80). The prevalence of gastro-oesophageal reflux disease symptoms was 21%. Smoking, excess alcohol, irritable bowel syndrome, increasing body mass index, a family history of upper gastrointestinal disease, increasing Townsend deprivation index, anticholinergic drugs (all P < 0.0001), weight gain, antidepressant drugs, inhaled bronchodilators, no educational attainment (all P < 0.01), south Asian origin (P = 0.02) and manual work (P < 0.05) were associated with gastro-oesophageal reflux disease symptoms. Multivariate logistic regression revealed increasing body mass index, a family history of upper gastrointestinal disease, irritable bowel syndrome, south Asian origin (all P < 0.0001), smoking, excess alcohol, no educational attainment and anticholinergic drugs (all P < 0.01) were independently associated with gastro-oesophageal reflux disease symptoms. CONCLUSIONS: Frequent gastro-oesophageal reflux disease symptoms affect 21% of the population. Increasing body mass index, a family history of upper gastrointestinal disease, irritable bowel syndrome, south Asian origin, smoking, excess alcohol, social deprivation and anticholinergic drugs are independently associated with gastro-oesophageal reflux disease symptoms.

There is considerable evidence to suggest that the identification and treatment of dyslipidaemia will reduce the risk of premature CHD, i.e. before the age of 65. Diagnosis of the cause of raised plasma lipid levels will enable appropriate decisions to be taken with regard to management. The cornerstone of treatment is nutritional counselling and attention to other major risk factors for CHD, particularly smoking and hypertension. For a small percentage of patients with severe hyperlipidaemia drug therapy is indicated. Appropriate drug choices need to be made based on the particular lipid abnormality to be treated. In general those patients with clinical vascular disease are treated more aggressively than those where the aim is primary prevention. More research is needed to determine individual risk more precisely and to allow proper targeting of therapy. Genetic factors, qualitative changes in lipoproteins, lipoprotein (a), fibrinogen, and other coagulation and thrombotic factors are likely to be important in individual risk assessment. There is no doubt that more information is needed from prospective studies of lipid-lowering therapy in terms of risk benefit for affected individuals. Hopefully the major studies currently underway will fill some of the gaps in our knowledge. Until then aggressive therapy with drugs should be reserved for those at highest risk where the benefit is likely to be greatest.