Zealand University Hospital

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. 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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 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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 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OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

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].

BACKGROUND: The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). METHODS: In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. RESULTS: After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). CONCLUSIONS: In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

Abstract The functions of, and interactions between, the innate and adaptive immune systems are vital for anticancer immunity. Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in the anticancer immune response and form the backbone of current successful cancer immunotherapies. Immune-checkpoint inhibitors are designed to target immune-inhibitory receptors that function to regulate the immune response, whereas adoptive cell-transfer therapies use CD8 + T cells with genetically modified receptors—chimaeric antigen receptors—to specify and enhance CD8 + T-cell functionality. New generations of cytotoxic T cells with genetically modified or synthetic receptors are being developed and evaluated in clinical trials. Furthermore, combinatory regimens might optimise treatment effects and reduce adverse events. This review summarises advances in research on the most prominent immune effectors in cancer and cancer immunotherapy, cytotoxic T cells, and discusses possible implications for future cancer treatment.

The global prevalence of diabetes is predicted to increase dramatically in the coming decades as the population grows and ages, in parallel with the rising burden of overweight and obesity, in both developed and developing countries. Cardiovascular disease represents the principal cause of death and morbidity among people with diabetes, especially in those with type 2 diabetes mellitus. Adults with diabetes have 2-4 times increased cardiovascular risk compared with adults without diabetes, and the risk rises with worsening glycaemic control. Diabetes has been associated with 75% increase in mortality rate in adults, and cardiovascular disease accounts for a large part of the excess mortality. Diabetes-related macrovascular and microvascular complications, including coronary heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, chronic renal disease, diabetic retinopathy and cardiovascular autonomic neuropathy are responsible for the impaired quality of life, disability and premature death associated with diabetes. Given the substantial clinical impact of diabetes as a cardiovascular risk factor, there has been a growing focus on diabetes-related complications. While some population-based studies suggest that the epidemiology of such complications is changing and that rates of all-cause and cardiovascular mortality among individuals with diabetes are decreasing in high-income countries, the economic and social burden of diabetes is expected to rise due to changing demographics and lifestyle especially in middle- and low-income countries. In this review we outline data from population-based studies on recent and long-term trends in diabetes-related complications.

This is the first European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses extra-intestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. It has been drafted by 21 ECCO members from 13 European countries. Although this is the first ECCO consensus guideline that primarily addresses EIMs, it is partly derived from, updates, and replaces previous ECCO consensus advice on EIMs, contained within the consensus guidelines for Crohn’s disease 1 [CD] and ulcerative colitis 2 [UC]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu ]. Briefly, topics were selected by the ECCO guidelines committee [GuiCom]. ECCO members were selected to form working groups. 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 Vienna in October 2014 and represent consensus with agreement of at least 80% of participants. Complete consensus [100% agreement] was reached for most statements. The supporting text was then finalised under the direction of each working group leader [VA, SV, FC, MH] before being integrated by the two consensus leaders [MH, FC]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/]. Up to 50% of patients with inflammatory bowel disease [IBD] experience at least one extra-intestinal manifestation [EIM], which can present before IBD is diagnosed. 34,5,6 EIMs adversely impact upon patients’ quality of life and some, such as primary sclerosing cholangitis [PSC] or venous thromboembolism [VTE], can be life-threatening. The probability of developing EIMs increases with disease duration and in patients who already have one EIM. 7 EIMs are more common in CD than UC, 7,8 particularly in patients with colonic CD; some EIMs, such as iritis/uveitis, are more common in women whereas PSC and ankylosing spondylitis are more common in males. 3 Most EIMs run in parallel with intestinal disease activity, 4 with the exception of ankylosing spondylitis and uveitis and with uncertainty regarding PSC and pyoderma gangrenosum [PG]. 9 The management of complex EIMs should be discussed in a multidisciplinary team meeting. Both peripheral and axial arthropathies occur in UC and CD, and belong to the spondyloarthritis [SpA] group of conditions (evidence level 2 [EL2]). They should be distinguished from arthralgia, which is more common. The prevalence of axial disease is equal between sexes and forms of IBD, but peripheral arthropathies are more common in CD [particularly affecting the colon] and in females [EL3] Diagnosis of axial SpA is based on the clinical feature of inflammatory low back pain associated with magnetic resonance imaging [MRI ]or radiographic features of sacroiliitis [EL 2]. Human leukocyte antigen B27 [HLA-B27] is associated with axial arthritis, but it has a lower prevalence than in idiopathic ankylosing spondylitis, making it unreliable as a diagnostic test in IBD [EL2] Radiological evidence of sacroiliitis occurs in 20–50% of patients with UC and CD, but progressive ankylosing spondylitis occurs in only 1–10% of patients [EL2]. MRI may identify early sacroiliitis in symptomatic patients with normal plain radiology [non-radiographic SpA] [EL2] Arthropathies associated with IBD belong to the SpA group of conditions. According to the Assessment in Spondyloarthritis International Society [ASAS] classification of 2009, 10 SpA are divided into axial and peripheral SpA, depending on the predominant symptoms. Diagnosis of axial SpA is based on magnetic resonance imaging [MRI] or radiographic features of sacroiliitis associated with clinical features of inflammatory low back pain. Radiological evidence of sacroiliitis is common in both UC and CD, occurring in 20–50 % of patients, 11,12,13 but progressive AS with syndesmophytes occurs in only 1–10 % of patients. 14,15,16 Early assessment using T1-weighted spin-echo [TISE], short tau inversion recovery [STIR], and fat-saturated T2-weighted sequences, are recommended for patients aged less than 40 years with inflammatory back pain lasting more than 3 months, to identify non-radiographic sacroiliitis. 17,18 Human leukocyte antigen [HLA]-B27 is found in 25–75% of patients with IBD and AS 11,19,20,21 but only in 7–15% of patients with isolated sacroiliitis. HLA-B27 positive IBD patients seem to be at risk for the development of AS 21 but, due to a lower prevalence than in idiopathic AS, it is unreliable as a diagnostic test in IBD. 22,23 Diagnosis of peripheral arthropathy and/or enthesitis associated with IBD is based on signs of inflammation and exclusion of other specific forms of arthritis [EL3]. Type I is an acute pauciarticular arthritis, affecting large joints, and is usually associated with active IBD. Type II is polyarticular, affecting a larger number of peripheral joints, and is independent of IBD activity [EL4] The peripheral arthritis of IBD is an inflammatory arthropathy but, unlike psoriatic arthritis and other inflammatory arthropathies, it is generally non-erosive. The ASAS guidelines for peripheral SpA included only six patients with IBD, 24 so the clinical classification of IBD-related peripheral arthropathies is usually based on a larger study of IBD patients. 25 On the basis of articular and two have been Type 1 is as pain with evidence of or affecting than joints, the large of the lower The are usually acute and than 10 and usually with IBD Type 2 more than joints, has a and the for or independent of IBD Diagnosis is on clinical based on features of inflammation and exclusion of other specific forms of in to arthritis, and peripheral arthritis has to be from may to and and have been less in IBD. inflammation at the of a to the to and and or is of SpA, with a prevalence of in IBD. arthritis in IBD is usually and and more common in CD, particularly in with colonic may that of bowel it usually with or the of IBD. prevalence in IBD from to in UC and in the of peripheral arthritis is only and in a of patients. The of axial is less and is to the of AS, and the of IBD. AS is a progressive with and affecting patients’ quality of It is to identify early axial SpA, to the to radiographic axial SpA that occurs in % by 2 years in with an or with active inflammation on The of IBD in the of SpA is by the that sacroiliitis and spondylitis occur in to of patients with IBD, whereas to of patients with AS or SpA have evidence of only The of HLA-B27 with AS is in IBD, but to a than in idiopathic AS This may to the between the of AS and IBD. and have more than for IBD in an and in IBD and of for AS were by IBD with a that and to the to the and and to a common the complex with axial SpA should be with and are [EL but with is recommended [EL2]. [EL2] and [EL2] are of early is the for or to [EL2] of inflammation is to peripheral arthritis or symptomatic are [EL but should be as as arthritis, [EL2] and [EL4] may have a is and in [EL2] for the of IBD-related arthropathy are based on in SpA, in IBD have been only or are with axial SpA should be with of the disease the of and in axial but with is in IBD. Although the risk for a larger study CD patients and UC patients that with low of was of was associated with disease activity with Crohn’s but this was by a in disease The of such as and may be with a lower risk of disease than and in are of is the in patients or to on the of on radiographic are less may of early axial SpA, of large are of inflammation is to peripheral is for the of and for symptomatic Although and are or only in ankylosing spondylitis, a 2014 of in patients with peripheral and recommended the for patients with short disease duration and a in that was to study the that be an in SpA patients with peripheral are with seem to can be in has been to be in 35 in patients with disease on quality of pain is common in IBD and may be associated with the of or the of associated with is associated with and usually the first 3 of to is usually Diagnosis of in is from a on radiographic is a risk for and patients who should [EL2] and are common in and patients with IBD disease or low activity, and The of in is based on assessment of by is as a at least lower than the for the between and risk is and to the has been should be as for and the for in the of risk low previous IBD is to and so can be to and peripheral and are and recommended as for IBD patients from for the and are based on risk such as 3 months, of and have been recommended in in the of risk the the for with patients at risk for of the and peripheral should the risk increases for each in the have been in patients with both and normal the that is the risk for in patients with IBD. between and risk The of is a previous by of the is in the of patients with IBD, who are patients aged between and 40 of patients have with a and has been in of IBD patients. of IBD patients can 3 years in a have in with have that in are similar in IBD to in the The of each risk to be has been of the of can be a of IBD. is common in IBD patients, and so may to risk of IBD. study a for in IBD women in a lower risk of CD and UC than in are with previous a in disease to a of and [EL2] are in should and for for the duration of is a for and are recommended the is less than patients, a of should for more [EL4] of disease activity is particularly in the in women or with previous of and other can [EL2] should be in patients with low and/or risk such as which risk in the of a of may be in who has been in IBD in aged to to and/or should be or and and from and/or should be should be in the recommended this usually at a of or should be only is with and increases in patients with IBD. large study in CD that of disease activity and of and were associated with a in of 4 The of and in has been in patients with IBD, in or is common in patients with IBD and should be as should and for that are for the of low in IBD and the risk of but and can be recommended for in IBD patients. to the of a for with is in women or of the is a and should be in patients with or patients, a before be are and have using or as are associated with only increases in and in is evidence that or other peripheral The evidence for and of in patients is patients with active disease should be according to guidelines with to and inflammatory activity, in to or should be in patients with IBD before can be an risk for patients with with more should be to a to an This should be from uveitis and based upon the of and this is or in patients with manifestations and patients should be by an with in inflammatory disease uveitis and are the most common manifestations of IBD. manifestations in IBD can be to and/or of the intestinal disease The classification of uveitis has been in the of guidelines 1 ]. of The most manifestations are or and or uveitis are more to be are occurring in less than but may to of uveitis a of 13 a of features from to to disease activity in the bowel and other extra-intestinal uveitis can be independent of bowel and other EIMs and may the of bowel symptoms. of with to and may be with and and and may as to which is is less common but has more to CD, uveitis is in and acute uveitis with may of a of the features of and The of to of should to an with in the management of and the of and the and the between and pain associated with of the and to be from to or other should for using a to for the of inflammatory and/or both the guidelines and of the International are in disease assessment may be in and of the of manifestations from of IBD in some this to of is to be to of patients in are study of only that patients with IBD are more to of with and and inflammatory disease as EIMs of IBD represent associated with and of both and into the or this may be associated with with and supporting in uveitis with and on I and are by may or or can be for symptomatic for or uveitis should be by an and or and [EL4] a is the of most is may be with following management of the bowel and to the of and uveitis should be with and uveitis and other the level of evidence with the evidence for of being in patients with uveitis but IBD. of and or have been from 3 or 4 the of and in uveitis and but is based upon evidence from the of only a IBD. and have each been to be in CD and or It is associated with disease and has a CD of and associated with UC, have been has been described in with IBD, particularly in patients with UC, and may be due to by T2-weighted is a disease that in and that to It can be associated with IBD. Diagnosis of is on clinical a be [EL3]. is usually based on that of the IBD. are in and forms can be with or [EL4] is and by or of in It the of the particularly the and usually occurs at of IBD in with and The CD, which may at as or or with present can the or 9 clinical can be and is usually the a The prevalence of in IBD from to in CD than UC and more common IBD patients. The of is that it be a the can be in of patients. is associated with IBD but with it is to disease activity, is based on that of the IBD. may be in or are with or may be gangrenosum can occur on the the but the are the and to 9 the form of or or but of the to the development of that that is on has is by the of a that a with with a between and in It can and is usually based on the of the following exclusion of other or venous is a of it can be in a of some a from the of the can in are but can be to other of UC patients a than that in The is but has been to and are by regarding the between and IBD activity, as it may parallel IBD activity or run an independent has a to following in more than of in the as the gangrenosum can be with or or or [EL4] The should be as it can be a is evidence that the of for between IBD and patients. is the of the most were and were with and or for the management of in patients with was first in The study on the of with was a of patients, patients with IBD. or was at 2 primary more patients in the group with in both were patients with the at The was with short duration of less than a of IBD patients with with to has the of should be a to be have the of in the of patients with of the to of the The of or is an but the advice of a should be should be in with a is of the group of acute that but can be distinguished by and It is by inflammatory or usually affecting the or can be It can be by It has only been as an IBD It is more common in women and in patients with colonic or other The is associated with active or prevalence are The have been such as a or an with are and have been to be should be in or and may such as and inflammation 2 ]. have the development of psoriatic and in patients with CD and UC an which seem to to the of the or the duration of and were the most of have been and have been are in of patients with clinical risk and of disease in patients with IBD that with psoriatic and by of patients psoriatic and of whereas and were were associated with IBD activity, but were more females and with of or were associated with for and 1 and has been can inflammation of the which is a and is usually upon to a is Most are with and can usually be [EL3] should be with the advice of a with and or in or in 50% of patients. with psoriatic that with and who a has been to be in the of the of have of to with The is derived from the and the is based on Up to of patients with IBD have and disease independent of IBD should be PSC is the most common disease specific to IBD, and may to of patients in some have been in IBD patients with normal of European of patients with PSC have IBD. According to and IBD in PSC is as UC and less as of sclerosing cholangitis such as or conditions have to be sclerosing cholangitis has similar and/or but usually in the of IBD. of PSC and pain. are and may be by of IBD. patients with IBD, a clinical for PSC is as this disease patients with in of sclerosing cholangitis have been a of PSC can be magnetic resonance Although common at some it has been that is of to a of PSC the of is and clinical of PSC is The ECCO consensus group that should be to is and/or is patients with should be as is recommended for an or independent of of sclerosing cholangitis should be PSC is normal in a with IBD and a should be to PSC [EL2] of patients, is normal with This group is as a disease which is associated with a of PSC are and may be a is only in patients and features of or PSC is is recommended in PSC patients with features of of and/or an should of sclerosing cholangitis [EL4] should the of PSC in an IBD are normal in of PSC patients. are usually is in of PSC patients and should the of which is found in to of PSC patients. features of are should be but have a low are in of PSC but are found in and IBD patients sclerosing cholangitis be is of sclerosing cholangitis is according to the other and to and is as sclerosing cholangitis in of to may be in PSC patients the for sclerosing patients may a more disease but specific management are The of PSC in an IBD It is to that from is lower than that of The of clinical the risk for at the level is and is a for in and in of PSC and PSC may be associated with such as 1 and PSC to and development in the and affecting and large inflammation the in and with an risk of with IBD have a of with IBD patients PSC or normal patients with PSC and IBD, present with is in in and features that PSC is associated with UC, IBD has specific disease is or the as inflammation This is by the of This be by It that IBD has a that may PSC has a Early that PSC is associated with as in other have The first study in and has been to IBD in to which is in and are in a in and The study was in the authors PSC of European using the and the the number of PSC risk to of a with PSC than with IBD, the of disease in PSC that are from of IBD. has been to to or in PSC or PSC Although should be and/or should be in patients with features of [EL3] the evidence for in PSC is in based on is to clinical has been by most an study to most be should be in patients with and such as or have been is an for and are under PSC patients with clinical or of or an is recommended to that may be to or and for [EL2]. is recommended The and early of such as and are to the management of patients with assessment for the of is are the and imaging may between and in should be in patients with as this may the risk of and particularly in patients in is most is a for in selected of that and PSC patients with disease or with of should be for may be in selected patients with on is the only that can are with to PSC patients with disease should be for according to with and selected with cholangitis can be for The and in PSC patients is due to the disease and the risk of PSC patients with to from this has been is a for that can the diagnostic of in in PSC patients with IBD is recommended 1 to 2 years of PSC with is the recommended strategy [EL2]. PSC patients evidence of IBD, is recommended years PSC is associated with a risk of and in patients with associated IBD, both before and may IBD and PSC have been diagnosed. with is recommended at and 1 to 2 years This should be is to in to is recommended imaging should be is for and in an of antigen and has been but are associated with a risk to of in PSC patients. On this to has been recommended or but from patients with IBD can and and [EL The prevalence of disease between to in ulcerative colitis and to in Crohn’s disease prevalence are of the and that colitis and or IBD patients, so of may be is and usually with but has been are in of IBD patients on risk for disease and the risk of of of is may occur in patients with and can be using and It has been in of patients with The of and to Most occur within the first of The may be and usually with and/or that to normal of the Up to of patients who have may to the and should be in the of an and a and by and that of and disease have been is a of IBD. It is more in the to thromboembolism or IBD are for both conditions and are with in with guidelines is is a of IBD, with a of in CD and in UC patients. active inflammation of the bowel may in in and is specific other than of the active IBD, a of on has been in IBD may be an CD, an associated inflammatory disease such as primary or are in IBD patients. an with inflammation has been of or to is usually associated with and and CD [EL3]. of have been due to is in IBD patients. and are more [EL3] The for acute is 4 in CD and in The clinical and of acute in IBD are similar to the Diagnosis is based on the of at least two of level the of and are to in IBD, as pain due to can be to from that by active IBD. an is found in of IBD patients. forms of acute The first is to and idiopathic and associated with The is due to the management of IBD or due to associated which to CD; and or The most common by of and has been described in IBD. or is It occurs in of IBD patients. is evidence that can disease which occurs within the first 3 to 4 of and has a The risk to be in who the are more to The risk of is evidence for a are an both within the and IBD The risk of is in CD but in of in IBD is in with in IBD is by the of a in most of The prevalence of such as or or been found to be and in patients with CD and UC, using and to of patients with PSC have the are found in of CD and of UC patients. are with is associated with IBD [EL and to be manifestations may be more common in IBD patients than in the [EL to be venous and The may and is a [EL and IBD patients with peripheral from a with of and pain. was more common in with and and and were present in IBD patients. was to disease activity in only of patients. was associated with in the other of and affecting the with due to affecting the and have been the IBD patients have been described with and of an by and on have been in CD patients who and have been as as acute have been described that are independent of disease activity and may the of IBD. venous should be in patients with a a of IBD, with or or IBD-related peripheral can be risk have been such as and and and and to but 3 should to and MRI are manifestations due to IBD are and a should first be the progressive peripheral for the prevalence of manifestations in IBD, from to but is by and study using the an for developing or of for CD and for UC, with a prevalence of a of study more than IBD an for or diagnostic for an risk of in with UC that may have represented a of IBD patients, between and at the the of peripheral as 10 and and years of IBD, that is in IBD. are to the of peripheral have been described with and and and of manifestations thromboembolism and to and peripheral is usually to IBD activity, of the bowel activity the are to and have been in may be have been is a to the of which have been associated with with a or as by the the are by the most manifestation in IBD patients. of is in 3 The of and are in IBD [EL particularly in women [EL inflammation to [EL has been to be in IBD [EL of and in a risk of thromboembolism in particularly and The risk of disease in IBD was by both and whereas the risk of and of were each by one were between CD and The by only two of patients, IBD patients, and one large of that may be to the IBD patients. primarily for the risk of and disease was a risk of in IBD patients years was in one only two This in patients to with a risk of to be risk of peripheral based on from two one large study and The of peripheral disease is low in IBD, affecting only of patients. have an in IBD, in to This is due to in the of and low prevalence in IBD The of risk or the risk in IBD patients a low This the risk in IBD patients who have inflammation to an between IBD activity and and was in a the risk of and was similar to the in patients with the risk was

BACKGROUND: Patients with infective endocarditis on the left side of the heart are typically treated with intravenous antibiotic agents for up to 6 weeks. Whether a shift from intravenous to oral antibiotics once the patient is in stable condition would result in efficacy and safety similar to those with continued intravenous treatment is unknown. METHODS: In a randomized, noninferiority, multicenter trial, we assigned 400 adults in stable condition who had endocarditis on the left side of the heart caused by streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci and who were being treated with intravenous antibiotics to continue intravenous treatment (199 patients) or to switch to oral antibiotic treatment (201 patients). In all patients, antibiotic treatment was administered intravenously for at least 10 days. If feasible, patients in the orally treated group were discharged to outpatient treatment. The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from the time of randomization until 6 months after antibiotic treatment was completed. RESULTS: After randomization, antibiotic treatment was completed after a median of 19 days (interquartile range, 14 to 25) in the intravenously treated group and 17 days (interquartile range, 14 to 25) in the orally treated group (P=0.48). The primary composite outcome occurred in 24 patients (12.1%) in the intravenously treated group and in 18 (9.0%) in the orally treated group (between-group difference, 3.1 percentage points; 95% confidence interval, -3.4 to 9.6; P=0.40), which met noninferiority criteria. CONCLUSIONS: In patients with endocarditis on the left side of the heart who were in stable condition, changing to oral antibiotic treatment was noninferior to continued intravenous antibiotic treatment. (Funded by the Danish Heart Foundation and others; POET ClinicalTrials.gov number, NCT01375257 .).

Abstract Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor–positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.

RATIONALE: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear. OBJECTIVES: To estimate whether mortality in mechanically ventilated patients has changed over time. METHODS: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models. MEASUREMENTS AND MAIN RESULTS: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80-0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67-0.92). CONCLUSIONS: Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved. Clinical trials registered with www.clinicaltrials.gov (NCT01093482).

PURPOSE: To provide evidence-based guidance on the clinical management of cancer cachexia in adult patients with advanced cancer. METHODS: A systematic review of the literature collected evidence regarding nutritional, pharmacologic, and other interventions, such as exercise, for cancer cachexia. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and systematic reviews of RCTs published from 1966 through October 17, 2019. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: The review included 20 systematic reviews and 13 additional RCTs. Dietary counseling, with or without oral nutritional supplements, was reported to increase body weight in some trials, but evidence remains limited. Pharmacologic interventions associated with improvements in appetite and/or body weight include progesterone analogs and corticosteroids. The other evaluated interventions either had no benefit or insufficient evidence of benefit to draw conclusions on efficacy. Limitations of the evidence include high drop-out rates, consistent with advanced cancer, as well as variability across studies in outcomes of interest and methods for outcome assessment. RECOMMENDATIONS: Dietary counseling may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. Enteral feeding tubes and parenteral nutrition should not be used routinely. In the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care; therefore, clinicians may choose not to prescribe medications specifically for the treatment of cancer cachexia. Nonetheless, when it is decided to trial a drug to improve appetite and/or improve weight gain, currently available pharmacologic interventions that may be used include progesterone analogs and short-term (weeks) corticosteroids.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

Despite the availabilty of imaging-based and mass-spectrometry-based methods for spatial proteomics, a key challenge remains connecting images with single-cell-resolution protein abundance measurements. Here, we introduce Deep Visual Proteomics (DVP), which combines artificial-intelligence-driven image analysis of cellular phenotypes with automated single-cell or single-nucleus laser microdissection and ultra-high-sensitivity mass spectrometry. DVP links protein abundance to complex cellular or subcellular phenotypes while preserving spatial context. By individually excising nuclei from cell culture, we classified distinct cell states with proteomic profiles defined by known and uncharacterized proteins. In an archived primary melanoma tissue, DVP identified spatially resolved proteome changes as normal melanocytes transition to fully invasive melanoma, revealing pathways that change in a spatial manner as cancer progresses, such as mRNA splicing dysregulation in metastatic vertical growth that coincides with reduced interferon signaling and antigen presentation. The ability of DVP to retain precise spatial proteomic information in the tissue context has implications for the molecular profiling of clinical samples.

Diabetes is on the rise worldwide, with a global prevalence in adults in 2017 being 8.8% of the world population, with the anticipation of a further increase to 9.9% by 2045. In total numbers, this reflects a population of 424.9 million people with diabetes worldwide in 2017, with an estimate of a 48% increase to 628.6 million people by 2045. Depending on age, global diabetes prevalence is about 5%, 10%, 15% and close to 20%, respectively, for the age groups 35-39, 45-49, 55-59 and 65-69 years. On a global scale, diabetes hits particularly 'middle aged' people between 40 and 59 years, which causes serious economic and social implications. Furthermore, diabetes affects especially low and middle income countries, as 77% of all people with diabetes worldwide live in those countries. In addition to overt diabetes, an estimated 352.1 million people worldwide are at risk of diabetes, i.e. have defined pre-diabetes, a figure which is anticipated to rise to 531.6 million by 2045. Some 70-75% of all patients with established coronary artery disease, e.g. with acute myocardial infarction, show concomitant diabetes or abnormal glucose regulation, i.e. close to 50% have overt diabetes, with as many as 20% of those being undiagnosed and another 25% having pre-diabetes.

Abstract Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data 1,2 . Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank 3 . This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.

IMPORTANCE: Hidradenitis suppurativa (HS) is relatively common, with the prevalence of 0.05% to 4.10%, yet many patients receive inadequate treatment. OBJECTIVE: To review the diagnosis, epidemiology, and treatment of HS with an emphasis on advances in the last 5 years. EVIDENCE REVIEW: A literature search was conducted using PubMed, MEDLINE (Medical Subject Headings [MeSH]), and EMBASE to include recently published treatment studies (searched from September 1, 2011, to May 1, 2017). Reviews, guidelines, conference abstracts, and studies with less than 10 patients were excluded. Furthermore, internet searches for guidelines on hidradenitis suppurativa using Baidu, Bing, Google, and Qwant browsers were performed. FINDINGS: The diagnosis of HS is made by lesion morphology (nodules, abscesses, tunnels, and scars), location (axillae, inframammary folds, groin, perigenital, or perineal), and lesion progression (2 recurrences within 6 months or chronic or persistent lesions for ≥3 months). HS is more common than was previously thought based on epidemiological analysis (0.05%-4.10%). Disability from HS can be significant. Patients with HS may have significant comorbidities (eg, obesity, metabolic syndrome, diabetes, and arthritis) and increased all-cause mortality (incidence rate ratio, 1.35 [95% CI, 1.15-1.59]). Antibiotic treatment with combinations of clindamycin and rifampicin, or ertapenem followed by combination rifampicin, moxifloxacin, and metronidazole for 6 months is effective. Adalimumab is effective in a significant proportion of patients and treatment with IL-1 and IL-12 receptor subunit beta 1 (Rb1) antibodies may also be useful. Tissue-sparing surgical techniques and carbon dioxide laser treatments also are available, but the evidence on clinical outcomes with these approaches is limited. CONCLUSIONS AND RELEVANCE: Hidradenitis suppurativa is more common than previously thought and may be treated by an array of pharmacological and surgical techniques. Hidradenitis suppurativa should be considered in the differential diagnosis of nodular lesions or sinus tracts present in the axillae, groin, perineal, and mammillary fold regions.

Importance: Colorectal surgery is associated with substantial morbidity rates and a lowered functional capacity. Optimization of the patient's condition in the weeks prior to surgery may attenuate these unfavorable sequelae. Objective: To determine whether multimodal prehabilitation before colorectal cancer surgery can reduce postoperative complications and enhance functional recovery. Design, Setting, and Participants: The PREHAB randomized clinical trial was an international, multicenter trial conducted in teaching hospitals with implemented enhanced recovery after surgery programs. Adult patients with nonmetastasized colorectal cancer were assessed for eligibility and randomized to either prehabilitation or standard care. Both arms received standard perioperative care. Patients were enrolled from June 2017 to December 2020, and follow-up was completed in December 2021. However, this trial was prematurely stopped due to the COVID-19 pandemic. Interventions: The 4-week in-hospital supervised multimodal prehabilitation program consisted of a high-intensity exercise program 3 times per week, a nutritional intervention, psychological support, and a smoking cessation program when needed. Main Outcomes and Measures: Comprehensive Complication Index (CCI) score, number of patients with CCI score more than 20, and improved walking capacity expressed as the 6-minute walking distance 4 weeks postoperatively. Results: In the intention-to-treat population of 251 participants (median [IQR] age, 69 [60-76] years; 138 [55%] male), 206 (82%) had tumors located in the colon and 234 (93%) underwent laparoscopic- or robotic-assisted surgery. The number of severe complications (CCI score >20) was significantly lower favoring prehabilitation compared with standard care (21 of 123 [17.1%] vs 38 of 128 [29.7%]; odds ratio, 0.47 [95% CI, 0.26-0.87]; P = .02). Participants in prehabilitation encountered fewer medical complications (eg, respiratory) compared with participants receiving standard care (19 of 123 [15.4%] vs 35 of 128 [27.3%]; odds ratio, 0.48 [95% CI, 0.26-0.89]; P = .02). Four weeks after surgery, 6-minute walking distance did not differ significantly between groups when compared with baseline (mean difference prehabilitation vs standard care 15.6 m [95% CI, -1.4 to 32.6]; P = .07). Secondary parameters of functional capacity in the postoperative period generally favored prehabilitation compared with standard care. Conclusions and Relevance: This PREHAB trial demonstrates the benefit of a multimodal prehabilitation program before colorectal cancer surgery as reflected by fewer severe and medical complications postoperatively and an optimized postoperative recovery compared with standard care. Trial Registration: trialregister.nl Identifier: NTR5947.

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

BACKGROUND: A validated tool for the dynamic severity assessment of hidradenitis suppurativa/acne inversa (HS) is lacking. OBJECTIVES: To develop and validate a novel dynamic scoring system to assess the severity of HS. METHODS: A Delphi voting procedure was conducted among the members of the European Hidradenitis Suppurativa Foundation (EHSF) to achieve consensus towards an initial HS Severity Score System (HS4). Strengths and weaknesses of HS4 were examined by a multicentre prospective study. Multivariate logistic regression, discriminant analysis and receiver operating characteristic curves, as well as examination for correlation (Spearman's rho) and agreement (Cohen's kappa) with existing scores, were engaged to recognize the variables for a new International HS4 (IHS4) that was established by a second Delphi round. RESULTS: Consensus HS4 was based on number of skin lesions, number of skin areas involved and Dermatology Life Quality Index (DLQI), and was evaluated by a sample of 236 patients from 11 centres. Subsequently, a multivariate regression model calculated adjusted odds ratios for several clinical signs. Nodules, abscesses and draining tunnels resulted as the scoring variables. Three candidate scores were presented to the second Delphi round. The resulting IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe disease. Cohen's kappa was fair (κ = 0·32) compared with Hurley classification, and moderate (κ = 0·49) compared with Expert Opinion. Correlation was good (ρ > 0·6) with Hurley classification, Expert Opinion, Physician's Global Assessment and Modified Sartorius score, and moderate for DLQI (ρ = 0·36). CONCLUSIONS: The novel IHS4 is a validated tool to dynamically assess HS severity and can be used both in real-life and the clinical trials setting.

BACKGROUND: The spread of injectate resulting from a transmuscular quadratus lumborum (TQL) block and a transverse oblique paramedian (TOP) TQL block has never been examined. The aim of this cadaveric study was to investigate by which pathway the injectate spreads cephalad into the thoracic paravertebral space and which nerves were dyed by the injectate cephalad and caudad to the diaphragm when performing a TQL and a TOP TQL block. We also aimed to investigate whether the thoracic and lumbar sympathetic trunks as well as the lumbar plexus were covered by the injectate. METHODS: Ultrasound-guided bilateral TQL and TOP TQL injections were administered in 8 cadavers. A total of 16 injections were performed. With the TQL injection, the curvilinear transducer was oriented in the transverse plane above the iliac crest at the posterior axillary line to identify the Shamrock sign. With the TOP TQL injection, the same transducer was placed with a TOP orientation 3 cm lateral to the L2 spinous process to identify the L2 transverse process and the adjoining quadratus lumborum muscle. For both techniques, the needle was advanced in-plane to the transducer, with the end point in the interfascial plane between the quadratus lumborum and psoas major muscles. Thirty milliliters of dye solution was injected bilaterally for each technique. The spread of the dye was evaluated by subsequent dissection. RESULTS: In all successful injections, the dye was seen to spread into the thoracic paravertebral space and the intercostal spaces to surround the somatic nerves and the thoracic sympathetic trunk. The main pathway of spread of injectate was posterior to the medial and lateral arcuate ligaments. Caudad to the diaphragm, the injected dye surrounded the subcostal, iliohypogastric, and ilioinguinal nerves in all cases, whereas the genitofemoral and lateral femoral cutaneous nerves were dyed in a varying degree. No dye was seen to surround the lumbar plexus, femoral nerve, or lumbar sympathetic trunk. The pattern of spread was similar with the TQL and TOP TQL injections. CONCLUSIONS: The spread of injectate with the TQL and TOP TQL approaches is cephalad from the lumbar point of administration between the quadratus lumborum and psoas major muscles, predominantly via a pathway posterior to the arcuate ligaments and into the thoracic paravertebral space to reach the somatic nerves and the thoracic sympathetic trunk in the intercostal and paravertebral spaces. The lumbar plexus and lumbar sympathetic trunk are not affected.