University College Hospital

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

Lethal reperfusion injury is a paradoxical type of myocardial injury caused by the restoration of coronary blood flow after an ischemic episode. This review focuses on the mechanisms of the injury, on attempts to protect the heart against it, and on promising new approaches to cardioprotection during percutaneous coronary intervention.

BACKGROUND: Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. METHODS: We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291. FINDINGS: Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. INTERPRETATION: Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. FUNDING: PROMIS is funded by the UK Government Department of Health, National Institute of Health Research-Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).

= .002); scans obtained in stage 3 (9-13 days) showed consolidation (19 of 21 scans [91%]) and a peak in the total CT score (mean, 7 ± 4); and scans obtained in stage 4 (≥14 days) showed gradual resolution of consolidation (15 of 20 scans [75%]) and a decrease in the total CT score (mean, 6 ± 4) without crazy-paving pattern. Conclusion In patients recovering from coronavirus disease 2019 (without severe respiratory distress during the disease course), lung abnormalities on chest CT scans showed greatest severity approximately 10 days after initial onset of symptoms. © RSNA, 2020.

BACKGROUND: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown. METHODS: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival. RESULTS: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group. CONCLUSIONS: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).

OBJECTIVE: To quantify the risk of future cardiovascular diseases, cancer, and mortality after pre-eclampsia. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Embase and Medline without language restrictions, including papers published between 1960 and December 2006, and hand searching of reference lists of relevant articles and reviews for additional reports. REVIEW METHODS: Prospective and retrospective cohort studies were included, providing a dataset of 3,488,160 women, with 198,252 affected by pre-eclampsia (exposure group) and 29,495 episodes of cardiovascular disease and cancer (study outcomes). RESULTS: After pre-eclampsia women have an increased risk of vascular disease. The relative risks (95% confidence intervals) for hypertension were 3.70 (2.70 to 5.05) after 14.1 years weighted mean follow-up, for ischaemic heart disease 2.16 (1.86 to 2.52) after 11.7 years, for stroke 1.81 (1.45 to 2.27) after 10.4 years, and for venous thromboembolism 1.79 (1.37 to 2.33) after 4.7 years. No increase in risk of any cancer was found (0.96, 0.73 to 1.27), including breast cancer (1.04, 0.78 to 1.39) 17 years after pre-eclampsia. Overall mortality after pre-eclampsia was increased: 1.49 (1.05 to 2.14) after 14.5 years. CONCLUSIONS: A history of pre-eclampsia should be considered when evaluating risk of cardiovascular disease in women. This association might reflect a common cause for pre-eclampsia and cardiovascular disease, or an effect of pre-eclampsia on disease development, or both. No association was found between pre-eclampsia and future cancer.

STUDY QUESTION: What is the optimal management of women with endometriosis based on the best available evidence in the literature? SUMMARY ANSWER: Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. WHAT IS KNOWN ALREADY: The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. LIMITATIONS, REASONS FOR CAUTION: We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. WIDER IMPLICATIONS OF THE FINDINGS: Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). TRIAL REGISTRATION NUMBER: NA.

This review provides a summary statement of recommended implementations of arterial spin labeling (ASL) for clinical applications. It is a consensus of the ISMRM Perfusion Study Group and the European ASL in Dementia consortium, both of whom met to reach this consensus in October 2012 in Amsterdam. Although ASL continues to undergo rapid technical development, we believe that current ASL methods are robust and ready to provide useful clinical information, and that a consensus statement on recommended implementations will help the clinical community to adopt a standardized approach. In this review, we describe the major considerations and trade-offs in implementing an ASL protocol and provide specific recommendations for a standard approach. Our conclusion is that as an optimal default implementation, we recommend pseudo-continuous labeling, background suppression, a segmented three-dimensional readout without vascular crushing gradients, and calculation and presentation of both label/control difference images and cerebral blood flow in absolute units using a simplified model.

BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS: There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

INTRODUCTION: The STROCSS guideline was developed in 2017 to improve the reporting quality of observational studies in surgery. Building on its impact and usefulness, we sought to update the guidelines two years after its publication. METHODS: A steering group was formed to review the existing guideline and propose amendments to the 17-item checklist. A Delphi consensus exercise was utilised to determine agreement across a list of proposed modifications to the STROCSS 2017 guideline. An expert panel of 46 surgeons were invited to assess the proposed updates via Google Forms. RESULTS: The response rate was 91% (n = 42/46). High agreement was reached across all the items and the guideline was finalised in the first round. The checklist maintained 17-items, with modifications primarily considered to improve content and readability. CONCLUSIONS: The STROCSS 2019 guideline is hereby presented as a considered update to improve reporting of cohort, cross-sectional and case-control studies in surgery.

STUDY QUESTION: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the diagnosis and treatment of women with POI. WHAT IS KNOWN ALREADY: NA. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology (ESHRE) members and professional organizations were asked to review the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46 recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on puberty induction resulted in five recommendations. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the guideline is that, due to the lack of data, many of the recommendations are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limitations, the guideline group is confident that this document will be able to guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline group has formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research on the key issues in POI. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: NA.

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).

The most important electron acceptor in the biosphere is molecular oxygen which, by virtue of its bi-radical nature, readily accepts unpaired electrons to give rise to a series of partially reduced species collectively known as reduced (or 'reactive') oxygen species (ROS). These include superoxide (O.2-), hydrogen peroxide (H2O2), hydroxyl radical (HO.) and peroxyl (ROO.) and alkoxyl (RO.) radicals which may be involved in the initiation and propagation of free radical chain reactions and which are potentially highly damaging to cells. Mechanisms have evolved to restrict and control such processes, partly by compartmentation, and partly by antioxidant defences such as chain-breaking antioxidant compounds capable forming stable free radicals (e.g. ascorbate, alpha-tocopherol) and the evolution of enzyme systems (e.g. superoxide dismutase, catalase, peroxidases) that diminish the intracellular concentration of the ROS. Although some ROS perform useful functions, the production of ROS exceeding the ability of the organism to mount an antioxidant defence results in oxidative stress and the ensuing tissue damage may be involved in certain disease processes. Evidence that ROS are involved in primary pathological mechanisms is a feature mainly of extraneous physical or chemical perturbations of which radiation is perhaps the major contributor. One of the important radiation-induced free-radical species is the hydroxyl radical which indiscriminately attacks neighbouring molecules often at near diffusion-controlled rates. Hydroxyl radicals are generated by ionizing radiation either directly by oxidation of water, or indirectly by the formation of secondary partially ROS. These may be subsequently converted to hydroxyl radicals by further reduction ('activation') by metabolic processes in the cell. Secondary radiation injury is therefore influenced by the cellular antioxidant status and the amount and availability of activating mechanisms. The biological response to radiation may be modulated by alterations in factors affecting these secondary mechanisms of cellular injury.

STUDY QUESTION: How should endometriosis be diagnosed and managed based on the best available evidence from published literature? SUMMARY ANSWER: The current guideline provides 109 recommendations on diagnosis, treatments for pain and infertility, management of disease recurrence, asymptomatic or extrapelvic disease, endometriosis in adolescents and postmenopausal women, prevention and the association with cancer. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition with a plethora of presentations in terms of not only the occurrence of lesions, but also the presence of signs and symptoms. The most important symptoms include pain and infertility. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 1 December 2020 and written in English were included in the literature review. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed within specialist subgroups and then presented to the core guideline development group (GDG) until consensus was reached. A stakeholder review was organized after finalization of the draft. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help clinicians to apply best care for women with endometriosis. Although studies mostly focus on women of reproductive age, the guideline also addresses endometriosis in adolescents and postmenopausal women. The guideline outlines the diagnostic process for endometriosis, which challenges laparoscopy and histology as gold standard diagnostic tests. The options for treatment of endometriosis-associated pain symptoms include analgesics, medical treatments and surgery. Non-pharmacological treatments are also discussed. For management of endometriosis-associated infertility, surgical treatment and/or medically assisted reproduction are feasible. While most of the more recent studies confirm previous ESHRE recommendations, there are five topics in which significant changes to recommendations were required and changes in clinical practice are to be expected. LIMITATIONS REASONS FOR CAUTION: The guideline describes different management options but, based on existing evidence, no firm recommendations could be formulated on the most appropriate treatments. Also, for specific clinical issues, such as asymptomatic endometriosis or extrapelvic endometriosis, the evidence is too scarce to make evidence-based recommendations. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in endometriosis care, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in endometriosis. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payments. C.M.B. reports grants from Bayer Healthcare and the European Commission; Participation on a Data Safety Monitoring Board or Advisory Board with ObsEva (Data Safety Monitoring Group) and Myovant (Scientific Advisory Group). A.B. reports grants from FEMaLE executive board member and European Commission Horizon 2020 grant; consulting fees from Ethicon Endo Surgery, Medtronic; honoraria for lectures from Ethicon; and support for meeting attendance from Gedeon Richter; A.H. reports grants from MRC, NIHR, CSO, Roche Diagnostics, Astra Zeneca, Ferring; Consulting fees from Roche Diagnostics, Nordic Pharma, Chugai and Benevolent Al Bio Limited all paid to the institution; a pending patent on Serum endometriosis biomarker; he is also Chair of TSC for STOP-OHSS and CERM trials. O.H. reports consulting fees and speaker's fees from Gedeon Richter and Bayer AG; support for attending meetings from Gedeon-Richter, and leadership roles at the Finnish Society for Obstetrics and Gynecology and the Nordic federation of the societies of obstetrics and gynecology. L.K. reports consulting fees from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; honoraria for lectures from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; support for attending meetings from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; he also has a leadership role in the German Society of Gynecological Endocrinology (DGGEF). M.K. reports grants from French Foundation for Medical Research (FRM), Australian Ministry of Health, Medical Research Future Fund and French National Cancer Institute; support for meeting attendance from European Society for Gynaecological Endoscopy (ESGE), European Congress on Endometriosis (EEC) and ESHRE; She is an advisory Board Member, FEMaLe Project (Finding Endometriosis Using Machine Learning), Scientific Committee Chair for the French Foundation for Research on Endometriosis and Scientific Committee Chair for the ComPaRe-Endometriosis cohort. A.N. reports grants from Merck SA and Ferring; speaker fees from Merck SA and Ferring; support for meeting attendance from Merck SA; Participation on a Data Safety Monitoring Board or Advisory Board with Nordic Pharma and Merck SA; she also is a board member of medical advisory board, Endometriosis Society, the Netherlands (patients advocacy group) and an executive board member of the World Endometriosis Society. E.S. reports grants from National Institute for Health Research UK, Rosetrees Trust, Barts and the London Charity; Royalties from De Gruyter (book editor); consulting fees from Hologic; speakers fees from Hologic, Johnson & Johnson, Medtronic, Intuitive, Olympus and Karl Storz; Participation in the Medicines for Women's Health Expert Advisory Group with Medicines and Healthcare Products Regulatory Agency (MHRA); he is also Ambassador for the World Endometriosis Society. C.T. reports grants from Merck SA; Consulting fees from Gedeon Richter, Nordic Pharma and Merck SA; speaker fees from Merck SA, all paid to the institution; and support for meeting attendance from Ferring, Gedeon Richter and Merck SA. The other authors have no conflicts of interest to declare. DISCLAIMER: www.eshre.eu/guidelines.).

BACKGROUND: Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. METHODS: Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. FINDINGS: We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). INTERPRETATION: Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. FUNDING: The Policy Research Programme, Department of Health, UK.

Neuroimaging studies have shown differential amygdala responses to masked ("unseen") emotional stimuli. How visual signals related to such unseen stimuli access the amygdala is unknown. A possible pathway, involving the superior colliculus and pulvinar, is suggested by observations of patients with striate cortex lesions who show preserved abilities to localize and discriminate visual stimuli that are not consciously perceived ("blindsight"). We used measures of right amygdala neural activity acquired from volunteer subjects viewing masked fear-conditioned faces to determine whether a colliculo-pulvinar pathway was engaged during processing of these unseen target stimuli. Increased connectivity between right amygdala, pulvinar, and superior colliculus was evident when fear-conditioned faces were unseen rather than seen. Right amygdala connectivity with fusiform and orbitofrontal cortices decreased in the same condition. By contrast, the left amygdala, whose activity did not discriminate seen and unseen fear-conditioned targets, showed no masking-dependent changes in connectivity with superior colliculus or pulvinar. These results suggest that a subcortical pathway to the right amygdala, via midbrain and thalamus, provides a route for processing behaviorally relevant unseen visual events in parallel to a cortical route necessary for conscious identification.