Cleveland Clinic Lerner College of Medicine

BACKGROUND: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis. METHODS: Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions. RESULTS: Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains. CONCLUSIONS: Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

In this review, the authors discuss the properties of chemokines and their receptors and highlight the roles of these chemoattractants in selected clinical disorders.

Abstract The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

CONTEXT: Statin drugs reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality. However, the optimal strategy and target level for lipid reduction remain uncertain. OBJECTIVE: To compare the effect of regimens designed to produce intensive lipid lowering or moderate lipid lowering on coronary artery atheroma burden and progression. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized active control multicenter trial (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) performed at 34 community and tertiary care centers in the United States comparing the effects of 2 different statins administered for 18 months. Intravascular ultrasound was used to measure progression of atherosclerosis. Between June 1999 and September 2001, 654 patients were randomized and received study drug; 502 had evaluable intravascular ultrasound examinations at baseline and after 18 months of treatment. INTERVENTIONS: Patients were randomly assigned to receive a moderate lipid-lowering regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg of atorvastatin. MAIN OUTCOME MEASURES: The primary efficacy parameter was the percentage change in atheroma volume (follow-up minus baseline). RESULTS: Baseline low-density lipoprotein cholesterol level (mean, 150.2 mg/dL [3.89 mmol/L] in both treatment groups) was reduced to 110 mg/dL (2.85 mmol/L) in the pravastatin group and to 79 mg/dL (2.05 mmol/L) in the atorvastatin group (P<.001). C-reactive protein decreased 5.2% with pravastatin and 36.4% with atorvastatin (P<.001). The primary end point (percentage change in atheroma volume) showed a significantly lower progression rate in the atorvastatin (intensive) group (P =.02). Similar differences between groups were observed for secondary efficacy parameters, including change in total atheroma volume (P =.02), change in percentage atheroma volume (P<.001), and change in atheroma volume in the most severely diseased 10-mm vessel subsegment (P<.01). For the primary end point, progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; 95% confidence interval [CI], 0.2% to 4.7%; P =.001) compared with baseline. Progression did not occur in the atorvastatin group (-0.4%; CI -2.4% to 1.5%; P =.98) compared with baseline. CONCLUSIONS: For patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis. These differences may be related to the greater reduction in atherogenic lipoproteins and C- reactive protein in patients treated with atorvastatin.

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

CONTEXT: Prior intravascular ultrasound (IVUS) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of regression using percent atheroma volume (PAV), the most rigorous IVUS measure of disease progression and regression. OBJECTIVE: To assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging. DESIGN AND SETTING: Prospective, open-label blinded end-points trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) was performed at 53 community and tertiary care centers in the United States, Canada, Europe, and Australia. A motorized IVUS pullback was used to assess coronary atheroma burden at baseline and after 24 months of treatment. Each pair of baseline and follow-up IVUS assessments was analyzed in a blinded fashion. PATIENTS: Between November 2002 and October 2003, 507 patients had a baseline IVUS examination and received at least 1 dose of study drug. After 24 months, 349 patients had evaluable serial IVUS examinations. INTERVENTION: All patients received intensive statin therapy with rosuvastatin, 40 mg/d. MAIN OUTCOME MEASURES: Two primary efficacy parameters were prespecified: the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also prespecified. RESULTS: The mean (SD) baseline low-density lipoprotein cholesterol (LDL-C) level of 130.4 (34.3) mg/dL declined to 60.8 (20.0) mg/dL, a mean reduction of 53.2% (P<.001). Mean (SD) high-density lipoprotein cholesterol (HDL-C) level at baseline was 43.1 (11.1) mg/dL, increasing to 49.0 (12.6) mg/dL, an increase of 14.7% (P<.001). The mean (SD) change in PAV for the entire vessel was -0.98% (3.15%), with a median of -0.79% (97.5% CI, -1.21% to -0.53%) (P<.001 vs baseline). The mean (SD) change in atheroma volume in the most diseased 10-mm subsegment was -6.1 (10.1) mm3, with a median of -5.6 mm3 (97.5% CI, -6.8 to -4.0 mm3) (P<.001 vs baseline). Change in total atheroma volume showed a 6.8% median reduction; with a mean (SD) reduction of -14.7 (25.7) mm3, with a median of -12.5 mm3 (95% CI, -15.1 to -10.5 mm3) (P<.001 vs baseline). Adverse events were infrequent and similar to other statin trials. CONCLUSIONS: Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden. Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients. Further studies are needed to determine the effect of the observed changes on clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00240318.

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 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Abstract Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV–host interactome and drug targets in the human protein–protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV–host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the “ Complementary Exposure ” pattern: the targets of the drugs both hit the HCoV–host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.

Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.

The development of these updated guidelines was commissioned by the AACE, TOS, and ASMBS Board of Directors and adheres to the AACE 2010 protocol for standardized production of clinical practice guidelines (CPG). Each recommendation was re-evaluated and updated based on the evidence and subjective factors per protocol. Examples of expanded topics in this update include: the roles of sleeve gastrectomy, bariatric surgery in patients with type-2 diabetes, bariatric surgery for patients with mild obesity, copper deficiency, informed consent, and behavioral issues. There are 74 recommendations (of which 56 are revised and 2 are new) in this 2013 update, compared with 164 original recommendations in 2008. There are 403 citations, of which 33 (8.2%) are EL 1, 131 (32.5%) are EL 2, 170 (42.2%) are EL 3, and 69 (17.1%) are EL 4. There is a relatively high proportion (40.4%) of strong (EL 1 and 2) studies, compared with only 16.5% in the 2008 AACE-TOS-ASMBS CPG. These updated guidelines reflect recent additions to the evidence base. Bariatric surgery remains a safe and effective intervention for select patients with obesity. A team approach to perioperative care is mandatory with special attention to nutritional and metabolic issues.

The nuclear factor-κB (NF-κB) transcription factor family has been considered the central mediator of the inflammatory process and a key participant in innate and adaptive immune responses. Coincident with the molecular cloning of NF-κB/RelA and identification of its kinship to the v-Rel oncogene, it was anticipated that NF-κB itself would be involved in cancer development. Oncogenic activating mutations in NF-κB genes are rare and have been identified only in some lymphoid malignancies, while most NF-κB activating mutations in lymphoid malignancies occur in upstream signaling components that feed into NF-κB. NF-κB activation is also prevalent in carcinomas, in which NF-κB activation is mainly driven by inflammatory cytokines within the tumor microenvironment. Importantly, however, in all malignancies, NF-κB acts in a cell type-specific manner: activating survival genes within cancer cells and inflammation-promoting genes in components of the tumor microenvironment. Yet, the complex biological functions of NF-κB have made its therapeutic targeting a challenge.

The number of surviving children born prematurely has increased substantially during the last 2 decades. The major goal of enteral nutrient supply to these infants is to achieve growth similar to foetal growth coupled with satisfactory functional development. The accumulation of knowledge since the previous guideline on nutrition of preterm infants from the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition in 1987 has made a new guideline necessary. Thus, an ad hoc expert panel was convened by the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition in 2007 to make appropriate recommendations. The present guideline, of which the major recommendations are summarised here (for the full report, see http://links.lww.com/A1480), is consistent with, but not identical to, recent guidelines from the Life Sciences Research Office of the American Society for Nutritional Sciences published in 2002 and recommendations from the handbook Nutrition of the Preterm Infant. Scientific Basis and Practical Guidelines, 2nd ed, edited by Tsang et al, and published in 2005. The preferred food for premature infants is fortified human milk from the infant's own mother, or, alternatively, formula designed for premature infants. This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants. These recommendations are based on a considered review of available scientific reports on the subject, and on expert consensus for which the available scientific data are considered inadequate.

This consensus statement presents a comprehensive and evidence-based set of guidelines for the care of postoperative nausea and vomiting (PONV) in both adult and pediatric populations. The guidelines are established by an international panel of experts under the auspices of the American Society of Enhanced Recovery and Society for Ambulatory Anesthesia based on a comprehensive search and review of literature up to September 2019. The guidelines provide recommendation on identifying high-risk patients, managing baseline PONV risks, choices for prophylaxis, and rescue treatment of PONV as well as recommendations for the institutional implementation of a PONV protocol. In addition, the current guidelines focus on the evidence for newer drugs (eg, second-generation 5-hydroxytryptamine 3 [5-HT3] receptor antagonists, neurokinin 1 (NK1) receptor antagonists, and dopamine antagonists), discussion regarding the use of general multimodal PONV prophylaxis, and PONV management as part of enhanced recovery pathways. This set of guidelines have been endorsed by 23 professional societies and organizations from different disciplines (Appendix 1).Guidelines currently available include the 3 iterations of the consensus guideline we previously published, which was last updated 6 years ago; a guideline published by American Society of Health System Pharmacists in 1999; a brief discussion on PONV management as part of a comprehensive postoperative care guidelines; focused guidelines published by the Society of Obstetricians and Gynecologists of Canada, the Association of Paediatric Anaesthetists of Great Britain & Ireland and the Association of Perianesthesia Nursing; and several guidelines published in other languages.The current guideline was developed to provide perioperative practitioners with a comprehensive and up-to-date, evidence-based guidance on the risk stratification, prevention, and treatment of PONV in both adults and children. The guideline also provides guidance on the management of PONV within enhanced recovery pathways.The previous consensus guideline was published 6 years ago with a literature search updated to October 2011. Several guidelines, which have been published since, are either limited to a specific populations or do not address all aspects of PONV management. The current guideline was developed based on a systematic review of the literature published up through September 2019. This includes recent studies of newer pharmacological agents such as the second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, a dopamine antagonist, neurokinin 1 (NK1) receptor antagonists as well as several novel combination therapies. In addition, it also contains an evidence-based discussion on the management of PONV in enhanced recovery pathways. We have also discussed the implementation of a general multimodal PONV prophylaxis in all at-risk surgical patients based on the consensus of the expert panel.

CD36 is a membrane glycoprotein present on platelets, mononuclear phagocytes, adipocytes, hepatocytes, myocytes, and some epithelia. On microvascular endothelial cells, CD36 is a receptor for thrombospondin-1 and related proteins and functions as a negative regulator of angiogenesis. On phagocytes, through its functions as a scavenger receptor recognizing specific oxidized phospholipids and lipoproteins, CD36 participates in internalization of apoptotic cells, certain bacterial and fungal pathogens, and modified low-density lipoproteins, thus contributing to inflammatory responses and atherothrombotic diseases. CD36 also binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption and possibly contributing to the pathogenesis of metabolic disorders, such as diabetes and obesity. On sensory cells, CD36 is involved in insect pheromone signaling and rodent fatty food preference. The signaling pathways downstream of CD36 involve ligand-dependent recruitment and activation of nonreceptor tyrosine kinases, specific mitogen-activated protein kinases, and the Vav family of guanine nucleotide exchange factors; modulation of focal adhesion constituents; and generation of intracellular reactive oxygen species. CD36 in many cells is localized in specialized cholesterol-rich membrane microdomains and may also interact with other membrane receptors, such as tetraspanins and integrins. Identification of the precise CD36 signaling pathways in specific cells elicited in response to specific ligands may yield novel targets for drug development.

BACKGROUND: Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score. METHODS: Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis. RESULTS: Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies. CONCLUSIONS: An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification.

Importance: Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection. MS affects an estimated 900 000 people in the US. MS typically presents in young adults (mean age of onset, 20-30 years) and can lead to physical disability, cognitive impairment, and decreased quality of life. This review summarizes current evidence regarding diagnosis and treatment of MS. Observations: MS typically presents in young adults aged 20 to 30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes such as internuclear ophthalmoplegia developing over several days. The prevalence of MS worldwide ranges from 5 to 300 per 100 000 people and increases at higher latitudes. Overall life expectancy is less than in the general population (75.9 vs 83.4 years), and MS more commonly affects women (female to male sex distribution of nearly 3:1). Diagnosis is made based on a combination of signs and symptoms, radiographic findings (eg, magnetic resonance imaging [MRI] T2 lesions), and laboratory findings (eg, cerebrospinal fluid-specific oligoclonal bands), which are components of the 2017 McDonald Criteria. Nine classes of disease-modifying therapies (DMTs), with varying mechanisms of action and routes of administration, are available for relapsing-remitting MS, defined as relapses at onset with stable neurologic disability between episodes, and secondary progressive MS with activity, defined as steadily increasing neurologic disability following a relapsing course with evidence of ongoing inflammatory activity. These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine, and 3 types of monoclonal antibodies. One additional DMT, ocrelizumab, is approved for primary progressive MS. These DMTs reduce clinical relapses and MRI lesions (new T2 lesions, gadolinium-enhancing lesions). Efficacy rates of current DMTs, defined by reduction in annualized relapse rates compared with placebo or active comparators, range from 29%-68%. Adverse effects include infections, bradycardia, heart blocks, macular edema, infusion reactions, injection-site reactions, and secondary autoimmune adverse effects, such as autoimmune thyroid disease. Conclusions and Relevance: MS is characterized by physical disability, cognitive impairment, and other symptoms that affect quality of life. Treatment with DMT can reduce the annual relapse rate by 29% to 68% compared with placebo or active comparator.

CONTEXT: The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. OBJECTIVE: To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). INTERVENTIONS: Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. MAIN OUTCOME MEASURES: The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. RESULTS: Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. CONCLUSIONS: Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.

Fecal microbial community changes are associated with numerous disease states, including cardiovascular disease (CVD). However, such data are merely associative. A causal contribution for gut microbiota in CVD has been further supported by a multitude of more direct experimental evidence. Indeed, gut microbiota transplantation studies, specific gut microbiota-dependent pathways, and downstream metabolites have all been shown to influence host metabolism and CVD, sometimes through specific identified host receptors. Multiple metaorganismal pathways (involving both microbe and host) both impact CVD in animal models and show striking clinical associations in human studies. For example, trimethylamine N-oxide and, more recently, phenylacetylglutamine are gut microbiota-dependent metabolites whose blood levels are associated with incident CVD risks in large-scale clinical studies. Importantly, a causal link to CVD for these and other specific gut microbial metabolites/pathways has been shown through numerous mechanistic animal model studies. Phenylacetylglutamine, for example, was recently shown to promote adverse cardiovascular phenotypes in the host via interaction with multiple ARs (adrenergic receptors)-a class of key receptors that regulate cardiovascular homeostasis. In this review, we summarize recent advances of microbiome research in CVD and related cardiometabolic phenotypes that have helped to move the field forward from associative to causative results. We focus on microbiota and metaorganismal compounds/pathways, with specific attention paid to short-chain fatty acids, secondary bile acids, trimethylamine N-oxide, and phenylacetylglutamine. We also discuss novel therapeutic strategies for directly targeting the gut microbiome to improve cardiovascular outcomes.