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1. Normal Gastrointestinal Mucosa at Biopsy and Overall Mortality: Nationwide Population-Based Cohort Study

Author: Ludvigsson JF, Sun J, Olén O, Song M, Halfvarson J, Roelstraete B, Khalili H, and Fang F
Subjects: normal mucosa, screening, mortality, cohort, Infectious and parasitic diseases, RC109-216
Abstract: Jonas F Ludvigsson,1– 3 Jiangwei Sun,1,4 Ola Olén,5– 7 Mingyang Song,8– 10 Jonas Halfvarson,11 Bjorn Roelstraete,1 Hamed Khalili,9,10,12 Fang Fang4 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; 3Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY, USA; 4Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 5Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 6Sachs’ Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden; 7Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; 8Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 9Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 10Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 11Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 12Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USACorrespondence: Jonas F Ludvigsson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 171 77, Sweden, Email jonasludvigsson@yahoo.comBackground: Normal gastrointestinal (GI) mucosa on endoscopy has been linked to a lower risk of colorectal cancer (CRC) but its association to overall death is unknown.Methods: We identified 466,987 individuals with a first GI biopsy 1965– 2016 with normal mucosa (60.6% upper GI and 39.4% lower GI) through all Swedish pathology departments (n = 28). They were individually matched to 2,321,217 reference individuals without a GI biopsy and also compared to 505,076 full siblings. Flexible parametric models were applied to estimate hazard ratio (HRs) and 95% confidence interval (95% CI) for death.Results: During a median follow-up of ∼ 11 years, 85,859 (18.39%) of individuals with normal mucosa and 377,653 (16.27%) of reference individuals died. This corresponded to incidence rates of 147.56/10,000 vs 127.90/10,000 person-years respectively (rate difference: 19.66/10,000 person-years), with the multivariable-adjusted HR of 1.21 (95% CI: 1.20– 1.22). Excess mortality was seen for both upper and lower biopsy with normal mucosa. Particularly higher HRs for death were seen in males, individuals biopsied when aged < 40 years, those without a prior record of GI disease, and those with high education. Mortality risk was most increased in the first five years after biopsy (HR = 1.34; 95% CI: 1.32– 1.36) but decreased thereafter. Having a GI biopsy with normal mucosa was associated with excess mortality from cardiovascular (CVD)disease (HR = 1.02; 95% CI: 1.01– 1.03), cancer (HR = 1.58; 95% CI: 1.56– 1.61), GI disease (HR = 1.65; 95% CI: 1.58– 1.71), and other causes (HR = 1.10; 95% CI: 1.08– 1.11). Sibling comparisons yielded similar results.Conclusion: Compared with individuals without a GI biopsy, those with a normal GI biopsy due to clinical symptoms had a higher mortality particularly in the first five years after biopsy, and especially from GI disease and cancer.Keywords: normal mucosa, screening, mortality, cohort
Published: 2022

2. Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis

Author: Moraes Holst L, Halfvarson J, Carlson M, Hedin C, Kruse R, Lindqvist CM, Bergemalm D, Almér S, Bresso F, Ling Lundström M, Repsilber D, D'Amato M, Keita Å, Hjortswang H, Söderholm J, Sundin J, Törnblom H, Simrén M, Strid H, Magnusson MK, and Öhman L
Subjects: inflammatory bowel diseases, gene expression, mucosal transcriptome, homeostasis, host response, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Luiza Moraes Holst,1 Jonas Halfvarson,2 Marie Carlson,3 Charlotte Hedin,4 Robert Kruse,5 Carl Mårten Lindqvist,6 Daniel Bergemalm,2 Sven Almér,4 Francesca Bresso,7 Maria Ling Lundström,3 Dirk Repsilber,6 Mauro D’Amato,8– 10 Åsa Keita,11 Henrik Hjortswang,12 Johan Söderholm,11 Johanna Sundin,13 Hans Törnblom,14 Magnus Simrén,14,15 Hans Strid,16 Maria K Magnusson,1 Lena Öhman1 1Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 2Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 3Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 4Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; 5Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 6School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 7Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden; 8Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 9IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; 10Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain; 11Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 12Department of Clinical and Experimental Science, Linköping University, Linköping, Sweden; 13Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden; 14Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 15Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 16Department of Internal Medicine, Södra Älvsborg Hospital, Borås, SwedenCorrespondence: Lena Öhman, Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, Tel +46703616499, Email lena.ohman@gu.seBackground: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohn’s disease (CD active).Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways.Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed.Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.Keywords: inflammatory bowel diseases, gene expression, mucosal transcriptome, homeostasis, host response
Published: 2022

3. Mucosal Gene Transcript Signatures in Treatment Naïve Inflammatory Bowel Disease: A Comparative Analysis of Disease to Symptomatic and Healthy Controls in the European IBD-Character Cohort

Author: Vatn SS, Lindstrøm JC, Moen AEF, Brackmann S, Tannæs TM, Olbjørn C, Bergemalm D, Keita V, Gomollon F, Detlie TE, Lüders T, Kalla R, Adams A, Satsangi J, Jahnsen J, Vatn MH, Halfvarson J, Ricanek P, and Nilsen H
Subjects: crohn’s disease, healthy controls, mitochondria, mucosal transcriptome, non-inflamed, prediction, symptomatic controls, ulcerative colitis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Simen Svendsen Vatn,1,2,&ast; Jonas Christoffer Lindstrøm,3,4,&ast; Aina EF Moen,1,4,5 Stephan Brackmann,1,2 Tone M Tannæs,1,5 Christine Olbjørn,1,6 Daniel Bergemalm,7 Åsa V Keita,8 Fernando Gomollon,9 Trond Espen Detlie,1,2 Torben Lüders,5 Rahul Kalla,10 Alex Adams,10,11 Jack Satsangi,10,11 Jørgen Jahnsen,1,2 Morten H Vatn,1 Jonas Halfvarson,7 Petr Ricanek,2 Hilde Nilsen1,5 On behalf of IBD-CHARACTER consortium1Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 2Department of Gastroenterology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway; 3Health Services Research Unit (HØKH), Akershus University Hospital, Lørenskog, Norway; 4Department of Methods Development and Analytics, Division of Infectious Disease Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway; 5Section for Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway; 6Department of Pediatric and Adolescent Medicine, Akershus University Hospital, Lørenskog, Norway; 7Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 8Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 9Digestive Diseases Unit, IIS Aragón, Zaragoza, Spain; 10Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, Division of Medical and Radiological Sciences, University of Edinburgh, Edinburgh, UK; 11Translational Gastroenterology Unit, Medical Sciences/ Experimental medicine Division, University of Oxford, Oxford, UK&ast;These authors contributed equally to this workCorrespondence: Simen Svendsen Vatn, Akershus University Hospital, Postbox 1000, Lørenskog, 1478, Norway, Tel +47 94277594, Email bikkjas@hotmail.comBackground: Studies of the mucosal transcriptomic landscape have given new insight into the pathogenesis of inflammatory bowel disease (IBD). Recently, the predictive biomarker potential of gene expression signatures has been explored. To further investigate the mucosal gene expression in IBD, we recruited a cohort of treatment naïve patients and compared them to both symptomatic and healthy controls.Methods: Altogether, 323 subjects were included: Crohn’s disease (N = 75), ulcerative colitis (N = 87) and IBD unclassified (N = 3). Additionally, there were two control groups: symptomatic controls (N = 131) and healthy controls (N = 27). Mucosal biopsies were collected during ileocolonoscopy and gene expression in inflamed and non-inflamed mucosa was explored. Gene expression profiling was performed using Agilent G3 Human Gene Expression 860K v3 One-Color microarray. We recorded information about treatment escalation to anti-TNF agents or surgery, and anti-TNF response, to explore predictive opportunities of the mucosal transcriptome.Results: Gene expression profiles in symptomatic controls in whom IBD had been excluded resembled that of IBD patients and diverged from that of healthy controls. In non-inflamed Crohn’s disease and ulcerative colitis, gene set enrichment analysis revealed dysregulation of pathways involved in basic cellular biological processes. Mitochondria-associated pathways were dysregulated both in non-inflamed and inflamed Crohn’s disease and ulcerative colitis (> 2.6 normalized enrichment scores
Published: 2022

4. Work Loss in Relation to Pharmacological and Surgical Treatment for Crohn’s Disease: A Population-Based Cohort Study

Author: Everhov ÅH, Sachs MC, Ludvigsson JF, Khalili H, Askling J, Neovius M, Myrelid P, Halfvarson J, Nordenvall C, Söderling J, and Olén O
Subjects: inflammatory bowel disease, sick leave, disability pension, tnf inhibitor, aminosalicylate, immunomodulator, Infectious and parasitic diseases, RC109-216
Abstract: Åsa H Everhov, 1, 2 Michael C Sachs, 2 Jonas F Ludvigsson, 3, 4 Hamed Khalili, 2, 5 Johan Askling, 2 Martin Neovius, 2 Pär Myrelid, 6, 7 Jonas Halfvarson, 8 Caroline Nordenvall, 9, 10 Jonas Söderling, 2 Ola Olén 1, 2, 11 on behalf of the SWIBREG study group 1Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; 2Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 4Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden; 5Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 6Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; 7Department of Surgery, County Council of Östergötland Linköping, Linköping, Sweden; 8Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 9Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 10Center for Digestive Disease, Division of Coloproctology, Karolinska University Hospital, Stockholm, Sweden; 11Department of Pediatric Gastroenterology and Nutrition, Sachs’ Children and Youth Hospital, Stockholm, SwedenCorrespondence: Åsa H EverhovDepartment of Surgery, Stockholm South General Hospital, Stockholm SE 118 61, SwedenTel +46 8 616 2349Email asa.hallqvist-everhov@ki.sePurpose: Patients with Crohn’s disease have increased work loss. We aimed to describe changes in work ability in relation to pharmacological and surgical treatments.Patients and Methods: We linked data from the Swedish National Patient Register, The Swedish Quality Register for Inflammatory Bowel Disease SWIBREG, The Prescribed Drug Register, The Longitudinal Integrated Database for Health Insurance and Labour Market Studies, and the Social Insurance Database. We identified working-age (19– 59 years) patients with incident Crohn’s disease 2006– 2013 and population comparator subjects matched by sex, birth year, region, and education level. We assessed the number of lost workdays due to sick leave and disability pension before and after treatments.Results: Of 3956 patients (median age 34 years, 51% women), 39% were treated with aminosalicylates, 52% with immunomodulators, 22% with TNF inhibitors, and 18% with intestinal surgery during a median follow-up of 5.3 years. Most patients had no work loss during the study period (median=0 days). For all treatments, the mean number of lost workdays increased during the months before treatment initiation, peaked during the first month of treatment and decreased thereafter, and was heavily influenced by sociodemographic factors and amount of work loss before first Crohn’s disease diagnosis. The mean increase in work loss days compared to pre-therapeutic level was ∼ 3 days during the first month of treatment for all pharmacological therapies and 11 days for intestinal surgery. Three months after treatment initiation, 88% of patients treated surgically and 90– 92% of patients treated pharmacologically had the same amount of work loss as before treatment start. Median time to return to work was 2 months for all treatments.Conclusion: In this regular clinical setting, patients treated surgically had more lost workdays than patients treated pharmacologically, but return to work was similar between all treatments.Keywords: inflammatory bowel disease, sick leave, disability pension, TNF inhibitor, aminosalicylate, immunomodulator
Published: 2020

5. Fecal microbiota profiles in treatment-naïve pediatric inflammatory bowel disease – associations with disease phenotype, treatment, and outcome

Author: Olbjørn C, Cvancarova Småstuen M, Thiis-Evensen E, Nakstad B, Vatn MH, Jahnsen J, Ricanek P, Vatn S, Moen AEF, Tannæs TM, Lindstrøm JC, Söderholm JD, Halfvarson J, Gomollón F, Casén C, Karlsson MK, Kalla R, Adams AT, Satsangi J, and Perminow G
Subjects: dysbiosis, Crohn´s disease, ulcerative colitis, Proteobacteria, biologic therapy, Faecalibacterium prausnitzii, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Christine Olbjørn,1,2 Milada Cvancarova Småstuen,3 Espen Thiis-Evensen,4 Britt Nakstad,1,2 Morten Harald Vatn,5 Jørgen Jahnsen,2,6 Petr Ricanek,2,6 Simen Vatn,2,6 Aina EF Moen,5 Tone M Tannæs,5 Jonas C Lindstrøm,7 Johan D Söderholm,8 Jonas Halfvarson,9 Fernando Gomollón,10 Christina Casén,11 Magdalena K Karlsson,11 Rahul Kalla,12 Alex T Adams,12,13 Jack Satsangi,12,13 Gøri Perminow14 1Department of Pediatric and Adolescent Medicine, Akershus University Hospital, Lørenskog, Norway; 2Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway; 3Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway; 4Department of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 5Department of Clinical Molecular Biology (EpiGen), Division of Medicine, Akershus University Hospital, Lørenskog, and University of Oslo, Oslo, Norway; 6Department of Gastroenterology, Akerhus University Hospital, Lørenskog, Norway; 7Institute of Clinical Medicine, University of Oslo, Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway; 8Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; 9Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; 10Digestive Diseases Unit, IIS Aragón, Zaragoza, Spain; 11Genetic-Analysis AS, Oslo, Norway; 12Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; 13Translational Gastroenterology Unit, Experimental Medicine Division, University of Oxford, Oxford, UK; 14Department of Pediatrics, Oslo University Hospital, Ullevål, Oslo, Norway Purpose: Imbalance in the microbiota, dysbiosis, has been identified in inflammatory bowel disease (IBD). We explored the fecal microbiota in pediatric patients with treatment-naïve IBD, non-IBD patients with gastrointestinal symptoms and healthy children, its relation to IBD subgroups, and treatment outcomes.Patients and methods: Fecal samples were collected from 235 children below 18 years of age. Eighty children had Crohn’s disease (CD), 27 ulcerative colitis (UC), 3 IBD unclassified, 50 were non-IBD symptomatic patients, and 75 were healthy. The bacterial abundance of 54 predefined DNA markers was measured with a 16S rRNA DNA-based test using GA-Map™ technology at diagnosis and after therapy in IBD patients.Results: Bacterial abundance was similarly reduced in IBD and non-IBD patients in 51 of 54 markers compared to healthy patients (P
Published: 2019

6. Birth weight, sex, and celiac disease: a nationwide twin study

Author: Kuja-Halkola R, Lebwohl B, Halfvarson J, Emilsson L, Magnusson PK, and Ludvigsson JF
Subjects: AUTOIMMUNE, GESTATIONAL AGE, GLUTEN, REGISTRIES, RISK FACTORS, TWINS, Infectious and parasitic diseases, RC109-216
Abstract: Ralf Kuja-Halkola,1 Benjamin Lebwohl,1,2 Jonas Halfvarson,3 Louise Emilsson,4–6 Patrik K Magnusson,1 Jonas F Ludvigsson1,2,7,8 1Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Department of Medicine, Celiac Disease Center, Columbia University Medical Center, Columbia University, New York, NY, USA; 3Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 4Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; 5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 6Centre for Clinical Research, Vårdcentralen Värmlands Nysäter, County Council of Värmland, Värmland, 7Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; 8Division of Epidemiology and Public Health, School of Medicine, City Hospital, University of Nottingham, Nottingham, UK Objective: Earlier research suggests that birth weight may be associated with celiac disease (CD), but the direction of association has been unclear potentially due to confounding effect from genetic and intrafamilial factors. Through within-twin analyses, we aimed to minimize confounding effects such as twins that share genetic and early environmental exposures.Materials and methods: Using the Swedish Twin Registry, we examined the birth weight of 146,830 twins according to the CD status. CD was defined as having villous atrophy according to a small intestinal biopsy reports.Results: The prevalence of diagnosed CD was 0.5% (n=669), and we included 407 discordant pairs of CD–non-CD twins. Comparing the 669 CD patients with non-CD twins, the association between birth weight and future CD was not statistically significant (odds ratio [OR] per 1000 g increase in birth weight: 1.16; 95% confidence interval [CI]=0.97–1.38). In males, the association was positive and statistically significant (OR=1.50; 95% CI=1.11–2.02). However, the association was not significant in within-pair analyses for both dizygotic and monozygotic twins and for both sexes.Conclusion: This population-based study found that in male twins, higher birth weight was associated with higher risk of CD. However, when comparing discordant twin pairs in within-twin pair analyses, there was no statistically significant association between birth weight, intrauterine growth, and future risk of CD. Keywords: autoimmune, gestational age, gluten, registries, risk factors, twins
Published: 2017

7. Real-World Outcomes of Patients Starting Intravenous and Transitioning to Subcutaneous Vedolizumab in Inflammatory Bowel Disease

Author: Lamichhane, N., Melas, N., Bergqvist, V., Ekholm, N.-P., Olén, O., Ludvigsson, J. F., Hjortswang, H., Marsal, J., Eriksson, C., and Halfvarson, J.
Published: 2024
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8. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus

Author: Abreu, M, Ahuja, V, Allez, M, Ananthakrishnan, A, Bemelman, W, Bernstein, C, Braun, J, Chowers, Y, Colombel, J-F, Danese, S, D'Haens, G, D'Hoore, A, Dignass, A, Dotan, I, Dubinsky, M, Ekbom, A, Fleshner, P, Gasche, C, Gassull, MA, Gearry, R, Ghosh, S, Gibson, P, Griffiths, A, Halfvarson, J, Hanauer, S, Harpaz, N, Hart, A, Hibi, T, Kamm, M, Kaplan, G, Kaser, A, Korelitz, B, Kotze, P, Koutroubakis, I, Kruis, W, Lakatos, P, Lewis, J, Lindsay, J, Loftus, E, Louis, E, Lukas, M, Magro, F, Mahadevan, U, Mantzaris, G, Mary, J-Y, McGovern, D, Moum, B, Munkholm, P, Neurath, M, Ng, S, O'Morain, C, Oresland, T, Panaccione, R, Panes, J, Panis, Y, Pemberton, J, Peyrin-Biroulet, L, Prantera, C, Rachmilewitz, D, Ran, Z, Reinisch, W, Remzi, F, Rhodes, J, Riddell, R, Rogler, G, Rubin, D, Sachar, D, Sandborn, W, Sands, B, Sartor, B, Schoelmerich, J, Schreiber, S, Siegel, C, Siegmund, B, Silverberg, M, Söderholm, J, Sood, A, Spinelli, A, Stange, E, Steinwurz, F, Targan, S, Travis, S, Turner, D, Tysk, C, Vatn, M, Vermeire, S, Watanabe, M, Yamamoto, T, Yamamoto-Furusho, J, Ananthakrishnan, Ashwin N, Kaplan, Gilaad G, Bernstein, Charles N, Burke, Kristin E, Lochhead, Paul J, Sasson, Alexa N, Agrawal, Manasi, Tiong, Jimmy Ho Tuan, Steinberg, Joshua, Kruis, Wolfgang, Steinwurz, Flavio, Ahuja, Vineet, Ng, Siew C, Rubin, David T, Colombel, Jean-Frederic, and Gearry, Richard
Published: 2022
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9. P1089 Disease characteristics at time of diagnosis of adult onset inflammatory bowel disease and the risk of venous thromboembolism in the modern era – A Swedish nationwide cohort study 2007-2021

Author: Bröms, G, primary, Forss, A, additional, Eriksson, J, additional, Linder, M, additional, Eriksson, C, additional, Askling, J, additional, Halfvarson, J, additional, Ludvigsson, J F, additional, and Olen, O, additional
Published: 2024
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10. P1047 Observational study of tofacitinib in Ulcerative Colitis in Sweden (ODEN) – Interim analysis of health-related quality of life and fatigue

Author: Nyberg, L, primary, Söderling, J, additional, Olén, O, additional, Strid, H, additional, Jäghult, S, additional, Halfvarson, J, additional, Hedin, C, additional, Jónsdóttir, S, additional, Hjortswang, H, additional, Cappelleri, J C, additional, Henrohn, D, additional, Seddighzadeh, M, additional, Marsal, J, additional, and Grip, O, additional
Published: 2024
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11. P296 Preclinical protein signatures in blood predict Crohn's disease and Ulcerative colitis several years before the diagnosis

Author: Grännö, O, primary, Salomon, B, additional, Lindqvist, C M, additional, Hedin, C R H, additional, Carlson, M, additional, Dannenberg, K, additional, Andersson, E, additional, Söderholm, J D, additional, Keita, Å V, additional, Öhman, L, additional, Magnusson, M K, additional, D’Amato, M, additional, Eriksson, C, additional, Hultdin, J, additional, Kruse, R, additional, Cao, Y, additional, Repsilber, D, additional, Bergemalm, D, additional, Grip, O, additional, Karling, P, additional, and Halfvarson, J, additional
Published: 2024
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12. P305 The serum protein profile across the IBD spectrum: Results from the COLLIBRI consortium

Author: Salomon, B, primary, Sudhakar, P, additional, Verstockt, B, additional, Ungaro, R C, additional, Aden, K, additional, D'Haens, G R, additional, Silverberg, M S, additional, Repsilber, D, additional, Vermeire, S, additional, and Halfvarson, J, additional
Published: 2024
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13. P941 Observational study of tofacitinib in ulcerative colitis in Sweden (ODEN) – Interim analysis of clinical and biomarker data

Author: Nyberg, L, primary, Söderling, J, additional, Olén, O, additional, Strid, H, additional, Jäghult, S, additional, Halfvarson, J, additional, Hedin, C, additional, Jónsdóttir, S, additional, Hjortswang, H, additional, Cappelleri, J, additional, Henrohn, D, additional, Seddighzadeh, M, additional, Marsal, J, additional, and Grip, O, additional
Published: 2024
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14. P219 Prognostic potential of mucosal proteins in Ulcerative Colitis

Author: Salomon, B, primary, Carlson, M, additional, Bergemalm, D, additional, Hedin, C R H, additional, Söderholm, J D, additional, Keita, Å V, additional, Carsten, A, additional, Grip, O, additional, Marsal, J, additional, Eriksson, C, additional, Strid, H, additional, Lindqvist, C M, additional, Öhman, L, additional, Magnusson, M K, additional, D’Amato, M, additional, Repsilber, D, additional, Kruse, R, additional, and Halfvarson, J, additional
Published: 2024
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15. P1113 Depressive symptoms in ulcerative colitis and Crohn's disease – differences in improvement at 1 year follow-up

Author: Selin, K A, primary, Repsilber, D, additional, Strid, H, additional, Lindqvist, C M, additional, Kruse, R, additional, Magnusson, M K, additional, Öhman, L, additional, Carlson, M, additional, Keita, Å V, additional, Söderholm, J D, additional, Halfvarson, J, additional, and Hedin, C R H, additional
Published: 2024
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16. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

Author: Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]
Published: 2023
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17. P151 Assessing comprehensive remission for Ulcerative Colitis in clinical practice: International consensus recommendations

Author: Schreiber, S W, primary, Danese, S, additional, Dignass, A, additional, Domènech, E, additional, Fantini, M, additional, Ferrante, M, additional, Halfvarson, J, additional, Hart, A, additional, Magro, F, additional, Lees, C, additional, Leone, S, additional, Pierik, M, additional, Field, P, additional, Schofield, H, additional, and Peyrin-Biroulet, L, additional
Published: 2023
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18. DOP11 A novel diagnostic serum protein signature for paediatric Inflammatory Bowel Disease: A discovery and validation study in two independent inception cohorts

Author: Bache-Wiig Mathisen, C, primary, Nyström, N, additional, Bazov, I, additional, Andersen, S, additional, Olbjørn, C, additional, Perminow, G, additional, Kristensen, V A, additional, Opheim, R, additional, Ricanek, P, additional, D`Amato, M, additional, Carlson, M, additional, Hedin, C R, additional, Keita, Å V, additional, Kruse, R, additional, Lindqvist, C M, additional, Magnusson, M K, additional, Salihovic, S, additional, Söderholm, J D, additional, Öhman, L, additional, Repsilber, D, additional, Høivik, M L, additional, and Halfvarson, J, additional
Published: 2023
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19. DOP14 Identification and validation of a lipidomic signature as a novel diagnostic biomarker of paediatric Inflammatory Bowel Disease

Author: Salihovic, S, primary, Nyström, N, additional, Bache-Wiig Mathisen, C, additional, Andersen, S, additional, Olbjørn, C, additional, Perminow, G, additional, Opheim, R, additional, Detlie, T E, additional, Huppertz-Hauss, G, additional, Bazov, I, additional, Kruse, R, additional, Lindqvist, C M, additional, Hedin, C R H, additional, Carlson, M, additional, Öhman, L, additional, Magnusson, M, additional, Keita, Å V, additional, Söderholm, J D, additional, D’Amato, M, additional, Orešič, M, additional, Repsilber, D, additional, Hyötyläinen, T, additional, Hoivik, M L, additional, and Halfvarson, J, additional
Published: 2023
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20. DOP27 Sequencing-based hematopoietic miRNA landscape reveals common and distinct features of autoimmune inflammatory phenotypes

Author: Juzenas, S., Hübenthal, M., Zeißig, S., Strüning, N., Keller, A., Schulte, D., D’Amato, M., Lindqvist, M., Kupčinskas, J., Schreiber, S., Halfvarson, J., Hemmrich-Stanisak, G., and Franke, A.
Published: 2022
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21. Health-related quality of life improves during one year of medical and surgical treatment in a European population-based inception cohort of patients with Inflammatory Bowel Disease — An ECCO-EpiCom study

Author: Burisch, J., Weimers, P., Pedersen, N., Cukovic-Cavka, S., Vucelic, B., Kaimakliotis, I., Duricova, D., Bortlik, M., Shonová, O., Vind, I., Avnstrøm, S., Thorsgaard, N., Krabbe, S., Andersen, V., Dahlerup, J.F., Kjeldsen, J., Salupere, R., Olsen, J., Nielsen, K.R., Manninen, P., Collin, P., Katsanos, K.H., Tsianos, E.V., Ladefoged, K., Lakatos, L., Ragnarsson, G., Björnsson, E., Bailey, Y., O'Morain, C., Schwartz, D., Odes, S., Valpiani, D., Boni, M.C., Jonaitis, L., Kupcinskas, L., Turcan, S., Barros, L., Magro, F., Lazar, D., Goldis, A., Nikulina, I., Belousova, E., Fernandez, A., Sanroman, L., Almer, S., Zhulina, Y., Halfvarson, J., Arebi, N., Diggory, T., Sebastian, S., Lakatos, P.L., Langholz, E., and Munkholm, P.
Published: 2014
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22. Health care and patients' education in a European inflammatory bowel disease inception cohort: An ECCO-EpiCom study

Author: Burisch, J., Vegh, Z., Pedersen, N., Čuković-Čavka, S., Turk, N., Kaimakliotis, I., Duricova, D., Bortlik, M., Shonová, O., Thorsgaard, N., Krabbe, S., Andersen, V., Dahlerup, J.F., Kjeldsen, J., Salupere, R., Olsen, J., Nielsen, K.R., Manninen, P., Collin, P., Katsanos, K.H., Tsianos, E.V., Ladefoged, K., Ragnarsson, G., Björnsson, E., Bailey, Y., O'Morain, C., Schwartz, D., Odes, S., Politi, P., Santini, A., Kiudelis, G., Kupcinskas, L., Turcan, S., Magro, F., Barros, L., Lazar, D., Goldis, A., Nikulina, I., Belousova, E., Sanromán, L., Martinez-Ares, D., Almer, S., Zhulina, Y., Halfvarson, J., Arebi, N., Houston, Y., Sebastian, S., Langholz, E., Lakatos, P.L., and Munkholm, P.
Published: 2014
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23. Environmental factors in a population-based inception cohort of inflammatory bowel disease patients in Europe — An ECCO-EpiCom study

Author: Burisch, J., Pedersen, N., Cukovic-Cavka, S., Turk, N., Kaimakliotis, I., Duricova, D., Bortlik, M., Shonová, O., Vind, I., Avnstrøm, S., Thorsgaard, N., Krabbe, S., Andersen, V., Dahlerup, J.F., Kjeldsen, J., Salupere, R., Olsen, J., Nielsen, K.R., Manninen, P., Collin, P., Katsanos, K.H., Tsianos, E.V., Ladefoged, K., Lakatos, L., Ragnarsson, G., Björnsson, E., Bailey, Y., O'Morain, C., Schwartz, D., Odes, S., Giannotta, M., Girardin, G., Kiudelis, G., Kupcinskas, L., Turcan, S., Barros, L., Magro, F., Lazar, D., Goldis, A., Nikulina, I., Belousova, E., Martinez-Ares, D., Hernandez, V., Almer, S., Zhulina, Y., Halfvarson, J., Arebi, N., Tsai, H.H., Sebastian, S., Lakatos, P.L., Langholz, E., and Munkholm, P.
Published: 2014
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24. DOP019 Immunomodulators reduce the risk of surgery and hospitalisation in Crohn’s disease in a prospective European population-based inception cohort: the Epi-IBD cohort

Author: Burisch, J, Andersen, V, Čuković-Čavka, S, Lakatos, P L, DʼInca, R, Magro, F, Arebi, N, Kievit, L, Kaimakliotis, I, Valpiani, D, Katsanos, K H, Vegh, Z, Dahlerup, J F, Fumery, M, Pedersen, N, Halfvarson, J, Belousova, E, Nielsen, K R, Turcan, S, Ellul, P, Kupcinskas, L, Oksanen, P, Duricova, D, Giannotta, M, Goldis, A, Hernandez, V, Salupere, R, Odes, S, Langholz, E, and Munkholm, P
Published: 2018
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25. OP001 Gut barrier dysfunction: a primary defect in twins with Crohn’s disease predominantly caused by genetic predisposition

Author: Keita, Å V, Lindqvist, C M, Öst, Å, Magana, C D L, Schoultz, I, and Halfvarson, J
Published: 2018
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26. LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis

Author: Assadi, G, Saleh, R, Hadizadeh, F, Vesterlund, L, Bonfiglio, F, Halfvarson, J, Törkvist, L, Eriksson, A S, Harris, H E, Sundberg, E, and D'Amato, M
Published: 2016
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27. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus

Author: Ananthakrishnan, Ashwin N, primary, Kaplan, Gilaad G, additional, Bernstein, Charles N, additional, Burke, Kristin E, additional, Lochhead, Paul J, additional, Sasson, Alexa N, additional, Agrawal, Manasi, additional, Tiong, Jimmy Ho Tuan, additional, Steinberg, Joshua, additional, Kruis, Wolfgang, additional, Steinwurz, Flavio, additional, Ahuja, Vineet, additional, Ng, Siew C, additional, Rubin, David T, additional, Colombel, Jean-Frederic, additional, Gearry, Richard, additional, Abreu, M, additional, Ahuja, V, additional, Allez, M, additional, Ananthakrishnan, A, additional, Bemelman, W, additional, Bernstein, C, additional, Braun, J, additional, Chowers, Y, additional, Colombel, J-F, additional, Danese, S, additional, D'Haens, G, additional, D'Hoore, A, additional, Dignass, A, additional, Dotan, I, additional, Dubinsky, M, additional, Ekbom, A, additional, Fleshner, P, additional, Gasche, C, additional, Gassull, MA, additional, Gearry, R, additional, Ghosh, S, additional, Gibson, P, additional, Griffiths, A, additional, Halfvarson, J, additional, Hanauer, S, additional, Harpaz, N, additional, Hart, A, additional, Hibi, T, additional, Kamm, M, additional, Kaplan, G, additional, Kaser, A, additional, Korelitz, B, additional, Kotze, P, additional, Koutroubakis, I, additional, Kruis, W, additional, Lakatos, P, additional, Lewis, J, additional, Lindsay, J, additional, Loftus, E, additional, Louis, E, additional, Lukas, M, additional, Magro, F, additional, Mahadevan, U, additional, Mantzaris, G, additional, Mary, J-Y, additional, McGovern, D, additional, Moum, B, additional, Munkholm, P, additional, Neurath, M, additional, Ng, S, additional, O'Morain, C, additional, Oresland, T, additional, Panaccione, R, additional, Panes, J, additional, Panis, Y, additional, Pemberton, J, additional, Peyrin-Biroulet, L, additional, Prantera, C, additional, Rachmilewitz, D, additional, Ran, Z, additional, Reinisch, W, additional, Remzi, F, additional, Rhodes, J, additional, Riddell, R, additional, Rogler, G, additional, Rubin, D, additional, Sachar, D, additional, Sandborn, W, additional, Sands, B, additional, Sartor, B, additional, Schoelmerich, J, additional, Schreiber, S, additional, Siegel, C, additional, Siegmund, B, additional, Silverberg, M, additional, Söderholm, J, additional, Sood, A, additional, Spinelli, A, additional, Stange, E, additional, Steinwurz, F, additional, Targan, S, additional, Travis, S, additional, Turner, D, additional, Tysk, C, additional, Vatn, M, additional, Vermeire, S, additional, Watanabe, M, additional, Yamamoto, T, additional, and Yamamoto-Furusho, J, additional
Published: 2022
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28. Trans-continental analysis of over, 2000 Inflammatory Bowel Disease patients implicates geography, disease type, and exposure to immunosuppression as drivers of SARS-CoV-2 seroprevalence : data from the ICARUS-IBD Consortium

Author: Wong, S. Y., Helmus, D., Marlow, L., Pazos, V. Martinez, Brann, S., Wellens, J., Kedia, S., Mak, J. W. Y., Bergemalm, Daniel, Argollo, M., Zaltman, C., Steinwurz, F., Rubin, D., Allez, M., Halfvarson, J., Abreu, M. T., Lindsay, J., Dutta, U., Silverberg, M. S., Ng, S. C., Ahuja, V., Watanabe, K., Vermeire, S., Colombel, J. F., Satsangi, J., Wong, S. Y., Helmus, D., Marlow, L., Pazos, V. Martinez, Brann, S., Wellens, J., Kedia, S., Mak, J. W. Y., Bergemalm, Daniel, Argollo, M., Zaltman, C., Steinwurz, F., Rubin, D., Allez, M., Halfvarson, J., Abreu, M. T., Lindsay, J., Dutta, U., Silverberg, M. S., Ng, S. C., Ahuja, V., Watanabe, K., Vermeire, S., Colombel, J. F., and Satsangi, J.
Published: 2022
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29. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases:an International Organization for Study of Inflammatory Bowel Diseases consensus

Author: Ananthakrishnan, A., Kaplan, G., Bernstein, C., Burke, Kristin E., Lochhead, Paul J., Sasson, Alexa N., Agrawal, Manasi, Tiong, Jimmy Ho Tuan, Steinberg, Joshua, Kruis, W., Steinwurz, Flavio, Ahuja, V., Ng, Siew C., Rubin, David T., Colombel, Jean Frederic, Gearry, Richard, Abreu, M., Allez, M., Bemelman, W., Braun, J., Chowers, Y., Colombel, J. F., Danese, S., D'Haens, G., D'Hoore, A., Dignass, A., Dotan, I., Dubinsky, M., Ekbom, A., Fleshner, P., Gasche, C., Gassull, M. A., Ghosh, S., Gibson, P., Griffiths, A., Halfvarson, J., Hanauer, S., Harpaz, N., Hart, A., Hibi, T., Kamm, M., Kaser, A., Korelitz, B., Kotze, P., Koutroubakis, I., Munkholm, P., Ananthakrishnan, A., Kaplan, G., Bernstein, C., Burke, Kristin E., Lochhead, Paul J., Sasson, Alexa N., Agrawal, Manasi, Tiong, Jimmy Ho Tuan, Steinberg, Joshua, Kruis, W., Steinwurz, Flavio, Ahuja, V., Ng, Siew C., Rubin, David T., Colombel, Jean Frederic, Gearry, Richard, Abreu, M., Allez, M., Bemelman, W., Braun, J., Chowers, Y., Colombel, J. F., Danese, S., D'Haens, G., D'Hoore, A., Dignass, A., Dotan, I., Dubinsky, M., Ekbom, A., Fleshner, P., Gasche, C., Gassull, M. A., Ghosh, S., Gibson, P., Griffiths, A., Halfvarson, J., Hanauer, S., Harpaz, N., Hart, A., Hibi, T., Kamm, M., Kaser, A., Korelitz, B., Kotze, P., Koutroubakis, I., and Munkholm, P.
Abstract: Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.
Published: 2022

30. Prevalence and Implications of Frailty in Older Adults With Incident Inflammatory Bowel Diseases : A Nationwide Cohort Study

Author: Kochar, Bharati, Jylhävä, Juulia, Söderling, Jonas, Ritchie, Christine S., Olsson, M., Hjortswang, H., Myrelid, P., Bengtsson, J., Strid, H., Andersson, M., Jäghult, S., Eberhardson, M., Nordenvall, C., Björk, J., Fagerberg, U. L., Rejler, Martin, Grip, O., Karling, P., Halfvarson, J., Ludvigsson, J. F., Khalili, H., Olén, O., Group, the SWIBREG Study, Kochar, Bharati, Jylhävä, Juulia, Söderling, Jonas, Ritchie, Christine S., Olsson, M., Hjortswang, H., Myrelid, P., Bengtsson, J., Strid, H., Andersson, M., Jäghult, S., Eberhardson, M., Nordenvall, C., Björk, J., Fagerberg, U. L., Rejler, Martin, Grip, O., Karling, P., Halfvarson, J., Ludvigsson, J. F., Khalili, H., Olén, O., and Group, the SWIBREG Study
Abstract: Background and Aims: We aimed to compare the risk of frailty in older adults with incident inflammatory bowel disease (IBD) and matched non-IBD comparators and assess the association between frailty and future hospitalizations and mortality. Methods: In a cohort of patients with incident IBD ≥60 years of age from 2007 to 2016 in Sweden identified using nationwide registers, we defined frailty using Hospital Frailty Risk Score. We compared prevalence of frailty in patients with IBD with age, sex, place of residency– and calendar year–matched population comparators. In the IBD cohort, we used Cox proportional hazards modeling to examine the associations between frailty risk and hospitalizations or mortality. Results: We identified 10,590 patients with IBD, 52% female with a mean age of 71 years of age, matched to 103,398 population-based comparators. Among patients with IBD, 39% had no risk for frailty, 49% had low risk for frailty, and 12% had higher risk for frailty. Mean Hospital Frailty Risk Score was 1.9 in IBD and 0.9 in matched comparators (P < .01). Older adults with IBD at higher risk for frailty had a 20% greater risk for mortality at 3 years compared with those who were not frail. Compared with nonfrail older patients with IBD, patients at higher risk for frailty had increased mortality (hazard ratio [HR], 3.22, 95% confidence interval [CI], 2.86–3.61), all-cause hospitalization (HR, 2.42; 95% CI, 2.24–2.61), and IBD-related hospitalization (HR, 1.50; 95% CI, 1.35–1.66). These associations were not attenuated after adjusting for comorbidities. Conclusions: Frailty is more prevalent in older adults with IBD than in matched comparators. Among older patients with IBD, frailty is associated with increased risk for hospitalizations and mortality.
Published: 2022
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31. Editorial: do thiopurines and biologics decrease the risk of colectomy? Authors’ reply

Author: Eriksson, C., Cao, Y., Rundquist, S., Zhulina, Y., Henriksson, I., Montgomery, S., and Halfvarson, J.
Published: 2017
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32. Changes in medical management and colectomy rates: a population‐based cohort study on the epidemiology and natural history of ulcerative colitis in Örebro, Sweden, 1963‐2010

Author: Eriksson, C., Cao, Y., Rundquist, S., Zhulina, Y., Henriksson, I., Montgomery, S., and Halfvarson, J.
Published: 2017
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33. Long‐term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients

Author: Angelison, L., Almer, S., Eriksson, A., Karling, P., Fagerberg, U., Halfvarson, J., Thörn, M., Björk, J., Hindorf, U., Löfberg, R., Bajor, A., Hjortswang, H., Hammarlund, P., Grip, O., Torp, J., Marsal, J., and Hertervig, E.
Published: 2017
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34. P788 Microbiota related disease activity and distribution in subgroups of inflammatory bowel disease

Author: Ricanek, P., Rahul, K., Ber, Y., Vatn, S., Finnby, L., Lindahl, T., Bergemalm, D., Carsten, A., Söderholm, J., Jahnsen, J., Gomollon, F., Halfvarson, J., Satsangi, J., Casen, C., and Vatn, M.H.
Published: 2017
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35. P695 The risk of proximal disease extension in patients with limited ulcerative colitis in a prospective European population-based inception cohort – the ECCO-EpiCom cohort

Author: Burisch, J., Halfvarson, J., Kupcinskas, L., Hernandez, V., Kaimakliotis, I., Valpiani, D., Pedersen, N., Duricova, D., Kievit, L., Dahlerup, J.F., Fumery, M., Salupere, R., Arebi, N., Nielsen, K.R., Giannotta, M., Oksanen, P., Katsanos, K.H., Vegh, Z., Ellul, P., Schwartz, D., Čuković-Čavka, S., DʼIncà, R., Turcan, S., Magro, F., Goldis, A., Langholz, E., Lakatos, P.L., and Munkholm, P.
Published: 2017
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36. P727 Change in Crohnʼs disease behavior in a prospective European population-based inception cohort – the ECCO-EpiCom cohort

Author: Burisch, J., Halfvarson, J., Kupcinskas, L., Hernandez, V., Kaimakliotis, I., Valpiani, D., Pedersen, N., Duricova, D., Kievit, L., Dahlerup, J.F., Fumery, M., Salupere, R., Arebi, N., Nielsen, K.R., Giannotta, M., Oksanen, P., Katsanos, K.H., Vegh, Z., Ellul, P., Schwartz, D., Čuković-Čavka, S., DʼIncà, R., Turcan, S., Magro, F., Goldis, A., Langholz, E., Lakatos, P.L., and Munkholm, P.
Published: 2017
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37. P694 Disease course during the first five years following diagnosis in a prospective European population-based inception cohort – the ECCO-EpiCom cohort

Author: Burisch, J., Halfvarson, J., Kupcinskas, L., Hernandez, V., Kaimakliotis, I., Valpiani, D., Pedersen, N., Duricova, D., Kievit, L., Dahlerup, J.F., Fumery, M., Salupere, R., Arebi, N., Nielsen, K.R., Giannotta, M., Oksanen, P., Katsanos, K.H., Vegh, Z., Ellul, P., Schwartz, D., Čuković-Čavka, S., DʼIncà, R., Turcan, S., Magro, F., Goldis, A., Langholz, E., Lakatos, P.L., and Munkholm, P.
Published: 2017
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38. P364 A Swedish observational study (SVEAH) on vedolizumab assessing effectiveness and healthcare resource utilization in patients with inflammatory bowel disease

Author: Eriksson, C., Rundquist, S., Lykiardopoulos, B., Karlén, P., Grip, O., Söderman, C., Almer, S., Hertervig, E., Gunnarsson, J., Delin, J., Strid, H., Sjöberg, M., Öberg, D., Hjortswang, H., and Halfvarson, J.
Published: 2017
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39. P061 Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease – IBD Character

Author: Adams, A., Kalla, R., Vatn, S., Bonfiglio, F., Nimmo, E., Kennedy, N., Ventham, N., Vatn, M., Ricanek, P., Bergemalm, D., Halfvarson, J., Söderholm, J., Pierik, M., Törkvist, L., Gomolln, F., Gut, I., Jahnsen, J., and Satsangi, J.
Published: 2017
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40. OP022 Proximity extension assay based proteins show immune cell specificity and can diagnose and predict outcomes in inflammatory bowel diseases: IBD Character study

Author: Kalla, R., Adams, A., Vatn, S., Bergemalm, D., Ricanek, P., Lindstrom, J., Ocklind, A., Nordberg, N., Kennedy, N., Ventham, N., Vatn, M., Söderholm, J., Pierik, M., Törkvist, L., Gomolln, F., Jahnsen, J., Halfvarson, J., and Satsangi, J.
Published: 2017
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41. DOP79 Biomarkers for IBD using OLINK Proteomics inflammation panel: Preliminary results from the COLLIBRI consortium

Author: Sudhakar, P, primary, Salomon, B, additional, Verstockt, B, additional, Ungaro, R, additional, Aden, K, additional, D’Haens, G, additional, Komori, K, additional, Guay, H, additional, Silverberg, M, additional, Vermeire, S, additional, and Halfvarson, J, additional
Published: 2022
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42. P342 Trans-continental analysis of over, 2000 Inflammatory Bowel Disease patients implicates geography, disease type, and exposure to immunosuppression as drivers of SARS-CoV-2 seroprevalence: data from the ICARUS-IBD Consortium

Author: Wong, S Y, primary, Helmus, D, additional, Marlow, L, additional, Martinez Pazos, V, additional, Brann, S, additional, Wellens, J, additional, Kedia, S, additional, Mak, J W Y, additional, Bergemalm, D, additional, Argollo, M, additional, Zaltman, C, additional, Steinwurz, F, additional, Rubin, D, additional, Allez, M, additional, Halfvarson, J, additional, Abreu, M T, additional, Lindsay, J, additional, Dutta, U, additional, Silverberg, M S, additional, Ng, S C, additional, Ahuja, V, additional, Watanabe, K, additional, Vermeire, S, additional, Colombel, J F, additional, and Satsangi, J, additional
Published: 2022
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43. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Author: Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., S. M. E., Ng, Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., S. M., Ng, Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., Ng, S. M. E., Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., Ng, S. M., Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Daly, Mark J. [0000-0002-0949-8752], Apollo - University of Cambridge Repository, Hugot, Jean-Pierre [0000-0002-8446-6056], UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Romagnoni, A, Jegou, S, VAN STEEN, Kristel, Wainrib, G, Hugot, JP, Peyrin-Biroulet, L, Chamaillard, M, Colombel, JF, Cottone, M, D'Amato, M, D'Inca, R, Halfvarson, J, Henderson, P, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Ng, SME, Oikonomou, I, Peeters, H, Proctor, DD, Rahier, JF, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Andrews, JM, Bampton, PA, Barclay, M, Florin, TH, Gearry, R, Krishnaprasad, K, Lawrance, IC, Mahy, G, Montgomery, GW, Radford-Smith, G, Roberts, RL, Simms, LA, Hanigan, K, Croft, A, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie, AM, Beck, K, Bernard, EJ, Binion, DG, Bitton, A, Brant, SR, Cho, JH, Cohen, A, Croitoru, K, Daly, MJ, Datta, LW, Deslandres, C, Duerr, RH, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, GR, Haritunians, T, Jobin, G, Katz, S, Lahaie, RG, McGovern, DP, Nelson, L, Ng, SM, Ning, K, Pare, P, Regueiro, MD, Rioux, JD, Ruggiero, E, Schumm, LP, Schwartz, M, Scott, R, Sharma, Y, Silverberg, MS, Spears, D, Steinhart, AH, Stempak, JM, Swoger, JM, Tsagarelis, C, Zhang, C, Zhao, HY, AERTS, Jan, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barnes, C, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, CM, Coffey, AJ, Mc Connell, J, Conrad, DF, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Frayling, TM, Freathy, RM, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Marchini, JL, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, McVean, G, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Munroe, PB, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Ovington, NR, Owen, MJ, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, JRB, Phillips, A, Plagnol, V, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Sawcer, SJ, Schuilenburg, H, Scott, CE, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stirrups, K, Stone, MA, Strachan, DP, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Tobin, MD, Travers, ME, Turnbull, C, Vukcevic, D, Wain, LV, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Yau, C, Young, AH, Zeggini, E, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Hurles, ME, Duncanson, A, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Kwiatkowski, DP, McCarthy, MI, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, JM, Bramon, E, Casas, JP, Corvin, A, Jankowski, J, Markus, HS, Palmer, CNA, Plomin, R, Rautanen, A, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, and Kwiatkowski, D
Subjects: Male, 692/4020/1503/257/1402, Genotype, Genotyping Techniques, LOCI, 45/43, lcsh:Medicine, Polymorphism, Single Nucleotide, Crohn's disease, genetics, genome wide association, Article, Deep Learning, Crohn Disease, INDEL Mutation, Genetics research, Humans, genetics, Genetic Predisposition to Disease, 129, lcsh:Science, Alleles, Science & Technology, genome wide association, RISK PREDICTION, 45, Models, Genetic, lcsh:R, Decision Trees, 692/308/2056, ASSOCIATION, Multidisciplinary Sciences, Crohn's disease, Logistic Models, Nonlinear Dynamics, ROC Curve, Area Under Curve, Science & Technology - Other Topics, lcsh:Q, Female, Neural Networks, Computer, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers. Tis work was supported by Fondation pour la Recherche Médical (ref DEI20151234405) and Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX. Te authors thank the students that participated to the wisdom of the crowd exercise.
Published: 2019

44. OC-015 Proximity extension assay technology identifies novel serum biomarkers for predicting inflammatory bowel disease: IBD character consortium

Author: Kalla, R, Kennedy, NA, Hjelm, F, Modig, E, Sundell, M, Söderholm, J, Andreassen, B, Bergemalm, D, Ventham, NT, Hjortswang, H, Petr, R, Vatn, MH, Halfvarson, J, Gullberg, M, and Satsangi, J
Published: 2015
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45. Technological readiness and implementation of genomic‐driven precision medicine for complex diseases

Author: Franks, P. W., primary, Melén, E., additional, Friedman, M., additional, Sundström, J., additional, Kockum, I., additional, Klareskog, L., additional, Almqvist, C., additional, Bergen, S. E., additional, Czene, K., additional, Hägg, S., additional, Hall, P., additional, Johnell, K., additional, Malarstig, A., additional, Catrina, A., additional, Hagström, H., additional, Benson, M., additional, Gustav Smith, J., additional, Gomez, M. F, additional, Orho‐Melander, M., additional, Jacobsson, B., additional, Halfvarson, J., additional, Repsilber, D., additional, Oresic, M., additional, Jern, C., additional, Melin, B., additional, Ohlsson, C., additional, Fall, T., additional, Rönnblom, L., additional, Wadelius, M., additional, Nordmark, G., additional, Johansson, Å., additional, Rosenquist, R., additional, and Sullivan, P. F., additional
Published: 2021
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46. Technological readiness and implementation of genomic-driven precision medicine for complex diseases

Author: Franks, P. W., Melén, E., Friedman, M., Sundström, Johan, Kockum, I., Klareskog, L., Almqvist, C., Bergen, S. E., Czene, K., Hägg, S., Hall, P., Johnell, K., Mälarstig, Anders, Catrina, A., Hagström, H., Benson, M., Gustav Smith, J., Gomez, M. F., Orho-Melander, M., Jacobsson, B., Halfvarson, J., Repsilber, D., Oresic, M., Jern, C., Melin, B., Ohlsson, C., Fall, Tove, Rönnblom, Lars, Wadelius, Mia, Nordmark, Gunnel, Johansson, Åsa, Rosenquist, R., Sullivan, P. F., Franks, P. W., Melén, E., Friedman, M., Sundström, Johan, Kockum, I., Klareskog, L., Almqvist, C., Bergen, S. E., Czene, K., Hägg, S., Hall, P., Johnell, K., Mälarstig, Anders, Catrina, A., Hagström, H., Benson, M., Gustav Smith, J., Gomez, M. F., Orho-Melander, M., Jacobsson, B., Halfvarson, J., Repsilber, D., Oresic, M., Jern, C., Melin, B., Ohlsson, C., Fall, Tove, Rönnblom, Lars, Wadelius, Mia, Nordmark, Gunnel, Johansson, Åsa, Rosenquist, R., and Sullivan, P. F.
Abstract: The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.
Published: 2021
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47. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease

Author: Kalla, R., Adams, A. T., Bergemalm, D., Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, D., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Bergemalm, D., Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, D., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
Abstract: Background: Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. Methods: We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. Results: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p=4.1x10(-23)] and oncostatin-M [OSM; p=3.7x10(-16)]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224-756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43-6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohns disease respectively. Conclusion: We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings., Funding Agencies|EU FP7 grant: IBD-CHARACTER [2858546]; Wellcome TrustWellcome TrustEuropean Commission
Published: 2021
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48. Association of celiac disease genes with inflammatory bowel disease in Finnish and Swedish patients

Author: Parmar, A S, Lappalainen, M, Paavola-Sakki, P, Halme, L, Färkkilä, M, Turunen, U, Kontula, K, Aromaa, A, Salomaa, V, Peltonen, L, Halfvarson, J, Törkvist, L, D'Amato, M, Saavalainen, P, and Einarsdottir, E
Published: 2012
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49. East–West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort

Author: Burisch, J, Pedersen, N, Čuković-Čavka, S, Brinar, M, Kaimakliotis, I, Duricova, D, Shonová, O, Vind, I, Avnstrøm, S, Thorsgaard, N, Andersen, V, Krabbe, S, Dahlerup, J F, Salupere, R, Nielsen, K R, Olsen, J, Manninen, P, Collin, P, Tsianos, E V, Katsanos, K H, Ladefoged, K, Lakatos, L, Björnsson, E, Ragnarsson, G, Bailey, Y, Odes, S, Schwartz, D, Martinato, M, Lupinacci, G, Milla, M, De Padova, A, DʼIncà, R, Beltrami, M, Kupcinskas, L, Kiudelis, G, Turcan, S, Tighineanu, O, Mihu, I, Magro, F, Barros, L F, Goldis, A, Lazar, D, Belousova, E, Nikulina, I, Hernandez, V, Martinez-Ares, D, Almer, S, Zhulina, Y, Halfvarson, J, Arebi, N, Sebastian, S, Lakatos, P L, Langholz, E, and Munkholm, P
Published: 2014
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50. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Author: Patsopoulos, NA, Baranzini, SE, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, AH, James, T, Replogle, J, Vlachos, IS, McCabe, C, Pers, TH, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, IP, Robbins, A, Andlauer, TFM, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, HB, Sellebjerg, F, Sorensen, PS, Ullum, H, Thorner, LW, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, CM, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, MD, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, MA, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, SD, Celius, EG, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, IL, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, SJ, Calabresi, P, Cree, BAC, Cross, A, Davis, M, de Bakker, PWI, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, IY, Gourraud, PA, Haines, JL, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, MH, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, CP, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, MA, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, RJ, Lechner-Scott, J, Leal, R, Moscato, P, Booth, DR, Stewart, GJ, Vucic, S, Pame, G, BamettO, M, Mason, D, GriffithS, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, BV, Charlesworth, J, Kilpatrick, TJ, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, WM, Kermode, AG, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, JF, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, JP, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, GW, Ng, SME, Oikonomnou, J, Peeters, H, Proctor, DD, Rahier, JF, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, DA, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, HF, Hauser, SL, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, LF, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, McCauley, JL, Oksenberg, JR, Oturai, A, Sawcer, S, Ivinson, AJ, Olsson, T, De Jager, PL, Patsopoulos, Na, Baranzini, Se, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, Ah, James, T, Replogle, J, Vlachos, I, Mccabe, C, Pers, Th, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, Ip, Robbins, A, Andlauer, Tfm, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, Hb, Sellebjerg, F, Sorensen, P, Ullum, H, Thorner, Lw, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, Cm, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, Md, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, Ma, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, Sd, Celius, Eg, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, Il, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, Sj, Calabresi, P, Cree, Bac, Cross, A, Davis, M, de Bakker, Pwi, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, Iy, Gourraud, Pa, Haines, Jl, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, Mh, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, Cp, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, Ma, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, Rj, Lechner-Scott, J, Leal, R, Moscato, P, Booth, Dr, Stewart, Gj, Vucic, S, Pame, G, Bametto, M, Mason, D, Griffiths, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, Bv, Charlesworth, J, Kilpatrick, Tj, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, Wm, Kermode, Ag, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, Jf, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, Gw, Ng, Sme, Oikonomnou, J, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, Km, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cna, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cca, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, Da, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, Hf, Hauser, Sl, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, Lf, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, Mccauley, Jl, Oksenberg, Jr, Oturai, A, Sawcer, S, Ivinson, Aj, Olsson, T, De Jager, Pl, Neurology, and Immunology
Subjects: 0301 basic medicine, Multiple Sclerosis, Quantitative Trait Loci, Inheritance Patterns, Cell Cycle Proteins, Genome-wide association study, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Major Histocompatibility Complex, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Gene Frequency, Autoimmune Process, medicine, Humans, RNA-Seq, X chromosome, Genetics, Chromosomes, Human, X, Multidisciplinary, Microglia, Multiple sclerosis, GTPase-Activating Proteins, Chromosome Mapping, Genomics, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Case-Control Studies, biology.protein, Genome-Wide Association Study, 030217 neurology & neurosurgery
Abstract: Genetic roots of multiple sclerosis The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. eaav7188 ; see also p. 1383
Published: 2019

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