St. Mary's Hospital

In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi–treated L4 larvae. We observed expression of 8,000–10,000 genes in the linker cell, 22–25% of which were up- or down-regulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67–dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.

The growing worldwide prevalence of type 2 diabetes mellitus in the young, as underlined by an earlier International Diabetes Federation (IDF) Consensus Statement 1, has highlighted a significant shortfall of data on the epidemiology of the disorder and the identification and treatment of children and adolescents at risk of progression to this disease. Urbanization, unhealthy diets, and increasingly sedentary lifestyles have contributed to increase the prevalence of childhood obesity, particularly in developing countries 2. Current treatment initiatives include school-based programs addressing physical activity and diet, which have been conducted with mixed success in reducing adiposity. There are limited safety data supporting the use of drugs for the treatment of obesity and related conditions such as type 2 diabetes in children and adolescents, and non-compliance in this population suggests that pharmacotherapy is unlikely to be effective long term 1. Although criteria have now been developed for bariatric surgery in teenagers 3, there are few evidence-based data available to support the increasing use of this modality in adolescents. Governments and society in general must be made more aware of the problems associated with obesity and the likelihood of progression to the metabolic syndrome in children and adolescents. Obesity, particularly in the central (abdominal) region, has been determined as a key factor in the etiology of type 2 diabetes 2. The prediction of health risks associated with obesity in youth is improved by the additional inclusion of waist circumference (WC) measure to the body mass index (BMI) percentile 4, 5. Such observations reinforce the importance of including WC in the assessment of childhood obesity to identify those at increased metabolic risk as a result of excess abdominal fat 5. The role of obesity can clearly be demonstrated in Japan, where a parallel increase in type 2 diabetes and obesity in children has occurred over the past few decades 6. Central (abdominal) obesity is also a key component in the IDF definition of metabolic syndrome in adults 2. The link between obesity, metabolic syndrome, and type 2 diabetes has already been characterized in adult populations 2. At present, 50–80% of almost 250 million adults worldwide with diabetes 7 are at risk of death from cardiovascular disease. Those with the metabolic syndrome are also at increased risk being twice as likely to die from, and three times as likely to have, cardiovascular complications as compared with those without the syndrome 8, 9. In addition, adults with the metabolic syndrome have a fivefold greater risk of developing type 2 diabetes 10. Already, one-quarter of the world’s adult population have metabolic syndrome 11, 12, and this condition is appearing with increasing frequency in children and adolescents, driven by the growing obesity epidemic in this young population 13-15. In 2004, the World Health Organization (WHO) reported that an estimated 22 million children younger than 5 yr of age and 10% of school-aged children, between 5 and 17 yr, were overweight or obese 16. WHO predicts that the prevalence of childhood obesity in developed and developing countries will continue to increase as has been seen in recent years. For example, from 1985 to 1997, in young Australians, the prevalence of overweight and obesity combined doubled and that of obesity trebled 17. In Thailand, the prevalence of obesity in those aged 5–12 yr increased from 12.2 to 15.6% in just 2 yr 18. In 2003–2004, 17.1% of children aged 2–19 yr in the USA were obese 19. Obesity is associated with an increase in cardiovascular risk factors (also indicators of metabolic syndrome) 20, and the persistence of these indicators from childhood and adolescence to young adulthood has been shown in several studies, including the Quebec Family Study 21, 22. Recently, the IDF released its guidelines for defining and diagnosing the metabolic syndrome in adults 2. The intention was to rationalize the existing multiple definitions of the syndrome and to avoid the confusion that arose as a result of conflicting opinions on the value of each set of criteria. The use of a single unified definition makes it possible to estimate the global prevalence of metabolic syndrome and make valid comparisons between nations. However, to date, there has not been a unified definition that can be used to assess risk in children and adolescents, and existing adult-based definitions of the metabolic syndrome may not be appropriate to address the problem in this age group. A study of adolescents using modified National Cholesterol Education Program (NCEP) [Adult Treatment Panel III (ATP III)] criteria 23 identified that 12% of the study group had the metabolic syndrome 24. When the ≥95th percentile of BMI was used as a cutoff point in the same study group, 31.3% were identified as having the syndrome, more than double of those previously found to be at risk. Duncan et al. 25 studied 991 adolescents (aged 12–19 yr) from National Health and Nutrition Examination Study (NHANES) 1999–2000 and used the ATP III definition modified for age. The overall prevalence of a metabolic syndrome phenotype among US adolescents increased from 4.2% in NHANES III (1988–1992) to 6.4% in NHANES 1999–2000. Based on population-weighted estimates, they estimated that more than 2 million US adolescents currently have a metabolic syndrome phenotype. In a population-based study of a Canadian Qji-Cree community involving 236 children aged 10–19 yr, Retnakaran et al. reported that 18.6% of the children met the criteria for the metabolic syndrome based on a pediatric metabolic syndrome definition based on the ATP III definition, and they used the ATP III definition modified for age and gender 26. Goodman et al. reported on a school-based, cross-sectional study of 1513 black, white, and Hispanic teenagers 27. Overall, the prevalence of ATP III-defined metabolic syndrome was 4.2% and that of the WHO-defined metabolic syndrome was 8.4%. The metabolic syndrome was found almost exclusively among obese teenagers in whom prevalence of the ATP III-defined metabolic syndrome was 19.5% and prevalence of WHO-defined metabolic syndrome 28 was 38.9%. No race or sex differences were present for ATP III definition. However, non-white teenagers were more likely to have metabolic syndrome by WHO criteria, and it was more common among girls if the WHO definition was used. Chi et al. have recently undertaken a literature review on definitions of the metabolic syndrome in children and adolescents published in the past decade 29. They noted that the prevalence of metabolic syndrome in pre-adolescent girls varies widely because of disagreement among proposed definitions of metabolic syndrome in pediatrics. They called for a consensus definition for the metabolic syndrome in children, which would allow researchers to make better temporal, biological, environmental, and social comparisons between data sets. The American College of Endocrinology definition 30 is not ideal in pediatric subjects as WC is rarely measured in children, and nomograms have only recently become available 31 for some ethnic groups but are not available for all. A recent paper has suggested yet another set of criteria with age- and gender-specific cutoff points 32. The variety of cutoff points used for the different components in this paper underlines the need for a single consistent definition with easily measurable components. Therefore, to date, no formal definition for the diagnosis of the metabolic syndrome in children and adolescents has been developed. The rapid increase in obesity highlights the urgency for a definition that could be used to further understand who is at high risk and to distinguish them from those with ‘simple’ uncomplicated obesity. The metabolic syndrome in adults is defined as a cluster of cardiovascular and diabetes risk factors including abdominal obesity, dyslipidemia, glucose intolerance, and hypertension 2. While the danger associated with clustering of components of the metabolic syndrome has been demonstrated in adults, where the presence of three or more components significantly increases the risk for coronary heart disease death/non-fatal myocardial infarction and the onset of new diabetes 33, few, if any, outcome data in children exist. While one definition, although with gender- and ethnicity-specific cutoff points, is suitable for use in the at-risk adult population 2, transposing a single definition to children and adolescents is problematic. Blood pressure, lipid levels, and anthropometric variables change with age and pubertal development. Puberty impacts on fat distribution and is known to cause a decrease both in insulin sensitivity, of approximately 30% with a complementary increase in insulin secretion 34, and in adiponectin levels 35. Therefore, single cutoff points cannot be used to define abnormalities in children. Instead, values above the 90th, 95th, or 97th percentile for gender and age are used. However, there has not been universal agreement as to which level to use for the criteria for the metabolic syndrome. The importance of the early identification of children at risk of developing the metabolic syndrome and subsequently progressing to type 2 diabetes and cardiovascular disease in later life must not be underestimated. From birth and before, circumstances can predispose a child to conditions such as obesity or dysglycemia. The presence of maternal gestational diabetes 36, low birth weight 37, infant feeding practices 38, early adiposity rebound 39, and genetic factors may all contribute to a child’s future level of risk. Being raised in an ‘obesogenic’ environment can also have a strong impact, as can the influence of socioeconomic factors 40, with weight gain often being observed as a positive correlate to affluence in developing countries. Longitudinal outcome studies and further research on the progression and etiology of the metabolic syndrome are urgently required to ascertain the long-term outcomes of abdominal obesity and clustering of the components of metabolic syndrome in at-risk children and to help improve future definitions of the syndrome. This new IDF definition of metabolic syndrome in children and adolescents was developed during a consensus workshop that brought together experts in the field of the metabolic syndrome and pediatrics. The purpose of the new definition of metabolic syndrome in children and adolescents is to expand on the IDF recommendations for managing type 2 diabetes in the young 1 and to provide a useful and unified tool for identifying those at risk. A clinically accessible diagnostic tool, avoiding measurements that may only be available in research settings, is needed to identify the metabolic syndrome in children and adolescents globally. This need has prompted the IDF to develop a definition that has used the limited data available from existing studies in youth. As with the adult criteria, we look on these new criteria as a starting point. As new information emerges, they can be modified. Inspired, in part, by the IDF worldwide definition of metabolic syndrome in adults 2, this new definition builds on previous studies investigating the prevalence of metabolic syndrome in children and adolescents, which have used modified adult criteria with varying cutoff points 12-14, 41, 42 (Table 1). The wide variety of cutoff points used has emphasized the need for a single consistent set of criteria, which is easily measurable and can be used as the basis for future work 29. Because of the developmental challenges presented by the age-related differences in children and adolescents, the new IDF definition of metabolic syndrome has been divided according to the following age groups: 6 to <10, 10 to <16, and ≥16 yr (Table 2). In all the three age groups, abdominal obesity is the ‘sine qua non’. We suggest that below the age of 10 yr, the metabolic syndrome as an entity is not diagnosed, although a strong message for weight reduction will be made for these children. At the age of 10 yr and more, a diagnosis of metabolic syndrome can be made. It requires the presence of abdominal obesity plus the presence of two or more of the other components (elevated triglycerides, low high-density lipoprotein (HDL)-cholesterol, high blood pressure, and elevated plasma glucose). The IDF adult criteria 2 can be used for adolescents aged ≥16 yr, while a modified version of these criteria will be applied to those aged 10 to <16 yr (use 90th percentile cutoff point for waist and <40 mg/dL of HDL for both sexes). On the basis of emerging new data, these criteria may change in the future. In adults, insulin resistance and abdominal obesity are considered to be significant causative factors in the development of the metabolic syndrome 9, 43, 44. The link between obesity, insulin resistance, and the risk of developing the metabolic syndrome has also been described in children 22, 27. With measurement of insulin resistance considered to be impractical for clinical use, abdominal adiposity was positioned as the ‘sine qua non’ in the IDF definition of metabolic syndrome in adults 2 and is recognized to be an independent risk factor for the development of cardiovascular disease in adults 45. Abdominal obesity can be easily assessed using the simple measure of WC, which is known to correlate more strongly with visceral adipose tissue (VAT) than BMI in adults 46 and is a strong predictor of cardiovascular disease risk factors in children 47. The correlation between WC and VAT has also been more recently demonstrated in children 48, further strengthening the existing evidence that WC is an effective measure of abdominal obesity 49 in the youth population. In children and adolescents, a number of studies have demonstrated a similar link between childhood obesity and elevated cardiovascular risk in later life. The Bogalusa Heart study showed that childhood overweight is related to the development of adverse risk factors (BMI, lipids, insulin, diabetes mellitus, and blood pressure) in adulthood and is attributable to the strong persistence of weight status from childhood to adulthood 50. Of the overweight children in the Bogalusa Heart study (BMI ≥95th percentile), 77% remained obese in adulthood. Furthermore, the Muscatine study demonstrated that in young adults, excess weight was the earliest predictor of coronary artery calcification 51. The ATP III definition, applied to a cohort of individuals aged 12–19 yr (NHANES III), identified that 4% of those studied were found to have the metabolic syndrome, with 80% of those meeting the criteria of being overweight 13. Using a modified version of the ATP III definition, metabolic syndrome in adolescents has also been linked to high levels of C-reactive protein, a pro-inflammatory marker. Of the five components of metabolic syndrome, C-reactive protein was higher only among those with abdominal obesity 41. Waist circumference in children is an independent predictor of insulin resistance, lipid levels, and blood pressure 4, 52-54– all components of metabolic syndrome. Moreover, in obese youth with similar BMI, insulin sensitivity is lower in those with high VAT and high waist/hip ratio 53, 54. Furthermore, insulin sensitivity decreases and insulin levels increase with increasing WC percentiles 3. These data, combined with the unequivocal evidence of the dangers of abdominal obesity in adulthood, support the use of abdominal obesity as the ‘sine qua non’ for the diagnosis of metabolic syndrome in children and adolescents. Percentiles rather than absolute values of WC have been used in the new criteria to compensate for varying degrees of development and ethnicity in the youth population. WC percentile data are becoming increasingly available worldwide 31, 55-58. Children with a WC >90th percentile are more likely to have multiple risk factors than those with a WC below this level 59. Several studies attempting to estimate the prevalence of metabolic syndrome in children and adolescents have already used the 90th percentile as a cutoff point for WC 13, 14, 41. We have also chosen to use the 90th percentile as a cutoff point for WC based on this existing evidence and aim to reassess criteria and cutoff points in 5 yr and modify the guidelines, if necessary, based on the new outcome data. Previous studies investigating the metabolic syndrome in children and adolescents have used a range of cutoff points primarily based on ATP III criteria for categorizing additional components of the syndrome, i.e., triglycerides, HDL-cholesterol, blood pressure, and fasting glucose (Table 1) 12-14, 41, 42. Other definitive sources include the National High Blood Pressure Education Program, which recommends blood pressure cutoff points of >90th or >95th percentile adjusted for height, age, and gender to identify ‘high normal’ blood pressure or prehypertension and high blood pressure or hypertension in children and adolescents 60. Cutoff points for impaired fasting glucose have previously followed recommendations by the American Diabetes Association (ADA) [100–125 mg/dL (≥5.6–6.9 mmol/L)] 61 and the NCEP/ATP III in adults [≥110 mg/dL (6.1 mmol/L)] 23, although the latter has recently changed to the lower ADA recommended levels 62. Criteria for defining lipid (triglyceride and HDL-cholesterol) imbalances are even less consistent in the youth population, with recommendations by the NCEP/ATP III (age specific), NHANES III (age and gender specific), and the National Growth and Health Study (age, gender, and ethnic specific), employing either absolute value or percentile cutoff points. In view of this lack of consistency, we believe that use of the adult levels for the present is wise until further information is available. We recommend the following topics as priorities for future research: Develop a better understanding of the relationship between body fat and its distribution in children and adolescents, e.g., dual energy X-ray absorptiometry (DEXA), WC, BMI, and height and weight percentiles; a) Explore whether early growth patterns predict future adiposity and features of the metabolic syndrome, diabetes, and cardiovascular disease and b) explore whether low birth weight predicts future metabolic syndrome, diabetes, and cardiovascular disease; Perform factor analysis in children and adolescents to establish grouping of metabolic characteristics – adiposity, dyslipidemia, hyperinsulinemia, hypoadiponectinemia, and insulin resistance; Investigate how should obesity in children could be better defined, e.g., weight/height, WC etc.; Develop ethnic-specific normal ranges for WC, ideally based on healthy values; Perform ethnic-specific studies of WC etc. vs. abdominal (truncal) fat based on magnetic resonance imaging and DEXA; Support studies of adiponectin, leptin, etc. in children and adolescents to determine if they may be predictors of metabolic syndrome in adulthood; Initiate long-term studies of multi-ethnic cohorts followed into adulthood to determine the natural history and effectiveness of intervention strategies, particularly lifestyle. In conclusion, to combat any conflict that could arise from these multiple interpretations of the metabolic syndrome in children and adolescents, the IDF consensus group has aimed primarily at developing a simple, easy-to-apply definition to begin using in the clinical setting. In the absence of definitive research findings at this time, the proposed IDF definition of the metabolic syndrome in children and adolescents (Table 2) adheres to the absolute values presented in the adult definition 2, with the exception of WC. As described previously, until such time that outcome data from studies in children and adolescents indicate otherwise, WC percentiles are recommended for use. Early detection, followed by treatment in the form of lifestyle intervention and possibly pharmacotherapy, if its safety has been clearly demonstrated, is vital in halting the progression of this syndrome pathway in the adolescent population. It is likely that this will reduce morbidity and mortality in adulthood, as well as minimize the global socioeconomic burden of cardiovascular disease and type 2 diabetes. The workshop was sponsored by an unrestricted educational grant to the IDF Task Force on Epidemiology and Prevention from sanofi-aventis.

BACKGROUND: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. METHODS: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). FINDINGS: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. INTERPRETATION: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. FUNDING: MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

OBJECTIVE: The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten. DESIGN: A multidisciplinary task force of 16 physicians from seven countries used the electronic database PubMed to review the literature for CD-related terms up to January 2011. Teams of physicians then suggested a definition for each term, followed by feedback of these definitions through a web survey on definitions, discussions during a meeting in Oslo and phone conferences. In addition to 'CD', the following descriptors of CD were evaluated (in alphabetical order): asymptomatic, atypical, classical, latent, non-classical, overt, paediatric classical, potential, refractory, silent, subclinical, symptomatic, typical, CD serology, CD autoimmunity, genetically at risk of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten intolerance, gluten sensitivity and gliadin-specific antibodies. RESULTS: CD was defined as 'a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals'. Classical CD was defined as 'CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required.' 'Gluten-related disorders' is the suggested umbrella term for all diseases triggered by gluten and the term gluten intolerance should not to be used. Other definitions are presented in the paper. CONCLUSION: This paper presents the Oslo definitions for CD-related terms.

This is a retrospective study of patients whose tracheas were impossible to intubate on a previous occasion. There is a correlation between the degree of difficulty and the anatomy of the oropharynx in the same patient. The study was initially on obstetric patients but was extended to nonobstetric surgical patients in order to increase the number of cases investigated. The incidence of failed intubations in the obstetric group over a 3-year period was seven out of 1980 cases, whereas in the surgical group the results were six out of 13,380 patients. Any screening test which adds to our ability to predict difficulty in intubation must be welcomed, as failure to intubate can potentially lead to fatality.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections that are becoming increasingly difficult to combat because of emerging resistance to all current antibiotic classes. The evolutionary origins of MRSA are poorly understood, no rational nomenclature exists, and there is no consensus on the number of major MRSA clones or the relatedness of clones described from different countries. We resolve all of these issues and provide a more thorough and precise analysis of the evolution of MRSA clones than has previously been possible. Using multilocus sequence typing and an algorithm, BURST, we analyzed an international collection of 912 MRSA and methicillin-susceptible S. aureus (MSSA) isolates. We identified 11 major MRSA clones within five groups of related genotypes. The putative ancestral genotype of each group and the most parsimonious patterns of descent of isolates from each ancestor were inferred by using BURST, which, together with analysis of the methicillin resistance genes, established the likely evolutionary origins of each major MRSA clone, the genotype of the original MRSA clone and its MSSA progenitor, and the extent of acquisition and horizontal movement of the methicillin resistance genes. Major MRSA clones have arisen repeatedly from successful epidemic MSSA strains, and isolates with decreased susceptibility to vancomycin, the antibiotic of last resort, are arising from some of these major MRSA clones, highlighting a depressing progression of increasing drug resistance within a small number of ecologically successful S. aureus genotypes.

BACKGROUND: Data concerning the efficacy of bilateral prophylactic oophorectomy for reducing the risk of gynecologic cancer in women with BRCA1 or BRCA2 mutations are limited. We investigated whether this procedure reduces the risk of cancers of the coelomic epithelium and breast in women who carry such mutations. METHODS: A total of 551 women with disease-associated germ-line BRCA1 or BRCA2 mutations were identified from registries and studied for the occurrence of ovarian and breast cancer. We determined the incidence of ovarian cancer in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of postoperative follow-up for both groups was at least eight years. RESULTS: Six women who underwent prophylactic oophorectomy (2.3 percent) received a diagnosis of stage I ovarian cancer at the time of the procedure; two women (0.8 percent) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9 percent) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the six women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95 percent confidence interval, 0.01 to 0.16). Of 99 women who underwent bilateral prophylactic oophorectomy and who were studied to determine the risk of breast cancer, breast cancer developed in 21 (21.2 percent), as compared with 60 (42.3 percent) in the control group (hazard ratio, 0.47; 95 percent confidence interval, 0.29 to 0.77). CONCLUSIONS: Bilateral prophylactic oophorectomy reduces the risk of coelomic epithelial cancer and breast cancer in women with BRCA1 or BRCA2 mutations.

International audience

The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of 'Quality Care: service standards for the healthcare of people with IBD' in 2009. The introduction of the Montreal classification for Crohn's disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn's disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn's and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).

Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence-based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non-life-threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.

There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.

BACKGROUND: Cross sectional studies have shown that 1-2% of patients with neurofibromatosis 1 (NF1) develop malignant peripheral nerve sheath tumours (MPNST). However, no population based longitudinal studies have assessed lifetime risk. METHODS: NF1 patients with MPNST were ascertained from two sources for our north west England population of 4.1 million in the 13 year period 1984-1996: the North West Regional NF1 Register and review of notes of patients with MPNST in the North West Regional Cancer Registry. RESULTS: Twenty-one NF1 patients developed MPNST, equivalent to an annual incidence of 1.6 per 1000 and a lifetime risk of 8-13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST (p<0.001). In Kaplan-Meier analyses, the five year survival from diagnosis was 21% for NF1 patients with MPNST, compared to 42% for sporadic cases of MPNST (p=0.09). One NF1 patient developed two separate MPNST in the radiation field of a previous optic glioma. CONCLUSION: The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.

BACKGROUND: Heart failure treatment depends partly on the underlying cause of the disease. We evaluated cardiovascular magnetic resonance (CMR) for the problem of differentiating dilated cardiomyopathy (DCM) from left ventricular (LV) dysfunction caused by coronary artery disease (CAD). METHODS AND RESULTS: Late gadolinium enhancement with CMR was performed in 90 patients with heart failure and LV systolic dysfunction (63 patients with DCM and unobstructed coronary arteries and 27 with significant CAD at angiography). We also studied 15 control subjects with no coronary risk factors and/or unobstructed coronary arteries. None (0%) of the control subjects had myocardial gadolinium enhancement; however, all patients (100%) with LV dysfunction and CAD had enhancement, which was subendocardial or transmural. In patients with DCM, there were 3 findings: no enhancement (59%); myocardial enhancement indistinguishable from the patients with CAD (13%); and patchy or longitudinal striae of midwall enhancement clearly different from the distribution in patients with CAD (28%). CONCLUSIONS: Gadolinium CMR is a powerful technique to distinguish DCM from LV dysfunction related to CAD and yields new insights in DCM. These data suggest that using the coronary angiogram as the arbiter for the presence of LV dysfunction caused by CAD could have lead to an incorrect assignment of DCM cause in 13% of patients, possibly because of coronary recanalization after infarction. The midwall myocardial enhancement in patients with DCM is similar to the fibrosis found at autopsy; it has not previously been visualized in vivo and warrants further investigation. CMR may become a useful alternative to routine coronary angiography in the diagnostic workup of DCM.

The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) commissioned this update of the 2002 guidance. The aim, as before, is to provide guidance on the appropriateness, method and frequency of screening for people at moderate and high risk from colorectal cancer. This guidance provides some new recommendations for those with inflammatory bowel disease and for those at moderate risk resulting from a family history of colorectal cancer. In other areas guidance is relatively unchanged, but the recent literature was reviewed and is included where appropriate.

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.

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

This paper provides a consolidated overview of public and healthcare professionals' attitudes towards vaccination in Europe by bringing together for the first time evidence across various vaccines, countries and populations. The paper relies on an extensive review of empirical literature published in English after 2009, as well as an analysis of unpublished market research data from member companies of Vaccines Europe. Our synthesis suggests that hesitant attitudes to vaccination are prevalent and may be increasing since the influenza pandemic of 2009. We define hesitancy as an expression of concern or doubt about the value or safety of vaccination. This means that hesitant attitudes are not confined only to those who refuse vaccination or those who encourage others to refuse vaccination. For many people, vaccination attitudes are shaped not just by healthcare professionals but also by an array of other information sources, including online and social media sources. We find that healthcare professionals report increasing challenges to building a trustful relationship with patients, through which they might otherwise allay concerns and reassure hesitant patients. We also find a range of reasons for vaccination attitudes, only some of which can be characterised as being related to lack of awareness or misinformation. Reasons that relate to issues of mistrust are cited more commonly in the literature than reasons that relate to information deficit. The importance of trust in the institutions involved with vaccination is discussed in terms of implications for researchers and policy-makers; we suggest that rebuilding this trust is a multi-stakeholder problem requiring a co-ordinated strategy.

The British Thoracic Society first published management guidelines for community acquired pneumonia in children in 2002 and covered available evidence to early 2000. These updated guidelines represent a review of new evidence since then and consensus clinical opinion where evidence was not found. This document incorporates material from the 2002 guidelines and supersedes the previous guideline document.

BACKGROUND: The unpredictability of anaphylactic reactions and the need for immediate, often improvised treatment will make controlled trials impracticable; other means must therefore be used to determine optimal management. OBJECTIVES: This study aimed to investigate the circumstances leading to fatal anaphylaxis. METHODS: A register was established including all fatal anaphylactic reactions in the UK since 1992 that could be traced from the certified cause of death. Data obtained from other sources suggested that deaths certified as due to anaphylaxis underestimate the true incidence. Details of the previous medical history, the reaction and necropsy were sought for all cases. RESULTS: Approximately half the 20 fatal reactions recorded each year in the UK were iatrogenic, and a quarter each due to food or insect venom. All fatal reactions thought to have been due to food caused difficulty breathing that in 86% led to respiratory arrest; shock was more common in iatrogenic and venom reactions. The median time to respiratory or cardiac arrest was 30 min for foods, 15 min for venom and 5 min for iatrogenic reactions. Twenty-eight per cent of fatal cases were resuscitated but died 3 h-30 days later, mostly from hypoxic brain damage. Adrenaline (epinephrine) was used in treatment of 62% of fatal reactions but before arrest in only 14%. CONCLUSIONS: Immediate recognition of anaphylaxis, early use of adrenaline, inhaled beta agonists and other measures are crucial for successful treatment. Nevertheless, a few reactions will be fatal whatever treatment is given; optimal management of anaphylaxis is therefore avoidance of the cause whenever this is possible. Predictable cross-reactivity between the cause of the fatal reaction and that of previous reactions had been overlooked. Adrenaline overdose caused at least three deaths and must be avoided. Kit for self-treatment had proved unhelpful for a variety of reasons; its success depends on selection of appropriate medication, ease of use and good training.

Anaphylaxis is a clinical emergency, and all healthcare professionals should be familiar with its recognition and acute and ongoing management. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Taskforce on Anaphylaxis. They aim to provide evidence-based recommendations for the recognition, risk factor assessment, and the management of patients who are at risk of, are experiencing, or have experienced anaphylaxis. While the primary audience is allergists, these guidelines are also relevant to all other healthcare professionals. The development of these guidelines has been underpinned by two systematic reviews of the literature, both on the epidemiology and on clinical management of anaphylaxis. Anaphylaxis is a potentially life-threatening condition whose clinical diagnosis is based on recognition of a constellation of presenting features. First-line treatment for anaphylaxis is intramuscular adrenaline. Useful second-line interventions may include removing the trigger where possible, calling for help, correct positioning of the patient, high-flow oxygen, intravenous fluids, inhaled short-acting bronchodilators, and nebulized adrenaline. Discharge arrangements should involve an assessment of the risk of further reactions, a management plan with an anaphylaxis emergency action plan, and, where appropriate, prescribing an adrenaline auto-injector. If an adrenaline auto-injector is prescribed, education on when and how to use the device should be provided. Specialist follow-up is essential to investigate possible triggers, to perform a comprehensive risk assessment, and to prevent future episodes by developing personalized risk reduction strategies including, where possible, commencing allergen immunotherapy. Training for the patient and all caregivers is essential. There are still many gaps in the evidence base for anaphylaxis.