Pennine Acute Hospitals NHS Trust

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

This is the third European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses ulcerative colitis [UC]. It has been drafted by 28 ECCO members from 14 European countries. It is derived from and updates the previous ECCO consensus advice on UC.1–3 All the authors recognise and are grateful to previous ECCO members who contributed to creating the previous consensus guidelines1–6 on which some of the text is based. Attention is also drawn to other ECCO consensus guidelines which have contributed to this endeavour, on extra-intestinal manifestations [EIMs],7 malignancy,8 imaging,9 small bowel endoscopy,10 opportunistic infections [OIs],11 surgery,12 endoscopy,13 pathology,14 anaemia,15 reproduction and pregnancy,16 and paediatric UC.17 The guideline has been condensed into two papers, the first detailing definitions, classification, diagnosis, imaging, pathology, and management of special situations [EIMs, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders of UC]; and the second describing current therapeutic management [treatment of active disease and maintenance of medically induced remission]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement. Working parties were established to review the consensus statements published in 2012,1–3 after which a recommendation was issued on whether they required revision based upon advances in the published literature. There was agreement that extensive review of histopathology, endoscopy, OI, anaemia, EIMs, surgery, and pregnancy was not required, as these subjects are reviewed in other recent ECCO guidelines7,11–16; rather, abbreviated text and selected statements from these guidelines specific to UC are provided. Paediatric UC is dealt with in a separate ECCO initiative17 which is currently being updated. Provisional ECCO statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds which included national representative participation by ECCO’s 35 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalised by the authors at a meeting in Barcelona in October 2015 and represent consensus with agreement of at least 80% of participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [FM, FC, AD, PG, FR], including an updated literature search to October 2016 of the most relevant [eight] journals, before being integrated by a consensus leader [MH]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/]. UC is a lifelong disease arising from an interaction between genetic and environmental factors, observed predominantly in developed countries. Its precise aetiology is unknown, and therefore curative medical therapy is not yet available. Within Europe there is an east-west and north-south gradient, but the incidence appears to have increased in southern and eastern countries during recent years.18–20 Patients may live with a considerable symptom burden and high risk of disability21 despite medical treatment.22 Clinicians must advise and treat patients on the basis of currently available information. Despite robust evidence from rigorously conducted randomised trials, the strict and somewhat necessarily restrictive inclusion and exclusion criteria in trial design may limit translation of such evidence to ‘real-world’ patients. Ulcerative colitis [UC] is a chronic inflammatory condition that causes continuous mucosal inflammation of the colon, usually without granulomas on biopsy. It affects the rectum and to a variable extent the colon in a continuous fashion, and is characterised by a relapsing and remitting course.23 Inflammatory bowel disease unclassified [IBDU] is the term best suited for a minority of cases in which a definitive distinction between UC, Crohn’s disease, or other causes of colitis cannot be made after taking into account the history, endoscopic appearance, histopathology of multiple mucosal biopsies, and appropriate radiology.23,24 Indeterminate colitis is a term reserved for pathologists to describe a colectomy specimen with overlapping features of UC and Crohn’s disease.24,25 Detailed information on definitions can be found in Supplementary material, available as Supplementary data at ECCO-JCC online.1,23,24,26–39 Distribution of UC [adapted from Silverberg et al.23]. Disease activity in UC [adapted from Truelove & Witts32]. Montréal classification of disease activity in UC [adapted from Silverberg et and et Disease extent whether therapy and and of It is by the extent at as and extensive colitis of inflammation the management and the of for a therapy in the of or is usually the for and therapy with is appropriate for extensive of colitis the risk of of or cancer and the and the of Patients with extensive colitis have the risk of with have a risk similar to the Patients with colitis an their risk that of patients with extensive colitis as disease patients with and extensive colitis are to have patients with not such It be that the extent at may the extent of disease as with and are to the extent of information and risk for of or colitis may in of patients with Disease and of of disease have not been imaging, and endoscopic including histopathology, on management is as and at of a inflammatory of disease It be to the of active colitis by and before which may causes of that active disease such as mucosal Crohn’s disease, or bowel and patients with active disease including to Patients with an appropriate also have to a from of patients are in at during a a of a relapsing after of Disease activity in the first after to an increased of of active a an was between the to first and the of a the the was patients a for the maintenance of in patients with at patients from to at and from to at in the of described the in patients in the first following of UC between and the most recent the of patients an during the first after was a or within the first but and an activity at least during the first is also UC, a chronic inflammatory was in and were in of patients with an inflammatory after of with who without such an were in with and mucosal The of bowel inflammation is also a risk for in patients with extensive Detailed information on the of can be found in Supplementary material, available as Supplementary data at ECCO-JCC and and are of have been with of The is not as in UC as is in Crohn’s disease for the of disease in colitis have been established for and patients a to following for colitis with to a is for and have been but has been to be to The most are and other such as and have also at has for and of disease a with endoscopic and to can be as a for in patients with inflammatory bowel disease of was with an increased risk of It must be that of these is specific for UC, they represent active with disease there is of The consensus group that the best to define is a of with and mucosal at classification of ulcerative colitis according to at is of as disease has a according to the of is as the for and of patients with UC to have disease and and with All current available for UC have an in with The risk of in patients with UC the of is an in patients with UC, as the risk for The of genetic or is not for the classification of ulcerative colitis Detailed information on can be found in Supplementary material, available as Supplementary data at ECCO-JCC of ulcerative colitis are upon extent and of disease and and and are bowel and colitis UC in and the may be made at small in incidence has been in some after the of UC appears to The inflammation in the rectum and in a and to a variable extent of the colon, or mucosal The extent of inflammation may or but after disease the of inflammation to the extent of previous in the of The that UC continuous inflammation been by of a in and of patients with active UC the of mucosal disease, and may according to disease in for extensive UC from most cases of Patients with active disease also of and patients with usually with and may in UC, or the of Crohn’s The of UC is usually are for or before medical advice is with a in with including and EIMs, in or and may the in of cases and can in of of ulcerative colitis or Crohn’s disease the risk for ulcerative colitis for before and the risk and of UC may to ulcerative colitis of patients with UC have an increased risk of the The risk of UC is in but is also in and of UC as as in of patients with Crohn’s disease in a and the of but may not the of the have a risk of the disease, which is extensive and to with who have or but the data are and during or are to a risk of UC in The of is to that of but not to the of is after the of UC, the on the of disease is and is to may the evidence from and a trial that with is medical the of and and extra-intestinal with and of inflammatory bowel disease or and previous be The of UC is in the context of or of colitis be and be and and for and and may be may be in patients with or disease on on the extent and of of patients with or activity is usually from on Patients with a may and bowel for of ulcerative colitis not It is established by imaging, and endoscopic including be with review after an may be The of UC is characterised by of and of continuous in of the as a by The that of patients a in The of of is usually during the first and may be characterised as continuous UC without or the recent the of patients with UC in from at the of to after of It is to the diagnosis, and of disease, as these and disease It is to the to to a diagnosis, but mucosal active UC as the of of the may to Crohn’s disease or be during the first and and The be including be and be diagnosis, have a inflammatory and and a for is an of of chronic inflammation may be in or The may as a of the chronic inflammatory or chronic active disease, and which the of an UC, and with the of with patients with an is with an and have been as to the for colectomy in after a of extensive colitis an increased risk of is specific to UC from or other causes of be to and for may be according to the medical history, for the of for or other or with are required at and may be required to disease is in patients with colitis This for and is a and has been with and ECCO guidelines with disease be in the of or of can in UC, not in patients with may not disease can or It be in patients who The for relevant in patients with colitis has not been but most of in the inclusion with on histopathology not necessarily but multiple are usually including information on can be reviewed in the ECCO Consensus on and in a recent The most are and are in to of patients with UC and in of patients with Crohn’s the current of these their for the of UC and for therapeutic is not such as and have been as of inflammation in appears to be the most the of in patients for in the of disease with endoscopic and in the of and to with the to between of a in the of UC a to inflammation and to be a to a of patients by and has been described in with a or inflammation in the rectum is to to inflammation in the is to as a and may be observed in patients with the of and or a in of the small bowel in to an is The of patients with inflammation to be similar to with of the as a is in to of patients with inflammation has been with a and a risk of after pouch a recent a similar in patients with an of inflammation with with a in of disease and of or inflammation from the into is and is observed in to of patients with extensive may in patients without which the that that from a of into the Patients with to be to a of which may an increased risk of colon in not to be with pouch of the small bowel be in cases of to UC from Crohn’s bowel by or or endoscopy, as reviewed in the ECCO consensus on in Crohn’s and small bowel in is not is the of an to Crohn’s disease in to an is for endoscopic disease activity in ulcerative colitis are available. The of a endoscopic is to of ulcerative colitis patients and to a for inflammatory bowel disease to is for patients criteria for to which may to increased and The classification of UC was by Truelove and in This classification is to be the for of in of to and the of patients with colitis have inflammatory or and with a for and of be to and to the extent of disease and for features that to The extent of disease with the of in a of the extent of disease was in and in The of mucosal by or two of small bowel is with a to the of colitis and may be required is as a on with high in which histopathology be with a within before is in patients with colitis is not in in patients on criteria for colitis with mucosal on the of these and of which can be by is of is appropriate at for or ulcerative colitis or colectomy Despite the of disease in risk of and of the of after has been a mucosal after of was with a risk of in of the patients with mucosal with of without of patients who endoscopic as a of inflammation at and on during of in to of patients that to endoscopic in patients with UC, who were the disease and endoscopic after and and then at the third were to patients with or between and in the of and colectomy were of mucosal was the with and a disease patients with UC with and in that with endoscopic as with to after patients in The most endoscopic of ulcerative colitis is with of inflammation and ulcerative colitis is by mucosal and at the and in a and The between and is usually and may within in in the endoscopic of disease activity is and have been to the of endoscopic and are within the for UC, which is for trial The Ulcerative Colitis of the and the of and each with or of This is the first endoscopic of in The is the of in the of the colon at the of the a of to the of a a was made to the of the a to a of that the of the from to for ulcerative for The endoscopic features of inflammation are and at least of the active colitis is characterised by a of to the of the and with a and mucosal to colitis is characterised by and in et to Crohn’s disease, in UC are in The of is a disease, mucosal can in of and The of in UC has therefore been the of information on colon can be found in Supplementary material, available as Supplementary data at ECCO-JCC Detailed information on can be found in Supplementary material, available as Supplementary data at ECCO-JCC in ulcerative multiple endoscopic be to by be are not or the is not UC, a an increased risk for and the be by a second is the most in the of and then management in a is to a the mucosal to the and extra-intestinal is for diagnosis, of disease and of and The following and updates of the ECCO guideline on UC is a chronic inflammatory to the of features have been and they can be into mucosal and information on on the can be found in Supplementary material, available as Supplementary data at ECCO-JCC a of ulcerative a of two from at least the colon the and the be be by including endoscopic of disease and current be by in or an before the features found in UC are observed in of patients within of the first of The distinction from colitis which is characterised by and is therefore a is the with the for the of ulcerative colitis and the of a inflammatory not ulcerative colitis at an after an may to and a definitive by features or has been as the with the for UC It can be in of patients within after this the of is but may into a the disease mucosal or mucosal and an or mucosal during the of disease least after The of ulcerative colitis is based upon the of and mucosal and a inflammatory with with active inflammation and The of features for UC has not been of UC is in of cases two or of the following features an and in the of of inflammation from to a of ulcerative colitis may the of of these is in the of from patients to an UC a of continuous inflammation that in the rectum and with a in The between the and the is can disease, the extent of during the of the disease or after may such as from continuous to inflammation of the of these features is to in the of to Crohn’s disease, the may features to and as as of and increased inflammation is usually not observed disease is characterised by the of active mucosal features to chronic mucosal such as and as as may mucosal is characterised by the of and inflammatory the can some features of such as with and of usually the of is from endoscopic mucosal inflammation may in cases with disease and has been with of mucosal inflammation following has been can be to between and active disease, as as to the of disease have been for this in therapeutic of or mucosal a definitions of from inflammation with to of the as in with of an increased with of or a high of been with a risk of The of histopathology to and to the level of inflammation may have in therapeutic mucosal is from endoscopic mucosal have a for diagnosis, with the at and endoscopic activity in and disease, but for The of histopathology as the or to disease activity is in to and may be in and with There and updates of the ECCO guideline on and is in UC, found in of for of et criteria for on the level of patients without or evidence of active disease, is an appropriate the of a to may be with the of or evidence of the criteria for of chronic disease are and the level is between and a of and of chronic disease is The most of in UC are of chronic disease, and a of or anaemia, and are but also be is by the as a in to a of in and in All UC patients be for anaemia, and this a and be with and is with and The level of with and is by the of and in et is in ulcerative colitis patients is Detailed information on and can be found in Supplementary material, available as Supplementary data at ECCO-JCC is the second most in UC, in of can be as and of with ulcerative colitis is based on of inflammation and exclusion of other specific of classification for has been but not is and affects in an This is and and is with disease is a and which affects small is of UC and can for to of is on the basis of features of inflammatory with or features of and The of is made according to the is the current as can inflammation before and The of management is the of of and of trial in patients is of the UC usually within Patients may from and Patients with usually or for symptom for be with a and are to be in with patients with active to or of are The and of and in are The of not as the to the risk of the with not is based on which be in patients with active UC, to or with disease and are the statements to in et Patients on therapy and or with a of be or other as these can statements & in et of is made on a be is usually based on that of the ulcerative are required in cases and can be with or usually affects the of the the and has a It is to disease and is based on that of the are usually or or may be can be with or and or are by a as most on the and to The of with disease activity is are to be the first of has been and has to in therefore be a to is not or are an but advice is to on and inflammation can be found in Supplementary material, available as Supplementary data at ECCO-JCC UC It can be and usually to and of the not to an and may has to UC, is has an and is The of to of to an usually of or or and have each been to be of in cases statements & in et the most condition UC chronic and are also in these patients. of the to treat UC have the to is a risk for and colon is as a in patients with for is and small is a be statements to in et was to the of and to the risk of in but therapy has been to to or the was with a disease and therefore be the of to disease with is the statements to in et or after of in UC patients is in et and in et on and disease can be found in Supplementary material, available as Supplementary data at ECCO-JCC Ulcerative colitis patients at risk of opportunistic infections are with in and with and a of infections be is an risk for opportunistic infections to are according to the for Disease and is as a by a that has under for can be or UC patients are not but may have as a of their medical in et is an risk for and in the risk of in a of for All for the of OI, and the of at a may an increased risk of This risk is of the and of but may be by the of OI, have not been to the risk of All ulcerative colitis patients be for at patients with also be is in patients with ulcerative colitis of is in inflammatory bowel disease, by the disease and by the be after of the may be required to of be in patients at risk and for at least after has patients who are with high to of the of in to of with therapy in ulcerative colitis be but therapy is not is the increased risk of UC patients be to is not a for in et UC patients also be for the be by not a with or is but they can the of in on or can be found in Supplementary material, available as Supplementary data at ECCO-JCC information on and can be found in Supplementary material, available as Supplementary data at ECCO-JCC of in patients with is increased and is in the be by a of history, and according to and national be at and before therapy are to the and are in of is to and be in patients being with with the Patients with therapy before patients with active UC and be after of in et of active therapy must be and for at least in et be to UC patients before and be before can to after & in et UC patients taking who be for infections and UC patients therapy infections with in et active infections are is statements to in et the risk of and infections with in et The to or infections in et therapy be during and disease be before Ulcerative colitis is an risk for with and are in to disease It to be established this to patients with ulcerative be disease, has been to be in patients without ulcerative colitis and is therefore disease, of be by risk and are of is in has been to be in of to and a of to an increased risk for with patients with inflammatory bowel disease are to can be found in Supplementary material, available as Supplementary data at ECCO-JCC There is evidence that ulcerative colitis affects of in with ulcerative colitis the for UC patients are to have similar as the but patients from of as they to not to be by UC can and in et causes and is in patients to a the of are and pouch in patients may to and by to an or in et The in after pouch is to that of subjects in et at a of disease, the risk of is the as in at a of active disease the risk of activity during pregnancy may the of ulcerative colitis Patients be to during to the most appropriate a with and is in et Disease activity at or during pregnancy is with and The risk of in from with ulcerative colitis not to be increased to most ulcerative colitis is of risk to the for and information on of can be found in Supplementary material, available as Supplementary data at ECCO-JCC of ulcerative colitis be in patients who to in to the risk of during pregnancy during pregnancy a high risk of and and are best and without to these UC patients who be to their to disease and pregnancy in et to their during pregnancy, with and be as the a is an in specific situations be in a with for UC during pregnancy can to during the first and to in the third but is to represent a risk for the in et information on endoscopy, and can be found in Supplementary material, available as Supplementary data at ECCO-JCC is that UC is with an increased risk of the risk between et described a including and that after of disease the risk was that the incidence of in UC patients was the risk of may have been has a incidence of at at and at This may the increased of the of that inflammation or the to maintenance therapy or The risk of cancer in ulcerative colitis is increased with the is with disease extent and or inflammatory activity has been that is disease a of may by this in patients who are at colitis or in patients with Patients with extensive colitis the risk of colitis patients an risk is not increased in patients with UC to the without may be an for and a of cancer an risk for cancer The most risk for are an increased risk of to and disease may be of previous inflammatory and have also been found to be a risk of is with an increased the risk

This new diagnostic consensus guideline is a joint project of the European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR] that now merges the former ECCO-ESGAR Imaging Guideline and the former ECCO Endoscopy Guideline, also including laboratory parameters. It has been drafted by 30 ECCO and ESGAR members from 17 European countries. All the authors recognize th e work of and are grateful to previous ECCO and ESGAR members who contributed tocreating the earlier consensus guidelines on imaging and endoscopy. The former guidelines have been condensed into this new diagnostic consensus guideline which consists of two papers: the first detailing assessment at initial diagnosis, to monitor treat ment and for the detection of complications; the second dealing with the available scoring systems and general considerations regarding the different diagnostic tools. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with ECCO participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement and ESGAR participants nominated by ESGAR. The following working parties were established: diagnostics at initial diagnosis, diagnostics for monitoring treatment in patients with known IBD, diagnostics for the detect ion of complications, scores for IBD, and general principles and technical aspects. Provisional guideline statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds. The first voting round introduced a more comprehensive voting procedure, in which each Guidelines participants voted on all statements by explicitly reviewing those statements together with their respective supporting text and references. The second voting round included optional national representative participation of ECCO’s 36 member countries and ESGAR’s 28 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalized by the authors at a face-to-face meeting in Barcelona in October 2017 and represent consensus with agreement of at least 80% of the present participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [SV, TK, GF, VA, EC], before being integrated by the consensus leaders [CM, JS, AS].

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.

Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0.74-34.40); early pregnancy loss (ORs, 1.40-6.25); late pregnancy loss (ORs, 1.31-20.09); pre-eclampsia (ORs, 1.37-3.49); placental abruption (ORs, 1.42-7.71) and intrauterine growth restriction (ORs, 1.24-2.92). Low-dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1.62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.

Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.

Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved

Incidentally detected abnormality in liver function tests is a common situation encountered by physicians across all disciplines. Many of these patients do not have primary liver disease as most of the commonly performed markers are not specific for the liver and are affected by myriad factors unrelated to liver disease. Also, many of these tests like liver enzyme levels do not measure the function of the liver, but are markers of liver injury, which is broadly of two types: hepatocellular and cholestatic. A combination of a careful history and clinical examination along with interpretation of pattern of liver test abnormalities can often identify type and aetiology of liver disease, allowing for a targeted investigation approach. Severity of liver injury is best assessed by composite scores like the Model for End Stage Liver Disease rather than any single parameter. In this review, we discuss the interpretation of the routinely performed liver tests along with the indications and utility of quantitative tests.

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days. Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings. Trial Registration: isrctn.org Identifier: ISRCTN16912075.

OBJECTIVE: To determine the association between daily levels of registered nurse (RN) and nursing assistant staffing and hospital mortality. DESIGN: This is a retrospective longitudinal observational study using routinely collected data. We used multilevel/hierarchical mixed-effects regression models to explore the association between patient outcomes and daily variation in RN and nursing assistant staffing, measured as hours per patient per day relative to ward mean. Analyses were controlled for ward and patient risk. PARTICIPANTS: 138 133 adult patients spending >1 days on general wards between 1 April 2012 and 31 March 2015. OUTCOMES: In-hospital deaths. RESULTS: Hospital mortality was 4.1%. The hazard of death was increased by 3% for every day a patient experienced RN staffing below ward mean (adjusted HR (aHR) 1.03, 95% CI 1.01 to 1.05). Relative to ward mean, each additional hour of RN care available over the first 5 days of a patient's stay was associated with 3% reduction in the hazard of death (aHR 0.97, 95% CI 0.94 to 1.0). Days where admissions per RN exceeded 125% of the ward mean were associated with an increased hazard of death (aHR 1.05, 95% CI 1.01 1.09). Although low nursing assistant staffing was associated with increases in mortality, high nursing assistant staffing was also associated with increased mortality. CONCLUSION: Lower RN staffing and higher levels of admissions per RN are associated with increased risk of death during an admission to hospital. These findings highlight the possible consequences of reduced nurse staffing and do not give support to policies that encourage the use of nursing assistants to compensate for shortages of RNs.

BACKGROUND: Laparoscopy is a common procedure in many surgical specialities. Complications arising from laparoscopy are often related to initial entry into the abdomen. Life-threatening complications include injury to viscera e.g. the bowel or bladder, or to vasculature e.g. major abdominal and anterior abdominal wall vessels. Minor complications can also occur, such as postoperative wound infection, subcutaneous emphysema, and extraperitoneal insufflation. There is no clear consensus as to the optimal method of laparoscopic entry into the peritoneal cavity. OBJECTIVES: To evaluate the benefits and risks of different laparoscopic entry techniques in gynaecological and non-gynaecological surgery. SEARCH METHODS: This updated review has drawn on the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group. In addition, MEDLINE, EMBASE, CENTRAL and PsycINFO were searched through to September 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which one laparoscopic entry technique was compared with another. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias, and extracted data. We expressed findings as Peto odds ratios (Peto ORs) with 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of evidence for the main comparisons using GRADE methods. MAIN RESULTS: The review included 46 RCTs including three multi-arm trials (7389 participants) and evaluated 13 laparoscopic entry techniques. Overall there was no evidence of advantage using any single technique for preventing major vascular or visceral complications. The evidence was generally of very low quality; the main limitations were imprecision and poor reporting of study methods. Open-entry versus closed-entry There was no evidence of a difference between the groups for vascular (Peto OR 0.14, 95% CI 0.00 to 6.82, three RCTs, n = 795, I(2) = n/a; very low quality evidence) or visceral injury (Peto OR 0.61, 95% CI 0.06 to 6.08, three RCTs, n = 795, I(2) = 0%; very low quality evidence). There was a lower risk of failed entry in the open-entry group (Peto OR 0.16, 95% CI 0.04 to 0.63, n = 665, two RCTs, I(2) = 0%; very low quality evidence). This suggests that for every 1000 patients operated on, 31 patients in the closed-entry group will have failed entry compared to between 1 to 20 patients in the open-entry group. No events were reported in any of the studies for mortality, gas embolism or solid organ injury. Direct trocar versus Veress needle entry There was a lower risk of vascular injury in the direct trocar group (Peto OR 0.13, 95% CI 0.03 to 0.66, five RCTs, n = 1522, I(2) = 0%; low quality evidence) and failed entry (Peto OR 0.21, 95% CI 0.14 to 0.30, seven RCTs, n = 3104; I ²= 0%; moderate quality evidence). This suggests that for every 1000 patients operated on, 8 patients in the Veress needle group will experience vascular injury compared to between 0 to 5 patients in the direct trocar group; and that 64 patients in the Veress needle group will experience failed entry compared to between 10 to 20 patients in the direct trocar group. The vascular injury significance is sensitive to choice of statistical analysis and may be unreliable. There was no evidence of a difference between the groups for visceral (Peto OR 1.02, 95% CI 0.06 to 16.24, four RCTs, n = 1438, I(2) = 49%; very low quality evidence) or solid organ injury (Peto OR 0.16, 95% Cl 0.01 to 2.53, two RCTs, n = 998, I(2) = n/a; very low quality evidence). No events were recorded for mortality or gas embolism. Direct vision entry versus Veress needle entry There was no evidence of a difference between the groups in the rates of visceral injury (Peto OR 0.15, 95% CI 0.01 to 2.34, one RCT, n = 194; very low quality evidence). Other primary outcomes were not reported. Direct vision entry versus open-entry There was no evidence of a difference between the groups in the rates of visceral injury (Peto OR 0.13, 95% CI 0.00 to 6.50, two RCTs, n = 392; low quality evidence), solid organ injury (Peto OR 6.16, 95% CI 0.12 to 316.67, one RCT, n = 60, I(2) = n/a; very low quality evidence), or failed entry (Peto OR 0.40, 95% CI 0.04 to 4.09, one RCT, n = 60; low quality evidence). Vascular injury was reported, however no events occurred. Our other primary outcomes were not reported. Radially expanding (STEP) trocars versus non-expanding trocars There was no evidence of a difference between the groups for vascular injury (Peto OR 0.24, 95% Cl 0.05 to 1.21, two RCTs, n = 331, I(2) = 0%; low quality evidence), visceral injury (Peto OR 0.13, 95% CI 0.00 to 6.37, two RCTs, n = 331, I(2) = n/a; low quality evidence), or solid organ injury (Peto OR 1.05, 95% CI 0.07 to 16.91, one RCT, n = 244; very low quality evidence). Other primary outcomes were not reported. Comparisons of other laparoscopic entry techniquesThere was a higher risk of failed entry in the group in which the abdominal wall was lifted before Veress needle insertion than in the not-lifted group (Peto OR 4.44, 95% CI 2.16 to 9.13, one RCT, n = 150; very low quality evidence). There was no evidence of a difference between the groups in rates of visceral injury or extraperitoneal insufflation. The studies had small numbers and excluded many patients with previous abdominal surgery, and women with a raised body mass index. These patients may have unusually high complication rates. AUTHORS' CONCLUSIONS: Overall, there is insufficient evidence to recommend one laparoscopic entry technique over another.An open-entry technique is associated with a reduction in failed entry when compared to a closed-entry technique, with no evidence of a difference in the incidence of visceral or vascular injury.An advantage of direct trocar entry over Veress needle entry was noted for failed entry and vascular injury. The evidence was generally of very low quality with small numbers of participants in most studies; our findings should be interpreted with caution.

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

BACKGROUND: Recreational drug use in men who have sex with men (MSM) is of concern because it might be linked to the transmission of HIV and other sexually transmitted infections. Evidence about drug use in HIV-diagnosed MSM in the UK is limited by representativeness of the study populations. We describe patterns of drug use and associations with sexual behaviours in HIV-diagnosed MSM in the UK. METHODS: We used data from the cross-sectional ASTRA study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. We examined data for MSM, assessing the prevalence of recreational drug use and polydrug use in the previous 3 months and associations with sociodemographic and HIV-related factors. We examined the association of polydrug use with measures of condomless sex in the previous 3 months and with other sexual behaviours. FINDINGS: Our analysis included data for 2248 MSM: 2136 (95%) were gay, 1973 (89%) were white, 1904 (85%) were on antiretroviral treatment (ART), and 1682 (76%) had a viral load of 50 copies per mL or lower. 1138 (51%) used recreational drugs in the previous 3 months; 608 (27%) used nitrites, 477 (21%) used cannabis, 460 (21%) used erectile dysfunction drugs, 453 (20%) used cocaine, 280 (13%) used ketamine, 258 (12%) used 3,4-methylenedioxy-N-methylamphetamine (MDMA), 221 (10%) used gamma-hydroxybutyrate or gamma-butyrolactone, 175 (8%) used methamphetamine, and 162 (7%) used mephedrone. In the 1138 individuals who used drugs, 529 (47%) used three or more drugs and 241 (21%) used five or more. Prevalence of injection drug use was 3% (n = 68). Drug use was independently associated with younger age (p < 0·0001), not being religious (p = 0·001), having an HIV-positive stable partner (p = 0·0008), HIV-serostatus disclosure (p = 0·009), smoking (p < 0·0001), evidence of harmful alcohol drinking (p = 0·0001), and ART non-adherence (p < 0·0001). Increasing polydrug use was associated with increasing prevalence of condomless sex (prevalence range from no drug use to use of five or more drugs was 24% to 78%), condomless sex with HIV-seroconcordant partners (17% to 69%), condomless sex with HIV-serodiscordant partners (10% to 25%), and higher-HIV-risk condomless sex after taking viral load into account (4% to 16%; p ≤ 0·005 for all). Associations were similar after adjustment for sociodemographic and HIV-related factors. Methamphetamine was more strongly associated with higher-HIV-risk condomless sex than were other commonly used drugs. INTERPRETATION: Polydrug use is prevalent in HIV-diagnosed MSM and is strongly associated with condomless sex. Specialist support services for MSM with HIV who use recreational drugs might be beneficial in the reduction of harm and prevention of ongoing transmission of HIV and other sexually transmitted infections. FUNDING: National Institute for Health Research.

BACKGROUND: From April through June 2008, we identified 12 patients in the intensive care unit and 3 patients on other wards infected with methicillin-resistant Staphylococcus aureus that was also resistant to linezolid. We investigated the mechanism of resistance--point mutations in domain V of 23S ribosomal RNA (rRNA) or presence of the cfr gene--involved in the outbreak. METHODS: Strains for the study were obtained in the intensive care unit and other wards. Minimal inhibitory concentrations were determined using automated methods, the E-test, or dilution in Mueller-Hinton agar in accordance with Clinical and Laboratory Standards Institute guidelines. Strains were genotyped using pulsed-field gel electrophoresis and were sequenced to determine the presence of point mutations in 23S rRNA. The presence of the cfr gene was determined by specific polymerase chain reaction. RESULTS: The minimal inhibitory concentrations of linezolid ranged from 16 mg/L to 32 mg/L, and all the strains were susceptible to tigecycline, vancomycin, and daptomycin. Typing of strains sequentially isolated by pulsed-field gel electrophoresis showed that each patient carried only 1 clonal type of linezolid-resistant, methicillin-resistant S. aureus as detected by sequential isolations. The presence of the cfr gene was confirmed in all the isolates. Furthermore, sequencing of domain V of 23S rRNA showed that the most common mechanism of linezolid resistance reported to date, mutation G2576T, was not detected in any of the strains analyzed. CONCLUSIONS: We report the presence of the cfr gene underlying the resistance mechanism involved in a clinical outbreak of linezolid-resistant S. aureus.

AIMS: Estimated central systolic blood pressure (cSBP) and amplification (Brachial SBP-cSBP) are non-invasive measures potentially prognostic of cardiovascular (CV) disease. No worldwide, multiple-device reference values are available. We aimed to establish reference values for a worldwide general population standardizing between the different available methods of measurement. How these values were significantly altered by cardiovascular risk factors (CVRFs) was then investigated. METHODS AND RESULTS: Existing data from population surveys and clinical trials were combined, whether published or not. Reference values of cSBP and amplification were calculated as percentiles for 'Normal' (no CVRFs) and 'Reference' (any CVRFs) populations. We included 45,436 subjects out of 82,930 that were gathered from 77 studies of 53 centres. Included subjects were apparently healthy, not treated for hypertension or dyslipidaemia, and free from overt CV disease and diabetes. Values of cSBP and amplification were stratified by brachial blood pressure categories and age decade in turn, both being stratified by sex. Amplification decreased with age and more so in males than in females. Sex was the most powerful factor associated with amplification with 6.6 mmHg (5.8-7.4) higher amplification in males than in females. Amplification was marginally but significantly influenced by CVRFs, with smoking and dyslipidaemia decreasing amplification, but increased with increasing levels of blood glucose. CONCLUSION: Typical values of cSBP and amplification in a healthy population and a population free of traditional CVRFs are now available according to age, sex, and brachial BP, providing values included from different devices with a wide geographical representation. Amplification is significantly influenced by CVRFs, but differently in men and women.

This inquiry originates in a conversation between the first two authors which concluded with the challenge that a Revans Institute for Action Learning & Research should not only be doing research b...

BACKGROUND: Pelvic adhesions can form secondary to inflammation, endometriosis, or surgical trauma. Strategies to reduce pelvic adhesion formation include placing barrier agents such as oxidised regenerated cellulose, polytetrafluoroethylene, and fibrin or collagen sheets between pelvic structures. OBJECTIVES: To evaluate the effects of barrier agents used during pelvic surgery on rates of pain, live birth, and postoperative adhesions in women of reproductive age. SEARCH METHODS: We searched the following databases in August 2019: the Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), Epistemonikos, and trial registries. We searched reference lists of relevant papers, conference proceedings, and grey literature sources. We contacted pharmaceutical companies for information and handsearched relevant journals and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) on the use of barrier agents compared with other barrier agents, placebo, or no treatment for prevention of adhesions in women undergoing gynaecological surgery. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for eligibility and risk of bias and extracted data. We calculated odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs) using a fixed-effect model. We assessed the overall quality of the evidence using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods. MAIN RESULTS: We included 19 RCTs (1316 women). Seven RCTs randomised women; the remainder randomised pelvic organs. Laparoscopy (eight RCTs) and laparotomy (11 RCTs) were the primary surgical techniques. Indications for surgery included myomectomy (seven RCTs), ovarian surgery (five RCTs), pelvic adhesions (five RCTs), endometriosis (one RCT), and mixed gynaecological surgery (one RCT). The sole indication for surgery in three of the RCTs was infertility. Thirteen RCTs reported commercial funding; the rest did not state their source of funding. No studies reported our primary outcomes of pelvic pain and live birth rate. Oxidised regenerated cellulose versus no treatment at laparoscopy or laparotomy (13 RCTs) At second-look laparoscopy, we are uncertain whether oxidised regenerated cellulose at laparoscopy reduced the incidence of de novo adhesions (OR 0.50, 95% CI 0.30 to 0.83, 3 RCTs, 360 participants; I² = 75%; very low-quality evidence) or of re-formed adhesions (OR 0.17, 95% CI 0.07 to 0.41, 3 RCTs, 100 participants; I² = 36%; very low-quality evidence). At second-look laparoscopy, we are uncertain whether oxidised regenerated cellulose affected the incidence of de novo adhesions after laparotomy (OR 0.72, 95% CI 0.42 to 1.25, 1 RCT, 271 participants; very low-quality evidence). However, the incidence of re-formed adhesions may have been reduced in the intervention group (OR 0.38, 95% CI 0.27 to 0.55, 6 RCTs, 554 participants; I² = 41%; low-quality evidence). No studies reported results on pelvic pain, live birth rate, adhesion score, or clinical pregnancy rate. Expanded polytetrafluoroethylene versus oxidised regenerated cellulose at gynaecological surgery (two RCTs) We are uncertain whether expanded polytetrafluoroethylene reduced the incidence of de novo adhesions at second-look laparoscopy (OR 0.93, 95% CI 0.26 to 3.41, 38 participants; very low-quality evidence). We are also uncertain whether expanded polytetrafluoroethylene resulted in a lower adhesion score (out of 11) (MD -3.79, 95% CI -5.12 to -2.46, 62 participants; very low-quality evidence) or a lower risk of re-formed adhesions (OR 0.13, 95% CI 0.02 to 0.80, 23 participants; very low-quality evidence) when compared with oxidised regenerated cellulose. No studies reported results regarding pelvic pain, live birth rate, or clinical pregnancy rate. Collagen membrane with polyethylene glycol and glycerol versus no treatment at gynaecological surgery (one RCT) Evidence suggests that collagen membrane with polyethylene glycol and glycerol may reduce the incidence of adhesions at second-look laparoscopy (OR 0.04, 95% CI 0.00 to 0.77, 47 participants; low-quality evidence). We are uncertain whether collagen membrane with polyethylene glycol and glycerol improved clinical pregnancy rate (OR 5.69, 95% CI 1.38 to 23.48, 39 participants; very low-quality evidence). One study reported adhesion scores but reported them as median scores rather than mean scores (median score 0.8 in the treatment group vs median score 1.2 in the control group) and therefore could not be included in the meta-analysis. The reported P value was 0.230, and no evidence suggests a difference between treatment and control groups. No studies reported results regarding pelvic pain or live birth rate. In total, 15 of the 19 RCTs included in this review reported adverse events. No events directly attributed to adhesion agents were reported. AUTHORS' CONCLUSIONS: We found no evidence on the effects of barrier agents used during pelvic surgery on pelvic pain or live birth rate in women of reproductive age because no trial reported these outcomes. It is difficult to draw credible conclusions due to lack of evidence and the low quality of included studies. Given this caveat, low-quality evidence suggests that collagen membrane with polyethylene glycol plus glycerol may be more effective than no treatment in reducing the incidence of adhesion formation following pelvic surgery. Low-quality evidence also shows that oxidised regenerated cellulose may reduce the incidence of re-formation of adhesions when compared with no treatment at laparotomy. It is not possible to draw conclusions on the relative effectiveness of these interventions due to lack of evidence. No adverse events directly attributed to the adhesion agents were reported. The quality of the evidence ranged from very low to moderate. Common limitations were imprecision and poor reporting of study methods. Most studies were commercially funded, and publication bias could not be ruled out.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 2, 2002 and previously updated in 2004, 2007 and 2010.Radiotherapy, open surgery and endolaryngeal excision (with or without laser) are all accepted modalities of treatment for early-stage glottic cancer. Case series suggest that they confer a similar survival advantage, however radiotherapy and endolaryngeal surgery offer the advantage of voice preservation. There has been an observed trend away from open surgery in recent years, however equipoise remains between radiotherapy and endolaryngeal surgery as both treatment modalities offer laryngeal preservation with similar survival rates. Opinions on optimal therapy vary across disciplines and between countries. OBJECTIVES: To compare the effectiveness of open surgery, endolaryngeal excision (with or without laser) and radiotherapy in the management of early glottic laryngeal cancer. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 8); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 18 September 2014. SELECTION CRITERIA: Randomised controlled trials comparing open surgery, endolaryngeal resection (with or without laser) and radiotherapy. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified only one randomised controlled trial, which compared open surgery and radiotherapy in 234 patients with early glottic laryngeal cancer. The overall risk of bias in this study was high.For T1 tumours, the five-year survival was 91.7% following radiotherapy and 100% following surgery and for T2 tumours, 88.8% following radiotherapy and 97.4% following surgery. There were no significant differences in survival between the two groups.For T1 tumours, the five-year disease-free survival rate was 71.1% following radiotherapy and 100.0% following surgery, and for the T2 tumours, 60.1% following radiotherapy and 78.7% following surgery. Only the latter comparison was statistically significant (P value = 0.036), but statistical significance would not have been achieved with a two-sided test.Data were not available on side effects, quality of life, voice outcomes or cost.We identified no randomised controlled trials that included endolaryngeal surgery. A number of trials comparing endolaryngeal resection and radiotherapy have terminated early because of difficulty recruiting participants. One randomised controlled trial is still ongoing. AUTHORS' CONCLUSIONS: There is only one randomised controlled trial comparing open surgery and radiotherapy but its interpretation is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis.

BACKGROUND: Electrical cardioversion in patients with atrial fibrillation is associated with an increased risk for embolic stroke. Screening for atrial thrombi with transesophageal echocardiography (TEE) before cardioversion should, in many patients, safely permit cardioversion to be done earlier than would be possible with prolonged conventional, anticoagulation therapy. OBJECTIVE: To compare the feasibility and safety of TEE-guided early cardioversion with those of conventional management of cardioversion in patients with atrial fibrillation. DESIGN: Randomized, multicenter clinical trial. SETTING: 10 hospitals in the United States, Europe, and Australia. PATIENTS: 126 patients who had atrial fibrillation lasting longer than 2 days and were having electrical cardioversion. INTERVENTION: Conventional therapy or early, TEE-guided cardioversion with short-term anticoagulation therapy. OUTCOME MEASURES: Feasibility outcome variables were frequency of cardioversion and times to cardioversion and sinus rhythm. Safety outcomes were ischemic stroke, transient ischemic attack, systemic embolization, bleeding, and detected episodes of clinical hemodynamic instability occurring as long as 4 weeks after cardioversion. RESULTS: 62 patients were randomly assigned to receive TEE-guided cardioversion; TEE was done in 56 (90%) of these patients. Atrial thrombi were detected in 7 patients (13%) and led to the postponement of cardioversion. Cardioversion was successful in 38 of 45 patients (84%) who had early cardioversion. No embolization occurred with this strategy. Of the 64 patients receiving conventional therapy, 37 (58%) had cardioversion, which was successful in 28 patients (76%). One patient had a peripheral embolic event. The time to cardioversion was shorter in the TEE group (0.6 weeks [95% CI, 0.3 to 0.9 weeks] compared with 4.8 weeks [CI, 3.8 to 5.7 weeks]; P < 0.01). The incidence of clinical hemodynamic instability and bleeding complications tended to be greater in the conventional therapy group. CONCLUSIONS: These results suggest that TEE-guided cardioversion with short-term anticoagulation therapy is feasible and safe. The use of TEE may allow cardioversion to be done earlier, may decrease the risk for embolism associated with cardioversion, and may be associated with less clinical instability than conventional therapy. A large, multicenter study to confirm these findings is currently under way.