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  • 1.
    Aberg, Fredrik
    et al.
    Univ Helsinki, Finland; Sahlgrens Univ Hosp, Sweden.
    Danford, Christopher J.
    Beth Israel Deaconess Med Ctr, MA 02215 USA.
    Thiele, Maja
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Talback, Mats
    Karolinska Inst, Sweden.
    Rasmussen, Ditlev Nytoft
    Odense Univ Hosp, Denmark.
    Jiang, Z. Gordon
    Beth Israel Deaconess Med Ctr, MA 02215 USA.
    Hammar, Niklas
    Karolinska Inst, Sweden.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    But, Anna
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Puukka, Pauli
    Univ Helsinki, Finland.
    Krag, Aleksander
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Sundvall, Jouko
    Finnish Inst Hlth & Welf, Finland.
    Erlund, Iris
    Finnish Inst Hlth & Welf, Finland.
    Salomaa, Veikko
    Finnish Inst Hlth & Welf, Finland.
    Stal, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Hultcrantz, Rolf
    Karolinska Inst, Sweden.
    Lai, Michelle
    Beth Israel Deaconess Med Ctr, MA 02215 USA.
    Afdhal, Nezam
    Beth Israel Deaconess Med Ctr, MA 02215 USA.
    Jula, Antti
    Finnish Inst Hlth & Welf, Finland.
    Mannisto, Satu
    Finnish Inst Hlth & Welf, Finland.
    Lundqvist, Annamari
    Finnish Inst Hlth & Welf, Finland.
    Perola, Markus
    Finnish Inst Hlth & Welf, Finland.
    Farkkila, Martti
    Univ Helsinki, Finland.
    Hagstrom, Hannes
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    A Dynamic Aspartate-to-Alanine Aminotransferase Ratio Provides Valid Predictions of Incident Severe Liver Disease2021In: HEPATOLOGY COMMUNICATIONS, ISSN 2471-254X, Vol. 5, no 6, p. 1021-1035Article in journal (Refereed)
    Abstract [en]

    The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.

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  • 2.
    Ahmad, Awais
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Rönnelid, Johan
    Uppsala Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test2022In: Diagnostics, ISSN 2075-4418, Vol. 12, no 7, article id 1572Article in journal (Refereed)
    Abstract [en]

    Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturers recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.

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  • 3.
    Ahmad, Awais
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Heijke, R.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Eriksson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes2021In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 203, no 1, p. 22-31Article in journal (Refereed)
    Abstract [en]

    Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjogrens syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver-kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti-nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD-associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2 center dot 9%) and three pSS (2 center dot 6%) cases were diagnosed with AILD. Among SLE-cases without known AILD (n = 272), 26 (9 center dot 6%) had PBC-associated autoantibodies, 15 (5 center dot 5%) AIH-associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC-associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7 center dot 4%), while one fulfilled the diagnostic PBC-criteria. AMA-M2 detected by immunoblot was the most common PBC-associated autoantibody in SLE (20 of 272, 7 center dot 4%). The prevalence of SMA (4 center dot 4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH-criteria. The patient with combined AIH/PBC-serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8 center dot 1%) had PBC-associated, 12 (10 center dot 8%) AIH-associated autoantibodies and two overlapped. PBC-associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD-associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody-negative and -positive patients.

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  • 4.
    Akbari, Camilla
    et al.
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Dodd, Maja
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Stål, Per
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. epartment of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Vessby, Johan
    Uppsala University Hospital, Uppsala, Sweden.
    Rorsman, Fredrik
    Uppsala University Hospital, Uppsala, Sweden.
    Zhang, Xiao
    Merck & Co., Inc., Rahway, NJ, USA.
    Wang, Tongtong
    Merck & Co., Inc., Rahway, NJ, USA.
    Jemielita, Thomas
    Merck & Co., Inc., Rahway, NJ, USA.
    Fernandes, Gail
    Merck & Co., Inc., Rahway, NJ, USA.
    Engel, Samuel S.
    Merck & Co., Inc., Rahway, NJ, USA.
    Hagström, Hannes
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Shang, Ying
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD2024In: JHEP Reports, ISSN 2589-5559, Vol. 6, no 2, article id 100915Article in journal (Refereed)
    Abstract [en]

    Background & aims: Long-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD.

    Methods: We conducted a cohort study with data from Swedish university hospitals. Patients (n = 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n = 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression.

    Results: MALO occurred in 111 (8.8%, incidence rate = 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate = 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio = 6.6; 95% CI = 5.2-8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72 at 10 years).

    Conclusions: This study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy.

    Impact and implications: Several implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.

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  • 5.
    Alfredsson, Joakim
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Heart Center, Department of Cardiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Omar, Kime
    Vastmanland Cty Hosp, Sweden.
    Csog, Jozsef
    Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Venetsanos, Dimitrios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Janzon, Magnus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Bleeding complications with clopidogrel or ticagrelor in ST-elevation myocardial infarction patients: A real life cohort study of two treatment strategies2020In: IJC Heart & Vasculature, E-ISSN 2352-9067, Vol. 27, article id 100495Article in journal (Refereed)
    Abstract [en]

    Introduction

    Dual antiplatelet therapy (DAPT), including potent P2Y12 inhibition after ST-elevation myocardial infarction (STEMI) is recommended in clinical guidelines. However, bleeding complications are common, and associated with worse outcomes. The aim of this study was to assess incidence of bleeding events with a clopidogrel-based compared to a ticagrelor-based DAPT strategy, in a real world population. Secondary aims were to assess ischemic complications and mortality.

    Methods and Results

    We identified 330 consecutive STEMI patients with a clopidogrel-based and 330 with a ticagrelor-based DAPT strategy. Patientś medical records were searched for bleeding and ischemic complications, over 6 months follow-up.

    The two groups were well balanced in baseline characteristics, age (69 years inboth groups), sex (31% vs 32% females), history of diabetes (19% vs 21%), hypertension (43% in both) and MI (17% vs 15%). There was no difference in CRUSADE bleeding score (28 vs 29). After discharge, there were more than twice as many bleeding events with a ticagrelor-based compared with a clopidogrel-based strategy (13.3% vs. 6.5%, p = 0.005). Bleeding events included significantly more severe bleeding complications (TIMI major/minor [5.8 vs 1.0, p = 0.001]) during the ticagrelor-based period. There was no significant difference in the composite of death, MI or stroke (7.8% vs 7.1%, p = 0.76).

    Conclusions

    In this observational study, a ticagrelor-based DAPT strategy was associated with significantly more bleeding complications, without any significant change in death, MI or stroke. Larger studies are needed to determine whether bleeding complications off-sets benefits with a more potent DAPT strategy in older and more comorbid real-life patients.

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  • 6.
    Anstee, Quentin M.
    et al.
    Newcastle Univ, England; Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Fdn Trust, England.
    Darlay, Rebecca
    Newcastle Univ, England.
    Cockell, Simon
    Newcastle Univ, England.
    Meroni, Marica
    Univ Milan, Italy.
    Govaere, Olivier
    Newcastle Univ, England.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Burt, Alastair D.
    Newcastle Univ, England; Univ Adelaide, Australia.
    Bedossa, Pierre
    Newcastle Univ, England.
    Palmer, Jeremy
    Newcastle Univ, England.
    Liu, Yang-Lin
    Newcastle Univ, England.
    Aithal, Guruprasad P.
    Univ Nottingham, England.
    Allison, Michael
    Cambridge Univ NHS Fdn Trust, England.
    Yki-Jarvinen, Hannele
    Univ Helsinki, Finland; Univ Cambridge, England; Univ Cambridge, England.
    Vacca, Michele
    Cambridge Univ NHS Fdn Trust, England; Helsinki Univ Hosp, Finland.
    Dufour, Jean-Francois
    Univ Bern, Switzerland.
    Invernizzi, Pietro
    Univ Milano Bicocca, Italy; Univ Milano Bicocca, Italy; San Gerardo Hosp, Italy.
    Prati, Daniele
    Univ Milan, Italy.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Francque, Sven
    Antwerp Univ Hosp, Belgium.
    Petta, Salvatore
    Univ Palermo, Italy.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Clement, Karine
    Sorbonne Univ, France.
    Ratziu, Vlad
    Sorbonne Univ, France.
    Schattenberg, Joern M.
    Johannes Gutenberg Univ Mainz, Germany.
    Valenti, Luca
    Univ Milan, Italy.
    Day, Christopher P.
    Newcastle Univ, England.
    Cordell, Heather J.
    Newcastle Univ, England.
    Daly, Ann K.
    Newcastle Univ, England; Newcastle Univ, England.
    Correction: Genome-wide association study of non- alcoholic fatty liver and steatohepatitis in a histologically characterised cohort ( vol 73, pp 505-515 , 2020 )2023In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 78, no 5, p. 1085-1086Article in journal (Other academic)
  • 7.
    Anstee, Quentin M.
    et al.
    Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Fdn Trust, England.
    Darlay, Rebecca
    Newcastle Univ, England.
    Cockell, Simon
    Newcastle Univ, England.
    Meroni, Marica
    Univ Milan, Italy.
    Govaere, Olivier
    Newcastle Univ, England.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Burt, Alastair D.
    Newcastle Univ, England; Univ Adelaide, Australia.
    Bedossa, Pierre
    Newcastle Univ, England.
    Palmer, Jeremy
    Newcastle Univ, England.
    Liu, Yang-Lin
    Newcastle Univ, England.
    Aithal, Guruprasad P.
    Nottingham Univ Hosp NHS Trust, England; Univ Nottingham, England.
    Allison, Michael
    Cambridge Univ NHS Fdn Trust, England.
    Yki-Jarvinen, Hannele
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Vacca, Michele
    Cambridge Univ NHS Fdn Trust, England; Univ Cambridge, England; Univ Cambridge, England.
    Dufour, Jean-Francois
    Univ Bern, Switzerland.
    Invernizzi, Pietro
    Univ Milano Bicocca, Italy; San Gerardo Hosp, Italy.
    Prati, Daniele
    Univ Milan, Italy.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Francque, Sven
    Antwerp Univ Hosp, Belgium.
    Petta, Salvatore
    Univ Palermo, Italy.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Clement, Karine
    Sorbonne Univ, France.
    Ratziu, Vlad
    Sorbonne Univ, France.
    Schattenberg, Joern M.
    Johannes Gutenberg Univ Mainz, Germany.
    Valenti, Luca
    Univ Milan, Italy.
    Day, Christopher P.
    Newcastle Univ, England.
    Cordell, Heather J.
    Newcastle Univ, England.
    Daly, Ann K.
    Newcastle Univ, England.
    Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort2020In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 73, no 3, p. 505-515Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Genetic factors associated with nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Results: Case-control analysis identified signals showing p values <= 5 x 10(-8) at 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1 x 10(-7) (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p = 8.2 x 10(-8)). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (>= F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. Conclusions: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individuals risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.

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  • 8.
    Anstee, Quentin M.
    et al.
    Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Fdn Trust, England.
    Darlay, Rebecca
    Newcastle Univ, England.
    Cockell, Simon
    Newcastle Univ, England.
    Meroni, Marica
    Univ Milan, Italy.
    Govaere, Olivier
    Newcastle Univ, England.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Burt, Alastair D.
    Newcastle Univ, England; Univ Adelaide, Australia.
    Bedossa, Pierre
    Newcastle Univ, England.
    Palmer, Jeremy
    Newcastle Univ, England.
    Liu, Yang-Lin
    Newcastle Univ, England.
    Aithal, Guruprasad P.
    Nottingham Univ Hosp NHS Trust, England; Univ Nottingham, England.
    Allison, Michael
    Cambridge Univ NHS Fdn Trust, England.
    Yki-Jarvinen, Hannele
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Vacca, Michele
    Cambridge Univ NHS Fdn Trust, England; Univ Cambridge, England; Univ Cambridge, England.
    Dufour, Jean-Francois
    Univ Bern, Switzerland.
    Invernizzi, Pietro
    Univ Milano Bicocca, Italy; Univ Milano Bicocca, Italy; San Gerardo Hosp, Italy.
    Prati, Daniele
    Univ Milan, Italy.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Francque, Sven
    Antwerp Univ Hosp, Belgium.
    Petta, Salvatore
    Univ Palermo, Italy.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Clement, Karine
    Sorbonne Univ, France.
    Ratziu, Vlad
    Sorbonne Univ, France.
    Schattenberg, Jorn M.
    Johannes Gutenberg Univ Mainz, Germany.
    Valenti, Luca
    Univ Milan, Italy.
    Day, Christopher P.
    Newcastle Univ, England.
    Cordell, Heather J.
    Newcastle Univ, England.
    Daly, Ann K.
    Newcastle Univ, England.
    Correction: Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort (vol 12, pg 505, 2020)2021In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 74, no 5, p. 1274-1275Article in journal (Other academic)
  • 9.
    Armandi, Angelo
    et al.
    Univ Turin, Italy; Univ Med Ctr, Germany.
    Sanavia, Tiziana
    Univ Turin, Italy.
    Younes, Ramy
    Boehringer Ingelheim Int GmbH, Germany.
    Caviglia, Gian Paolo
    Univ Turin, Italy.
    Rosso, Chiara
    Univ Turin, Italy.
    Govaere, Olivier
    Newcastle Univ, England.
    Liguori, Antonio
    Fdn Policlin Univ A Gemelli IRCCS, Italy; Fdn Policlin Univ A Gemelli IRCCS, Italy; Univ Cattolica Sacro Cuore, Italy.
    Francione, Paolo
    Fdn IRCCS Ca Granda Osped Maggiore Policlin, Italy.
    Gallego-Duran, Rocio
    Virgen Rocio Univ Hosp, Spain.
    Ampuero, Javier
    Virgen Rocio Univ Hosp, Spain.
    Pennisi, Grazia
    Univ Palermo, Italy.
    Aller, Rocio
    Hosp Clin Valladolid, Spain.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Burt, Alastair
    Newcastle Univ, England.
    David, Ezio
    Univ Turin, Italy.
    Vecchio, Fabio
    Dipartimento Univ Med & Chirurg Traslazionale, Italy.
    Maggioni, Marco
    Ca Granda IRCCS Fdn, Italy.
    Cabibi, Daniela
    Univ Palermo, Italy.
    Mcleod, Duncan
    Westmead Hosp, Australia.
    Pareja, Maria Jesus
    Hosp Univ Valme, Spain.
    Zaki, Marco Y. W.
    Newcastle Univ, England; Minia Univ, Egypt.
    Stal, Per
    Karolinska Univ Hosp, Sweden; Huddinge Karolinska Inst, Sweden.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Fracanzani, Anna Ludovica
    Fdn IRCCS Ca Granda Osped Maggiore Policlin, Italy; Univ Milan, Italy.
    Valenti, Luca
    Univ Milan, Italy; Fdn IRCCS Ca Granda Osped Maggiore Policlin Milano, Italy.
    Grieco, Antonio
    Dipartimento Univ Med & Chirurg Traslazionale, Italy.
    Miele, Luca
    Fdn Policlin Univ A Gemelli IRCCS, Italy; Fdn Policlin Univ A Gemelli IRCCS, Italy; Univ Cattolica Sacro Cuore, Italy.
    Fariselli, Piero
    Univ Turin, Italy.
    Eslam, Mohammed
    Univ Sydney, Australia.
    Petta, Salvatore
    Univ Palermo, Italy.
    Hagstroem, Hannes
    Karolinska Univ Hosp, Sweden; Huddinge Karolinska Inst, Sweden.
    George, Jacob
    Univ Sydney, Australia.
    Schattenberg, Joern M.
    Univ Med Ctr, Germany; Saarland Univ, Germany.
    Romero-Gomez, Manuel
    Virgen Rocio Univ Hosp, Spain.
    Anstee, Quentin Mark
    Newcastle Univ, England; Newcastle Tyne Hosp NHS Fdn Trust, England.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease2024In: Gut, ISSN 0017-5749, E-ISSN 1468-3288Article in journal (Refereed)
    Abstract [en]

    Objective Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. Design We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. Results Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 mu g/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 mu g/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 mu g/L and 272 mu g/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). Conclusions This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.

  • 10.
    Axelrad, Jordan E.
    et al.
    NYU, NY USA.
    Olen, Ola
    Karolinska Inst, Sweden; Stockholm South Gen Hosp, Sweden; Karolinska Inst, Sweden.
    Soderling, Jonas
    Karolinska Inst, Sweden.
    Roelstraete, Bjorn
    Karolinska Inst, Sweden.
    Khalili, Hamed
    Massachusetts Gen Hosp, MA USA.
    Song, Mingyang
    Faye, Adam
    NYU, NY USA.
    Eberhardson, Michael
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Karolinska Inst, Sweden.
    Halfvarson, Jonas
    Orebro Univ, Sweden.
    Ludvigsson, Jonas F.
    Karolinska Inst, Sweden; Orebro Univ Hosp, Sweden; Columbia Univ, NY USA.
    Inflammatory Bowel Disease and Risk of Colorectal Polyps: A Nationwide Population-Based Cohort Study From Sweden2023In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, article id jjad056Article in journal (Refereed)
    Abstract [en]

    Background: Inflammatory bowel disease [IBD] has been linked to an increased risk of colorectal neoplasia. However, the types and risks of specific polyp types in IBD are less clear. Methods: We identified 41 880 individuals with IBD (Crohns disease [CD: n = 12 850]; ulcerative colitis [UC]: n = 29 030]) from Sweden matched with 41 880 reference individuals. Using Cox regression, we calculated adjusted hazard ratios [aHRs] for neoplastic colorectal polyps [tubular, serrated/sessile, advanced and villous] defined by histopathology codes. Results: During follow-up, 1648 [3.9%] IBD patients and 1143 [2.7%] reference individuals had an incident neoplastic colorectal polyp, corresponding to an incidence rate of 46.1 and 34.2 per 10 000 person-years, respectively. This correlated to an aHR of 1.23 (95% confidence interval [CI] 1.12-1.35) with the highest HRs seen for sessile serrated polyps [8.50, 95% CI 1.10-65.90] and traditional serrated adenomas [1.72, 95% CI 1.02-2.91]. aHRs for colorectal polyps were particularly elevated in those diagnosed with IBD at a young age and at 10 years after diagnosis. Both absolute and relative risks of colorectal polyps were higher in UC than in CD [aHRs 1.31 vs 1.06, respectively], with a 20-year cumulative risk difference of 4.4% in UC and 1.5% in CD, corresponding to one extra polyp in 23 patients with UC and one in 67 CD patients during the first 20 years after IBD diagnosis. Conclusions: In this nationwide population-based study, there was an increased risk of neoplastic colorectal polyps in IBD patients. Colonoscopic surveillance in IBD appears important, especially in UC and after 10 years of disease.

  • 11.
    Bakke, Ingunn
    et al.
    NTNU Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway.
    Walaas, Gunnar Andreas
    NTNU Norwegian Univ Sci & Technol, Norway.
    Bruland, Torunn
    NTNU Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway.
    Royset, Elin Synnove
    NTNU Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway; St Olavs Univ Hosp, Norway.
    van Beelen Granlund, Atle
    NTNU Norwegian Univ Sci & Technol, Norway; NTNU Norwegian Univ Sci & Technol, Norway.
    Escudero-Hernández, Celia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Christian Albrechts Univ Kiel, Germany; Univ Hosp Schleswig Holstein, Germany.
    Thorsvik, Silje
    NTNU Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway.
    Münch, Andreas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Sandvik, Arne Kristian
    NTNU Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway; NTNU Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway.
    Ostvik, Ann Elisabet
    NTNU Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway; St Olavs Univ Hosp, Norway.
    Mucosal and faecal neutrophil gelatinase-associated lipocalin as potential biomarkers for collagenous colitis2021In: Journal of gastroenterology, ISSN 0944-1174, E-ISSN 1435-5922, Vol. 56, no 10, p. 914-927Article in journal (Refereed)
    Abstract [en]

    Background Collagenous colitis (CC) is an inflammatory bowel disease where chronic diarrhoea is the main symptom. Diagnostic markers distinguishing between CC and other causes of chronic diarrhoea remain elusive. This study explores neutrophil gelatinase-associated lipocalin (NGAL) and its mRNA lipocalin2 (LCN2) as histological and faecal disease markers in CC. Methods NGAL/LCN2 were studied in colonic biopsies from CC patients before and during budesonide treatment using RNA sequencing (n = 9/group), in situ hybridization (ISH) (n = 13-22/group) and immunohistochemistry (IHC) (n = 14-25/group). Faecal samples from CC (n = 3-28/group), irritable bowel syndrome diarrhoea (IBS-D) (n = 14) and healthy controls (HC) (n = 15) were assayed for NGAL and calprotectin. Results NGAL/LCN2 protein and mRNA expression were upregulated in active CC vs HC, and vs paired samples of treated CC in clinical remission. IHC and ISH localized increased NGAL/LCN2 mainly to epithelium of active CC, compared to almost absence in HC and treated CC. In contrast, calprotectin was solely expressed in immune cells. Despite great individual differences, faecal NGAL was significantly increased in active CC compared to HC, IBS-D and treated CC and had high test sensitivity. Faecal calprotectin levels were variably increased in active CC, but the values remained below usual clinical cut-offs. Conclusion NGAL/LCN2 is upregulated in the epithelium of active CC and reduced during budesonide-induced clinical remission to the level of HC and IBD-S. This was reflected in NGAL faecal concentrations. We propose NGAL as an IHC marker for disease activity in CC and a potential faecal biomarker discriminating CC from HC and IBS-D.

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  • 12.
    Balkhed, Wile
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Åberg, Fredrik O.
    Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki University, Helsinki, Finland.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Repeated measurements of non-invasive fibrosis tests to monitor the progression of non-alcoholic fatty liver disease: A long-term follow-up study2022In: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 42, no 7, p. 1546-1556Article in journal (Refereed)
    Abstract [en]

    Background and Aims: The presence of advanced hepatic fibrosis is the prime marker for the prediction of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Blood-based non-invasive tests (NITs) have been developed to evaluate fibrosis and identify patients at risk. Current guidelines propose monitoring the progression of NAFLD using repeated NITs at 2-3-year intervals. The aim of this study was to evaluate the association of changes in NITs measured at two time points with the progression of NAFLD.

    Methods. We retrospectively included NAFLD patients with NIT measurements in whom the baseline hepatic fibrosis stage had been assessed by biopsy or transient elastography (TE). Subjects underwent follow-up visits at least 1 year from baseline to evaluate the progression of NAFLD. NAFLD progression was defined as the development of end-stage liver disease or fibrosis progression according to repeat biopsy or TE. The following NITs were calculated at baseline and follow-up: Fibrosis-4 (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet ratio index (APRI) and dynamic aspartate-to-alanine aminotransferase ratio (dAAR).

    Results: One hundred and thirty-five patients were included with a mean follow-up of 12.6 +/- 8.5 years. During follow-up, 41 patients (30%) were diagnosed with progressive NAFLD. Change in NIT scores during follow-up was significantly associated with disease progression for all NITs tested except for NFS. However, the diagnostic precision was suboptimal with area under the receiver operating characteristics 0.56-0.64 and positive predictive values of 0.28-0.36 at sensitivity fixed at 90%.

    Conclusions: Change of FIB-4, NFS, APRI, and dAAR scores is only weakly associated with disease progression in NAFLD. Our findings do not support repeated measurements of these NITs for monitoring the course of NAFLD.

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  • 13.
    Barazanji, Nawroz
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Hamilton, Paul J.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Icenhour, Adriane
    Ruhr University Bochum, Bochum, Germany.
    Simon, Rozalyn
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Bednarska, Olga
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Tapper, Sofie
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Tisell, Anders
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    Lundberg, Peter
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Engström, Maria
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Walter, Susanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Irritable bowel syndrome in women: Association between decreased insular subregion volumes and gastrointestinal symptoms2022In: NeuroImage: Clinical, E-ISSN 2213-1582, Vol. 35, article id 103128Article in journal (Refereed)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a chronic pain disorder characterized by disturbed interactions between the gut and the brain with depression as a common comorbidity. In both IBS and depression, structural brain alterations of the insular cortices, key structures for pain processing and interoception, have been demonstrated but the specificity of these findings remains unclear. We compared the gray matter volume (GMV) of insular cortex (IC) subregions in IBS women and healthy controls (HC) and examined relations to gastrointestinal (GI) symptoms and glutamate + glutamine (Glx) concentrations. We further analyzed GMV of IC subregions in women with major depression (MDD) compared to HC and addressed possible differences between depression, IBS, IBS with depression and HC.

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  • 14.
    Bednarska, Olga
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Biskou, Olga
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Israelsen, Hans
    Nord Rebalance AS, Denmark.
    Tinnerfelt Winberg, Martin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Walter, Susanna
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Keita, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    A postbiotic fermented oat gruel may have a beneficial effect on the colonic mucosal barrier in patients with irritable bowel syndrome2022In: Frontiers in Nutrition, E-ISSN 2296-861X, Vol. 9, article id 1004084Article in journal (Refereed)
    Abstract [en]

    Background: Impaired intestinal permeability and microbial dysbiosis are important pathophysiological mechanisms underlying irritable bowel syndrome (IBS). ReFerm (R)( ), also called Profermin (R), is a postbiotic product of oat gruel fermented with Lactobacillus plantarum 299v. In this study, we investigated whether ReFerm (R) has a beneficial effect on the intestinal epithelial barrier function in patients with IBS.Materials and methods: Thirty patients with moderate to severe IBS-diarrhoea (IBS-D) or IBS-mixed (IBS-M) were treated with enema containing ReFerm (R) or placebo. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment with ReFerm (R) or placebo twice daily. The biopsies were mounted in Ussing chambers, and paracellular and transcellular permeabilities were measured for 120 min. In addition, the effects of ReFerm (R) or placebo on the epithelial barrier were investigated in vitro using Caco-2 cells.Results: ReFerm (R) reduced paracellular permeability (p < 0.05) and increased transepithelial resistance (TER) over time (p < 0.01), whereas the placebo had no significant effect in patients. In ReFerm (R)-treated Caco-2 cells, paracellular and transcellular permeabilities were decreased compared to the control (p < 0.05) and placebo (p < 0.01). TER was increased in Caco-2 ReFerm (R)-treated cells, and normalised TER was increased in ReFerm (R)-treated Caco-2 cells compared to control (p < 0.05) and placebo-treated (p < 0.05) cells.Conclusion: ReFerm (R) significantly reduced paracellular permeability and improved TER in colonic biopsies collected from patients with IBS and in a Caco-2 cell model. Our results offer new insights into the potential benefits of ReFerm (R) in IBS management. Further studies are needed to identify the molecular mechanisms underlying the barrier-protective properties of ReFerm (R).

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  • 15.
    Bednarska, Olga
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Nyhlin, Nils
    Örebro Univ, Sweden.
    Schmidt, Peter Thelin
    Ersta Hosp, Sweden; Karolinska Inst, Sweden.
    Johansson, Gabriele Wurm
    Lund Univ, Sweden.
    Toth, Ervin
    Lund Univ, Sweden.
    Lindfors, Perjohan
    Karolinska Inst, Sweden; Aleris Gastromottagningen City, Sweden.
    The Effectiveness and Tolerability of a Very Low-Volume Bowel Preparation for Colonoscopy Compared to Low and High-Volume Polyethylene Glycol-Solutions in the Real-Life Setting2022In: Diagnostics, ISSN 2075-4418, Vol. 12, no 5, article id 1155Article in journal (Refereed)
    Abstract [en]

    Adequate bowel cleansing is essential for high-quality colonoscopy. Recently, a new very low-volume 1 litre (1L) polyethylene glycol (PEG) plus ascorbate solution (ASC) has been introduced. Our aims were to assess the effectiveness and tolerability of this product compared to low-volume 2L PEG-ASC and high-volume 4L PEG solutions, in a real-life setting. In six endoscopy units in Sweden, outpatients undergoing colonoscopy were either prescribed solutions according to local routines, or the very low-volume solution in split dose regimen. Bowel cleansing effectiveness and patient experience was assessed using the Boston Bowel preparation scale (BBPS) and a patient questionnaire. A total of 1098 patients (mean age 58 years, 52% women) were included. All subsegment and the total BBPS scores were significantly greater for 1L PEG-ASC in comparison to other solutions (p < 0.05 for 1L PEG-ASC and 4L PEG for transverse and left colon, otherwise p < 0.001). Nausea was more frequent with 1L PEG-ASC compared to 2L PEG-ASC (p < 0.001) and vomiting were more often reported compared to both other solutions (p < 0.01 and p < 0.05 for 2L PEG-ASC and 4L PEG, respectively). Smell, taste, and total experience was better for 1L PEG-ASC compared to 4L PEG (p < 0.001), and similar compared to the 2L PEG-ASC. In conclusion, 1L PEG-ASC leads to better bowel cleansing compared to 2L PEG-ASC or 4L PEG products, with similar or greater patient satisfaction.

  • 16.
    Bergquist, Annika
    et al.
    Karolinska Univ Hosp, Sweden; European Reference Network Hepatol Dis, Sweden.
    Weismüller, Tobias J.
    Univ Bonn, Germany.
    Levy, Cynthia
    Univ Miami, FL USA; Univ Miami, FL USA.
    Rupp, Christian
    Heidelberg Univ Hosp, Germany.
    Joshi, Deepak
    Kings Coll Hosp London, England.
    Nayagam, Jeremy Shanika
    Kings Coll Hosp London, England; Pomeranian Med Univ, Poland.
    Montano-Loza, Aldo J.
    Univ Alberta, Canada.
    Lytvyak, Ellina
    Univ Alberta, Canada.
    Wunsch, Ewa
    Med Univ Warsaw, Poland.
    Milkiewicz, Piotr
    Med Univ Warsaw, Poland.
    Zenouzi, Roman
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Schramm, Christoph
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Cazzagon, Nora
    Univ Padua, Italy; Univ Padua, Italy.
    Floreani, Annarosa
    Univ Padua, Italy.
    Liby, Ingalill Friis
    Sahlgrens Univ Hosp, Sweden.
    Wiestler, Miriam
    Hannover Med Sch, Germany; European Reference Network Hepatol Dis, Germany.
    Wedemeyer, Heiner
    Hannover Med Sch, Germany; European Reference Network Hepatol Dis, Germany.
    Zhou, Taotao
    Univ Bonn, Germany.
    Strassburg, Christian P.
    Univ Bonn, Germany.
    Rigopoulou, Eirini
    Gen Univ Hosp Larissa, Greece.
    Dalekos, George
    Gen Univ Hosp Larissa, Greece.
    Narasimman, Manasa
    Univ Miami, FL USA.
    Verhelst, Xavier
    Ghent Univ Hosp, Belgium; Univ Ghent, Belgium.
    Degroote, Helena
    Univ Ghent, Belgium; European Reference Network Hepatol Dis, Belgium.
    Vesterhus, Mette
    Oslo Univ Hosp, Norway; Univ Bergen, Norway; Haraldsplass Deaconess Hosp, Norway.
    Kremer, Andreas E.
    Friedrich Alexander Univ Erlangen Nurnberg, Germany; Univ Hosp Erlangen, Germany; Univ Hosp Zurich, Switzerland.
    Buendgens, Bennet
    Univ Duisburg, Germany.
    Rorsman, Fredrik
    Univ Hosp, Sweden.
    Nilsson, Emma
    Lund Univ, Sweden; Skåne Univ Hosp, Sweden.
    Jorgensen, Kristin Kaasen
    Akershus Univ Hosp, Norway.
    von Seth, Erik
    Karolinska Univ Hosp, Sweden; European Reference Network Hepatol Dis, Stockholm, Sweden.
    Cornillet Jeannin, Martin
    Karolinska Univ Hosp, Sweden.
    Nyhlin, Nils
    Örebro Univ, Sweden.
    Martin, Harry
    Univ Coll Hosp NHS Fdn Trust, England.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Wiencke, Kristine
    Oslo Univ Hosp, Norway.
    Werner, Marten
    Umeå Univ, Sweden.
    Beretta-Piccoli, Benedetta Terziroli
    Univ Svizzera Italiana, Switzerland.
    Marzioni, Marco
    Univ Politecn Marche, Italy.
    Isoniemi, Helena
    Helsinki Univ Hosp, Finland.
    Arola, Johanna
    Univ Helsinki, Finland.
    Wefer, Agnes
    Karolinska Univ Hosp, Sweden.
    Soderling, Jonas
    Karolinska Inst, Sweden.
    Farkkila, Martti
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Lenzen, Henrike
    Hannover Med Sch, Germany; European Reference Network Hepatol Dis, Hannover, Germany; Univ Duisburg, Univ Hosp Essen, Germany.
    The International PSC Study Group,
    Impact on follow-up strategies in patients with primary sclerosing cholangitis2023In: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 43, no 1, p. 127-138Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival.

    Methods: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality.

    Results: A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed.

    Conclusions: Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures.

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  • 17.
    Bergram, Martin
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Iredahl, Fredrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Åby.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Rådholm, Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Kärna.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Low awareness of non-alcoholic fatty liver disease in patients with type 2 diabetes in Swedish Primary Health Care2022In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 57, no 1, p. 60-69Article in journal (Refereed)
    Abstract [en]

    Objectives Non-alcoholic fatty liver disease (NAFLD) is more common in patients with type 2 diabetes mellitus (T2DM) compared to individuals without. Recent guidelines recommend screening for NAFLD in patients with T2DM. Our aim was to investigate the prevalence of NAFLD in patients with T2DM in a Swedish primary health care setting, how they are cared for and assess the risk of biochemical signs of advanced fibrosis. Material and methods In this cohort study, patients with T2DM from five primary health care centers were included. Medical records were retrospectively reviewed and living habits, medical history, results of diagnostic imaging and anthropometric and biochemical features were noted in a standardized form. The risk of steatosis and advanced fibrosis was assessed using commonly used algorithms (FLI, HSI, NAFLD-LFS, NAFLD ridge score, FIB-4 and NFS). Results In total 350 patients were included. Diagnostic imaging had been performed in 132 patients and of these, 34 (26%) had steatosis, which was not noted in the medical records in 16 (47%) patients. One patient with steatosis had been referred to a hepatologist. Of assessable patients, 71-97% had a high to intermediate risk of steatosis and 29-65% had an intermediate to high risk of advanced fibrosis according to the algorithms used. Conclusion This study indicates a high prevalence of NAFLD among T2DM patients in Swedish primary care. Patients with known NAFLD were followed up to a very low extent. Using fibrosis algorithms in primary health care would result in many patients needing further assessment in secondary care.

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  • 18.
    Biskou, Olga
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Meira de Faria, Felipe
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Walter, Susanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Tinnerfelt Winberg, Martin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Haapaniemi, Staffan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Myrelid, Pär
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Söderholm, Johan D
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Keita, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Increased Numbers of Enteric Glial Cells in the Peyers Patches and Enhanced Intestinal Permeability by Glial Cell Mediators in Patients with Ileal Crohns Disease2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 3, article id 335Article in journal (Refereed)
    Abstract [en]

    Enteric glial cells (EGC) are known to regulate gastrointestinal functions; however, their role in Crohns disease (CD) is elusive. Microscopic erosions over the ileal Peyers patches are early signs of CD. The aim of this work was to assess the localization of EGC in the follicle and interfollicular region of the Peyers patches and in the lamina propria and study the effects of EGC mediators on barrier function in CD patients and non-inflammatory bowel disease (non-IBD) controls. EGC markers, glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β) were quantified by immunofluorescence and Western blotting. Both markers showed significantly more EGC in the Peyers patches and lamina propria of CD patients compared to the non-IBD controls. In CD patients there were significantly more EGC in Peyers patches compared to lamina propria, while the opposite pattern was seen in controls. Barrier function studies using Ussing chambers showed increased paracellular permeability by EGC mediators in CD patients, whereas permeability decreased by the mediators in controls. We show the accumulation of EGC in Peyers patches of CD patients. Moreover, EGC mediators induced barrier dysfunction in CD patients. Thus, EGC might have harmful impacts on ongoing inflammation and contribute to the pathophysiology of the disease.

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  • 19.
    Bjorlykke, Kristin H.
    et al.
    Akershus Univ Hosp, Norway; Univ Oslo, Norway.
    Jahnsen, Jorgen
    Akershus Univ Hosp, Norway; Univ Oslo, Norway.
    Brynskov, Jorn
    Herlev Hosp, Denmark.
    Molander, Pauliina
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Eberhardson, Michael
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Karolinska Inst, Sweden.
    Davidsdottir, Loa G.
    Univ Hosp Iceland, Iceland.
    Sipponen, Taina
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Hjortswang, Henrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Karolinska Inst, Sweden.
    Goll, Guro Lovik
    Diakonhjemmet Hosp, Norway.
    Syversen, Silje Watterdal
    Diakonhjemmet Hosp, Norway.
    Langholz, Ebbe
    Herlev Hosp, Denmark; Univ Copenhagen, Denmark.
    Jorgensen, Kristin K.
    Akershus Univ Hosp, Norway.
    Steenholdt, Casper
    Herlev Hosp, Denmark.
    Therapeutic drug monitoring in inflammatory bowel disease: implementation, utilization, and barriers in clinical practice in Scandinavia2023In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 58, no 1, p. 25-33Article in journal (Refereed)
    Abstract [en]

    Background and aims Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. Methods A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. Results In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors &gt;90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01-0.09], p &lt; 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p &lt; 0.001), and by physicians managing &gt;10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. Conclusion TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.

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  • 20. Order onlineBuy this publication >>
    Blomdahl, Julia
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Non-Alcoholic Fatty Liver Disease: Insights into Alcohol Consumption, Genetics, and Proteomics2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    NAFLD (Non-Alcoholic Fatty Liver Disease) affects approximately a quarter of the global population and is closely linked to type 2 diabetes mellitus and obesity. The disease spectrum ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular cancer. However, accurately predicting which patients will experience a progressive disease course remains a significant challenge. The variant gene of PNPLA3 is known to be associated with NAFLD and a more progressive disease, although its precise function remains unclear.   

    Patients with NAFLD typically consume small to moderate amounts of alcohol, with recommended thresholds set at a maximum of 210 gram per week for males and 140 grams per week in females. However, the impact of alcohol consumption on liver disease in NAFLD remains disputed, with conflicting research findings.   

    Liver biopsy is considered the gold standard for diagnosing NAFLD. However, due to its impracticality for such a large population with the condition, various non-invasive methods have been explored for diagnosing and evaluating NAFLD.  

    This thesis aimed to investigate the potential effects of moderate alcohol consumption on NAFLD histology, explore the potential role of variant PNPLA3 in NAFLD, and assess the use of proteomics in classifying fibrosis.  

    In Papers I and II, moderate alcohol consumption was assessed through questionnaires, clinical interviews, and measurement of the direct alcohol biomarker phosphatidylethanol (PEth). Paper I, a cross-sectional study including 86 participants, showed an association between moderate consumption and advanced fibrosis. Moderate consumption was defined as consuming more than 66 grams of ethanol per week or a PEth-value over 50 ng/mL. Notably, individuals with both moderate alcohol consumption and a diagnosis of type 2 diabetes exhibited significantly more advanced fibrosis. Paper II was a cohort study where 82 participants were followed over 17.2 years. Similarly, participants with moderate alcohol consumption displayed significant fibrosis progression. The strongest association was observed in participants with PEth-value of 48 ng/mL or higher, or those with binge drinking.  

    In Paper III, the potential role of variant PNPLA3 was explored, exhibiting impaired autophagic flux and reduced lipophagy in variant PNPLA3 cells. Liver biopsies of NAFLD individuals with variant PNPLA3 displayed an accumulation of lipid droplets positive for both PNPLA3 and LC3 (a common marker of the autophagosome). This suggests that PNPLA3 is part of the lipophagy process, which is impaired in the variant gene and contributes to steatosis.  

    Paper IV examined two independent NAFLD cohorts. In the discovery cohort, 60 participants with biopsy-proven NAFLD were included, while 59 participants were included in the validation cohort. The study evaluated 266 proteins and found that a biomarker model combining ACE2, HGF, and IGFBP-7 distinguished between different fibrosis stages (F0–1 and F2–4) in both cohorts.  

    In summary, measuring phosphatidylethanol is advisable in NAFLD patient evaluations. Elevated PEth-levels (≥48 ng/mL) or alcohol consumption exceeding 66 grams per week should warrant advice to abstain from alcohol. PNPLA3 is implicated in NAFLD pathophysiology, potentially through impaired lipophagy. While its clinical application remains uncertain, genetic profiling for NAFLD risk assessment may become part of future non-invasive approaches. Additionally, proteomics holds promise for non-invasive NAFLD assessment, with the combination of ACE2, HGF, and IGFBP-7 identifying significant fibrosis in two separate cohorts. 

    List of papers
    1. Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus
    Open this publication in new window or tab >>Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus
    2021 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 115, article id 154439Article in journal (Refereed) Published
    Abstract [en]

    Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Whether moderate alcohol consumption plays a role for progression of NAFLD is disputed. Moreover, it is not known which tool is ideal for assessment of alcohol consumption in NAFLD. This study aimed to evaluate if moderate alcohol consumption assessed with different methods, including the biological marker phosphatidylethanol (PEth), is associated with advanced fibrosis in NAFLD. Methods: We conducted a cross-sectional study of patients with biopsy-proven NAFLD. All participants were clinically evaluated with medical history, blood tests, and anthropometric measurements. Alcohol consumption was assessed using PEth in blood, the questionnaire AUDIT-C, and clinical interview. Findings: 86 patients were included of which 17% had advanced fibrosis. All participants reported alcohol consumption &lt; 140 g/week. Average weekly alcohol consumption was higher in the group with advanced fibrosis. Moderate alcohol consumption, independently of the method of assessment, was associated with increased probability of advanced fibrosis (adjusted OR 5.5-9.7, 95% CI 1.05-69.6). Patients with type 2 diabetes mellitus (T2DM) consuming moderate amounts of alcohol had a significantly higher rate of advanced fibrosis compared with those consuming low amounts (50.0-60.0% vs. 33-21.6%, p &lt; 0.05). Conclusions: Moderate alcohol consumption, irrespective of assessment method (clinical interview, AUDIT-C, and PEth), was associated with advanced fibrosis. PEth in blood &gt;= 50 ng/mL may be a biological marker indicating increased risk for advanced fibrosis in NAFLD. Patients with T2DM consuming moderate amounts of alcohol had the highest risk of advanced fibrosis, indicating a synergistic effect of insulin resistance and alcohol on the histopathological progression of NAFLD. (C) 2020 The Author(s). Published by Elsevier Inc.

    Place, publisher, year, edition, pages
    Elsevier, 2021
    Keywords
    Non-alcoholic fatty liver disease; Alcohol drinking; Type 2 diabetes mellitus; Phosphatidylethanol
    National Category
    Surgery
    Identifiers
    urn:nbn:se:liu:diva-173399 (URN)10.1016/j.metabol.2020.154439 (DOI)000608790700005 ()33246008 (PubMedID)2-s2.0-85097192291 (Scopus ID)
    Note

    Funding Agencies|Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC)

    Available from: 2021-02-20 Created: 2021-02-20 Last updated: 2023-10-23Bibliographically approved
    2. Moderate alcohol consumption is associated with significant fibrosis progression in NAFLD
    Open this publication in new window or tab >>Moderate alcohol consumption is associated with significant fibrosis progression in NAFLD
    2023 (English)In: HEPATOLOGY COMMUNICATIONS, ISSN 2471-254X, Vol. 7, no 1Article in journal (Refereed) Published
    Abstract [en]

    The effect of moderate alcohol consumption on NAFLD histology is disputed. Assessment of alcohol consumption is commonly performed with interview or questionnaires. Phosphatidylethanol (PEth) in blood is a highly sensitive and specific alcohol biomarker, which only forms in the presence of ethanol. PEth has hitherto not been evaluated in longitudinal NAFLD studies. This study aimed to examine the impact of moderate alcohol consumption on histologic progression and evaluate the utility of PEth in NAFLD. NAFLD patients with serial biopsies were reviewed for inclusion in the study. At baseline, all patients reported alcohol consumption &lt;140 g/week. Anthropometric and biochemical measurements were performed at baseline and follow-up. Alcohol consumption was assessed thoroughly at follow-up with clinical interview, the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) questionnaire, and analysis of PEth in whole blood. Eighty-two patients were included. Mean follow-up time was 17.2 years (SD & PLUSMN;6.0). Patients with significant fibrosis progression (defined as progression of & GE;2 stages or development of cirrhosis-related complications) reported higher alcohol consumption and had significantly higher PEth. Consumption &gt;66-96 g/week (but &lt;140 g) (i.e. moderate alcohol consumption) was associated with increased risk of significant fibrosis progression compared with no or low consumption. PEth & GE;48 ng/mL and binge drinking showed the highest risk for significant fibrosis progression (aOR: 5.9; 95% CI: 1.6-21.4) and aOR: 5.1; 95% CI: 1.4-18.1, respectively). NAFLD patients consuming moderate amounts of alcohol are at increased risk for significant fibrosis progression and development of cirrhosis-related complications. PEth is a potential biomarker to assess harmful alcohol consumption in NAFLD. Patients reporting moderate consumption or exhibiting PEth & GE;48 ng/mL should be advised to reduce alcohol consumption.

    Place, publisher, year, edition, pages
    LIPPINCOTT WILLIAMS & WILKINS, 2023
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-197483 (URN)10.1097/HC9.0000000000000003 (DOI)001038261400003 ()36633482 (PubMedID)
    Note

    Funding Agencies|~ALF Grants; Region Ostergoetland; Medical Research Council of Southeast Sweden [752871]

    Available from: 2023-09-12 Created: 2023-09-12 Last updated: 2024-02-08
    3. PNPLA3 variant M148 causes resistance to starvation-mediated lipid droplet autophagy in human hepatocytes
    Open this publication in new window or tab >>PNPLA3 variant M148 causes resistance to starvation-mediated lipid droplet autophagy in human hepatocytes
    Show others...
    2019 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 120, no 1, p. 343-356Article in journal (Refereed) Published
    Abstract [en]

    The mechanism of how patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant M148 is associated with increased risk of development of hepatic steatosis is still debated. Here, we propose a novel role of PNPLA3 as a key player during autophagosome formation in the process of lipophagy. A human hepatocyte cell line, HepG2 cells, expressing recombinant I148 or 148M, was used to study lipophagy under energy deprived conditions, and lipid droplet morphology was investigated using florescence microscopy, image analysis and biochemical assays. Autophagic flux was studied using the golden-standard of LC3-II turnover in combination with the well characterized GFP-RFP-LC3 vector. To discriminate between, perturbed autophagic initiation and lysosome functionality, lysosomes were characterized by Lysotracker staining and LAMP1 protein levels as well as activity and activation of cathepsin B. For validation, human liver biopsies genotyped for I148 and 148M were analyzed for the presence of LC3-II and PNPLA3 on lipid droplets. We show that the M148-PNPLA3 variant is associated with lipid droplets that are resistant to starvation-mediated degradation. M148 expressing hepatocytes reveal decreased autophagic flux and reduced lipophagy. Both I148-PNPLA3 and M148-PNPLA3 colocalize and interact with LC3-II, but the M148-PNPLA3 variant has lower ability to bind LC3-II. Together, our data indicate that PNPLA3 might play an essential role in lipophagy in hepatocytes and furthermore that the M148-PNPLA3 variant appears to display a loss in this activity, leading to decreased lipophagy.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2019
    Keywords
    adiponutrin; lipophagy; liver; steatosis
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:liu:diva-153347 (URN)10.1002/jcb.27378 (DOI)000450823500032 ()30171718 (PubMedID)2-s2.0-85052837166 (Scopus ID)
    Note

    Funding Agencies|Swedish Research Foundation [11284]; Crafoord Foundation; Swedish Diabetes Foundation; Albert Pahlsson Foundation; Dr Per Hakansson Foundation

    Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2023-10-23Bibliographically approved
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  • 21.
    Blomdahl, Julia
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus2021In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 115, article id 154439Article in journal (Refereed)
    Abstract [en]

    Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Whether moderate alcohol consumption plays a role for progression of NAFLD is disputed. Moreover, it is not known which tool is ideal for assessment of alcohol consumption in NAFLD. This study aimed to evaluate if moderate alcohol consumption assessed with different methods, including the biological marker phosphatidylethanol (PEth), is associated with advanced fibrosis in NAFLD. Methods: We conducted a cross-sectional study of patients with biopsy-proven NAFLD. All participants were clinically evaluated with medical history, blood tests, and anthropometric measurements. Alcohol consumption was assessed using PEth in blood, the questionnaire AUDIT-C, and clinical interview. Findings: 86 patients were included of which 17% had advanced fibrosis. All participants reported alcohol consumption &lt; 140 g/week. Average weekly alcohol consumption was higher in the group with advanced fibrosis. Moderate alcohol consumption, independently of the method of assessment, was associated with increased probability of advanced fibrosis (adjusted OR 5.5-9.7, 95% CI 1.05-69.6). Patients with type 2 diabetes mellitus (T2DM) consuming moderate amounts of alcohol had a significantly higher rate of advanced fibrosis compared with those consuming low amounts (50.0-60.0% vs. 33-21.6%, p &lt; 0.05). Conclusions: Moderate alcohol consumption, irrespective of assessment method (clinical interview, AUDIT-C, and PEth), was associated with advanced fibrosis. PEth in blood &gt;= 50 ng/mL may be a biological marker indicating increased risk for advanced fibrosis in NAFLD. Patients with T2DM consuming moderate amounts of alcohol had the highest risk of advanced fibrosis, indicating a synergistic effect of insulin resistance and alcohol on the histopathological progression of NAFLD. (C) 2020 The Author(s). Published by Elsevier Inc.

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  • 22.
    Blomdahl, Julia
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Moderate alcohol consumption is associated with significant fibrosis progression in NAFLD2023In: HEPATOLOGY COMMUNICATIONS, ISSN 2471-254X, Vol. 7, no 1Article in journal (Refereed)
    Abstract [en]

    The effect of moderate alcohol consumption on NAFLD histology is disputed. Assessment of alcohol consumption is commonly performed with interview or questionnaires. Phosphatidylethanol (PEth) in blood is a highly sensitive and specific alcohol biomarker, which only forms in the presence of ethanol. PEth has hitherto not been evaluated in longitudinal NAFLD studies. This study aimed to examine the impact of moderate alcohol consumption on histologic progression and evaluate the utility of PEth in NAFLD. NAFLD patients with serial biopsies were reviewed for inclusion in the study. At baseline, all patients reported alcohol consumption &lt;140 g/week. Anthropometric and biochemical measurements were performed at baseline and follow-up. Alcohol consumption was assessed thoroughly at follow-up with clinical interview, the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) questionnaire, and analysis of PEth in whole blood. Eighty-two patients were included. Mean follow-up time was 17.2 years (SD & PLUSMN;6.0). Patients with significant fibrosis progression (defined as progression of & GE;2 stages or development of cirrhosis-related complications) reported higher alcohol consumption and had significantly higher PEth. Consumption &gt;66-96 g/week (but &lt;140 g) (i.e. moderate alcohol consumption) was associated with increased risk of significant fibrosis progression compared with no or low consumption. PEth & GE;48 ng/mL and binge drinking showed the highest risk for significant fibrosis progression (aOR: 5.9; 95% CI: 1.6-21.4) and aOR: 5.1; 95% CI: 1.4-18.1, respectively). NAFLD patients consuming moderate amounts of alcohol are at increased risk for significant fibrosis progression and development of cirrhosis-related complications. PEth is a potential biomarker to assess harmful alcohol consumption in NAFLD. Patients reporting moderate consumption or exhibiting PEth & GE;48 ng/mL should be advised to reduce alcohol consumption.

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  • 23.
    Bonfiglio, Ferdinando
    et al.
    School of Biological Sciences, Monash University, Clayton, VIC, Australia; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Liu, Xingrong
    Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Smillie, Christopher
    Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
    Pandit, Anita
    Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA.
    Kurilshikov, Alexander
    Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
    Bacigalupe, Rodrigo
    Department of Microbiology and Immunology, Rega Instituut, KU Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven 3000, Belgium.
    Zheng, Tenghao
    School of Biological Sciences, Monash University, Clayton, VIC, Australia; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Nim, Hieu
    School of Biological Sciences, Monash University, Clayton, VIC, Australia.
    Garcia-Etxebarria, Koldo
    Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastian, Spain.
    Bujanda, Luis
    Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastian, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Universidad del País Vasco (UPV/EHU), San Sebastian, Spain.
    Andreasson, Anna
    Division of Clinical Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Agreus, Lars
    Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Walter, Susanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Abecasis, Gonçalo
    Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA.
    Eijsbouts, Chris
    Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
    Jostins, Luke
    Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK; Christ Church, University of Oxford, Oxford, UK.
    Parkes, Miles
    Division of Gastroenterology, Department of Medicine, University of Cambridge, Cambridge, UK.
    Hughes, David A
    MRC Integrative Epidemiology Unit at University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
    Timpson, Nicholas
    MRC Integrative Epidemiology Unit at University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
    Raes, Jeroen
    Department of Microbiology and Immunology, Rega Instituut, KU Leuven, Leuven, Belgium; Center for Microbiology, VIB, Leuven 3000, Belgium.
    Franke, Andre
    Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
    Kennedy, Nicholas A
    IBD Pharmacogenetics, College of Medicine and Health, University of Exeter, Exeter, UK.
    Regev, Aviv
    Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA.
    Zhernakova, Alexandra
    Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
    Simren, Magnus
    Dept of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Camilleri, Michael
    Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
    DAmato, Mauro
    School of Biological Sciences, Monash University, Clayton, VIC, Australia; Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.
    GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome2021In: Cell Genomics, E-ISSN 2666-979X, Vol. 1, no 3, article id 100069Article in journal (Refereed)
    Abstract [en]

    Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p = 5.0 × 10-8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.

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  • 24.
    Boursier, Jerome
    et al.
    Ctr Hosp Univ Angers, France; Univ Angers, France.
    Hagstrom, Hannes
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Moreau, Clemence
    Univ Angers, France.
    Bonacci, Martin
    Intercept Pharmaceut, England; Intercept Pharmaceut Inc, NY USA.
    Cure, Sandrine
    Intercept Pharmaceut, England; Intercept Pharmaceut Inc, NY USA.
    Ampuero, Javier
    Univ Seville, Spain.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Tallab, Lilian
    Karolinska Inst, Sweden.
    Canivet, Clemence M.
    Ctr Hosp Univ Angers, France; Univ Angers, France.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Sanchez, Yolanda
    Univ Seville, Spain.
    Dincuff, Eloise
    Ctr Hosp Univ Angers, France.
    Lucena, Ana
    Univ Seville, Spain.
    Roux, Marine
    Univ Angers, France.
    Riou, Jeremie
    Univ Angers, France.
    Trylesinski, Aldo
    Intercept Pharmaceut, England; Intercept Pharmaceut Inc, NY USA.
    Romero-Gomez, Manuel
    Univ Seville, Spain.
    Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events2022In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 76, no 5, p. 1013-1020Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD. Methods: A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort. Of these patients, 594 also had a baseline liver biopsy. The main study outcome during follow-up was occurrence of LREs, a composite endpoint combining cirrhosis complications and/or hepatocellular carcinoma. Discriminative ability was evaluated using Harrells C-index. Results: FIB4 and VCTE showed good accuracy for the prediction of LREs, with Harrells C-indexes &gt;0.80 (0.817 [0.768-0.866] vs. 0.878 [0.835-0.921], respectively, p = 0.059). In the biopsy subgroup, Harrells C-indexes of histological fibrosis staging and VCTE were not significantly different (0.932 [0.910-0.955] vs. 0.881 [0.832-0.931], respectively, p = 0.164), while both significantly outperformed FIB4 for the prediction of LREs. FIB4 and VCTE were independent predictors of LREs in the whole study cohort. The stepwise FIB4-VCTE algorithm accurately stratified the risk of LREs: compared to patients with "FIB4 &lt;1.30", those with "FIB4 &gt;- 1.30 then VCTE &lt;8.0 kPa" had similar risk of LREs (adjusted hazard ratio [aHR] 1.3; 95% CI 0.3-6.8), whereas the risk of LREs significantly increased in patients with "FIB4 &gt;1.30 then VCTE 8.0-12.0 kPa" (aHR 3.8; 95% CI 1.3-10.9), and even more for those with "FIB4 &gt;-1.30 then VCTE &gt;12.0 kPa" (aHR 12.4; 95% CI 5.1- 30.2). Conclusion: VCTE and FIB4 accurately stratify patients with NAFLD based on their risk of LREs. These non-invasive tests are alternatives to liver biopsy for the identification of patients in need of specialized management. Lay summary: The amount of fibrosis in the liver is closely associated with the risk of liver-related complications in nonalcoholic fatty liver disease (NAFLD). Liver biopsy currently remains the reference standard for the evaluation of fibrosis, but its application is limited by its invasiveness. Therefore, we evaluated the ability of non-invasive liver fibrosis tests to predict liver-related complications in NAFLD. Our results show that the blood test FIB4 and transient elastography stratify the risk of liver-related complications in NAFLD, and that transient elastography has similar prognostic accuracy as liver biopsy. These results support the use of non-invasive liver fibrosis tests instead of liver biopsy for the management of patients with NAFLD.(C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  • 25.
    Bureychak, Tetyana
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Olsen Faresjö, Åshild
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Sjödahl, Jenny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Norlin, Anna-Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Mantorp.
    Walter, Susanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Symptoms and health experience in irritable bowel syndrome with focus on men2022In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 34, no 11, article id e14430Article in journal (Refereed)
    Abstract [en]

    Background Irritable bowel syndrome (IBS) is a disorder with a predominance in women; IBS in men is less studied. The present study evaluated symptoms as well as health and social experiences of men with IBS. Methods This cross-sectional study included 293 patients with IBS (64 men) and 363 non-IBS controls (62 men). Gastrointestinal symptom diaries were filled in prospectively, and data on comorbidities and healthcare-seeking behavior were assessed by questionnaires. Men with IBS were compared with men without IBS and women with IBS. Key results Compared with women with IBS, men with IBS had fewer contacts with the healthcare system, fewer psychiatric comorbidities, fewer sleeping problems, and less chronic pain. Urgency to defecate and nausea were less common, and stool frequency was higher in men with IBS. There was no difference between men with and without IBS in terms of educational level, satisfaction with household economy, or living with a partner. In contrast, women with IBS more often lived alone, were more often dissatisfied with household economy, and had a lower educational level than women without IBS. Men with IBS had the same proportion of full-time employment as men without IBS but in contrast, the proportion of women with IBS in full-time employment was only 34%, compared to 50% of the women without IBS. Conclusion and inferences The present study improves the understanding of mens experiences of IBS and suggests that sex and gender may be integrated into the biopsychosocial model of IBS.

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  • 26.
    Caravaca, April S.
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden; SetPoint Med Inc, CA 91355 USA.
    Levine, Yaakov A.
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden; SetPoint Med Inc, CA 91355 USA; Feinstein Inst Med Res, NY 11030 USA.
    Drake, Anna
    SetPoint Med Inc, CA 91355 USA.
    Eberhardson, Michael
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden.
    Olofsson, Peder S.
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden; Feinstein Inst Med Res, NY 11030 USA.
    Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation2022In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 15, article id 730407Article in journal (Refereed)
    Abstract [en]

    Crohns disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean +/- SEM) sham: 124 +/- 14 mm(2), VNS: 62 +/- 14 mm(2), p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.

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  • 27.
    Casado Bedmar, Maria Teresa
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Meira de Faria, Felipe
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Biskou, Olga
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Lindqvist, Carl Mårten
    Orebro Univ, Sweden.
    Ranasinghe, Purnika Damindi
    Queens Univ Belfast, North Ireland.
    Bednarska, Olga
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Peterson, Christer
    Uppsala Univ, Sweden; Diagnost Dev, Sweden.
    Walter, Susanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Carlson, Marie
    Uppsala Univ, Sweden.
    Keita, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Elevated F-EDN correlates with mucosal eosinophil degranulation in patients with IBS - A possible association with microbiota?2022In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 111, no 3, p. 655-665Article in journal (Refereed)
    Abstract [en]

    Eosinophils have been linked to functional dyspepsia; however, less is known about their role in irritable bowel syndrome (IBS). This study tested the hypothesis of alterations in levels of fecal eosinophil-derived neurotoxin (F-EDN) and eosinophil density and degranulation within the colonic mucosa of IBS patients compared with healthy controls (HC). Colonic biopsies were collected from 37 IBS patients and 20 HC and analyzed for eosinophil numbers and local degranulation of eosinophil cationic protein (ECP) by histologic procedures. Fecal samples were collected for F-EDN and microbiota analysis. Differentiated 15HL-60 cells were used in vitro to investigate the direct effect of live bacteria on eosinophil activation measured by a colorimetric assay with o-phenylenediamine (OPD) substrate. We observed a higher number of eosinophils and increased extracellular ECP in the mucosa of IBS patients compared with HC. Moreover, F-EDN levels in IBS samples were elevated compared with HC and positively correlated to extracellular ECP. Metagenomic analysis showed significant correlations between bacterial composition and eosinophil measurements in both HC and IBS patients. In vitro experiments revealed an increased degranulation of 15HL-60 after stimulation with Salmonella typhimurium, Salmonella enterica, and Yersinia enterocolitica. To conclude, we could demonstrate alterations related to eosinophils in IBS, and, for the first time, a positive correlation between F-EDN levels and degranulated eosinophils in the colonic mucosa of IBS patients. Together our results suggest that eosinophils play a role in the pathophysiology of IBS and the mechanisms might be linked to an altered microbiota.

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  • 28.
    Daferera, Niki
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Escudero-Hernandez, Celia
    Univ Kiel, Germany; Univ Hosp Schleswig Holstein, Germany.
    Nyström, Sofia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Hjortswang, Henrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Ignatova, Simone
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Ström, Magnus
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Münch, Andreas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Collagenous Colitis Mucosa Is Characterized by an Expansion of Nonsuppressive FoxP3(+) T Helper Cells2021In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 27, no 9, p. 1482-1490Article in journal (Refereed)
    Abstract [en]

    Background and Aim: Increased frequencies of T regulatory (Treg) cells, key players in immune regulation, have been reported in inflammatory bowel diseases, including collagenous colitis (CC). However, traditional Treg identification techniques might have misinterpreted the frequencies of Treg cells in CC. Thus, we investigated the presence of genuine Treg cells in CC. Methods: Treg cells were analyzed in mucosal and peripheral blood samples of CC patients before and during treatment with the corticosteroid drug budesonide and in healthy controls. Samples were analyzed by flow cytometry by classifying CD3(+) CD4(+) cells as activated FoxP3(high)CD45RA. Treg cells, resting FoxP3(dim)CD45RA(+) Treg cells, and nonsuppressive FoxP3(dim)CD45RA-T helper cells. Traditional gating strategies that classified Treg cells as CD25(high)CD127(lo)(w), FoxP3(+)CD127(low), and CD4(+)CD25(+)FoxP3(+) were also used to facilitate comparison with previous studies. Results: Activated and resting Treg cell frequencies did not change in active CC mucosa or peripheral blood and were not affected by budesonide treatment. Instead, nonsuppressive FoxP3(dim)CD45RA-T helper cells were increased in active CC mucosa, and budesonide helped restore them to normal levels. In contrast, traditional Treg cell gating strategies resulted in increased Treg cell frequencies in active CC mucosa. No alterations were found in peripheral blood samples, independently of patient treatment or gating techniques. Conclusion: Previously reported increase of Treg cells is a result of incomplete Treg phenotyping, which included nonsuppressive FoxP3(dim)CD45RA - T helper cells. Because budesonide did not affect Treg percentage, its therapeutic effect in CC might involve alternative mechanisms.

  • 29.
    Daferera, Niki
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Nyström, Sofia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hjortswang, Henrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Ignatova, Simone
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Ström, Magnus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Münch, Andreas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Mucosa associated invariant T and natural killer cells in active and budesonide treated collagenous colitis patients2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 981740Article in journal (Refereed)
    Abstract [en]

    IntroductionCollagenous colitis (CC) is an inflammatory bowel disease, which usually responds to budesonide treatment. Our aim was to study the immunological background of the disease. MethodsAnalyses of peripheral and mucosal MAIT (mucosa associated invariant T cells) and NK (natural killer) cells were performed with flow cytometry. Numbers of mucosal cells were calculated using immunohistochemistry. We studied the same patients with active untreated CC (au-CC) and again while in remission on budesonide treatment. Budesonide refractory patients and healthy controls were also included. The memory marker CD45R0 and activation marker CD154 and CD69 were used to further study the cells. Finally B cells, CD4(+) and CD8(+) T cells were also analysed. ResultsThe percentages of circulating CD56(dim)CD16(+) NK cells as well as MAIT cells (CD3(+)TCRVa7.2(+)CD161(+)) were decreased in au-CC compared to healthy controls. This difference was not seen in the mucosa; where we instead found increased numbers of mucosal CD4(+) T cells and CD8(+) T cells in au-CC. Mucosal immune cell numbers were not affected by budesonide treatment. In refractory CC we found increased mucosal numbers of MAIT cells, CD4(+) and CD8(+) T cells compared to au-CC. DiscussionPatients with active collagenous colitis have lower percentages of circulating MAIT and NK cells. However, there was no change of these cells in the colonic mucosa. Most mucosal cell populations were increased in budesonide refractory as compared to au-CC patients, particularly the number of MAIT cells. This may indicate that T cell targeting therapy could be an alternative in budesonide refractory CC.

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  • 30.
    Demmer, Sina
    et al.
    Heidelberg Univ, Germany.
    Kleindienst, Nikolaus
    Heidelberg Univ, Germany.
    Hjortswang, Henrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Thomann, Philipp
    Odenwald Dist Healthcare Ctr, Germany.
    Ebert, Matthias
    Heidelberg Univ, Germany.
    Reindl, Wolfgang
    Heidelberg Univ, Germany.
    Thomann, Anne
    Heidelberg Univ, Germany.
    Validation of the German version of the Short Health Scale - a brief, valid and reliable instrument to assess health-related quality of life in German-speaking patients with inflammatory bowel diseases2023In: Zeitschrift für Gastroenterologie - German Journal of Gastroenterology, ISSN 0044-2771, E-ISSN 1439-7803, Vol. 61, no 09, p. 1207-1213Article in journal (Refereed)
    Abstract [en]

    Background Health-related quality of life (hrQoL) may be the most important patient-reported outcome for patients with chronic disorders. The Short Health Scale (SHS) is a brief four-item instrument to assess hrQoL in patients with bowel disorders. This study examined the validity, reliability and sensitivity of the German translation of the SHS in a cohort of outpatients with inflammatory bowel diseases (IBD).Methods The study was preregistered in April 2021 ( https://doi.org/10.17605/OSF.IO/S82D9 ). Outpatients with IBD (n=225) in different stages of disease activity (as determined by the Harvey-Bradshaw index or partial Mayo score) completed the German SHS and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) as an established measure of hrQoL to examine the convergent validity. To assess reliability, a subset of patients (n=30) in remission completed the same questionnaires after 4-8 weeks. Sensitivity to change was established from questionnaires of patients with either decreased (n=15) or increased (n=16) disease activity after 3-6 months.Results The internal consistency of the German SHS was high (Cronbachs a=0.860). SHS total scores correlated strongly with sIBDQ scores (?=-0.760, p&lt;0.001) and disease activity (?=0.590, p&lt;0.001). Retest reliability was high (?=0.695, p&lt;0.001). Sensitivity to change was statistically significant for patients with decreased (p=0.013) but not increased (p=0.134) disease activity.Conclusion The German version of the SHS is a valid and reliable tool to measure hrQoL in persons with IBD.

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  • 31.
    Eberhardson, Michael
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Karolinska Inst, Sweden.
    Levine, Yaakov A.
    Karolinska Inst, Sweden; SetPoint Med, CA 91355 USA.
    Tarnawski, Laura
    Karolinska Inst, Sweden.
    Olofsson, Peder S.
    Karolinska Inst, Sweden; Feinstein Inst Med Res, NY USA.
    The brain-gut axis, inflammatory bowel disease and bioelectronic medicine2021In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 33, no 6, p. 349-356Article, review/survey (Refereed)
    Abstract [en]

    The hallmark of inflammatory bowel diseases (IBD) is chronic intestinal inflammation with typical onset in adolescents and young adults. An abundance of neutrophils is seen in the inflammatory lesions, but adaptive immunity is also an important player in the chronicity of the disease. There is an unmet need for new treatment options since modern medicines such as biological therapy with anti-cytokine antibodies still leave a substantial number of patients with persisting disease activity. The role of the central nervous system and its interaction with the gut in the pathophysiology of IBD have been brought to attention both in animal models and in humans after the discovery of the inflammatory reflex. The suggested control of gut immunity by the brain-gut axis represents a novel therapeutic target suitable for bioelectronic intervention. In this review, we discuss the role of the inflammatory reflex in gut inflammation and the recent advances in the treatment of IBD by intervening with the brain-gut axis through bioelectronic devices.

  • 32.
    Eberhardson, Michael
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Karolinska Inst, Sweden.
    Myrelid, Pär
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Söderling, Jonas K.
    Karolinska Inst, Sweden.
    Ekbom, Anders
    Karolinska Inst, Sweden.
    Everhov, Åsa H.
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Hedin, Charlotte R. H.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Neovius, Martin
    Karolinska Inst, Sweden.
    Ludvigsson, Jonas F.
    Karolinska Inst, Sweden; Orebro Univ Hosp, Sweden; Univ Nottingham, England; Columbia Univ Coll Phys & Surg, NY USA.
    Olén, Ola
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Tumour necrosis factor inhibitors in Crohns disease and the effect on surgery rates2022In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 24, no 4, p. 470-483Article in journal (Refereed)
    Abstract [en]

    Aim Surgery is an important therapeutic option for Crohns disease. The need for first bowel surgery seems to have decreased with the introduction of tumour necrosis factor inhibitors (TNFi; adalimumab or infliximab). However, the impact of TNFi on the need for intestinal surgery in Crohns disease patients irrespective of prior bowel resection is not known. The aim of this work is to compare the incidence of bowel surgery in Crohns disease patients who remain on TNFi treatment versus those who discontinue it. Method We performed a nationwide register-based observational cohort study in Sweden of all incident and prevalent cases of Crohns disease who started first-line TNFi treatment between 2006 and 2017. Patients were categorized according to TNFi treatment retention less than or beyond 1 year. The study cohort was evaluated with regard to incidence of bowel surgery from 12 months after the first ever TNFi dispensation. Results We identified 5003 Crohns disease patients with TNFi exposure: 3748 surgery naive and 1255 with bowel surgery prior to TNFi initiation. Of these patients, 7% (n = 353) were subjected to abdominal surgery during the first 12 months after the start of TNFi and were subsequently excluded from the main analysis. A majority (62%) continued TNFi for 12 months or more. Treatment with TNFi for less than 12 months was associated with a significantly higher surgery rate compared with patients who continued on TNFi for 12 months or more (hazard ratio 1.26, 95% CI 1.09-1.46; p = 0.002). Conclusion Treatment with TNFi for less than 12 months was associated with a higher risk of bowel surgery in Crohns disease patients compared with those who continued TNFi for 12 months or more.

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  • 33.
    Edin, Carl
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Scheffel, Tobias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Markus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics. AMRA Medical AB, Sweden.
    Swahn, Eva
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Östgren, Carl Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Primary Care Center, Primary Health Care Center Ekholmen.
    Engvall, Jan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Ebbers, Tino
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV). AMRA Medical AB, Sweden.
    Lundberg, Peter
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Carlhäll, Carl-Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Ectopic fat is associated with cardiac remodeling - A comprehensive assessment of regional fat depots in type 2 diabetes using multi-parametric MRI.2022In: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 9, article id 813427Article in journal (Refereed)
    Abstract [en]

    Background: Different regional depots of fat have distinct metabolic properties and may relate differently to adverse cardiac remodeling. We sought to quantify regional depots of body fat and to investigate their relationship to cardiac structure and function in Type 2 Diabetes (T2D) and controls.

    Methods: From the SCAPIS cohort in Linköping, Sweden, we recruited 92 subjects (35% female, mean age 59.5 ± 4.6 years): 46 with T2D and 46 matched controls. In addition to the core SCAPIS data collection, participants underwent a comprehensive magnetic resonance imaging examination at 1.5 T for assessment of left ventricular (LV) structure and function (end-diastolic volume, mass, concentricity, ejection fraction), as well as regional body composition (liver proton density fat fraction, visceral adipose tissue, abdominal subcutaneous adipose tissue, thigh muscle fat infiltration, fat tissue-free thigh muscle volume and epicardial adipose tissue).

    Results: Compared to the control group, the T2D group had increased: visceral adipose tissue volume index (P < 0.001), liver fat percentage (P < 0.001), thigh muscle fat infiltration percentage (P = 0.02), LV concentricity (P < 0.001) and LV E/e'-ratio (P < 0.001). In a multiple linear regression analysis, a negative association between liver fat percentage and LV mass (St Beta -0.23, P < 0.05) as well as LV end-diastolic volume (St Beta -0.27, P < 0.05) was found. Epicardial adipose tissue volume and abdominal subcutaneous adipose tissue volume index were the only parameters of fat associated with LV diastolic dysfunction (E/e'-ratio) (St Beta 0.24, P < 0.05; St Beta 0.34, P < 0.01, respectively). In a multivariate logistic regression analysis, only visceral adipose tissue volume index was significantly associated with T2D, with an odds ratio for T2D of 3.01 (95% CI 1.28-7.05, P < 0.05) per L/m2 increase in visceral adipose tissue volume.

    Conclusions: Ectopic fat is predominantly associated with cardiac remodeling, independently of type 2 diabetes. Intriguingly, liver fat appears to be related to LV structure independently of VAT, while epicardial fat is linked to impaired LV diastolic function. Visceral fat is associated with T2D independently of liver fat and abdominal subcutaneous adipose tissue.

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  • 34.
    Ericson, Elke
    et al.
    AstraZeneca, Sweden.
    Bergenholm, Linnea
    AstraZeneca, Sweden.
    Andreasson, Anne-Christine
    AstraZeneca, Sweden.
    Dix, Carly I
    AstraZeneca, England.
    Knöchel, Jane
    AstraZeneca, Sweden.
    Hansson, Sara F.
    AstraZeneca, Sweden.
    Lee, Richard
    Ionis Pharmaceut, CA USA; Verve Therapeut, MA USA.
    Schumi, Jennifer
    AstraZeneca, MD USA.
    Antonsson, Madeleine
    AstraZeneca, Sweden.
    Fjellström, Ola
    AstraZeneca, Sweden.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Liljeblad, Mathias
    AstraZeneca, Sweden.
    Carlsson, Björn
    AstraZeneca, Sweden.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Linden, Daniel
    AstraZeneca, Sweden; Univ Gothenburg, Sweden.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Hepatic patatin-like phospholipase domain-containing 3 levels are increased in I148M risk allele carriers and correlate with NAFLD in humans2022In: Hepatology Communications, ISSN 2471-254X, Vol. 6, no 10, p. 2689-2701Article in journal (Refereed)
    Abstract [en]

    In nonalcoholic fatty liver disease (NAFLD) the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant is a contributor. In mice, the Pnpla3 148M variant accumulates on lipid droplets and probably leads to sequestration of a lipase cofactor leading to impaired mobilization of triglycerides. To advance our understanding of the localization and abundance of PNPLA3 protein in humans, we used liver biopsies from patients with NAFLD to investigate the link to NAFLD and the PNPLA3 148M genotype. We experimentally qualified an antibody against human PNPLA3. Hepatic PNPLA3 protein fractional area and localization were determined by immunohistochemistry in biopsies from a well-characterized NAFLD cohort of 67 patients. Potential differences in hepatic PNPLA3 protein levels among patients related to degree of steatosis, lobular inflammation, ballooning, and fibrosis, and PNPLA3 I148M gene variants were assessed. Immunohistochemistry staining in biopsies from patients with NAFLD showed that hepatic PNPLA3 protein was predominantly localized to the membranes of small and large lipid droplets in hepatocytes. PNPLA3 protein levels correlated strongly with steatosis grade (p = 0.000027) and were also significantly higher in patients with lobular inflammation (p = 0.009), ballooning (p = 0.022), and significant fibrosis (stage 2-4, p = 0.014). In addition, PNPLA3 levels were higher in PNPLA3 rs738409 148M (CG, GG) risk allele carriers compared to 148I (CC) nonrisk allele carriers (p = 0.0029). Conclusion: PNPLA3 protein levels were associated with increased hepatic lipid content and disease severity in patients with NAFLD and were higher in PNPLA3 rs738409 (148M) risk allele carriers. Our hypothesis that increased hepatic levels of PNPLA3 may be part of the pathophysiological mechanism of NAFLD is supported.

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  • 35.
    Eriksson, Carl
    et al.
    Orebro Univ, Sweden; Karolinska Inst, Sweden.
    Rundquist, Sara
    Orebro Univ, Sweden.
    Lykiardopoulos, Vyron
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Udumyan, Ruzan
    Orebro Univ, Sweden.
    Karlen, Per
    Danderyd Hosp, Sweden.
    Grip, Olof
    Skane Univ Hosp, Sweden.
    Soderman, Charlotte
    St Goran Hosp, Sweden.
    Almer, Sven
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hertervig, Erik
    Skane Univ Hosp, Sweden.
    Marsal, Jan
    Skane Univ Hosp, Sweden.
    Gunnarsson, Jenny
    Kungalv Hosp, Sweden.
    Malmgren, Carolina
    Takeda Pharma AB, Sweden.
    Delin, Jenny
    Ersta Hosp, Sweden.
    Strid, Hans
    Sodra Alvsborgs Hosp, Sweden.
    Sjoberg, Mats
    Skaraborgs Hosp, Sweden.
    Oberg, David
    Sunderby Hosp, Sweden.
    Bergemalm, Daniel
    Orebro Univ, Sweden.
    Hjortswang, Henrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Halfvarson, Jonas
    Orebro Univ, Sweden.
    Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study2021In: Therapeutic Advances in Gastroenterology, ISSN 1756-283X, E-ISSN 1756-2848, Vol. 14, article id 17562848211023386Article in journal (Refereed)
    Abstract [en]

    Background: Prospectively and systematically collected real-world data on vedolizumab are scarce. We aimed to assess the long-term clinical effectiveness of vedolizumab in inflammatory bowel disease (IBD). Methods: This study was a prospective, observational, multicentre study. Overall, 286 patients with active IBD were included (Crohns disease, n = 169; ulcerative colitis, n = 117). The primary outcomes were clinical response at week 12 and clinical remission at week 52, based on the Harvey Bradshaw Index and the partial Mayo Clinic score. Secondary outcomes included clinical remission at week 12, clinical response at week 52, corticosteroid-free clinical remission at week 52, changes in biochemical measures, and health-related quality of life (HRQoL). Results: At baseline, 88% of the patients were exposed to anti-TNF and 41% of the patients with Crohns disease had undergone &gt; 1 surgical resection. At week 12, clinical response was 27% and remission 47% in Crohns disease; corresponding figures in ulcerative colitis were 52% and 34%. Clinical response, remission and corticosteroid-free remission at week 52 were 22%, 41% and 40% in Crohns disease and 49%, 47% and 46% in ulcerative colitis, respectively. A statistically significant decrease in median faecal-calprotectin and C-reactive protein was observed at 12 and 52 weeks in patients with Crohns disease and ulcerative colitis. The HRQoL measures Short Health Scale and EuroQol 5-Dimensions improved in both Crohns disease and ulcerative colitis patients (p &lt; 0.001). Clinical disease activity at baseline was inversely associated with clinical remission at week 52. Conclusion: Vedolizumab proved effective for the treatment of refractory IBD in clinical practice.

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  • 36.
    Eriksson, Carl
    et al.
    Orebro Univ, Sweden; Karolinska Inst, Sweden.
    Visuri, Isabella
    Orebro Univ, Sweden.
    Vigren, Lina
    GHP Gastro Ctr Skane, Sweden.
    Nilsson, Linda
    Danderyd Hosp, Sweden.
    Kärnell, Anders
    Merck Sharp & Dohme Sweden AB, Sweden.
    Hjortswang, Henrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Bergemalm, Daniel
    Orebro Univ, Sweden.
    Almer, Sven
    Karolinska Inst, Sweden.
    Hertervig, Erik
    Skane Univ Hosp, Sweden.
    Karlén, Per
    Danderyd Hosp, Sweden.
    Strid, Hans
    Sodra Alvsborg Hosp, Sweden.
    Halfvarson, Jonas
    Orebro Univ, Sweden.
    Clinical effectiveness of golimumab in ulcerative colitis: a prospective multicentre study based on the Swedish IBD Quality Register, SWIBREG2021In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 56, no 11, p. 1304-1311Article in journal (Refereed)
    Abstract [en]

    Objectives Clinical trials demonstrated that golimumab is effective in anti-TNF naive patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. Materials and methods This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore &gt;= 2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by &gt;= 3 points or 30% from baseline) and remission (defined as a Mayo score of &lt;= 2 with no individual subscores &gt;1). Results Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p &lt; .01) and the faecal calprotectin decreased from 862 (335-1759) mu g/g to 90 (34-169) mu g/g (p &lt; .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5-1188.9). Conclusions The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.

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  • 37.
    Escudero-Hernández, Celia
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Münch, Andreas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Østvik, Ann-Elisabet
    Norwegian University of Science and Technology (NTNU), Trondheim, Norway; St Olav’s University Hospital, Trondheim, Norway.
    Granlund, Atle van Beelen
    Norwegian University of Science and Technology (NTNU), Trondheim, Norway; St Olav’s University Hospital, Trondheim, Norway.
    Koch, Stefan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis2020In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 14, no 7, p. 962-973Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Diarrhoea is a common, debilitating symptom of gastrointestinal disorders. Pathomechanisms probably involve defects in trans-epithelial water transport, but the role of aquaporin [AQP] family water channels in diarrhoea-predominant diseases is unknown. We investigated the involvement of AQPs in the pathobiology of collagenous colitis [CC], which features chronic, watery diarrhoea despite overtly normal intestinal epithelial cells [IECs].

    METHODS: We assessed the expression of all AQP family members in mucosal samples of CC patients before and during treatment with the corticosteroid drug budesonide, steroid-refractory CC patients and healthy controls. Samples were analysed by genome-wide mRNA sequencing [RNA-seq] and quantitative real-time PCR [qPCR]. In some patients, we performed tissue microdissection followed by RNA-seq to explore the IEC-specific CC transcriptome. We determined changes in the protein levels of the lead candidates in IEC by confocal microscopy. Finally, we investigated the regulation of AQP expression by corticosteroids in model cell lines.

    RESULTS: Using qPCR and RNA-seq, we identified loss of AQP8 expression as a hallmark of active CC, which was reverted by budesonide treatment in steroid-responsive but not refractory patients. Consistently, decreased AQP8 mRNA and protein levels were observed in IECs of patients with active CC, and steroid drugs increased AQP8 expression in model IECs. Moreover, low APQ8 expression was strongly associated with higher stool frequency in CC patients.

    CONCLUSION: Down-regulation of epithelial AQP8 may impair water resorption in active CC, resulting in watery diarrhoea. Our results suggest that AQP8 is a potential drug target for the treatment of diarrhoeal disorders.

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  • 38.
    Escudero-Hernández, Celia
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    van Beelen Granlund, Atle
    Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Bruland, Torunn
    Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway.
    Sandvik, Arne Kristian
    Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway; Department of Gastroenterology and Hepatology, St Olav’s University Hospital, Trondheim, Norway.
    Koch, Stefan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology.
    Østvik, Ann Elisabet
    Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway; Department of Gastroenterology and Hepatology, St Olav’s University Hospital, Trondheim, Norway.
    Münch, Andreas
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Transcriptomic profiling of collagenous colitis identifies hallmarks of non-destructive inflammatory bowel disease.2021In: Cellular and molecular gastroenterology and hepatology, ISSN 2352-345X, Vol. 12, no 2, p. 665-687, article id S2352-345X(21)00082-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: The pathophysiology of the inflammatory bowel disease collagenous colitis (CC) is poorly described. Our aim was to use RNA sequencing of mucosal samples from patients with active CC, CC in remission, refractory CC, ulcerative colitis (UC), and controls to gain insight into CC pathophysiology, identify genetic signatures linked to CC, and uncover potentially druggable disease pathways.

    METHODS: We performed whole transcriptome sequencing of CC samples from patients before and during treatment with the corticosteroid drug budesonide, CC steroid-refractory patients, UC patients, and healthy controls (n=9-13). Bulk mucosa and laser-captured microdissected intestinal epithelial cell (IEC) gene expression were analyzed by gene-set enrichment and gene-set variation analyses to identify significant pathways and cells, respectively, altered in CC. Leading genes and cells were validated using reverse transcription quantitative PCR and/or immunohistochemistry.

    RESULTS: We identified an activation of the adaptive immune response to bacteria and viruses in active CC that could be mediated by dendritic cells. Moreover, IECs display hyperproliferation and increased antigen presentation in active CC. Further analysis revealed that genes related to the immune response (DUOX2, PLA2G2A, CXCL9), DNA transcription (CTR9), protein processing (JOSD1, URI1) and ion transport (SLC9A3) remained dysregulated even after budesonide-induced remission. Budesonide-refractory CC patients fail to restore normal gene expression, and displayed a transcriptomic profile close to UC.

    CONCLUSIONS: Our study confirmed the implication of innate and adaptive immune responses in CC, governed by IECs and dendritic cells, respectively; and identified ongoing epithelial damage. Refractory CC could share pathomechanisms with UC.

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  • 39.
    Farahat, Taghreed M.
    et al.
    Menoufia Univ, Egypt.
    Ungan, Mehmet
    Ankara Univ, Turkey.
    Vilaseca, Josep
    Barcelona Esquerra Primary Hlth Care Consortium, Spain; Univ Barcelona, Spain; Cent Univ Catalonia, Spain.
    Ponzo, Jacqueline
    Univ Republica, Uruguay.
    Gupta, Pramendra Prasad
    BP Koirala Inst Hlth Sci, Nepal.
    Schreiner, Andrew D.
    Med Univ South Carolina, SC 29425 USA.
    Al Sharief, Wadeia
    Family Med Soc, U Arab Emirates; Arab Board Med Specializat Council, U Arab Emirates; Med Educ & Res Dept, U Arab Emirates.
    Casler, Kelly
    Ohio State Univ, OH 43210 USA.
    Abdelkader, Tafat
    Algerian Soc Gen Med, Algeria.
    Abenavoli, Ludovico
    Magna Graecia Univ Catanzaro, Italy.
    Alami, Fatima-Zohra Mchich
    Natl Collect Gen Practitioners Marocco MG Maroc, Morocco.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Jabir, Muntadar S.
    Iraqi Family Phys Soc, Iraq.
    Armstrong, Matthew J.
    Univ Hosp Birmingham NHS Fdn Trust, England.
    Osman, Mona H.
    Amer Univ Beirut, Lebanon.
    Wiegand, Johannes
    Univ Leipzig, Germany.
    Attia, Dina
    Beni Suef Univ, Egypt.
    Verhoeven, Veronique
    Univ Antwerp, Belgium.
    Amir, Ashraf Abdul Qayoum
    Int Med Ctr Hosp Jeddah, Saudi Arabia.
    Hegazy, Nagwa N.
    Menoufia Univ, Egypt.
    Tsochatzis, Emmanuel A.
    Royal Free Hosp, England; UCL, England.
    Fouad, Yasser
    Minia Univ, Egypt.
    Cortez-Pinto, Helena
    Univ Lisbon, Portugal.
    The paradigm shift from NAFLD to MAFLD: A global primary care viewpoint2022In: Liver international (Print), ISSN 1478-3223, E-ISSN 1478-3231, Vol. 42, no 6, p. 1259-1267Article, review/survey (Refereed)
    Abstract [en]

    n/a

  • 40.
    Fiehn, Anne-Marie Kanstrup
    et al.
    Zealand Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Miehlke, Stephan
    Univ Hosp Eppendorf, Germany; Univ Hosp Eppendorf, Germany.
    Aust, Daniela
    Univ Hosp Dresden, Germany.
    Vieth, Michael
    Klinikum Bayreuth, Germany.
    Bonderup, Ole
    Silkeborg Hosp, Denmark.
    Fernandez-Banares, Fernando
    Hosp Univ Mutua Terrassa, Spain; Ctr Invest Biomed Red Enfermedades Hepat & Digest, Spain.
    Mihaly, Emese
    Semmelweis Univ, Hungary.
    Kupcinskas, Juozas
    Lithuanian Univ Hlth Sci, Lithuania.
    Madisch, Ahmed
    CRH Clin Siloah, Germany.
    Munck, Lars Kristian
    Univ Copenhagen, Denmark; Zealand Univ Hosp, Denmark.
    Nacak, Tanju
    Dr Falk Pharma GmbH, Germany.
    Mohrbacher, Ralf
    Dr Falk Pharma GmbH, Germany.
    Mueller, Ralph
    Dr Falk Pharma GmbH, Germany.
    Greinwald, Roland
    Dr Falk Pharma GmbH, Germany.
    Münch, Andreas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Distribution of histopathological features along the colon in microscopic colitis2021In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 36, p. 151-159Article in journal (Refereed)
    Abstract [en]

    Purpose The diagnosis microscopic colitis (MC) consisting of collagenous colitis (CC) and lymphocytic colitis (LC) relies on histological assessment of mucosal biopsies from the colon. The optimal biopsy strategy for reliable diagnosis of MC is controversial. The aim of this study was to evaluate the distribution of histopathological features of MC throughout the colon. Methods Mucosal biopsies from multiple colonic segments of patients with MC who participated in one of the three prospective European multicenter trials were analyzed. Histological slides were stained with hematoxylin-and-eosin, a connective tissue stain, and CD3 in selected cases. Results In total, 255 patients were included, 199 and 56 patients with CC and LC, respectively. Both groups exhibited a gradient with more pronounced inflammation in the lamina propria in the proximal colon compared with the distal colon. Similarly, the thickness of the subepithelial collagenous band in CC showed a gradient with higher values in the proximal colon. The mean number of intraepithelial lymphocytes was &gt; 20 in all colonic segments in patients within both subgroups. Biopsies from 86 to 94% of individual segments were diagnostic, rectum excluded. Biopsies from non-diagnostic segments often showed features of another subgroup of MC. Conclusion Conclusively, although the severity of the histological changes in MC differed in the colonic mucosa, the minimum criteria required for the diagnosis were present in the random biopsies from the majority of segments. Thus, our findings show MC to be a pancolitis, rectum excluded, questioning previously proclaimed patchiness throughout the colon.

  • 41.
    Forsgren, Mikael F
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Karlsson, Markus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Medical radiation physics.
    Dahlström, Nils
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Norén, Bengt
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ignatova, Simone
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Sinkus, Ralph
    King's College London, United Kingdom.
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Lundberg, Peter
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Medical radiation physics. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Biomarkers of liver fibrosis: prospective comparison of multimodal magnetic resonance, serum algorithms and transient elastography.2020In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 55, no 7, p. 848-859Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Accurate biomarkers for quantifying liver fibrosis are important for clinical practice and trial end-points. We compared the diagnostic performance of magnetic resonance imaging (MRI), including gadoxetate-enhanced MRI and 31P-MR spectroscopy, with fibrosis stage and serum fibrosis algorithms in a clinical setting. Also, in a subset of patients, MR- and transient elastography (MRE and TE) was evaluated when available.

    METHODS: Patients were recruited prospectively if they were scheduled to undergo liver biopsy on a clinical indication due to elevated liver enzyme levels without decompensated cirrhosis. Within a month of the clinical work-up, an MR-examination and liver needle biopsy were performed on the same day. Based on late-phase gadoxetate-enhanced MRI, a mathematical model calculated hepatobiliary function (relating to OATP1 and MRP2). The hepatocyte gadoxetate uptake rate (KHep) and the normalised liver-to-spleen contrast ratio (LSC_N10) were also calculated. Nine serum fibrosis algorithms were investigated (GUCI, King's Score, APRI, FIB-4, Lok-Index, NIKEI, NASH-CRN regression score, Forns' score, and NAFLD-fibrosis score).

    RESULTS: The diagnostic performance (AUROC) for identification of significant fibrosis (F2-4) was 0.78, 0.80, 0.69, and 0.78 for MRE, TE, LSC_N10, and GUCI, respectively. For the identification of advanced fibrosis (F3-4), the AUROCs were 0.93, 0.84, 0.81, and 0.82 respectively.

    CONCLUSION: MRE and TE were superior for non-invasive identification of significant fibrosis. Serum fibrosis algorithms developed for specific liver diseases are applicable in this cohort of diverse liver diseases aetiologies. Gadoxetate-MRI was sufficiently sensitive to detect the low function losses associated with fibrosis. None was able to efficiently distinguish between stages within the low fibrosis stages.Lay summaryExcessive accumulation of scar tissue, fibrosis, in the liver is an important aspect in chronic liver disease. To replace the invasive needle biopsy, we have explored non-invasive methods to assess liver fibrosis. In our study we found that elastographic methods, which assess the mechanical properties of the liver, are superior in assessing fibrosis in a clinical setting. Of interest from a clinical trial point-of-view, none of the tested methods was sufficiently accurate to distinguish between adjacent moderate fibrosis stages.

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  • 42.
    Gawel, Danuta
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Serra I Musach, Jordi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Lilja, Sandra
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Aagesen, Jesper
    Reg Jonkoping Cty, Sweden.
    Arenas, Alex
    Univ Rovira and Virgili, Spain.
    Asking, Bengt
    Reg Jonkoping Cty, Sweden.
    Bengner, Malin
    Reg Jonkoping Cty, Sweden.
    Bjorkander, Janne
    Reg Jonkoping Cty, Sweden.
    Biggs, Sophie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hjortswang, Henrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Karlsson, Jan-Erik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Köpsen, Mattias
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Jung Lee, Eun Jung
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Yonsei Univ, South Korea.
    Lentini, Antonio
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Li, Xinxiu
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Martinez, David
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Matussek, Andreas
    Reg Jonkoping Cty, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nestor, Colm
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Schäfer, Samuel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Seifert, Oliver
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Sonmez, Ceylan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Stjernman, Henrik
    Reg Jonkoping Cty, Sweden.
    Tjärnberg, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Wu, Simon
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Åkesson, Karin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Shalek, Alex K.
    MIT, MA 02139 USA; MIT, MA 02139 USA; MIT, MA 02139 USA; Broad Inst MIT and Harvard, MA 02142 USA; Ragon Inst MGH MIT and Harvard, MA USA.
    Stenmarker, Margaretha
    Reg Jonkoping Cty, Sweden; Inst Clin Sci, Sweden.
    Zhang, Huan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Benson, Mikael
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Correction: A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases (vol 11, 47, 2019)2020In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 12, no 1, article id 37Article in journal (Other academic)
    Abstract [en]

    An amendment to this paper has been published and can be accessed via the original article.

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  • 43.
    Gerdin, Linda
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Surg Clin Jonkoping Cty, Sweden.
    Gonzalez-Castro, Ana M.
    Univ Autonoma Barcelona, Spain; Univ Autonoma Barcelona, Spain.
    Ericson, Ann-Charlott
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Persborn, Mats
    Surg Clin Jonkoping Cty, Sweden.
    Santos, Javier
    Univ Autonoma Barcelona, Spain; Univ Autonoma Barcelona, Spain; Ctr Invest Biomed Red Enfermedades Hepat & Digest, Spain.
    Walter, Susanna
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Keita, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Vicario, Maria
    Univ Autonoma Barcelona, Spain; Univ Autonoma Barcelona, Spain; Ctr Invest Biomed Red Enfermedades Hepat & Digest, Spain; Nestle Res Soc Prod Nestle SA, Switzerland.
    Söderholm, Johan D
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Acute psychological stress increases paracellular permeability and modulates immune activity in rectal mucosa of healthy volunteers2023In: United European Gastroenterology journal, ISSN 2050-6406, E-ISSN 2050-6414, Vol. 11, no 1, p. 31-41Article in journal (Refereed)
    Abstract [en]

    Background Psychological stress and increased permeability are implicated as contributing factors in the initiation and worsening of gastrointestinal diseases. A link between stress and intestinal permeability has been shown in animal models as well as in human small intestine, but stress effects on the human colorectal mucosal barrier has not been reported. Objective To investigate the potential effects of acute psychological stress on colorectal mucosal barrier function and to explore stress-induced molecular events in the rectal mucosa under healthy conditions. Methods Endoscopic biopsies were taken from the rectosigmoid region of healthy volunteers, who had been subjected to dichotomous listening stress and after a control session, respectively. Paracellular and transcellular permeability were assessed in modified Ussing chambers. RNA expression (microarray technology confirmed by quantitative real-time polymerase chain reaction) and biological pathway analysis were used to investigate the local mucosal response to acute stress. Results Dichotomous listening stress induced a subjective and objective stress response, and significantly increased paracellular but not transcellular permeability. We also identified a stress-induced reduction in RNA expression of genes related to immune cell activation and maturation (CR2, CD20, TCLA1, BANK1, CD22, FDCSP), signaling molecules of homing of immune cells to the gut (chemokines: CCL21, CXCL13, and CCL19, and receptors: CCR7, CXCR5), and innate immunity (DUOX2). Eight of the 10 top down-regulated genes are directly involved in B cell activation, signaling and migration. The systemic stress response correlated positively with paracellular permeability and negatively with DUOX2 expression. Conclusion Dichotomous listening stress increases paracellular permeability and modulates immune cell activity in the rectal mucosa. Further studies are warranted to identify the primary mechanisms of stress-mediated reduction of mucosal defensive activity and barrier dysfunction, and their potential implications for gastrointestinal disorders.

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  • 44.
    Govaere, Olivier
    et al.
    Newcastle Univ, England.
    Cockell, Simon
    Newcastle Univ, England.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Queen, Rachel
    Newcastle Univ, England.
    Younes, Ramy
    Newcastle Univ, England; Univ Turin, Italy.
    Vacca, Michele
    Univ Cambridge, England.
    Alexander, Leigh
    SomaL Inc, CO 80301 USA.
    Ravaioli, Federico
    Newcastle Univ, England; Univ Bologna, Italy.
    Palmer, Jeremy
    Newcastle Univ, England.
    Petta, Salvatore
    Univ Palermo, Italy.
    Boursier, Jerome
    Angers Univ Hosp, France.
    Rosso, Chiara
    Univ Turin, Italy.
    Johnson, Katherine
    Newcastle Univ, England.
    Wonders, Kristy
    Newcastle Univ, England.
    Day, Christopher P.
    Newcastle Univ, England.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Oresic, Matej
    Orebro Univ, Sweden.
    Darlay, Rebecca
    Newcastle Univ, England.
    Cordell, Heather J.
    Newcastle Univ, England.
    Marra, Fabio
    Univ Florence, Italy.
    Vidal-Puig, Antonio
    Univ Cambridge, England.
    Bedossa, Pierre
    Newcastle Univ, England; Sorbonne Univ, France.
    Schattenberg, Joern M.
    Univ Hosp Mainz, Germany.
    Clement, Karine
    Sorbonne Univ, France.
    Allison, Michael
    Cambridge Univ NHS Fdn Trust, England.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Ratziu, Vlad
    Sorbonne Univ, France.
    Daly, Ann K.
    Newcastle Univ, England.
    Anstee, Quentin M.
    Newcastle Univ, England; Newcastle Tyne Hosp NHS Trust, England.
    Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis2020In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 12, no 572, article id eaba4448Article in journal (Refereed)
    Abstract [en]

    The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.

  • 45.
    Govaere, Olivier
    et al.
    Newcastle Univ, England; Katholieke Univ Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Hasoon, Megan
    Newcastle Univ, England.
    Alexander, Leigh
    SomaLogic Inc, CO USA.
    Cockell, Simon
    Newcastle Univ, England.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Schattenberg, Joern M.
    Univ Hosp Mainz, Germany.
    Boursier, Jerome
    Angers Univ Hosp, France.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Ratziu, Vlad K.
    Sorbonne Univ, France.
    Daly, Ann K. M.
    Newcastle Univ, England.
    Anstee, Quentin M.
    Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Trust, England.
    LITMUS Investigators,
    A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures2023In: Nature Metabolism, E-ISSN 2522-5812, Vol. 5, no 4, p. 572-578Article in journal (Refereed)
    Abstract [en]

    Govaere et al. integrate circulating protein data from more than 300 patients with non-alcoholic fatty liver disease (NAFLD) with transcriptomics and develop a non-invasive diagnostics tool to identify patients with at-risk NAFLD based on body mass index, type 2 diabetes status and four circulating proteins. Non-alcoholic fatty liver disease (NAFLD) is a common, progressive liver disease strongly associated with the metabolic syndrome. It is unclear how progression of NAFLD towards cirrhosis translates into systematic changes in circulating proteins. Here, we provide a detailed proteo-transcriptomic map of steatohepatitis and fibrosis during progressive NAFLD. In this multicentre proteomic study, we characterize 4,730 circulating proteins in 306 patients with histologically characterized NAFLD and integrate this with transcriptomic analysis in paired liver tissue. We identify circulating proteomic signatures for active steatohepatitis and advanced fibrosis, and correlate these with hepatic transcriptomics to develop a proteo-transcriptomic signature of 31 markers. Deconvolution of this signature by single-cell RNA sequencing reveals the hepatic cell types likely to contribute to proteomic changes with disease progression. As an exemplar of use as a non-invasive diagnostic, logistic regression establishes a composite model comprising four proteins (ADAMTSL2, AKR1B10, CFHR4 and TREM2), body mass index and type 2 diabetes mellitus status, to identify at-risk steatohepatitis.

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  • 46.
    Govaere, Olivier
    et al.
    Newcastle Univ, England.
    Petersen, Sine Kragh
    Univ Gothenburg, Sweden.
    Martinez-Lopez, Nuria
    Albert Einstein Coll Med, NY 10461 USA; Albert Einstein Coll Med, NY 10461 USA.
    Wouters, Jasper
    VIB KU Leuven, Belgium; Katholieke Univ Leuven, Belgium.
    Van Haele, Matthias
    Katholieke Univ Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Mancina, Rosellina M.
    Univ Gothenburg, Sweden.
    Jamialahmadi, Oveis
    Univ Gothenburg, Sweden.
    Bilkei-Gorzo, Orsolya
    Univ Gothenburg, Sweden.
    Lassen, Pierre Bel
    Sorbonne Univ, France.
    Darlay, Rebecca
    Newcastle Univ, England.
    Peltier, Julien
    Newcastle Univ, England.
    Palmer, Jeremy M.
    Newcastle Univ, England.
    Younes, Ramy
    Newcastle Univ, England; Univ Turin, Italy.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Aithal, Guruprasad P.
    Nottingham Univ Hosp NHS Trust, England; Univ Nottingham, England.
    Allison, Michael
    Cambridge Univ NHS Fdn Trust, England.
    Vacca, Michele
    Univ Cambridge, England.
    Göransson, Melker
    AstraZeneca, Sweden.
    Berlinguer-Palmini, Rolando
    Newcastle Univ, England.
    Clark, James E.
    Newcastle Univ, England.
    Drinnan, Michael J.
    Newcastle Univ, England.
    Yki-Jarvinen, Hannele
    Univ Helsinki, Finland; Univ Helsinki, Finland.
    Dufour, Jean-Francois
    Univ Bern, Switzerland; Univ Bern, Switzerland.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Francque, Sven
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Petta, Salvatore
    Univ Palermo, Italy.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Schattenberg, Jorn M.
    Univ Hosp Mainz, Germany.
    Day, Christopher P.
    Newcastle Univ, England.
    Cordell, Heather J.
    Newcastle Univ, England.
    Topal, Baki
    Univ Hosp Leuven, Belgium; Katholieke Univ Leuven, Belgium.
    Clement, Karine
    Sorbonne Univ, France.
    Romeo, Stefano
    Univ Gothenburg, Sweden.
    Ratziu, Vlad
    Univ Paris Diderot, France.
    Roskams, Tania
    Katholieke Univ Leuven, Belgium; Univ Hosp Leuven, Belgium.
    Daly, Ann K.
    Newcastle Univ, England.
    Anstee, Quentin M.
    Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Trust, England.
    Trost, Matthias
    Newcastle Univ, England.
    Härtlova, Anetta
    Univ Gothenburg, Sweden; Newcastle Univ, England.
    Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease2022In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 76, no 5, p. 1001-1012Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1(-/-) and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a proinflammatory phenotype and the release of cytokines such as TNF-alpha Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

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  • 47.
    Gruneau, Lina
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Henriksson, Martin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Disease Progression Modeling for Economic Evaluation in Nonalcoholic Fatty Liver Disease-A Systematic Review2023In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 21, no 2, p. 283-298Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Globally, 25% of people have nonalcoholic fatty liver disease (NAFLD), and, currently, there are no approved pharmacologic treatments for NAFLD. With a slow disease progression, long-term impact of pharmacologic treatments can be assessed only by complementing emerging clinical trial evidence with data from other sources in disease progression modeling. Although this modeling is crucial for economic evaluation studies assessing the clinical and economic con-sequences of new treatments, the approach to modeling the natural history of NAFLD differs in contemporary research. This systematic literature review investigated modeling of the natural history of NAFLD.METHODS: A systematic literature review was conducted searching PubMed, Scopus, Cochrane, and the National Health Service Economic Evaluation Database to identify articles focusing on modeling of the natural history of NAFLD. Model structure and transition probabilities were extracted from included studies.RESULTS: Of the 28 articles identified, differences were seen in model structure and data input. Clear definitions of nonalcoholic steatohepatitis and NAFLD often were lacking; differences in the granularity of modeling fibrosis progression, the approach to disease regression, and modeling of advanced liver disease varied across studies. Observed transition probabilities for F0 to F1, F1 to F2, F2 to F3, and F3 to compensated cirrhosis varied between 0.059 to 0.095, 0.023 to 0.140, 0.018 to 0.070, and 0.040 to 0.118, respectively.CONCLUSIONS: The difference in disease progression modeling for seemingly similar models warrants further inquiry regarding how to model the natural course of NAFLD. Such differences may have a large impact when assessing the value of emerging pharmacologic treatments.

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  • 48.
    Gruneau, Lina
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Sandström, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Henriksson, Martin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Cost-effectiveness analysis of noninvasive tests to identify advanced fibrosis in non-alcoholic fatty liver disease2023In: HEPATOLOGY COMMUNICATIONS, ISSN 2471-254X, Vol. 7, no 7, article id e00191Article in journal (Refereed)
    Abstract [en]

    Background: Advanced fibrosis is associated with end-stage liver disease (ESLD) and mortality in NAFLD. As treatments specifically targeted at NAFLD are lacking, patient management focuses on surveillance for early detection of complications related to end-stage liver disease. Although current and emerging diagnostic tools for the detection of advanced fibrosis are crucial for surveillance, their added value is unclear. The aim of this study was to evaluate the costs and health outcomes of noninvasive tests in patient management strategies for diagnosing advanced fibrosis in NAFLD patients. Method: A decision analytical model was developed to evaluate 13 patient management strategies, including a no-testing strategy and 12 diagnostic algorithms with noninvasive tests (fibrosis 4-score, enhanced liver fibrosis, vibration controlled transient elastography), and liver biopsy. Model inputs were synthesized from the literature and Swedish registries. Lifetime health care costs, life years, quality-adjusted life years, clinical outcomes, and incremental cost-effectiveness ratios were calculated for a cohort of 55-year-old patients diagnosed with NAFLD. Result: The cost per quality-adjusted life year was above (sic)50 000 for all diagnostic algorithms compared to no-testing. The cost per quality-adjusted life year of the most promising diagnostic algorithm (fibrosis 4-score, enhanced liver fibrosis, vibration controlled transient elastography, and liver biopsy) was similar to(sic)181 000 compared with no testing. Sensitivity analysis indicated that if treatment slowed down disease progression, the value of testing increased. Conclusion: The result questions the overall value of comprehensive diagnostic testing in a broad NAFLD population in current routine clinical care. The role of noninvasive tests may change if evidence-based treatments to slow down disease progression emerge.

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  • 49.
    Gummesson, Christina
    et al.
    Malmo Univ, Sweden.
    Alm, Stina
    Umea Univ, Sweden.
    Cederborg, Anna
    Univ Gothenburg, Sweden.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Hellman, Jarl
    Uppsala Univ, Sweden.
    Hjelmqvist, Hans
    Orebro Univ, Sweden.
    Hultin, Magnus
    Umea Univ, Sweden.
    Jood, Katarina
    Univ Gothenburg, Sweden.
    Leanderson, Charlotte
    Karolinska Inst, Sweden.
    Lindahl, Bertil
    Uppsala Univ, Sweden.
    Moller, Riitta
    Karolinska Inst, Sweden.
    Rosengren, Bjorn
    Lund Univ, Sweden.
    Sjalander, Anders
    Umea Univ, Sweden.
    Svensson, Peter J.
    Lund Univ, Sweden.
    Sarnblad, Stefan
    Orebro Univ, Sweden.
    Tejera, Alexander
    Lund Univ, Sweden.
    Entrustable professional activities (EPAs) for undergraduate medical education - development and exploration of social validity2023In: BMC Medical Education, E-ISSN 1472-6920, Vol. 23, no 1, article id 635Article in journal (Refereed)
    Abstract [en]

    BackgroundThe development of entrustable professional activities (EPAs) as a framework for work-based training and assessment in undergraduate medical education has become popular. EPAs are defined as units of a professional activity requiring adequate knowledge, skills, and attitudes, with a recognized output of professional labor, independently executable within a time frame, observable and measurable in its process and outcome, and reflecting one or more competencies. Before a new framework is implemented in a specific context, it is valuable to explore social validity, that is, the acceptability by relevant stakeholders.AimThe aim of our work was to define Core EPAs for undergraduate medical education and further explore the social validity of the constructs.Method and materialIn a nationwide collaboration, EPAs were developed using a modified Delphi procedure and validated according to EQual by a group consisting of teachers nominated from each of the seven Swedish medical schools, two student representatives, and an educational developer (n = 16). In the next step, social validity was explored in a nationwide survey. The survey introduced the suggested EPAs. For each EPA, the importance of the EPA was rated, as was the raters perception of the present graduates required level of supervision when performing the activity. Free-text comments were also included and analyzed.ResultsTen Core EPAs were defined and validated. The validation scores for EQual ranged from 4.1 to 4.9. The nationwide survey had 473 responders. All activities were rated as "important" by most responders, ranging from 54 to 96%. When asked how independent current graduates were in performing the ten activities, 6 to 35% reported "independent". The three themes of the free text comments were: relevant target areas and content; definition of the activities; and clinical practice and learning.ConclusionTen Core EPAs were defined and assessed as relevant for Swedish undergraduate medical education. There was a consistent gap between the perceived importance and the certainty that the students could perform these professional activities independently at the time of graduation. These results indicate that the ten EPAs may have a role in undergraduate education by creating clarity for all stakeholders.

  • 50.
    Hagstrom, Hannes
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Bu, Dawei
    Univ Texas Southwestern Med Ctr Dallas, TX USA.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Hegmar, Hannes
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Zhang, Ningyan
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    An, Zhiqiang
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    Stal, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Scherer, Philipp E.
    Univ Texas Southwestern Med Ctr Dallas, TX USA; Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Serum levels of endotrophin are associated with nonalcoholic steatohepatitis2021In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 56, no 4, p. 437-442Article in journal (Refereed)
    Abstract [en]

    Background and aims

    There are no currently available biomarkers that can accurately indicate the presence of non-alcoholic steatohepatitis (NASH). We investigated the association between endotrophin, a cleavage product of collagen type 6α3, and disease severity in patients with non-alcoholic fatty liver disease (NAFLD).

    Methods

    We measured serum endotrophin levels in 211 patients with NAFLD and nine healthy controls. Liver biopsy data was available for 141 (67%) of the patients. Associations between endotrophin and the presence of NASH and advanced fibrosis were investigated alone and in combination with standard clinical parameters using logistic regression.

    Results

    A total of 211 patients were enrolled in this study, consisting of 108 (51%) men and 103 (49%) women with a mean age of 55.6 years. 58 (27%) of the patients had advanced fibrosis. Of those with biopsy data, 87 (62%) had NASH. Serum levels of endotrophin were significantly higher in patients with NAFLD than those in healthy controls (37[±12] vs. 17[±7] ng/mL, p<.001). Serum levels of endotrophin were also significantly higher in patients with NASH than in those without NASH (40[±12] vs. 32[±13] ng/mL, p<.001). A model using age, sex, body mass index and levels of alanine aminotransferase (ALT), glucose and endotrophin effectively predicted the presence of NASH in a derivation (AUROC 0.83, 95%CI = 0.74–0.92) and validation cohort (AUROC 0.71, 95%CI = 0.54–0.88). There was no significant association between serum levels of endotrophin and advanced fibrosis.

    Conclusions

    These data suggest that serum endotrophin could be a valuable biomarker for diagnosing NASH, but not for detecting advanced fibrosis in NAFLD.

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