Whittington Hospital

During active disease, patients with systemic-onset juvenile chronic arthritis (S-JCA) demonstrate a rise and fall in serum interleukin-6 (IL-6) that parallels the classic quotidian fever. To investigate the possibility that this cytokine profile results from a difference in the control of IL-6 expression, we examined the 5' flanking region of the IL-6 gene for polymorphisms. A G/C polymorphism was detected at position -174. In a group of 383 healthy men and women from a general practice in North London, the frequency of the C allele was 0.403 (95% confidence interval 0.37-0.44). In comparison, 92 patients with S-JCA had a different overall genotype frequency, especially those with onset of disease at < 5 yr of age. This was mainly due to the statistically significant lower frequency of the CC genotype in this subgroup. When comparing constructs of the 5' flanking region (-550-+61 bp) in a luciferase reporter vector transiently transfected into HeLa cells, the -174C construct showed 0.624+/-0.15-fold lower expression than the -174G construct. After stimulation with LPS or IL-1, expression from the -174C construct did not significantly change after 24 h, whereas expression from the -174G construct increased by 2.35+/-0.10- and 3.60+/-0.26-fold, respectively, compared with the unstimulated level. Plasma levels of IL-6 were also measured in 102 of the healthy subjects, and the C allele was found to be associated with significantly lower levels of plasma IL-6. These results suggest that there is a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. The reduced frequency of the potentially protective CC genotype in young S-JCA patients may contribute to its pathogenesis. Similarly the individual's IL-6 genotype may be highly relevant in other conditions where IL-6 has been implicated, such as atherosclerosis.

BACKGROUND: Educational outreach visits (EOVs) have been identified as an intervention that may improve the practice of healthcare professionals. This type of face-to-face visit has been referred to as university-based educational detailing, academic detailing, and educational visiting. OBJECTIVES: To assess the effects of EOVs on health professional practice or patient outcomes. SEARCH STRATEGY: For this update, we searched the Cochrane EPOC register to March 2007. In the original review, we searched multiple bibliographic databases including MEDLINE and CINAHL. SELECTION CRITERIA: Randomised trials of EOVs that reported an objective measure of professional performance or healthcare outcomes. An EOV was defined as a personal visit by a trained person to healthcare professionals in their own settings. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. We used bubble plots and box plots to visually inspect the data. We conducted both quantitative and qualitative analyses. We used meta-regression to examine potential sources of heterogeneity determined a priori. We hypothesised eight factors to explain variation across effect estimates. In our primary visual and statistical analyses, we included only studies with dichotomous outcomes, with baseline data and with low or moderate risk of bias, in which the intervention included an EOV and was compared to no intervention. MAIN RESULTS: We included 69 studies involving more than 15,000 health professionals. Twenty-eight studies (34 comparisons) contributed to the calculation of the median and interquartile range for the main comparison. The median adjusted risk difference (RD) in compliance with desired practice was 5.6% (interquartile range 3.0% to 9.0%). The adjusted RDs were highly consistent for prescribing (median 4.8%, interquartile range 3.0% to 6.5% for 17 comparisons), but varied for other types of professional performance (median 6.0%, interquartile range 3.6% to 16.0% for 17 comparisons). Meta-regression was limited by the large number of potential explanatory factors (eight) with only 31 comparisons, and did not provide any compelling explanations for the observed variation in adjusted RDs. There were 18 comparisons with continuous outcomes, with a median adjusted relative improvement of 21% (interquartile range 11% to 41%). There were eight trials (12 comparisons) in which the intervention included an EOV and was compared to another type of intervention, usually audit and feedback. Interventions that included EOVs appeared to be slightly superior to audit and feedback. Only six studies evaluated different types of visits in head-to-head comparisons. When individual visits were compared to group visits (three trials), the results were mixed. AUTHORS' CONCLUSIONS: EOVs alone or when combined with other interventions have effects on prescribing that are relatively consistent and small, but potentially important. Their effects on other types of professional performance vary from small to modest improvements, and it is not possible from this review to explain that variation.

Journal Article EPILEPSY AND THE TEMPORAL LOBES: A CLINICAL, ELECTROENCEPHALOGRAPHIC AND NEUROPATHOLOGICAL STUDY OF THE BRAIN IN EPILEPSY, WITH PARTICULAR REFERENCE TO THE TEMPORAL LOBES Get access J. H. MARGERISON, J. H. MARGERISON 1St. Bartholomew's Hospital and the Whittington HospitalLondon Search for other works by this author on: Oxford Academic PubMed Google Scholar J. A. N. CORSELLIS J. A. N. CORSELLIS 2Runwell HospitalWickford, Essex Search for other works by this author on: Oxford Academic PubMed Google Scholar Brain, Volume 89, Issue 3, September 1966, Pages 499–530, https://doi.org/10.1093/brain/89.3.499 Published: 01 September 1966

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.

S ummary . Malonyldialdehyde (MDA) formation, a measure of polyunsaturated fat autoxidation, was estimated in normal human red cells incubated in vitro. Exposure to oxygen under a variety of conditions did not induce autoxidation. Exposure to hydrogen peroxide was either by the addition of a hydrogen peroxide solution or by incubation in an atmosphere saturated with hydrogen peroxide vapour. A pattern of MDA formation was established with both methods. Lack of reproducibility, a feature of previous methods of measuring the susceptibility of red cells to exogenous peroxide, could be overcome by (i) catalase inhibition, (ii) attention to the non‐linear relation between packed‐cell volume and MDA formation, and (iii) elimination of potentially misleading coloured complexes on spectroscopy. A number of recognized antioxidants inhibited peroxide‐induced MDA formation. Inhibition was proportional to the logarithm of the antioxidant concentration. Under certain conditions pre‐incubation with nucleosides and with lecithin protected the cells against autoxidation on subsequent exposure to peroxide. Peroxide‐induced cell autoxidation was also influenced by plasma, bovine albumin, and ascorbic acid. Haemolysis was an invariable consequence of autoxidation. Similarities and dissimilarities between autoxidation and antioxidation in free lipid emulsions and in organized biological structures were examined and discussed in the light of the experimental findings.

BACKGROUND: The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS: TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS: Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION: TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. FUNDING: University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.

Navigation in ever-changing environments requires effective motor behaviours. Many insects have developed adaptive movement patterns which increase their success in achieving navigational goals. A conserved brain area in the insect brain, the Lateral Accessory Lobe, is involved in generating small scale search movements which increase the efficacy of sensory sampling. When the reliability of an essential navigational stimulus is low, searching movements are initiated whereas if the stimulus reliability is high, a targeted steering response is elicited. Thus the network mediates an adaptive switching between motor patterns. We developed Spiking Neural Network models to explore how an insect inspired architecture could generate adaptive movements in relation to changing sensory inputs. The models are able to generate a variety of adaptive movement patterns, the majority of which are of the zig-zagging kind, as seen in a variety of insects. Furthermore, these networks are robust to noise. Because a large spread of network parameters lead to the zig-zagging movement dynamics, we conclude that the investigated network architecture is inherently well suited to generating adaptive movement patterns.

Education and debateShould we screen for gestational diabetes?R J Jarrett wrote to us arguing that gestational diabetes was a muddled concept that provided uncertain benefits for mother and infant.We invited Richard Beard and colleagues to put the other side of the argument and make the case for screening all pregnant women for gestational diabetes

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Simon Wright discusses four sexually transmitted diseases commonly seen at sexual health clinics. He describes the management issues involved and ways in which information and advice can be given to minimise patients' distress.

Remember the essays you used to write as a student? You would browse through the indexes of books and journals until you came across a paragraph that looked relevant, and copied it out. If anything you found did not fit in with the theory you were proposing, you left it out. This, more or less, constitutes the methodology of the journalistic review—an overview of primary studies which have not been identified or analysed in a systematic (standardised and objective) way. #### Summary points A systematic review is an overview of primary studies that used explicit and reproducible methods A meta-analysis is a mathematical synthesis of the results of two or more primary studies that addressed the same hypothesis in the same way Although meta-analysis can increase the precision of a result, it is important to ensure that the methods used for the review were valid and reliable In contrast, a systematic review is an overview of primary studies which contains an explicit statement of objectives, materials, and methods and has been conducted according to explicit and reproducible methodology (fig 1). Fig 1 Methodology for a systematic review of randomised controlled trials1 Some advantages of the systematic review are given in box. When a systematic review is undertaken, not only must the search for relevant articles be thorough and objective, but the criteria used to reject articles as “flawed” must be explicit and independent of the results of those trials. The most enduring and useful systematic reviews, notably those undertaken by the Cochrane Collaboration, are regularly updated to incorporate new evidence.2 ### Box 1: Advantages of systematic reviews3 RETURN TO TEXT

Abstract Objective: To investigate the relation between decreased maternal food intake and risk factors for coronary heart disease in adult Design: Cross sectional study. Subjects: 169 subjects exposed to malnutrition in utero (intrauterine group) during the siege of Leningrad (now St Petersburg) in 1941-4; 192 subjects born in Leningrad just before rationing began, before the siege (infant group); and 188 subjects born concurrently with the first two groups but outside the area of the siege (unexposed group). Setting: Ott Institute of Obstetrics and Gynaecology, St Petersburg. Main outcome measures: Development of risk factors for coronary heart disease and diabetes mellitus—obesity, blood pressure, glucose tolerance, insulin concentrations, lipids, albumin excretion rate, and clotting factors. Results: There was no difference between the subjects exposed to starvation in utero and those starved during infant life in: ( a ) glucose tolerance (mean fasting glucose: intrauterine group 5.2(95% confidence interval 5.1 to 5.3), infant group 5.3 (5.1 to 5.5), P=0.94; mean 2 hour glucose: intrauterine group 6.1 (5.8 to 6.4), infant group 6.0 (5.7 to 6.3), P=0.99);( b ) insulin concentration; ( c ) blood pressure; ( d )lipid concentration; or ( e ) coagulation factors. Concentrations of von Willebrand factor were raised in the intrauterine group (156.5 (79.1 to 309.5)) compared with the infant group (127.6 (63.9 to 254.8); P&lt;0.001), and female subjects in the intrauterine group had a stronger interaction between obesity and both systolic (P=0.01) and diastolic (P=0.04) blood pressure than in the infant group. Short adult stature was associated with raised concentrations of glucose and insulin 2 hours after a glucose load—independently of siege exposure. Subjects in the unexposed group had non-systematic differences in subscapular to triceps skinfold ratio, diastolic blood pressure, and clotting factors compared with the exposed groups. Conclusions :Intrauterine malnutrition was not associated with glucose intolerance, dyslipidaemia, hypertension, or cardiovascular disease in adulthood. Subjects exposed to malnutrition showed evidence of endothelial dysfunction and a stronger influence of obesity on blood pressure. Key messages Relations between intrauterine growth and adult disease such as diabetes and cardiovascular disease have been linked to poor nutrition during pregnancy In this study, however, intrauterine exposure to malnutrition was not associated with glucose intolerance Intrauterine malnutrition did not affect insulin concentration, blood pressure, or concentration of lipids or coagulation factors Concentration of von Willebrand factor, a marker of endothelial damage, was raised in the subjects exposed to intrauterine malnutrition Obesity and blood pressure were more strongly related in subjects exposed to intrauterine malnutrition than in subjects either unexposed to malnutrition or exposed to malnutrition only as infants

This article updates our previous review of Ki67 published in Histopathology 10 years ago. In this period the numbers of papers published featuring this antibody has increased 10-fold from 338 to 3489 indicating the considerable enthusiasm with which this antibody has been studied. This review attempts to provide an update on the characterization of the Ki67 protein, its function and its use as a prognostic or diagnostic tool.

BACKGROUND: Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. OBJECTIVES: To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. DATA SOURCES: Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. REVIEW METHODS: Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study. RESULTS: Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials. DURATION: Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing. LIMITATIONS: The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies. CONCLUSIONS: BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

BACKGROUND: A series of small, mainly uncontrolled, studies have suggested that techniques adapted from cognitive-behavioural therapy (CBT) for depression can improve outcome in psychosis, but no large randomised controlled trial of intensive treatment for medication-resistant symptoms of psychosis has previously been published. METHOD: Sixty participants who each had at least one positive and distressing symptom of psychosis that was medication-resistant were randomly allocated between a CBT and standard care condition (n = 28) and a standard care only control condition (n = 32). Therapy was individualised, and lasted for nine months. Multiple assessments of outcome were used. RESULTS: Over nine months, improvement was significant only in the treatment group, who showed a 25% reduction on the BPRS. No other clinical, symptomatic or functioning measure changed significantly. Participants had a low drop-out rate from therapy (11%), and expressed high levels of satisfaction with treatment (80%). Fifty per cent of the CBT group were treatment responders (one person became worse), compared with 31% of the control group (three people became worse and another committed suicide). CONCLUSIONS: CBT for psychosis can improve overall symptomatology. The findings provide evidence that even a refractory group of clients with a long history of psychosis can engage in talking about psychotic symptoms and their meaning, and this can improve outcome.

BACKGROUND: Educational courses for doctors and medical students are increasingly offered via the Internet. Despite much research, course developers remain unsure about what (if anything) to offer online and how. Prospective learners lack evidence-based guidance on how to choose between the options on offer. We aimed to produce theory driven criteria to guide the development and evaluation of Internet-based medical courses. METHODS: Realist review - a qualitative systematic review method whose goal is to identify and explain the interaction between context, mechanism and outcome. We searched 15 electronic databases and references of included articles, seeking to identify theoretical models of how the Internet might support learning from empirical studies which (a) used the Internet to support learning, (b) involved doctors or medical students; and (c) reported a formal evaluation. All study designs and outcomes were considered. Using immersion and interpretation, we tested theories by considering how well they explained the different outcomes achieved in different educational contexts. RESULTS: 249 papers met our inclusion criteria. We identified two main theories of the course-in-context that explained variation in learners' satisfaction and outcomes: Davis's Technology Acceptance Model and Laurillard's model of interactive dialogue. Learners were more likely to accept a course if it offered a perceived advantage over available non-Internet alternatives, was easy to use technically, and compatible with their values and norms. 'Interactivity' led to effective learning only if learners were able to enter into a dialogue - with a tutor, fellow students or virtual tutorials - and gain formative feedback. CONCLUSIONS: Different modes of course delivery suit different learners in different contexts. When designing or choosing an Internet-based course, attention must be given to the fit between its technical attributes and learners' needs and priorities; and to ways of providing meaningful interaction. We offer a preliminary set of questions to aid course developers and learners consider these issues.

BACKGROUND & AIMS: The development of non-invasive liver fibrosis tests may enable earlier identification of patients with non-alcoholic fatty liver disease (NAFLD) requiring referral to secondary care. We developed and evaluated a pathway for the management of patients with NAFLD, aimed at improving the detection of cases of advanced fibrosis and cirrhosis, and avoiding unnecessary referrals. METHODS: This was a prospective longitudinal cohort study, with analyses performed before and after introduction of the pathway, and comparisons made to unexposed controls. We used a 2-step algorithm combining the use of Fibrosis-4 score followed by the ELF™ test if required. RESULTS: In total, 3,012 patients were analysed. Use of the pathway detected 5 times more cases of advanced fibrosis (Kleiner F3) and cirrhosis (odds ratio [OR]5.18;95%CI2.97-9.04; p <0.0001), while reducing unnecessary referrals from primary care to secondary care by 81% (OR0.193; 95%CI 0.111-0.337; p <0.0001). Although it was used for only 48% of referrals, significant benefits were observed in practices exposed to the pathway compared to those which were not, with unnecessary referrals falling by 77% (OR0.23; 95% CI0.658-0.082; p = 0.006) and a 4-fold improvement in detection of cases of advanced fibrosis and cirrhosis (OR4.32; 95% CI1.52-12.25; p = 0.006). Compared to referrals made before the introduction of the pathway, unnecessary referrals fell from 79/83 referrals (95.2%) to 107/152 (70.4%), representing an 88% reduction in unnecessary referrals when the pathway was followed (OR0.12; 95%CI0.042-0.349; p <0.0001). CONCLUSIONS: The use of non-invasive blood tests for liver fibrosis improves the detection of advanced fibrosis and cirrhosis, while reducing unnecessary referrals in patients with NAFLD. This strategy improves resource use and benefits patients. LAY SUMMARY: Non-alcoholic fatty liver disease effects up to 30% of the population but only a minority of cases develop liver disease. Our study has shown that established blood tests can be used in primary care to stratify patients with fatty liver disease, leading to a reduction in unnecessary referrals by 80% and greatly improving the detection of cases of advanced fibrosis and cirrhosis.

Heart failure from iron overload causes 71% of deaths in thalassaemia major, yet reversal of siderotic cardiomyopathy has been reported. In order to determine the changes in myocardial iron during treatment, we prospectively followed thalassaemia patients commencing intravenous desferrioxamine for iron-induced cardiomyopathy during a 12-month period. Cardiovascular magnetic resonance assessments were performed at baseline, 3, 6 and 12 months of treatment, and included left ventricular (LV) function and myocardial and liver T2*, which is inversely related to iron concentration. One patient died. The six survivors showed progressive improvements in myocardial T2* (5.1 +/- 1.9 to 8.1 +/- 2.8 ms, P = 0.003), liver iron (9.6 +/- 4.3 to 2.1 +/- 1.5 mg/g, P = 0.001), LV ejection fraction (52 +/- 7.1% to 63 +/- 6.4%, P = 0.03), LV volumes (end diastolic volume index 115 +/- 17 to 96 +/- 3 ml, P = 0.03; end systolic volume index 55 +/- 16 to 36 +/- 6 ml, P = 0.01) and LV mass index (106 +/- 14 to 95 +/- 13, P = 0.01). Iron cleared more slowly from myocardium than liver (5.0 +/- 3.3% vs. 39 +/- 23% per month, P = 0.02). These prospective data confirm that siderotic heart failure is often reversible with intravenous iron chelation with desferrioxamine. Myocardial T2* improves in concert with LV volumes and function during recovery, but iron clearance from the heart is considerably slower than from the liver.

There are unacceptable delays in the implementation of many findings of research. This results in suboptimal care for patients. A number of approaches may be effective in speeding up implementation, including evidence based guidelines, the influence of opinion leaders, and computer based decision support systems. An integrated approach to speeding up this process by means of a number of mechanisms is likely to be most effective. The results of systematic reviews of the research literature should be incorporated into programmes of continuing medical education and clinical audit. Professional associations have an important role to play in ensuring that research based information is included in educational activities and clinical guidelines. Purchasers of health care could promote the uptake of research findings during contract negotiations. Improved methods of informing health care users and the public about evidence of effectiveness could also have an impact. Policy makers should take more account of the results of research when formulating recommendations. Methods of improving the implementation of research findings require further investigation and greater resources devoted to them.

BACKGROUND: Recurrent pregnancy loss (RPL), defined as 3 or more consecutive miscarriages, is widely attributed either to repeated chromosomal instability in the conceptus or to uterine factors that are poorly defined. We tested the hypothesis that abnormal cyclic differentiation of endometrial stromal cells (ESCs) into specialized decidual cells predisposes to RPL, based on the observation that this process may not only be indispensable for placenta formation in pregnancy but also for embryo recognition and selection at time of implantation. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of mid-secretory endometrial biopsies demonstrated that RPL is associated with decreased expression of the decidual marker prolactin (PRL) but increased levels of prokineticin-1 (PROK1), a cytokine that promotes implantation. These in vivo findings were entirely recapitulated when ESCs were purified from patients with and without a history of RPL and decidualized in culture. In addition to attenuated PRL production and prolonged and enhanced PROK1 expression, RPL was further associated with a complete dysregulation of both markers upon treatment of ESC cultures with human chorionic gonadotropin, a glycoprotein hormone abundantly expressed by the implanting embryo. We postulated that impaired embryo recognition and selection would clinically be associated with increased fecundity, defined by short time-to-pregnancy (TTP) intervals. Woman-based analysis of the mean and mode TTP in a cohort of 560 RPL patients showed that 40% can be considered "superfertile", defined by a mean TTP of 3 months or less. CONCLUSIONS: Impaired cyclic decidualization of the endometrium facilitates implantation yet predisposes to subsequent pregnancy failure by disabling natural embryo selection and by disrupting the maternal responses to embryonic signals. These findings suggest a novel pathological pathway that unifies maternal and embryonic causes of RPL.