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  • 1.
    Adams, Yvonne
    et al.
    Univ Copenhagen, Denmark.
    Clausen, Anne Skovsbo
    Copenhagen Univ Hosp, Denmark; Copenhagen Univ Hosp, Denmark.
    Jensen, Peter Ostrup
    Lager, Malin
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Natl Reference Lab Borrel, Div Clin Microbiol, Other Tick Borne Bacter, Lab Med, Reg Jonkoping Cty, Jonkoping, Sweden.
    Wilhelmsson, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Natl Reference Lab Borrel, Div Clin Microbiol, Other Tick Borne Bacter, Lab Med, Reg Jonkoping Cty, Jonkoping, Sweden.
    Jonsson Henningsson, Anna
    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 Microbiology. Natl Reference Lab Borrel, Div Clin Microbiol, Other Tick Borne Bacter, Lab Med, Reg Jonkoping Cty, Jonkoping, Sweden.
    Lindgren, Per-Eric
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Natl Reference Lab Borrel, Div Clin Microbiol, Other Tick Borne Bacter, Lab Med, Reg Jonkoping Cty, Jonkoping, Sweden.
    Faurholt-Jepsen, Daniel
    Copenhagen Univ Hosp, Denmark.
    Mens, Helene
    Copenhagen Univ Hosp, Denmark.
    Kraiczy, Peter
    Goethe Univ Frankfurt, Germany.
    Kragh, Kasper Norskov
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Bjarnsholt, Thomas
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Kjaer, Andreas
    Copenhagen Univ Hosp, Denmark; Copenhagen Univ Hosp, Denmark.
    Lebech, Anne-Mette
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Jensen, Anja R.
    Univ Copenhagen, Denmark.
    3D blood-brain barrier-organoids as a model for Lyme neuroborreliosis highlighting genospecies dependent organotropism2023In: ISCIENCE, ISSN 2589-0042, Vol. 26, no 1, article id 105838Article in journal (Refereed)
    Abstract [en]

    Lyme neuroborreliosis (LNB), a tick-borne infection caused by spirochetes within the Borrelia burgdorferi sensu lato (s.L.) complex, is among the most prevalent bacterial central nervous system (CNS) infections in Europe and the US. Here we have screened a panel of low- passage B. burgdorferi s.l. isolates using a novel, human-derived 3D blood-brain barrier (BBB)-organoid model. We show that human-derived BBB-organoids support the entry of Borrelia spirochetes, leading to swelling of the organoids and a loss of their structural integrity. The use of the BBB-organoid model highlights the organotropism between B. burgdorferi s.l. genospecies and their ability to cross the BBB contributing to CNS infection.

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  • 2.
    Agelii, M. Leu
    et al.
    Gothenburg Univ, Sweden.
    Andersson, M. L. E.
    Lund Univ, Sweden; Spenshult Res & Dev Ctr, Sweden.
    Jones, B. L.
    Univ Pittsburgh, PA USA.
    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.
    Kastbom, Alf
    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.
    Hafstrom, I
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Forslind, K.
    Lund Univ, Sweden; Helsingborgs Hosp, Sweden.
    Gjertsson, I
    Gothenburg Univ, Sweden.
    Disease activity trajectories in rheumatoid arthritis: a tool for prediction of outcome2021In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Objective Predicting treatment response and disease progression in rheumatoid arthritis (RA) remains an elusive endeavour. Identifying subgroups of patients with similar progression is essential for understanding what hinders improvement. However, this cannot be achieved with response criteria based on current versus previous Disease Activity Scores, as they lack the time component. We propose a longitudinal approach that identifies subgroups of patients while capturing their evolution across several clinical outcomes simultaneously (multi-trajectories). Method For exploration, the RA cohort BARFOT (n = 2829) was used to identify 24 month post-diagnosis simultaneous trajectories of 28-joint Disease Activity Score and its components. Measurements were available at inclusion (0), 3, 6, 12, 24, and 60 months. Multi-trajectories were found with latent class growth modelling. For validation, the TIRA-2 cohort (n = 504) was used. Radiographic changes, assessed by the modified Sharp van der Heijde score, were correlated with trajectory membership. Results Three multi-trajectories were identified, with 39.6% of the patients in the lowest and 18.9% in the highest (worst) trajectory. Patients in the worst trajectory had on average eight tender and six swollen joints after 24 months. Radiographic changes at 24 and 60 months were significantly increased from the lowest to the highest trajectory. Conclusion Multi-trajectories constitute a powerful tool for identifying subgroups of RA patients and could be used in future studies searching for predictive biomarkers for disease progression. The evolution and shape of the trajectories in TIRA-2 were very similar to those in BARFOT, even though TIRA-2 is a newer cohort.

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  • 3. Order onlineBuy this publication >>
    Ahlbeck, Lars
    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, Allergy Center.
    Intralymphatic Immunotherapy: A Novel Route to Ameliorate Allergic Rhinitis Due to Pollen2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Allergy to pollen and animal dander is a major public health problem. Close to 30% of the population have symptoms from the upper and/or lower respiratory tract when they meet fur animals or pollen. Whereas symptom-relieving medications have a good to sufficient effect on about 80% of those affected, a large group of 10–20% have severe symptoms, despite medication, with an impact on well-being and ability to work. In Sweden, the annual cost of allergy was calculated at €1.3 billion in 2014.

    Immunotherapy is effective in treating and preventing pollen allergy and allergic asthma, but is expensive, complicated, requiring 40 injections, and takes more than three years to complete if subcutaneous injections are used. Tablets placed under the tongue are another method, with one tablet taken every day for three years. Only 1.5‰ receive such treatment, yet just over 3% would need it.

    With intralymphatic immunotherapy, a small dose of allergen is given in a lymph node in the groin on 3 occasions, one month apart. As this method takes only eight weeks, it is a much faster and less costly treatment. However, although several studies have shown that the treatment is safe, its efficacy remains the subject of doubt.

    Our pilot study in 2012, with a 3-year follow-up to 2015, showed encouraging results, and was followed by a double-blind randomised study with 72 participants from 2014 to 2018. The research subjects then received treatment with birch and grass pollen extract or one extract and a placebo. Regardless of treatment, symptoms, quality of life and medication consumption improved during the birch and grass pollen seasons in the 3 years after treatment. Increased frequencies of T-regulatory lymphocytes may explain the non-specific effects.

    In 2017 to 2018, we conducted a double-blind study with 38 participants, half of whom received placebo and half, active treatment. In this study, we saw no difference between the treatment groups in the first year after treatment. However, after discontinuation and unblinding in 2019, i.e., two years after treatment, the actively treated group improved in terms of symptoms, and quality of life was improved compared with the placebo group despite less need for medication. T-regulatory lymphocytes increased one year after treatment only in the actively treated group.

    A long-term follow-up of the research subjects from our two larger studies in 2022, i.e., five to eight years after treatment, showed in the double-blind study without a pure placebo that the scores for symptoms, medication use, and quality of life remained as low as after the first three years. In the placebo-controlled study, a statistically significant improvement in symptoms remained during the grass pollen season. Analysing the two studies together, symptom improvement was significant even during the birch pollen season. Thus, although the effect does not seem to diminish, those who did not receive birch, but only grass, needed to use more medication during the birch pollen season in 2022, seven to eight years after treatment. Moreover, those who did not receive grass but only birch needed more medication during the grass pollen season. This may suggest that the non-specific effect begins to wane after seven to eight years.

    Allergy to pollen is a major problem for individuals and society, where symptom-relieving treatment with drugs is not enough for many. They can be helped with immunotherapy, which takes at least three years, is expensive and fraught with side effects. In contrast, intralymphatic immunotherapy involves three injections over eight weeks. Our three studies show that the treatment is safe and indicate that it has a clinical effect up to eight years after treatment. T-regulatory cells appear to be important to the immunological mechanism, leading to tolerance to pollen.

    List of papers
    1. Intralymphatic allergen immunotherapy against pollen allergy. A 3-year open follow-up study of 10 patients
    Open this publication in new window or tab >>Intralymphatic allergen immunotherapy against pollen allergy. A 3-year open follow-up study of 10 patients
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    2018 (English)In: Annals of Allergy, Asthma & Immunology, ISSN 1081-1206, E-ISSN 1534-4436, Vol. 121, no 5, p. 626-627Article in journal, Letter (Refereed) Published
    Abstract [en]

    To date, allergen immunotherapy (AIT) is the only treatment that affects the long-term development of allergic rhinoconjunctivitis and induces clinical tolerance primarily by stimulating regulatory T (Treg) cells, attenuating T helper 2 (Th2) responses and synthesis of blocking antibodies1. Conventional AIT with subcutaneous injections, sublingual tablets or drops is effective, but consumes time and resources 2.

    Place, publisher, year, edition, pages
    Elsevier, 2018
    Keywords
    Immunotherapy, Intralymphatic, Allergy, Rhinoconjunctivitis, T-cells
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-150594 (URN)10.1016/j.anai.2018.07.010 (DOI)000448665400022 ()30021119 (PubMedID)
    Note

    Funding agencies: Region Ostergotland; Allergy Center in Linkoping; Medical Research Council of Southeast Sweden (FORSS); Bergh Foundation; Asthma and Allergy Association of Sweden

    Available from: 2018-08-28 Created: 2018-08-28 Last updated: 2024-01-02Bibliographically approved
    2. Intralymphatic immunotherapy with one or two allergens renders similar clinical response in patients with allergic rhinitis due to birch and grass pollen
    Open this publication in new window or tab >>Intralymphatic immunotherapy with one or two allergens renders similar clinical response in patients with allergic rhinitis due to birch and grass pollen
    Show others...
    2022 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 52, no 6, p. 747-759Article in journal (Refereed) Published
    Abstract [en]

    Introduction

    There is a need for a fast, efficient and safe way to induce tolerance in patients with severe allergic rhinitis. Intralymphatic immune therapy has been shown to be effective.

    Methods

    Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abello), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analysed by flow cytometry and Luminex.

    Results

    The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment with one or two allergens. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased 3 years after treatment.

    Conclusions

    Intralymphatic immunotherapy with one or two allergens in patients with grass and birch pollen allergy was safe, effective and may be associated with bystander immune modulatory responses.

    Place, publisher, year, edition, pages
    Chichester, United Kingdom: Wiley-Blackwell Publishing Inc., 2022
    Keywords
    allergy; intralymphatic immunotherapy; hypersensitivity; rhinoconjunctivitis immunotherapy; intralymphatic; allergy
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:liu:diva-184407 (URN)10.1111/cea.14138 (DOI)000776517300001 ()35332591 (PubMedID)2-s2.0-85127382771 (Scopus ID)
    Note

    Funding Agencies: Region Östergotland; Medical Research Council of Southeast Sweden (FORSS); Th Bergh Foundation; Asthma and Allergy Association

    Available from: 2022-04-21 Created: 2022-04-21 Last updated: 2023-11-27Bibliographically approved
    3. Intralymphatic immunotherapy with birch and grass pollen extracts. A randomized double-blind placebo-controlled clinical trial
    Open this publication in new window or tab >>Intralymphatic immunotherapy with birch and grass pollen extracts. A randomized double-blind placebo-controlled clinical trial
    Show others...
    2023 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 53, no 8, p. 809-820Article in journal (Refereed) Published
    Abstract [en]

    IntroductionThere is a need to evaluate the safety and efficacy of intralymphatic immunotherapy (ILIT) for inducing tolerance in patients with allergic rhinitis. MethodsThirty-seven patients with seasonal allergic symptoms to birch and grass pollen and skin prick test >3 mm and/or IgE to birch and timothy >0.35 kU/L were randomized to either ILIT, with three doses of 0.1 mL of birch pollen and 5-grass pollen allergen extracts on aluminium hydroxide (10,000 SQ-U/ml; ALK-Abello) or placebo using ultrasound-guided intralymphatic injections at monthly intervals. Daily combined symptom medical score and rhinoconjunctivitis total symptom score were recorded during the peak pollen seasons the year before and after treatment. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were recorded annually starting 2 years after treatment. Circulating proportions of T helper cell subsets and allergen-induced cytokine and chemokine production were analysed using flow cytometry and ELISA. ResultsThere were no differences between the groups related to daily combined symptom medical score the year before and after treatment. Two years after ILIT (after unblinding), the actively treated group reported significantly fewer symptoms, lower medication use and improved quality of life than did the placebo group. After the pollen seasons the year after ILIT, T regulatory cell frequencies and grass-induced IFN-gamma levels increased only in the actively treated group. ConclusionIn this randomized controlled trial, ILIT with birch and grass pollen extract was safe and accompanied by immunological changes. Further studies are required to confirm or refute the efficacy of the treatment.

    Place, publisher, year, edition, pages
    WILEY, 2023
    Keywords
    allergy; hypersensitivity; intralymphatic immunotherapy; rhinoconjunctivitis
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:liu:diva-193405 (URN)10.1111/cea.14307 (DOI)000962776700001 ()37013723 (PubMedID)
    Note

    Funding Agencies|Astma- och Allergifoerbundet; Region OEstergoetland; Medical Research Council of Southeast Sweden (FORSS); Bergh Foundation

    Available from: 2023-05-03 Created: 2023-05-03 Last updated: 2023-11-27
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  • 4.
    Ahlbeck, Lars
    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, Medicine Center, Allergy Center.
    Ahlberg, Emelie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Björkander, Janne
    Acad Hlth & Care, Sweden.
    Aldén, Caroline
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Papapavlou, Georgia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Palmberg, Laura
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström Kronander, Ulla
    Region Östergötland, Medicine Center, Allergy Center.
    Retsas, Pavlos
    Region Östergötland, Medicine Center, Allergy Center.
    Nordenfelt, Patrik
    Cty Hosp Ryhov, Sweden.
    Togö, Totte
    Region Östergötland, Medicine Center, Allergy Center.
    Johansen, Pål
    Univ Zurich, Switzerland.
    Rolander, Bo
    Acad Hlth & Care, Sweden.
    Duchén, Karel
    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, Medicine Center, Allergy Center. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Intralymphatic immunotherapy with one or two allergens renders similar clinical response in patients with allergic rhinitis due to birch and grass pollen2022In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 52, no 6, p. 747-759Article in journal (Refereed)
    Abstract [en]

    Introduction

    There is a need for a fast, efficient and safe way to induce tolerance in patients with severe allergic rhinitis. Intralymphatic immune therapy has been shown to be effective.

    Methods

    Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abello), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analysed by flow cytometry and Luminex.

    Results

    The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment with one or two allergens. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased 3 years after treatment.

    Conclusions

    Intralymphatic immunotherapy with one or two allergens in patients with grass and birch pollen allergy was safe, effective and may be associated with bystander immune modulatory responses.

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  • 5.
    Ahlbeck, Lars
    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, Medicine Center, Allergy Center.
    Ahlberg, Emelie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Stuivers, Linn
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Bjorkander, Janne
    Futurum, Sweden.
    Nyström Kronander, Ulla
    Region Östergötland, Medicine Center, Allergy Center.
    Retsas, Pavlos
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Govindaraj, Dhanapal
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Duchén, Karel
    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, Medicine Center, Allergy Center.
    Intralymphatic immunotherapy with birch and grass pollen extracts. A randomized double-blind placebo-controlled clinical trial2023In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 53, no 8, p. 809-820Article in journal (Refereed)
    Abstract [en]

    IntroductionThere is a need to evaluate the safety and efficacy of intralymphatic immunotherapy (ILIT) for inducing tolerance in patients with allergic rhinitis. MethodsThirty-seven patients with seasonal allergic symptoms to birch and grass pollen and skin prick test >3 mm and/or IgE to birch and timothy >0.35 kU/L were randomized to either ILIT, with three doses of 0.1 mL of birch pollen and 5-grass pollen allergen extracts on aluminium hydroxide (10,000 SQ-U/ml; ALK-Abello) or placebo using ultrasound-guided intralymphatic injections at monthly intervals. Daily combined symptom medical score and rhinoconjunctivitis total symptom score were recorded during the peak pollen seasons the year before and after treatment. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were recorded annually starting 2 years after treatment. Circulating proportions of T helper cell subsets and allergen-induced cytokine and chemokine production were analysed using flow cytometry and ELISA. ResultsThere were no differences between the groups related to daily combined symptom medical score the year before and after treatment. Two years after ILIT (after unblinding), the actively treated group reported significantly fewer symptoms, lower medication use and improved quality of life than did the placebo group. After the pollen seasons the year after ILIT, T regulatory cell frequencies and grass-induced IFN-gamma levels increased only in the actively treated group. ConclusionIn this randomized controlled trial, ILIT with birch and grass pollen extract was safe and accompanied by immunological changes. Further studies are required to confirm or refute the efficacy of the treatment.

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  • 6.
    Ahlberg, Emelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Al-Kaabawi, Ahmed
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Thune, Rebecka
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Simpson, Melanie Rae
    Norwegian Univ Sci & Technol NTNU, Norway.
    Pedersen, Sindre Andre
    Norwegian Univ Sci & Technol NTNU, Norway.
    Cione, Erika
    Univ Calabria, Italy.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Tingö, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Orebro Univ, Sweden; Orebro Univ, Sweden.
    Breast milk microRNAs: Potential players in oral tolerance development2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1154211Article, review/survey (Refereed)
    Abstract [en]

    Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex biological fluid contains numerous immunologically active factors such as microorganisms, immunoglobulins, cytokines and microRNAs (miRNAs). Here, we set out to predict the function of the top 10 expressed miRNAs in human breast milk, focusing on their relevance in oral tolerance development and allergy prevention in the infant. The top expressed miRNAs in human breast milk were identified on basis of previous peer-reviewed studies gathered from a recent systematic review and an updated literature search. The miRNAs with the highest expression levels in each study were used to identify the 10 most common miRNAs or miRNA families across studies and these were selected for subsequent target prediction. The predictions were performed using TargetScan in combination with the Database for Annotation, Visualization and Integrated Discovery. The ten top expressed miRNAs were: let-7-5p family, miR-148a-3p, miR-30-5p family, miR-200a-3p + miR-141-3p, miR-22-3p, miR-181-5p family, miR-146b-5p, miR-378a-3p, miR-29-3p family, miR-200b/c-3p and miR-429-3p. The target prediction identified 3,588 potential target genes and 127 Kyoto Encyclopedia of Genes and Genomes pathways; several connected to the immune system, including TGF-b and T cell receptor signaling and T-helper cell differentiation. This review highlights the role of breast milk miRNAs and their potential contribution to infant immune maturation. Indeed, breast milk miRNAs seem to be involved in several pathways that influence oral tolerance development.

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  • 7.
    Ahlberg, Emelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Tingö, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Orebro Univ, Sweden.
    Evaluation of five column-based isolation kits and their ability to extract miRNA from human milk2021In: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 25, no 16, p. 7973-7979Article in journal (Refereed)
    Abstract [en]

    MicroRNA can be found in various body fluids, including breast milk. MicroRNA may be transferred from mother to infant via breast milk and potentially regulate the development of the infants immune system on a post-transcriptional level. This study aimed to determine the microRNA extraction efficiency of five RNA extraction kits from human skim milk samples. Their efficiency was determined by comparing microRNA concentrations, total RNA yield and purity. Furthermore, hsa-miR-148a-3p expression and the recovery of an exogenous control, cel-miR-39-3p, were quantified using qPCR. Each kit extracted different amounts of microRNA and total RNA, with one kit tending to isolate the highest amount of both RNA species. Based on these results, the extraction kit ReliaPrep (TM) miRNA Cell and Tissue Miniprep System from Promega was found to be the most appropriate kit for microRNA extraction from human skim milk. Moreover, further research is needed to establish a standardized protocol for microRNA extraction from breast milk.

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  • 8.
    Ahlberg, Emelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Martí Generó, Magalí Martí
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Govindaraj, Dhanapal
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Severin, Elisabet
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Duchén, Karel
    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, Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Tingö, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Orebro Univ, Sweden.
    Immune-related microRNAs in breast milk and their relation to regulatory T cells in breastfed children2023In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 34, no 4, article id e13952Article in journal (Refereed)
    Abstract [en]

    BackgroundThe immunomodulatory capacity of breast milk may partially be mediated by microRNAs (miRNA), small RNA molecules that regulate gene expression on a post-transcriptional level and are hypothesized to be involved in modulation of immunological pathways. Here, we evaluate the expression of immune-related miRNAs in breast milk after pre- and postnatal supplementation with Limosilactobacillus reuteri and omega-3 (omega-3) polyunsaturated fatty acids (PUFAs), and the association to infant regulatory T cell (Treg) frequencies. MethodsOne-hundred and twenty women included in a double-blind, randomized, placebo-controlled allergy intervention trial received L. reuteri and/or omega-3 PUFAs daily from gestational week 20. Using Taqman qPCR, 24 miRNAs were analyzed from breast milk obtained at birth (colostrum) and after 3 months (mature milk) of lactation. The proportion of activated and resting Treg cells were analyzed in infant blood using flow cytometry at 6, 12, and 24 months. ResultsRelative expression changed significantly over the lactation period for most of the miRNAs; however, the expression was not significantly influenced by any of the supplements. Colostrum miR-181a-3p correlated with resting Treg cell frequencies at 6 months. Colostrum miR-148a-3p and let-7d-3p correlated with the frequencies of activated Treg cells at 24 months, as did mature milk miR-181a-3p and miR-181c-3p. ConclusionMaternal supplementation with L. reuteri and omega-3 PUFAs did not significantly affect the relative miRNA expression in breast milk. Interestingly, some of the miRNAs correlate with Treg subpopulations in the breastfed children, supporting the hypothesis that breast milk miRNAs could be important in infant immune regulation. Trial registrationClinicalTrials.gov-ID: NCT01542970.

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  • 9.
    Ahlstrom, Christina A. A.
    et al.
    US Geol Survey, AK 99508 USA.
    Woksepp, Hanna
    Kalmar Cty Reg, Sweden; Linnaeus Univ, Sweden.
    Sandegren, Linus
    Uppsala Univ, Sweden.
    Ramey, Andrew M. M.
    US Geol Survey, AK 99508 USA.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Reg, Sweden.
    Exchange of Carbapenem-Resistant Escherichia coli Sequence Type 38 Intercontinentally and among Wild Bird, Human, and Environmental Niches2023In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336Article in journal (Refereed)
    Abstract [en]

    Carbapenem-resistant bacteria are a threat to public health globally and have been found in the environment as well as the clinic. Some bacterial clones are associated with carbapenem resistance genes, such as Escherichia coli sequence type 38 (ST38) and the carbapenemase gene bla(OXA-48). Carbapenem-resistant Enterobacteriaceae (CRE) are a global threat to human health and are increasingly being isolated from nonclinical settings. OXA-48-producing Escherichia coli sequence type 38 (ST38) is the most frequently reported CRE type in wild birds and has been detected in gulls or storks in North America, Europe, Asia, and Africa. The epidemiology and evolution of CRE in wildlife and human niches, however, remains unclear. We compared wild bird origin E. coli ST38 genome sequences generated by our research group and publicly available genomic data derived from other hosts and environments to (i) understand the frequency of intercontinental dispersal of E. coli ST38 clones isolated from wild birds, (ii) more thoroughly measure the genomic relatedness of carbapenem-resistant isolates from gulls sampled in Turkey and Alaska, USA, using long-read whole-genome sequencing and assess the spatial dissemination of this clone among different hosts, and (iii) determine whether ST38 isolates from humans, environmental water, and wild birds have different core or accessory genomes (e.g., antimicrobial resistance genes, virulence genes, plasmids) which might elucidate bacterial or gene exchange among niches. Our results suggest that E. coli ST38 strains, including those resistant to carbapenems, are exchanged between humans and wild birds, rather than separately maintained populations within each niche. Furthermore, despite close genetic similarity among OXA-48-producing E. coli ST38 clones from gulls in Alaska and Turkey, intercontinental dispersal of ST38 clones among wild birds is uncommon. Interventions to mitigate the dissemination of antimicrobial resistance throughout the environment (e.g., as exemplified by the acquisition of carbapenem resistance by birds) may be warranted.IMPORTANCE Carbapenem-resistant bacteria are a threat to public health globally and have been found in the environment as well as the clinic. Some bacterial clones are associated with carbapenem resistance genes, such as Escherichia coli sequence type 38 (ST38) and the carbapenemase gene bla(OXA-48). This is the most frequently reported carbapenem-resistant clone in wild birds, though it was unclear if it circulated within wild bird populations or was exchanged among other niches. The results from this study suggest that E. coli ST38 strains, including those resistant to carbapenems, are frequently exchanged among wild birds, humans, and the environment. Carbapenem-resistant E. coli ST38 clones in wild birds are likely acquired from the local environment and do not constitute an independent dissemination pathway within wild bird populations. Management actions aimed at preventing the environmental dissemination and acquisition of antimicrobial resistance by wild birds may be warranted.

  • 10.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Frick, Anna
    State Alaska Dept Hlth & Social Serv, AK USA.
    Pongratz, Catherine
    State Alaska Dept Hlth & Social Serv, AK USA.
    Spink, Kimberly
    State Alaska Dept Hlth & Social Serv, AK USA.
    Xavier, Catherine
    State Alaska Dept Hlth & Social Serv, AK USA.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Council, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Genomic comparison of carbapenem-resistant Enterobacteriaceae from humans and gulls in Alaska2021In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 25, p. 23-25Article in journal (Refereed)
    Abstract [en]

    Objectives: Wildlife may harbour clinically important antimicrobial-resistant bacteria, but the role of wildlife in the epidemiology of antimicrobial-resistant bacterial infections in humans is largely unknown. In this study, we aimed to assess dissemination of the bla(KPC) carbapenemase gene among humans and gulls in Alaska. Methods: We performed whole-genome sequencing to determine the genetic context of bla(KPC) in bacterial isolates from all four human carbapenemase-producing Enterobacteriaceae (CPE) infections reported in Alaska between 2013-2018 and to compare the sequences with seven previously reported CPE isolates from gull faeces within the same region and time period. Results: Genomic analysis of CPE isolates suggested independent acquisition events among humans with no evidence for direct transmission of bla(KPC) between people and gulls. However, some isolates shared conserved genetic elements surrounding bla(KPC), suggesting possible exchange between species. Conclusion: Our results highlight the genomic plasticity associated with bla(KPC) and demonstrate that sampling of wildlife may be useful for identifying clinically relevant antimicrobial resistance not observed through local passive surveillance in humans. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

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  • 11.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK USA; US Geol Survey, AK 99508 USA.
    Scott, Laura C.
    US Geol Survey, AK USA.
    Woksepp, Hanna
    Reg Kalmar Cty, Sweden; Linnaeus Univ, Sweden.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Reg Kalmar Cty, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK USA.
    Environmental antimicrobial resistance gene detection from wild bird habitats using two methods: A commercially available culture-independent qPCR assay and culture of indicator bacteria followed by whole-genome sequencing2023In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 33, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Objectives: A variety of methods have been developed to detect antimicrobial resistance (AMR) in differ-ent environments to better understand the evolution and dissemination of this public health threat. Com-parisons of results generated using different AMR detection methods, such as quantitative PCR (qPCR) and whole-genome sequencing (WGS), are often imperfect, and few studies have analysed samples in parallel to evaluate differences. In this study, we compared bacterial culture and WGS to a culture-independent commercially available qPCR assay to evaluate the concordance between methods and the utility of each in answering research questions regarding the presence and epidemiology of AMR in wild bird habitats.Methods: We first assessed AMR gene detection using qPCR in 45 bacterial isolates from which we had existing WGS data. We then analysed 52 wild bird faecal samples and 9 spatiotemporally collected water samples using culture-independent qPCR and WGS of phenotypically resistant indicator bacterial isolates.Results: Overall concordance was strong between qPCR and WGS of bacterial isolates, although concor-dance differed among antibiotic classes. Analysis of wild bird faecal and water samples revealed that more samples were determined to be positive for AMR via qPCR than via culture and WGS of bacterial isolates, although qPCR did not detect AMR genes in two samples from which phenotypically resistant isolates were found.Conclusions: Both qPCR and culture followed by sequencing may be effective approaches for characteris-ing AMR genes harboured by wild birds, although data streams produced using these different tools may have advantages and disadvantages that should be considered given the application and sample matrix.Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

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  • 12.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    van Toor, Marielle L.
    Linnaeus Univ, Sweden.
    Woksepp, Hanna
    Kalmar Cty Hosp, Sweden.
    Chandler, Jeffrey C.
    USDA APHIS WS, CO 80521 USA.
    Reed, John A.
    US Geol Survey, AK 99508 USA.
    Reeves, Andrew B.
    US Geol Survey, AK 99508 USA.
    Waldenstrom, Jonas
    Linnaeus Univ, Sweden.
    Franklin, Alan B.
    USDA APHIS WS, CO 80521 USA.
    Douglas, David C.
    US Geol Survey, AK 99801 USA.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Dept Infect Dis, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Evidence for continental-scale dispersal of antimicrobial resistant bacteria by landfill-foraging gulls2021In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 764, article id 144551Article, review/survey (Refereed)
    Abstract [en]

    Anthropogenic inputs into the environment may serve as sources of antimicrobial resistant bacteria and alter the ecology and population dynamics of synanthropic wild animals by providing supplemental forage. In this study, we used a combination of phenotypic and genomic approaches to characterize antimicrobial resistant indicator bacteria, animal telemetry to describe host movement patterns, and a novel modeling approach to combine information from these diverse data streams to investigate the acquisition and long-distance dispersal of antimicrobial resistant bacteria by landfill-foraging gulls. Our results provide evidence that gulls acquire antimicrobial resistant bacteria from anthropogenic sources, which they may subsequently disperse across and between continents via migratory movements. Furthermore, we introduce a flexible modeling framework to estimate the relative dispersal risk of antimicrobial resistant bacteria in western North America and adjacent areas within East Asia, which may be adapted to provide information on the risk of dissemination of other organisms and pathogens maintained by wildlife through space and time. Published by Elsevier B.V.

  • 13.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Woksepp, Hanna
    Kalmar Cty Hosp, Sweden; Linnaeus Univ, Sweden.
    Sandegren, Linus
    Uppsala Univ, Sweden.
    Mohsin, Mashkoor
    Univ Agr Faisalabad, Pakistan.
    Hasan, Badrul
    Uppsala Univ, Sweden; Anim Bacteriol Sect, Australia.
    Muzyka, Denys
    Inst Expt & Clin Vet Med, Ukraine.
    Hernandez, Jorge
    Kalmar Cty Hosp, Sweden.
    Aguirre, Filip
    Kalmar Cty Hosp, Sweden.
    Tok, Atalay
    Uppsala Univ, Sweden.
    Söderman, Jan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Olsen, Bjorn
    Uppsala Univ, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Kalmar Cty, Sweden.
    Genomically diverse carbapenem resistant Enterobacteriaceae from wild birds provide insight into global patterns of spatiotemporal dissemination2022In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 824, article id 153632Article in journal (Refereed)
    Abstract [en]

    Carbapenem resistant Enterobacteriaceae (CRE) are a threat to public health globally, yet the role of the environment in the epidemiology of CRE remains elusive. Given that wild birds can acquire CRE, likely from foraging in anthropogenically impacted areas, and may aid in the maintenance and dissemination of CRE in the environment, a spatiotemporal comparison of isolates from different regions and timepoints may be useful for elucidating epidemiological information. Thus, we characterized the genomic diversity of CRE from fecal samples opportunistically collected from gulls (Larus spp.) inhabiting Alaska (USA), Chile, Spain, Turkey, and Ukraine and from black kites (Milvus migrans) sampled in Pakistan and assessed evidence for spatiotemporal patterns of dissemination. Within and among sampling locations, a high diversity of carbapenemases was found, including Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-beta-lactamase (NDM), oxacillinase (OXA), and Verona integron Metallo beta-lactamase (VIM). Although the majority of genomic comparisons among samples did not provide evidence for spatial dissemination, we did find strong evidence for dissemination among Alaska, Spain, and Turkey. We also found strong evidence for temporal dissemination among samples collected in Alaska and Pakistan, though the majority of CRE clones were transitory and were not repeatedly detected among locations where samples were collected longitudinally. Carbapenemase-producing hypervirulent K. pneumoniae was isolated from gulls in Spain and Ukraine and some isolates harbored antimicrobial resistance genes conferring resistance to up to 10 different antibiotic classes, including colistin. Our results are consistent with local acquisition of CRE by wild birds with spatial dissemination influenced by intermediary transmission routes, likely involving humans. Furthermore, our results support the premise that anthropogenicallyassociated wild birds may be good sentinels for understanding the burden of clinically-relevant antimicrobial resistance in the local human population.

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  • 14. Order onlineBuy this publication >>
    Ahmad, Awais
    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.
    Autoantibodies in healthy blood donors, rheumatic and autoimmune liver diseases2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Autoimmunity is a common phenomenon where the immune system recognises the body's own tissues. Autoimmunity can lead to disease if tissue damage occurs. Autoimmune diseases affect 5–10% of the global population and in many of these autoantibodies can be detected. The autoantibodies can be detected with several different methods. In this thesis, line immunoassays and fluorescence enzyme immunoassay were used to investigate the presence of autoantibodies in blood donors and various disease groups. Line immunoassays use strips while fluorescence enzyme immunoassay uses wells. The strips and wells are coated with proteins that are allowed to react with serum samples from the patient. In the presence of autoantibodies, either a color change (line immunoassay) or a light reaction (fluorescence enzyme immunoassay) occurs.

    Study I and II: With the EuroLine -Autoimmune Liver Diseases- (IgG) line immunoassay, the presence of autoantibodies associated with autoimmune liver diseases was analysed in blood donors, patients with autoimmune liver diseases and patients with SLE. Autoantibodies could be detected in several blood donors. A very rare autoantibody, anti-LC- 1, was more common in blood donors than in patients with autoimmune liver diseases. Despite the presence of the autoantibodies, no association was seen with abnormal liver values in blood donors or patients with SLE. By raising the cut-off, the number of "false positive" results decreased. However, this could not correct the problem with anti-LC-1, which seems to indicate that there is a problem with the LC-1 antigen so that non-specific reactions are detected. The risk of developing autoimmune liver disease was considered to be low in the SLE patients, as none of these patients developed autoimmune liver disease despite several years of follow-up. Most of the positive findings with the EuroLine immunoassay could not be confirmed with other methods, indicating that this method is very sensitive.

    Study III: With the EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) line immunoassay, the rare autoantibodies anti-Th/To and anti-NOR90 could be detected as frequently in blood donors as in patients with systemic sclerosis. Most of the other autoantibodies were more common in patients with systemic sclerosis compared to blood donors and other disease groups. Some of these autoantibodies were associated with specific clinical manifestations, including renal involvement in patients with SLE. These findings need to be verified.

    Study IV: Autoantibodies that bind the U1-RNP protein (anti-U1-RNP) can be detected in patients with SLE. Patients with anti-U1-RNP can be further analysed for the presence of autoantibodies against the protein RNP 70kDa (anti-RNP70). However, the clinical value of further analysis of anti-RNP70 is uncertain. In this study, fluorescence enzyme immunoassay was used to analyse anti-U1-RNP positive samples for anti-RNP70 to evaluate whether it added anything of clinical value in SLE patients. Presence of anti-U1-RNP was associated with low white blood cell counts and less organ damage. However, analysis of anti-RNP70 in patients with SLE did not add any additional clinical information.

    Conclusion: Euroline -Autoimmune Liver Diseases- (IgG) and EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) are tools that are of value in the diagnosis of autoimmune liver diseases and systemic sclerosis, but the methods have high sensitivity which can lead to false positive results. By raising the cut-off, the risk of this can be reduced. Some rare antibodies were found more frequently in blood donors than in patients with the different disease groups, suggesting potential problems with the antigen source. Subtyping of anti-RNP70 in SLE patients with anti-U1-RNP did not add anything of clinical value.

    List of papers
    1. Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes
    Open this publication in new window or tab >>Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes
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    2021 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 203, no 1, p. 22-31Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2021
    Keywords
    autoantibodies; autoimmune hepatitis; primary biliary cholangitis; Sjogrens syndrome; systemic lupus erythematosus
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-170539 (URN)10.1111/cei.13512 (DOI)000573490000001 ()32910463 (PubMedID)2-s2.0-85091690857 (Scopus ID)
    Note

    Funding Agencies|Swedish Rheumatism Association; Region ostergotland (ALF grants); Swedish Society of Medicine; King Gustaf Vs 80-year Anniversary foundation; King Gustaf V and Queen Victorias Freemasons foundation

    Available from: 2020-10-16 Created: 2020-10-16 Last updated: 2024-02-05Bibliographically approved
    2. Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test
    Open this publication in new window or tab >>Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test
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    2022 (English)In: Diagnostics, ISSN 2075-4418, Vol. 12, no 7, article id 1572Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    MDPI, 2022
    Keywords
    autoimmune liver disease; AIH; PBC; PML; Sp100; gp210; AMA-M2; EUROLINE
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:liu:diva-187446 (URN)10.3390/diagnostics12071572 (DOI)000831404600001 ()35885478 (PubMedID)
    Note

    Funding Agencies|Region Ostergotland (ALF grants) [RO932055]

    Available from: 2022-08-23 Created: 2022-08-23 Last updated: 2024-02-05
    3. Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis
    Open this publication in new window or tab >>Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis
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    2022 (English)In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 9, no 1, article id e000732Article in journal (Refereed) Published
    Abstract [en]

    ObjectiveSLE, primary Sjogrens syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-alpha, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-alpha was quantified by ELISA. Self-reported data on Raynauds phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-alpha levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.

    Place, publisher, year, edition, pages
    BMJ PUBLISHING GROUP, 2022
    Keywords
    Sjogrens Syndrome; Scleroderma; Systemic; Lupus Erythematosus; Interferon Type I; Autoantibodies
    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:liu:diva-191220 (URN)10.1136/lupus-2022-000732 (DOI)000906026900002 ()36581379 (PubMedID)
    Note

    Funding Agencies|King Gustaf V and Queen Victorias Freemasons Foundation; King Gustaf Vs 80-year Anniversary Foundation; Gustafsson Foundation; Swedish Rheumatism Association, Region OEstergoetland (ALF grants)

    Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2024-02-05
    4. Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus
    Open this publication in new window or tab >>Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus
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    2023 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 12, article id 10398Article in journal (Refereed) Published
    Abstract [en]

    The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjogrens syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p < 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value.

    Place, publisher, year, edition, pages
    MDPI, 2023
    Keywords
    autoantibodies; mixed connective tissue disease; primary Sjogrens syndrome; small nuclear ribonucleoprotein antibodies; systemic lupus erythematosus
    National Category
    Dentistry
    Identifiers
    urn:nbn:se:liu:diva-196857 (URN)10.3390/ijms241210398 (DOI)001014922500001 ()37373545 (PubMedID)
    Available from: 2023-08-24 Created: 2023-08-24 Last updated: 2024-02-05
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  • 15.
    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.
    Brylid, Andre
    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.
    Saleh, Muna Atallah
    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.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Enocsson, Helena
    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.
    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.
    Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus2023In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 12, article id 10398Article in journal (Refereed)
    Abstract [en]

    The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjogrens syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p < 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value.

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  • 16.
    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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  • 17.
    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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  • 18.
    Ahmadpour, Doryaneh
    et al.
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala. Chalmers Univ Technol, Sweden.
    Kristoffersson, Anna
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Fredrikson, Mats
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences, Forum Östergötland.
    Link, Yumin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping.
    Eriksson, Anne
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Iacobaeus, Ellen
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Landtblom, Anne-Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping. Uppsala Univ, Sweden.
    Haghighi, Sara
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping. Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Inventory study of an early pandemic COVID-19 cohort in South-Eastern Sweden, focusing on neurological manifestations2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 1, article id e0280376Article in journal (Refereed)
    Abstract [en]

    BackgroundNeurological manifestations in patients with COVID-19 have been reported previously as outcomes of the infection.The purpose of current study was to investigate the occurrence of neurological signs and symptoms in COVID-19 patients, in the county of ostergotland in southeastern Sweden. MethodsThis is a retrospective, observational cohort study. Data were collected between March 2020 and June 2020. Information was extracted from medical records by a trained research assistant and physician and all data were validated by a senior neurologist. ResultsSeventy-four percent of patients developed at least one neurological symptom during the acute phase of the infection. Headache (43%) was the most common neurological symptom, followed by anosmia and/or ageusia (33%), confusion (28%), hallucinations (17%), dizziness (16%), sleep disorders in terms of insomnia and OSAS (Obstructive Sleep Apnea) (9%), myopathy and neuropathy (8%) and numbness and tingling (5%). Patients treated in the ICU had a higher male presentation (73%). Several risk factors in terms of co-morbidities, were identified. Hypertension (54.5%), depression and anxiety (51%), sleep disorders in terms of insomnia and OSAS (30%), cardiovascular morbidity (28%), autoimmune diseases (25%), chronic lung diseases (24%) and diabetes mellitus type 2 (23%) founded as possible risk factors. ConclusionNeurological symptoms were found in the vast majority (74%) of the patients. Accordingly, attention to neurological, mental and sleep disturbances is warranted with involvement of neurological expertise, in order to avoid further complications and long-term neurological effect of COVID-19. Furthermore, risk factors for more severe COVID-19, in terms of possible co-morbidities that identified in this study should get appropriate attention to optimizing treatment strategies in COVID-19 patients.

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  • 19.
    Al Abri, Seif
    et al.
    Minist Hlth, Oman.
    Kasaeva, Thereza
    Who Global TB Programme, Switzerland.
    Migliori, Giovanni Battista
    Ist Clin Sci Maugeri IRCCS, Italy.
    Goletti, Delia
    Natl Inst Infect Dis Lazzaro Spallanzani IRCCS, Italy; ESCMID Study Grp Mycobacteria, Switzerland.
    Zenner, Dominik
    IOM, Belgium.
    Denholm, Justin
    Royal Melbourne Hosp, Australia; Victorian TB Programme, Australia.
    Al Maani, Amal
    Royal Hosp, Oman; Minist Hlth, Oman.
    Cirillo, Daniela Maria
    San Rafaele Sci Inst, Italy.
    Schön, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Lillebaek, Troels
    Univ Copenhagen, Denmark.
    Al-Jardani, Amina
    Minist Hlth, Oman.
    Go, Un-Yeong
    Int TB Res Ctr, South Korea.
    Dias, Hannah Monica
    WHO Global TB Programme Unit Policy Strategy and In, Switzerland.
    Tiberi, Simon
    Barts Hlth NHS Trust, England; Queen Mary Univ London, England.
    Al Yaquobi, Fatma
    Minist Hlth, Oman.
    Khamis, Faryal Ali
    Minist Hlth, Oman.
    Kurup, Padmamohan
    Muscat Governorate, Oman.
    Wilson, Michael
    Zero TB Initiat, South Africa.
    Memish, Ziad
    Alfaisal Univ, Saudi Arabia; Emory Univ, GA 30322 USA.
    Al Maqbali, Ali
    North Bathinah Governorate, Oman.
    Akhtar, Muhammad
    WHO MENA Reg TB Programme, Egypt.
    Wejse, Christian
    Univ Aarhus, Denmark; ESCMID Study Grp Travel and Migrat, Switzerland.
    Petersen, Eskild
    Minist Hlth, Oman; Univ Aarhus, Denmark; ESCMID Emerging Infect Task Force, Switzerland.
    Tools to implement the World Health Organization End TB Strategy: Addressing common challenges in high and low endemic countries2020In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 92, p. S60-S68Article in journal (Refereed)
    Abstract [en]

    Aim: The purpose of this viewpoint is to summarize the advantages and constraints of the tools and strategies available for reducing the annual incidence of tuberculosis (TB) by implementing the World Health Organization (WHO) End TB Strategy and the linked WHO TB Elimination Framework, with special reference to Oman. Methods: The case-study was built based on the presentations and discussions at an international workshop on TB elimination in low incidence countries organized by the Ministry of Health, Oman, which took place from September 5 to September 7, 2019, and supported by the WHO and European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Results: Existing tools were reviewed, including the screening of migrants for latent TB infection (LTBI) with interferon-gamma release assays, clinical examination for active pulmonary TB (APTB) including chest X-rays, organization of laboratory services, and the existing centres for mandatory health examination of pre-arrival or arriving migrants, including examination for APTB. The need for public-private partnerships to handle the burden of screening arriving migrants for active TB was discussed at length and different models for financing were reviewed. Conclusions: In a country with a high proportion of migrants from high endemic countries, screening for LTBI is of high priority. Molecular typing and the development of public-private partnerships are needed. (C) 2020 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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  • 20.
    Alffenaar, J. W. C.
    et al.
    Univ Sydney, Australia; Westmead Hosp, Australia.
    Stocker, S. L.
    Univ Sydney, Australia; St Vincents Hosp, Australia; Univ NSW, Australia.
    Forsman, L. Davies
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Garcia-Prats, A.
    Stellenbosch Univ, South Africa; Univ Wisconsin, WI USA.
    Heysell, S. K.
    Univ Virginia, VA USA.
    Aarnoutse, R. E.
    Radboud Univ Nijmegen Med Ctr, Netherlands.
    Akkerman, O. W.
    Univ Groningen, Netherlands; Univ Groningen, Netherlands.
    Aleksa, A.
    Grodno State Med Univ, BELARUS.
    van Altena, R.
    Asian Harm Reduct Network AHRN, Myanmar; Med Act Myanmar MAM, Myanmar.
    de Onata, W. Arrazola
    Belgian Sci Inst Publ Hlth, Belgium.
    Bhavani, P. K.
    Indian Council Med Res Natl Inst Res TB, India.
    Vant Boveneind-Vrubleuskaya, N.
    Univ Groningen, Netherlands; Metropolitan Publ Hlth Serv, Netherlands.
    Carvalho, A. C. C.
    Fundacao Oswaldo Cruz, Brazil.
    Centis, R.
    Ist Ricovero & Cura Carattere Sci IRCCS, Italy.
    Chakaya, J. M.
    Kenyatta Univ, Kenya; Univ Liverpool Liverpool Sch Trop Med, England.
    Cirillo, D. M.
    IRCCS San Raffaele Sci Inst, Italy.
    Cho, J. G.
    Univ Sydney, Australia; Westmead Hosp, Australia; Parramatta Chest Clin, Australia.
    Ambrosio, L. D.
    Publ Hlth Consulting Grp, Switzerland.
    Dalcolmo, M. P.
    Funda Oswaldo Cruz Fiocruz, Brazil.
    Denti, P.
    Univ Cape Town, South Africa.
    Dheda, K.
    Univ Cape Town, South Africa; Univ Cape Town Lung Inst, South Africa; South African MRC Ctr Study Antimicrobial Resista, South Africa; London Sch Hyg & Trop Med, England.
    Fox, G. J.
    Univ Sydney, Australia; Woolcock Inst Med Res, Australia.
    Hesseling, A. C.
    Stellenbosch Univ, South Africa.
    Kim, H. Y.
    Univ Sydney, Australia; Westmead Hosp, Australia.
    Koser, C. U.
    Univ Cambridge, England.
    Marais, B. J.
    Univ Sydney, Australia; Childrens Hosp Westmead, Australia.
    Margineanu, I
    Univ Groningen, Netherlands.
    Martson, A. G.
    Univ Liverpool, England.
    Torrico, M. Munoz
    Inst Nacl Enfermedades Resp, Mexico.
    Nataprawira, H. M.
    Univ Padjadjaran, Indonesia.
    Ong, C. W. M.
    Natl Univ Singapore, Singapore; Natl Univ Singapore Hosp, Singapore.
    Otto-Knapp, R.
    German Cent Comm TB DZK, Germany.
    Peloquin, C. A.
    Univ Florida, FL USA.
    Silva, D. R.
    Univ Fed Rio Grande do Sul, Brazil.
    Ruslami, R.
    Univ Padjadjaran, Indonesia.
    Santoso, P.
    Univ Padjadjaran, Indonesia.
    Savic, R. M.
    Univ Calif San Francisco, CA USA.
    Singla, R.
    Natl Inst TB & Resp Dis, India.
    Svensson, E. M.
    Radboud Univ Nijmegen Med Ctr, Netherlands; Uppsala Univ, Sweden.
    Skrahina, A.
    Republican Res & Pract Ctr Pulmonol & TB, BELARUS.
    van Soolingen, D.
    Natl Inst Publ Hlth & Environm, Netherlands.
    Srivastava, S.
    Univ Texas Hlth Sci Ctr Tyler, TX USA.
    Tadolini, M.
    IRCCS Azienda Osped Univ Bologna, Italy; Alma Mater Studiorum Univ Bologna, Italy.
    Tiberi, S.
    Queen Mary Univ London, England.
    Thomas, T. A.
    Univ Virginia, VA USA.
    Udwadia, Z. F.
    PD Hinduja Natl Hosp & Med Res Ctr, India.
    Vu, D. H.
    Hanoi Univ Pharm, Vietnam.
    Zhang, W.
    Fudan Univ, Peoples R China.
    Mpagama, S. G.
    Kilimanjaro Christian Med Univ Coll, Tanzania; Kibongoto Infect Dis Hosp, Tanzania.
    Schön, Thomas
    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 Infectious Diseases. Kalmar Cty Hosp, Sweden.
    Migliori, G. B.
    Grodno State Med Univ, BELARUS.
    Clinical standards for the dosing and management of TB drugs2022In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 26, no 6, p. 483-499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on best practice for dosing and management of TB drugs.

    METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.

    RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.

    CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

  • 21.
    Alfsnes, Kristian
    et al.
    Norwegian Inst Publ Hlth, Norway.
    Lagerqvist, Nina
    Publ Hlth Agcy Sweden, Sweden.
    Vene, Sirkka
    Publ Hlth Agcy Sweden, Sweden.
    Bohlin, Jon
    Norwegian Inst Publ Hlth, Norway.
    Verner-Carlsson, Jenny
    Publ Hlth Agcy Sweden, Sweden.
    Ekqvist, David
    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 Infectious Diseases.
    Brave, Andreas
    Publ Hlth Agcy Sweden, Sweden.
    Holmes, Edward C.
    Univ Sydney, Australia; Univ Sydney, Australia.
    Shi, Weifeng
    Shandong First Med Univ & Shandong Acad Med Sci, Peoples R China.
    Pettersson, John H-O
    Publ Hlth Agcy Sweden, Sweden; Univ Sydney, Australia; Univ Sydney, Australia; Uppsala Univ, Sweden.
    Retrospective meta-transcriptomic identification of severe dengue in a traveller returning from Africa to Sweden, 19902021In: One Health, ISSN 2352-7714, Vol. 12, article id 100217Article in journal (Refereed)
    Abstract [en]

    Pathogens associated with haemorrhagic fever commonly have zoonotic origins. The first documented imported case of likely viral severe haemorrhagic fever in Sweden occurred in 1990. Despite extensive study, no aetiological agent was identified. Following retrospective investigation with total RNA-sequencing of samples collected between 7 and 36 days from onset of symptoms we identified dengue virus 3 (DENV-3) and a human pegivirus (HPgV). We conclude that the patient likely suffered from haemorrhagic symptoms due to an atypical severe and undiagnosed dengue infection.

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  • 22.
    Amirhosseini, Mehdi
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Alkaissi, Hammoudi
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Hultman, Per
    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, Clinical pathology.
    Havarinasab, Said
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Autoantibodies in outbred Swiss Webster mice following exposure to gold and mercury2021In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 412, article id 115379Article in journal (Refereed)
    Abstract [en]

    Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored. Serum antinuclear antibodies (ANA), polyclonal B-cell activation, hypergammaglobulinemia and tissue immune complex deposition are the main features of metal-induced autoimmunity in inbred mice. However, inbred mouse strains do not represent the genetic heterogeneity in humans. In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl2) in drinking water, caused IgG antinucleolar antibodies (ANoA) after 5 weeks in SW mice accompanied by immune complex deposition in kidneys and spleen. Serum IgG antibodies corresponding to anti-fibrillarin, and anti-PM/Scl-100 antibodies, were observed in mercury-exposed SW mice. Gold and mercury trigger systemic autoimmune response in genetically heterogeneous outbred SW mice and suggest them as an appropriate model to study xenobiotic-induced autoimmunity.

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  • 23.
    Andersson, Anna-Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Efferocytosis of Apoptotic Neutrophils Enhances Control of Mycobacterium tuberculosis in HIV-Coinfected Macrophages in a Myeloperoxidase-Dependent Manner2020In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 12, no 3, p. 235-247Article in journal (Refereed)
    Abstract [en]

    Tuberculosis remains a big threat, with 1.6 million deaths in 2017, including 0.3 million deaths among patients with HIV. The risk of developing active disease increases considerably during an HIV coinfection. Alveolar macrophages are the first immune cells to encounter the causative agent Mycobacterium tuberculosis, but during the granuloma formation other cells are recruited in order to combat the bacteria. Here, we have investigated the effect of efferocytosis of apoptotic neutrophils by M. tuberculosis and HIV-coinfected macrophages in a human in vitro system. We found that the apo-ptotic neutrophils enhanced the control of M. tuberculosis in single and HIV-coinfected macrophages, and that this was dependent on myeloperoxidase (MPO) and reactive oxygen species in an autophagy-independent manner. We show that MPO remains active in the apoptotic neutrophils and can be harnessed by infected macrophages. In addition, MPO inhibition removed the suppression in M. tuberculosis growth caused by the apoptotic neutrophils. Antimycobacterial components from apoptotic neutrophils could thus increase the microbicidal activity of macrophages during an M. tuberculosis/HIV coinfection. This cooperation between innate immune cells could thereby be a way to compensate for the impaired adaptive immunity against M. tuberculosis seen during a concurrent HIV infection.

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  • 24.
    Andersson, Blanka
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Jonsson Nordvall, Michaela
    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 Microbiology.
    Welin, Amanda
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Lerm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Department of Infectious Diseases and Clinical Microbiology, Kalmar County Hospital, Kalmar, Sweden.
    A novel mycobacterial growth inhibition assay employing live-cell imaging of virulent M. tuberculosis and monitoring of host cell viability2020In: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 124, article id 101977Article in journal (Refereed)
    Abstract [en]

    Our aim was to develop a Mycobacterium tuberculosis (Mtb) growth inhibition assay (MGIA) as a summary estimate of host immune control of virulent Mtb. Mycobacterial growth inhibition (MGI) using previously frozen human PBMCs infected with H37Rv was assessed by live-cell imaging (Incucyte (c)) complemented by imaging flow cytometry analysis of phagocytosis. MGI measured as relative fluorescence units (RFU) was calibrated to time to positive culture (TTP) in BACTEC 960 MGIT. At a MOI (multiplicity of infection) of 5, there was a wide range of MGI of blood donors (1.1*10(6)-2.7*10(6) RFU, n = 14). Intra- and inter-assay variability were at most 17.5 and 20.7 CV%. Cell viability at day 5 was 57 and 62% monitored by the LDH and Draq7 assays respectively. There was a strong correlation between a readout for Mtb growth using CFU counts or TTP compared to RFU (r2 >= 0.96). Our MGIA enabling live-cell imaging and monitoring of cell viability was able to detect a wide range of Mtb growth inhibition by PBMCs and was calibrated to several readout options for bacterial growth. This MGIA may be valuable as a surrogate marker of host immunity in a personalized medicine approach.

  • 25.
    Andersson, Linnea I.
    et al.
    Linnaeus Univ, Sweden.
    Sjoestroem, Dick J.
    Linnaeus Univ, Sweden.
    Quach, Huy Quang
    Mayo Clin, MN 55905 USA.
    Haegerstroem, Kim
    Dept Clin Chem & Transfus Med, Sweden.
    Hurler, Lisa
    Semmelwe Univ, Hungary.
    Kajdacsi, Erika
    Semmelwe Univ, Hungary.
    Cervenak, Laszlo
    Semmelwe Univ, Hungary.
    Prohaszka, Zoltan
    Semmelwe Univ, Hungary.
    Toonen, Erik J. M.
    R&D Dept, Netherlands.
    Mohlin, Camilla
    Linnaeus Univ, Sweden.
    Mollnes, Tom Eirik
    Univ Oslo, Norway; Nordland Hosp, Norway.
    Sandgren, Per
    Karolinska Inst, Sweden.
    Tjernberg, Ivar
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Dept Clin Chem & Transfus Med, Sweden.
    Nilsson, Per H.
    Linnaeus Univ, Sweden; Linnaeus Univ, Sweden.
    Storage of Transfusion Platelet Concentrates Is Associated with Complement Activation and Reduced Ability of Platelets to Respond to Protease-Activated Receptor-1 and Thromboxane A2 Receptor2024In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 2, article id 1091Article in journal (Refereed)
    Abstract [en]

    Platelet activation and the complement system are mutually dependent. Here, we investigated the effects of storage time on complement activation and platelet function in routinely produced platelet concentrates. The platelet concentrates (n = 10) were stored at 22 degrees C for seven days and assessed daily for complement and platelet activation markers. Additionally, platelet function was analyzed in terms of their responsiveness to protease-activated receptor-1 (PAR-1) and thromboxane A2 receptor (TXA(2)R) activation and their capacity to adhere to collagen. Complement activation increased over the storage period for all analyzed markers, including the C1rs/C1-INH complex (fold change (FC) = 1.9; p < 0.001), MASP-1/C1-INH complex (FC = 2.0; p < 0.001), C4c (FC = 1.8, p < 0.001), C3bc (FC = 4.0; p < 0.01), and soluble C5b-9 (FC = 1.7, p < 0.001). Furthermore, the levels of soluble platelet activation markers increased in the concentrates over the seven-day period, including neutrophil-activating peptide-2 (FC = 2.5; p < 0.0001), transforming growth factor beta 1 (FC = 1.9; p < 0.001) and platelet factor 4 (FC = 2.1; p < 0.0001). The ability of platelets to respond to activation, as measured by surface expression of CD62P and CD63, decreased by 19% and 24% (p < 0.05) for PAR-1 and 69-72% (p < 0.05) for TXA(2)R activation, respectively, on Day 7 compared to Day 1. The extent of platelet binding to collagen was not significantly impaired during storage. In conclusion, we demonstrated that complement activation increased during the storage of platelets, and this correlated with increased platelet activation and a reduced ability of the platelets to respond to, primarily, TXA(2)R activation.

  • 26.
    Andersson, Viktoria
    et al.
    Karolinska Univ Hosp, Sweden.
    Froberg, Gabrielle
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Dahl, Victor
    Aarhus Univ Hosp, Sweden; Aarhus Univ GloHAU, Denmark; Statens Serum Inst, Denmark.
    Chryssanthou, Erja
    Karolinska Univ Hosp, Sweden.
    Giske, Christian
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Schön, Thomas
    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 Infectious Diseases. Karolinska Univ Hosp, Sweden.
    Forsman, Lina
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    The In vitro Activity of Carbapenems Alone and in Combination with β-lactamase Inhibitors against Difficult-to-treat Mycobacteria; Mycobacterium tuberculosis, Mycobacterium abscessus, and Mycobacterium avium Complex: A Systematic Review2023In: INTERNATIONAL JOURNAL OF MYCOBACTERIOLOGY, ISSN 2212-5531, Vol. 12, no 3, p. 211-225Article, review/survey (Refereed)
    Abstract [en]

    Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium tuberculosis (MTB), as well as nontuberculous mycobacteria such as the Mycobacterium abscessus complex (MABC) and Mycobacterium avium complex (MAC). Recently, new carbapenems and combinations of carbapenems with beta-lactamase inhibitors have become available, but activity data in vitro against mycobacteria are so far scarce. Therefore, we performed a systematic review collating the minimum inhibitory concentrations (MICs) of carbapenems, with or without a beta-lactamase inhibitors for MTB, MABC, and MAC. The databases PubMed and Web of Science were searched for the relevant articles in English up until September 21, 2022. Screening of studies was performed by two independent reviewers. MIC data by recommended methods with at least five individual MICs were included. Data were reported as MIC range, MIC50, modal MIC, and/or histograms when individual MICs were available. The study protocol was registered at PROSPERO (CRD42021258537). After screening, a total of 75 studies with MIC data for carbapenems with or without beta-lactamase inhibitors were included in the review. For MTB, the oral carbapenem tebipenem combined with the beta-lactamase inhibitor clavulanic acid resulted in the most significant reduction of MICs. For MABC, the addition of avibactam to tebipenem resulted in a 64-fold reduction of modal MIC. Data were insufficient for the analysis of MAC. Carbapenems, and in particular the novel oral compound tebipenem, in combination with clavulanic acid for MTB and avibactam for MABC may be an untapped potential for difficult-to-treat mycobacterial infections.

  • 27.
    Andraos, Rama
    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, Medicine Center, Department of Rheumatology.
    Ahmad, Awais
    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.
    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.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    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.
    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.
    Hesselstrand, Roger
    Lund Univ, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Andreasson, Kristofer
    Lund 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.
    Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjogrens syndrome and systemic sclerosis2022In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 9, no 1, article id e000732Article in journal (Refereed)
    Abstract [en]

    ObjectiveSLE, primary Sjogrens syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-alpha, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-alpha was quantified by ELISA. Self-reported data on Raynauds phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-alpha levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.

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  • 28. Antimycobacterial Susceptibility Testing Group,
    Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment2022In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 59, no 4Article in journal (Other academic)
    Abstract [en]

    Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.

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  • 29.
    Aoun, Mike
    et al.
    Karolinska Inst, Sweden.
    Coelho, Ana
    Karolinska Inst, Sweden.
    Kraemer, Alexander
    Karolinska Inst, Sweden.
    Saxena, Amit
    Karolinska Inst, Sweden.
    Sabatier, Pierre
    Karolinska Inst, Sweden.
    Beusch, Christian Michel
    Karolinska Inst, Sweden.
    Loennblom, Erik
    Karolinska Inst, Sweden.
    Geng, Manman
    Xian JiaotongUniv, Peoples R China.
    Do, Nhu-Nguyen
    Karolinska Inst, Sweden; Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany.
    Xu, Zhongwei
    Karolinska Inst, Sweden.
    Zhang, Jingdian
    Karolinska Inst, Sweden.
    He, Yibo
    Karolinska Inst, Sweden.
    Romero Castillo, Laura
    Karolinska Inst, Sweden.
    Abolhassani, Hassan
    Karolinska Univ Hosp, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Viljanen, Johan
    Uppsala Univ, Sweden.
    Rorbach, Joanna
    Karolinska Inst, Sweden.
    Fernandez Lahore, Gonzalo
    Karolinska Inst, Sweden.
    Gjertsson, Inger
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    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.
    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.
    Kihlberg, Jan
    Uppsala Univ, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden; IM Sechenov First Moscow State Med Univ, Russia.
    Burkhardt, Harald
    Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany; Goethe Univ, Germany.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Xian JiaotongUniv, Peoples R China.
    Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice2023In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 220, no 11, article id e20230101Article in journal (Refereed)
    Abstract [en]

    B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

  • 30.
    Appelgren, Daniel
    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.
    Enocsson, Helena
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Skogman, Barbro H
    Center for Clinical Research Dalarna-Uppsala University, Region Dalarna and Faculty of Medicine and Health Sciences, Örebro University.
    Nordberg, Marika
    Åland Central Hospital, Department of Infectious Diseases, AX-22 100 Mariehamn, Åland, Finland.
    Perander, Linda
    Åland Central Hospital, Department of Infectious Diseases, AX-22 100 Mariehamn, Åland, Finland.
    Nyman, Dag
    Bimelix AB, AX-22 100 Mariehamn, Åland, Finland.
    Nyberg, Clara
    Åland Central Hospital, Department of Infectious Diseases, AX-22 100 Mariehamn, Åland, Finland.
    Knopf, Jasmin
    Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), DE-91 054 Erlangen, Germany.
    Muñoz, Luis E
    Department of Internal Medicine 3-Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), DE-91 054 Erlangen, Germany.
    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.
    Sjöwall, Johanna
    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 Infectious Diseases.
    Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections.2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 1, article id E43Article in journal (Refereed)
    Abstract [en]

    Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (rs = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.

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  • 31.
    Appelgren, Daniel
    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.
    Puli, Srinivasulu
    Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Hellmark, Thomas
    Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Pochard, Pierre
    LBAI, UMR1227, Univ Brest, Inserm, CHU de Brest, Brest, France.
    Pers, Jacques-Olivier
    LBAI, UMR1227, Univ Brest, Inserm, Brest, France.
    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.
    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.
    Segelmark, Mårten
    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, Medicine Center, Department of Nephrology. Department of Clinical Sciences in Lund, Nephrology, Lund University and Skåne University Hospital, Lund, Sweden.
    Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction2023In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 213, no 2, p. 190-201Article in journal (Refereed)
    Abstract [en]

    Regulatory B (Breg) cells can dampen inflammation, autoreactivity, and transplant rejection. We investigated the frequencies, phenotypes, and function of Breg cells in granulomatosis with polyangiitis (GPA) to gain further knowledge as to whether there are numerical alterations or limitations of their ability to regulate T-cell function. Frequencies and phenotypes of CD24hiCD27+ and CD24hiCD38hi B-cells in the blood were determined with flow cytometry in 37 GPA patients (22 in remission and 15 with active disease) and 31 healthy controls (HC). A co-culture model was used to study the capacity of Breg cells to regulate T-cell activation and proliferation in cells from 10 GPA patients in remission and 12 HC. T-cell cytokine production in vitro and levels in plasma were determined with enzyme-linked immunosorbent assay. Frequencies of CD24hiCD27+ B-cells were reduced both during active disease and remission compared with HC (P = 0.005 and P = 0.010, respectively), whereas CD24hiCD38hi B-cells did not differ. Patient CD24hiCD27+ B-cells exhibited decreased expression of CD25 but increased expression of PD-L1 and PD-L2 during remission. B-cells from GPA patients regulated T-cell proliferation but failed to regulate interferon (IFN)-γproduction (median T-cells alone 222 ng/ml vs. T-cells + B-cells 207 ng/ml, P = 0.426). IFN-γwas also elevated in patient plasma samples (P = 0.016). In conclusion, GPA patients exhibit altered numbers and phenotypes of CD24hiCD27+ B-cells. This is accompanied by a disability to control T-cell production of Th1-type cytokines during remission, which might be of fundamental importance for the granulomatous inflammation that characterizes the chronic phase of this disease. © 2023 The Author(s). Published by Oxford University Press on behalf of the British Society for Immunology.

  • 32.
    Arkema, Elizabeth V. V.
    et al.
    Karolinska Inst, Sweden.
    Saleh, Muna Atallah
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Simard, Julia F. F.
    Karolinska Inst, Sweden; Stanford Univ, CA USA.
    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.
    Epidemiology and Damage Accrual of Systemic Lupus Erythematosus in Central Sweden: A Single-Center Population-Based Cohort Study Over 14 Years From ostergotland County2023In: ACR OPEN RHEUMATOLOGY, ISSN 2578-5745, Vol. 5, no 8, p. 426-432Article in journal (Refereed)
    Abstract [en]

    ObjectiveVariations in prevalence and incidence of systemic lupus erythematosus (SLE) within a geographically defined area of central Sweden over a time period of 14 years were examined. Longitudinal differences in disease activity, laboratory test results, and damage accrual were investigated. MethodsAdults (aged & GE;18 years) residing in ostergotland County between 2008 and 2021 (mean adult population: 357,000 citizens) with confirmed SLE were identified and followed prospectively until death, December 31, 2021, or emigration. We estimated annual incidence per 100,000 inhabitants stratified by sex and age. Linear regression with year of diagnosis as the outcome assessed whether each clinical measurement at diagnosis varied over time. ResultsPrevalence on December 31, 2021, was 71.5 of 100,000 (87% female). One hundred twenty-six new cases were identified during the study period, yielding a mean annual incidence of 3.0 of 100,000 inhabitants; this was higher in females (4.8/100,000) than in males (1.2/100,000). Mean age at diagnosis was 43.7 years (SD 17.3). Age at diagnosis and disease activity measures increased over the calendar year of diagnosis (P &lt; 0.05) whereas disease manifestations, including lupus nephritis, did not vary significantly. Accrual of organ damage was demonstrated over time since diagnosis and stratified by sex, lupus nephritis, and corticosteroid-related damage. Approximately 40% developed damage within 5 years. ConclusionSLE prevalence and incidence estimates remained constant over 14 years, and disease phenotypes at SLE onset were similar. SLE was diagnosed also among older individuals with a smaller female-to-male ratio. Estimates of prevalence and incidence were comparable to previous Scandinavian reports but lower than observed in registry data from the US and the UK.

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  • 33.
    Arnason, Sigurdur
    et al.
    Dept Clin Sci Intervent & Technol CLINTEC, Sweden; Astrid Lindgrens Childrens Hosp, Sweden.
    Molewijk, Kesia
    Orebro Univ, Sweden.
    Henningsson, Anna J.
    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 Microbiology. Laboratory Medicine, Region Jönköping County, Sweden.
    Tjernberg, Ivar
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Reg Kalmar Cty, Sweden.
    Skogman, Barbro H.
    Orebro Univ, Sweden; Uppsala Univ, Sweden; Karolinska Inst, Sweden.
    Brain damage markers neuron-specific enolase (NSE) and S100B in serum in children with Lyme neuroborreliosis-detection and evaluation as prognostic biomarkers for clinical outcome2022In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 41, p. 1051-1057Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis (LB) is the most common tick-borne infection in Europe, with Lyme neuroborreliosis (LNB) its second most frequent clinical manifestation. Prognostic factors for clinical outcomes in LNB have not been identified. Elevated serum levels of the brain damage markers neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) have been associated with poor clinical outcomes in other disorders of the central nervous system. The aim of this study is to assess NSE and S100B in serum as prognostic biomarkers for clinical outcomes in paediatric LNB patients. Children evaluated for LNB (n= 121) in Sweden were prospectively included during 2010-2014, serum samples were collected on admission, and all children underwent a 2-month follow-up. Patients with pleocytosis and anti-Borrelia antibodies in cerebrospinal fluid (CSF) were classified as having LNB (n= 61). Controls were age- and gender-matched non-LNB patients (n= 60). NSE was elevated in 38/61 (62%) LNB patients and in 31/60 (52%) controls. S100B was elevated in 3/60 (5%) LNB patients and 0/59 (0%) controls. NSE and S100B concentrations did not differ significantly when comparing LNB patients with controls. No differences were found in the concentrations when comparing the clinical recovery of LNB patients at the 2-month follow-up. NSE was detectable in the majority of LNB patients and controls, whereas S100B was detectable in only a few LNB patients and no controls. NSE and S100B in serum cannot be recommended as prognostic biomarkers for clinical outcomes in children with LNB.

  • 34.
    Arnqvist, Hans
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Westerlund, Malin C.
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Fredrikson, Mats
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    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.
    Nordwall, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Impact of HbA(1c) Followed 32 Years From Diagnosis of Type 1 Diabetes on Development of Severe Retinopathy and Nephropathy: The VISS Study2022In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 45, no 11, p. 2675-2682Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To evaluate HbA(1c) followed from diagnosis, as a predictor of severe microvascular complications (i.e., proliferative diabetic retinopathy [PDR] and nephropathy [macroalbuminuria]). RESEARCH DESIGN AND METHODS In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age from 1983 to 1987 in southeast Sweden were followed from diagnosis until 2019. Long-term weighted mean HbA(1c) (wHbA(1c)) was calculated by integrating the area under all HbA(1c) values. Complications were analyzed in relation to wHbA(1c) categorized into five levels. RESULTS After 32 years, 9% had no retinopathy, 64% non-PDR, and 27% PDR, and 83% had no microalbuminuria, 9% microalbuminuria, and 8% macroalbuminuria. Patients with near-normal wHbA(1c) did not develop PDR or macroalbuminuria. The lowest wHbA(1c) values associated with development of PDR and nephropathy (macroalbuminuria) were 7.3% (56 mmol/mol) and 8.1% (65 mmol/mol), respectively. The prevalence of PDR and macroalbuminuria increased with increasing wHbA(1c), being 74% and 44% in the highest category, wHbA(1c) &gt;9.5% (&gt;80 mmol/mol). In comparison with the follow-up done after 20-24 years duration, the prevalence of PDR had increased from 14 to 27% and macroalbuminuria from 4 to 8%, and both appeared at lower wHbA(1c) values. CONCLUSIONS wHbA(1c) followed from diagnosis is a very strong biomarker for PDR and nephropathy, the prevalence of both still increasing 32 years after diagnosis. To avoid PDR and macroalbuminuria in patients with type 1 diabetes, an HbA(1c) &lt;7.0% (53 mmol/mol) and as normal as possible should be recommended when achievable without severe hypoglycemia and with good quality of life.

  • 35.
    Arora, Anmol
    et al.
    Univ Cambridge, England.
    Alderman, Joseph E.
    Univ Birmingham, England; Univ Hosp Birmingham NHS Fdn Trust, England; Univ Birmingham, England; Univ Birmingham, England.
    Palmer, Joanne
    Univ Hosp Birmingham NHS Fdn Trust, England; Univ Birmingham, England; Univ Birmingham, England.
    Ganapathi, Shaswath
    Sandwell & West Birmingham Hosp NHS Trust, England.
    Laws, Elinor
    Univ Birmingham, England; Univ Hosp Birmingham NHS Fdn Trust, England; Univ Birmingham, England; Univ Birmingham, England.
    Mccradden, Melissa D.
    Hosp Sick Children, Canada; Peter Gilgan Ctr Res & Learning, Canada; Dalla Lana Sch Publ Hlth, Canada.
    Oakden-Rayner, Lauren
    Univ Adelaide, Australia.
    Pfohl, Stephen R.
    Google Res, CA USA.
    Ghassemi, Marzyeh
    MIT, MA USA; Inst Med Engn & Sci, MA USA; Vector Inst, Canada.
    Mckay, Francis
    Univ Oxford, England.
    Treanor, Darren
    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, Clinical pathology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Leeds Teaching Hosp NHS Trust, England; Univ Leeds, England.
    Rostamzadeh, Negar
    Google Res, Canada.
    Mateen, Bilal
    UCL, England; Wellcome Trust Res Labs, England.
    Gath, Jacqui
    STANDING Together, England.
    Adebajo, Adewole O.
    STANDING Together, England.
    Kuku, Stephanie
    UCL, England.
    Matin, Rubeta
    Oxford Univ Hosp NHS Fdn Trust, England.
    Heller, Katherine
    Google Res, CA USA.
    Sapey, Elizabeth
    Univ Birmingham, England; Univ Hosp Birmingham NHS Fdn Trust, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England.
    Sebire, Neil J.
    Great Ormond St Hosp Biomed Res Ctr, England; Univ Hosp London, England.
    Cole-Lewis, Heather
    Google Res, CA USA.
    Calvert, Melanie
    Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England.
    Denniston, Alastair
    Univ Birmingham, England; Univ Hosp Birmingham NHS Fdn Trust, England; Univ Birmingham, England; Univ Birmingham, England; Univ Birmingham, England; UCL, England; UCL, England.
    Liu, Xiaoxuan
    Univ Birmingham, England; Univ Hosp Birmingham NHS Fdn Trust, England; Univ Birmingham, England; Univ Birmingham, England.
    The value of standards for health datasets in artificial intelligence-based applications2023In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170XArticle in journal (Refereed)
    Abstract [en]

    Artificial intelligence as a medical device is increasingly being applied to healthcare for diagnosis, risk stratification and resource allocation. However, a growing body of evidence has highlighted the risk of algorithmic bias, which may perpetuate existing health inequity. This problem arises in part because of systemic inequalities in dataset curation, unequal opportunity to participate in research and inequalities of access. This study aims to explore existing standards, frameworks and best practices for ensuring adequate data diversity in health datasets. Exploring the body of existing literature and expert views is an important step towards the development of consensus-based guidelines. The study comprises two parts: a systematic review of existing standards, frameworks and best practices for healthcare datasets; and a survey and thematic analysis of stakeholder views of bias, health equity and best practices for artificial intelligence as a medical device. We found that the need for dataset diversity was well described in literature, and experts generally favored the development of a robust set of guidelines, but there were mixed views about how these could be implemented practically. The outputs of this study will be used to inform the development of standards for transparency of data diversity in health datasets (the STANDING Together initiative). A systematic review, combined with a stakeholder survey, presents an overview of current practices and recommendations for dataset curation in health, with specific focuses on data diversity and artificial intelligence-based applications.

  • 36.
    Arvidsson, Åsa
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Lafta, Gihan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Sönnerbrandt, Martina
    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 Infectious Diseases.
    Sundelin, Karin
    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 Infectious Diseases.
    Paues, Jakob
    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 Infectious Diseases.
    The cascade of care for pregnant women with latent tuberculosis infection in a high-income country2023In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 55, no 9, p. 635-645Article in journal (Refereed)
    Abstract [en]

    Background: Pregnant women have an increased risk of developing active tuberculosis (TB). The Public Health Agency of Sweden recommends screening of active TB and latent tuberculosis infection (LTBI) among pregnant women from countries with high TB incidence at Maternal Health Care (MHC) clinics. In ostergotland County, Sweden, a screening program has been active since 2013. The aim of this study was to evaluate this screening program and the cascade of care for LTBI among pregnant women in ostergotland county.Methods: Data were obtained from pregnant women screened for TB at MHC clinics and subsequently referred to the pulmonary medicine clinic or the clinic of infectious diseases in ostergotland County between 2013 and 2018. The Public Health Agency of Swedens national database for active TB was used to analyse if any women developed active TB up to two years after the screening process.Results: A total of 439 women were included. Nine cases of active TB were discovered during the screening process and two developed active TB afterward. 177 women were recommended LTBI treatment and variables significantly associated with a decreased likelihood of being recommended treatment were increasing age, time in Sweden, and parity. 137 women received and 112 (82%) completed treatment. 14 women discontinued treatment due to adverse effects.Conclusion: Screening of pregnant women from countries with high TB incidence at MHC clinics led to the discovery of several cases of active TB. The completion rate of LTBI treatment was high and few discontinued due to adverse effects.

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  • 37.
    Badam, Tejaswi
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering. Skovde Univ, Sweden.
    Hellberg, Sandra
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Bhai Mehta, Ratnesh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Lechner-Scott, Jeannette
    Univ Newcastle, Australia; Hunter Med Res Inst, Australia; John Hunter Hosp, Australia.
    Lea, Rodney A.
    Univ Newcastle, Australia; Hunter Med Res Inst, Australia; Queensland Univ Technol, Australia.
    Tost, Jorg
    CEA Inst Biol Francois Jacob, France.
    Mariette, Xavier
    Univ Paris Saclay, France.
    Svensson-Arvelund, Judit
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    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.
    Berg, Göran
    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, Department of Gynaecology and Obstetrics in Linköping.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. 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.
    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.
    CD4(+) T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases2022In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 17, no 9, p. 1040-1055Article in journal (Refereed)
    Abstract [en]

    Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.

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  • 38.
    Bai, Xiangning
    et al.
    Oslo Univ Hosp, Norway; Karolinska Inst, Sweden.
    Ylinen, Elisa
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Zhang, Ji
    Minist Primary Ind, New Zealand.
    Salmenlinna, Saara
    Finnish Inst Hlth & Welf, Finland.
    Halkilahti, Jani
    Finnish Inst Hlth & Welf, Finland.
    Saxen, Harri
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Narayanan, Aswathy
    Karolinska Inst, Sweden.
    Jahnukainen, Timo
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Matussek, Andreas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Oslo Univ Hosp, Norway; Karolinska Inst, Sweden; Univ Oslo, Norway; Laboratory Medicine, Jönköping Region County, Jönköping, Sweden.
    Comparative Genomics of Shiga Toxin-Producing Escherichia coli Strains Isolated from Pediatric Patients with and without Hemolytic Uremic Syndrome from 2000 to 2016 in FinlandIn: Microbiology Spectrum, E-ISSN 2165-0497Article in journal (Refereed)
    Abstract [en]

    Shiga toxin-producing Escherichia coli (STEC) is a serious public health burden worldwide which causes outbreaks of gastrointestinal diseases and the fatal hemolytic uremic syndrome (HUS) characterized by the triad of mechanical hemolytic anemia, thrombocytopenia, and acute renal failure. Understanding the mechanism underlying the disease severity and patient outcome is of high importance. Shiga toxin-producing Escherichia coli (STEC) infection can cause mild to severe illness, such as nonbloody or bloody diarrhea, and the fatal hemolytic uremic syndrome (HUS). The molecular mechanism underlying the variable pathogenicity of STEC infection is not fully defined so far. Here, we performed a comparative genomics study on a large collection of clinical STEC strains collected from STEC-infected pediatric patients with and without HUS in Finland over a 16-year period, aiming to identify the bacterial genetic factors that can predict the risk to cause HUS and poor renal outcome. Of 240 STEC strains included in this study, 52 (21.7%) were from pediatric patients with HUS. Serotype O157:H7 was the main cause of HUS, and Shiga toxin gene subtype stx2a was significantly associated with HUS. Comparative genomics and pangenome-wide association studies identified a number of virulence and accessory genes overrepresented in HUS-associated STEC compared to non-HUS STEC strains, including genes encoding cytolethal distending toxins, type III secretion system effectors, adherence factors, etc. No virulence or accessory gene was significantly associated with risk factors for poor renal outcome among HUS patients assessed in this study, including need for and duration of dialysis, presence and duration of anuria, and leukocyte counts. Whole-genome phylogeny and multiple-correspondence analysis of pangenomes could not separate HUS STEC from non-HUS STEC strains, suggesting that STEC strains with diverse genetic backgrounds may independently acquire genetic elements that determine their varied pathogenicity. Our findings indicate that nonbacterial factors, i.e., characteristics of the host immunity, might affect STEC virulence and clinical outcomes. IMPORTANCE Shiga toxin-producing Escherichia coli (STEC) is a serious public health burden worldwide which causes outbreaks of gastrointestinal diseases and the fatal hemolytic uremic syndrome (HUS) characterized by the triad of mechanical hemolytic anemia, thrombocytopenia, and acute renal failure. Understanding the mechanism underlying the disease severity and patient outcome is of high importance. Using comparative genomics on a large collection of clinical STEC strains from STEC-infected patients with and without HUS, our study provides a reference of STEC genetic factors/variants that can be used as predictors of the development of HUS, which will aid risk assessment at the early stage of STEC infection. Additionally, our findings suggest that nonbacterial factors may play a primary role in the renal outcome in STEC-infected patients with HUS; further studies are needed to validate this.

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  • 39.
    Bai, Xiangning
    et al.
    Karolinska Inst, Sweden; Chinese Ctr Dis Control & Prevent, Peoples R China.
    Zhang, Ji
    Massey Univ, New Zealand.
    Hua, Ying
    Karolinska Inst, Sweden; Southern Med Univ, Peoples R China.
    Jernberg, Cecilia
    Publ Hlth Agcy Sweden, Sweden.
    Xiong, Yanwen
    Chinese Ctr Dis Control & Prevent, Peoples R China.
    French, Nigel
    Massey Univ, New Zealand.
    Löfgren, Sture
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Jonkoping Reg Cty, Jonkoping, Sweden.
    Hedenstrom, Ingela
    Publ Hlth Agcy Sweden, Sweden.
    Ambikan, Anoop
    Karolinska Inst, Sweden.
    Mernelius, Sara
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Matussek, Andreas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Genomic Insights Into Clinical Shiga Toxin-Producing Escherichia coli Strains: A 15-Year Period Survey in Jonkoping, Sweden2021In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 12, article id 627861Article in journal (Refereed)
    Abstract [en]

    Shiga toxin-producing Escherichia coli (STEC) are important foodborne pathogens that can cause human infections ranging from asymptomatic carriage to bloody diarrhea (BD) and fatal hemolytic uremic syndrome (HUS). However, the molecular mechanism of STEC pathogenesis is not entirely known. Here, we demonstrated a large scale of molecular epidemiology and in-depth genomic study of clinical STEC isolates utilizing clinical and epidemiological data collected in Region Jonkoping County, Sweden, over a 15-year period. Out of 184 STEC isolates recovered from distinct patients, 55 were from patients with BD, and 129 were from individuals with non-bloody stools (NBS). Five individuals developed HUS. Adults were more associated with BD. Serotypes O157:H7, O26:H11, O103:H2, O121:H19, and O104:H4 were more often associated with BD. The presence of Shiga toxin-encoding gene subtypes stx(2a), stx(2a) + stx(2c), and stx(1a) + stx(2c) was associated with BD, while stx(1)(a) was associated with milder disease. Multiplex virulence and accessory genes were correlated with BD; these genes encode toxins, adhesion, autotransporters, invasion, and secretion system. A number of antimicrobial resistance (AMR) genes, such as aminoglycoside, aminocoumarin, macrolide, and fluoroquinolone resistance genes, were prevalent among clinical STEC isolates. Whole-genome phylogeny revealed that O157 and non-O157 STEC isolates evolved from distinct lineages with a few exceptions. Isolates from BD showed more tendency to cluster closely. In conclusion, this study unravels molecular trait of clinical STEC strains and identifies genetic factors associated with severe clinical outcomes, which could contribute to management of STEC infections and disease progression if confirmed by further functional validation.

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  • 40.
    Baig, Sharmin
    et al.
    Statens Serum Inst, Denmark.
    Larsen, Anders Rhod
    Statens Serum Inst, Denmark.
    Simoes, Patricia Martins
    Hosp Civils Lyon, France.
    Laurent, Frederic
    Hosp Civils Lyon, France.
    Johannesen, Thor Bech
    Statens Serum Inst, Denmark.
    Lilje, Berit
    Statens Serum Inst, Denmark.
    Tristan, Anne
    Hosp Civils Lyon, France.
    Schaumburg, Frieder
    Univ Hosp Munster, Germany.
    Egyir, Beverly
    Univ Ghana, Ghana.
    Cirkovic, Ivana
    Univ Belgrade, Serbia.
    Nimmo, Graeme R.
    Griffith Univ, Australia.
    Spiliopoulou, Iris
    Univ Patras, Greece.
    Blanc, Dominique S.
    Lausanne Univ Hosp, Switzerland; Univ Lausanne, Switzerland.
    Mernelius, Sara
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. i Laboratory Medicine, Jönköping, Region Jönköping County, Sweden.
    Fossum Moen, Aina Elisabeth
    Akershus Univ Hosp, Norway; Univ Oslo, Norway.
    David, Michael Z.
    Univ Penn, PA 19104 USA.
    Skytt Andersen, Paal
    Statens Serum Inst, Denmark; Univ Copenhagen, Denmark.
    Stegger, Marc
    Statens Serum Inst, Denmark.
    Evolution and Population Dynamics of Clonal Complex 152 Community-Associated Methicillin-Resistant Staphylococcus aureus2020In: mSphere, E-ISSN 2379-5042, Vol. 5, no 4, article id e00226-20Article in journal (Refereed)
    Abstract [en]

    Since the late 1990s, changes in the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) were recognized with the emergence of community-associated MRSA (CA-MRSA). CA-MRSA belonging to clonal complex 152 (CC152), carrying the small staphylococcal cassette chromosome mec (SCCmec) type V and encoding the Panton-Valentine leukocidin (PVL), has been observed in Europe. The aim of this study was to investigate its origin, evolution, and dissemination. Whole-genome sequencing was performed on a global collection of 149 CC152 isolates spanning 20 years (93 methicillin-susceptible S. aureus [MSSA] and 56 MRSA isolates). Core genome phylogeny, Bayesian inference, in silico resistance analyses, and genomic characterization were applied. Phylogenetic analysis revealed two major distinct clades, one dominated by MSSA and the other populated only by MRSA. The MSSA isolates were predominately from sub-Saharan Africa, whereas MRSA was almost exclusively from Europe. The European MRSA isolates all harbored an SCCmec type V (5C2&5) element, whereas other SCCmec elements were sporadically detected in MRSA from the otherwise MSSA-dominated clade, including SCCmec types IV (2B), V (5C2), and XIII (9A). In total, 93% of the studied CC152 isolates were PVL positive. Bayesian coalescent inference suggests an emergence of the European CC152-MRSA in the 1990s, while the CC152 lineage dates back to the 1970s. The CA-MRSA CC152 clone mimics the European CC80 CA-MRSA lineage by its emergence from a PVL-positive MSSA ancestor from North Africa or Europe. The CC152 lineage has acquired SCCmec several times, but acquisition of SCCmec type V (5C2&5) seems associated with expansion of MRSA CC152 in Europe. IMPORTANCE Understanding the evolution of CA-MRSA is important in light of the increasing importance of this reservoir in the dissemination of MRSA. Here, we highlight the story of the CA-MRSA CC152 lineage using whole-genome sequencing on an international collection of CC152. We show that the evolution of this lineage is novel and that antibiotic usage may have the potential to select for the phage-encoded Panton-Valentine leukocidin. The diversity of the strains correlated highly to geography, with higher level of resistance observed among the European MRSA isolates. The mobility of the SCCmec element is mandatory for the emergence of novel MRSA lineages, and we show here distinct acquisitions, one of which is linked to the successful clone found throughout Europe today.

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  • 41.
    Baldimtsi, Evangelia
    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, Medicine Center, Department of Endocrinology.
    Papadopoulou, Nektaria
    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, Medicine Center, Department of Endocrinology. Natl & Kapodistrian Univ Athens, Greece; UNESCO Chair Adolescent Hlth Care, Greece.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlberg, Jeanette
    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, Medicine Center, Department of Endocrinology. Orebro Univ, Sweden.
    The role of chemokines in type 1 diabetes-associated neuropathy2023In: ENDOCRINOLOGY DIABETES & METABOLISM, ISSN 2398-9238, Vol. 6, no 3, article id e419Article in journal (Refereed)
    Abstract [en]

    Introduction: To investigate whether circulating chemokines contribute to the development of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes (T1D). Methods: Fifty-two patients with childhood-onset T1D (mean age 28 +/- 4 yrs.; diabetes duration 19.5 +/- 5.5 yrs.) and 19 control subjects (mean age 26.5 +/- 4.5 yrs.) were included in a cross-sectional analysis of this long-term longitudinal cohort study. A subgroup of 24 patients was followed prospectively for a further 10 yrs. Plasma levels of Th1-(CXCL9, CXCL10 and CXCL11), Th2-(CCL17 and CCL22) and Th17-associated (CXCL8 and CCL20) chemokines were assessed in all subjects. Additionally, the TID patients underwent clinical examination and electroneurography. Results: The frequency of neuropathy was 21% (11/52). Higher levels of CXCL9 levels were found in patients with DPN compared with control subjects (p = .019); by contrast, no difference between patients without DPN and control subjects was seen after adjustment for multiple comparisons. In patients with DPN, CXCL10 correlated negatively with suralis MCV and suralis SNAP (rho -0.966, p &lt; .001 and rho -0.738, p &lt;.001, respectively) and was positively correlated with the vibration perception threshold (rho 0.639, p = .034), while CXCL8 correlated negatively with the cold perception threshold (rho -0.645, p = .032). The frequency of neuropathy increased to 54% (13/24) in the subgroup of 23 TID patients, followed by an additional 10 yrs. Conclusions: Changes in Th1-and Th17-associated chemokines were associated with impaired peripheral sensory nerve function and nerve conduction after long disease duration in childhood-onset T1D.

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  • 42.
    Ballante, Flavio
    et al.
    Karolinska Inst, Sweden.
    Turkina, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ntzouni, Maria
    Linköping University, Faculty of Medicine and Health Sciences, Core Facility.
    Magnusson, Karl-Eric
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Vikström, Elena
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Modified N-acyl-L-homoserine lactone compounds abrogate Las-dependent quorum-sensing response in human pathogen Pseudomonas aeruginosa2023In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 10, article id 1264773Article in journal (Refereed)
    Abstract [en]

    Quorum sensing (QS) is a mode of cell-cell communication that bacteria use to sense population density and orchestrate collective behaviors. The common opportunistic human pathogen Pseudomonas aeruginosa employs QS to regulate a large set of genes involved in virulence and host-pathogen interactions. The Las circuit positioned on the top of the QS hierarchy in P. aeruginosa makes use of N-acyl-L-homoserine lactones (AHLs) as signal molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C12-HSL). Disabling QS circuits by certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), has been proposed as a strategy to attenuate bacterial pathogenicity. In this study, four new AHL analogs were designed by incorporating a tert-butoxycarbonyl Boc group in amide and beta-keto (3-oxo) moiety. Compounds were evaluated on a molecular and phenotypic basis as a QSI using the screening strategy linked to the assignment of the Las QS system in P. aeruginosa. Using a LasR-based bioreporter, we found that the compounds decreased LasR-controlled light activity and competed efficiently with natural 3O-C12-HSL. The compounds reduced the production of the cognate 3O-C12-HSL and certain virulence traits, like total protease activity, elastase activity, pyocyanin production, and extracellular DNA release. Furthermore, a quantitative proteomic approach was used to study the effect of the compounds on QS-regulated extracellular proteins. Among the four compounds tested, one of them showed the most significant difference in the appearance of the 3O-C12-HSL-responsive reference proteins related to QS communication and virulence, i.e., a distinct activity as a QSI. Moreover, by combining experimental data with computational chemistry, we addressed the effect of LasR protein flexibility on docking precision and assessed the advantage of using a multi-conformational docking procedure for binding mode prediction of LasR modulators. Thus, the four new AHL compounds were tested for their interaction with the AHL-binding site in LasR to identify the key interferences with the activity of LasR. Our study provides further insight into molecular features that are required for small-molecule modulation of LasR-dependent QS communication in P. aeruginosa. This should facilitate rational design of the next generation of antivirulence tools to study and manipulate QS-controlled fitness in bacteria and, thereby, handle bacterial infections in a new way.

  • 43.
    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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  • 44.
    Barbulescu, Andrei
    et al.
    Karolinska Inst, Sweden.
    Askling, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Chatzidionysiou, Katerina
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Forsblad-dElia, Helena
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    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.
    Lindstrom, Ulf
    Univ Gothenburg, Sweden.
    Turesson, Carl
    Lund Univ, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Effectiveness of baricitinib and tofacitinib compared with bDMARDs in RA: results from a cohort study using nationwide Swedish register data2022In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 61, no 10, p. 3952-3962Article in journal (Refereed)
    Abstract [en]

    Objectives To describe the use of baricitinib and tofacitinib by Swedish RA patients and to compare their effectiveness with that of biologic DMARDs (bDMARDs). Methods RA patients who initiated baricitinib (n = 1420), tofacitinib (n = 316), abatacept (n = 1050), IL-6 inhibitors (IL-6is; n = 849), rituximab (n = 1101) or TNF inhibitors (TNFis; n = 6036) between January 2017 and November 2019 were followed for a minimum of 1 year using data from several linked Swedish national registers. Proportions reaching a good EULAR 28-joint DAS (DAS28) response, HAQ Disability Index (HAQ-DI) improvement &gt;0.2 units and Clinical Disease Activity Index (CDAI) remission were compared at 1 year, imputing discontinued treatments as non-response. Additionally, we compared drug retention and changes in DAS28, HAQ-DI and CDAI from baseline to 3 months after treatment initiation. Results On average, baricitinib, and particularly tofacitinib, were initiated as later lines of therapy and more frequently as monotherapy compared with rituximab and TNFi. Adjusted 1 year response proportions were consistently lower on TNFi compared with baricitinib, with differences of -4.3 percentage points (95% CI -8.7, 0.1) for good EULAR response, -9.9 (-14.4 to -5.4) for HAQ-DI improvement and -6.0 (-9.8 to -2.2) for CDAI remission. Comparisons with non-TNFi bDMARDs also favoured baricitinib, but not consistently. Treatment responses for tofacitinib were only marginally lower than those for baricitinib and generally similar to those of bDMARDs, with precision limited by low power. Comparisons of drug retention and changes in disease activity from baseline to 3 months supported the 1 year findings. Conclusions Baricitinib and tofacitinib showed at least equivalent effectiveness compared with bDMARDs after exploring several different effectiveness measures.

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  • 45.
    Barstad, Bjorn
    et al.
    Stavanger Univ Hosp, Norway; Univ Bergen, Norway.
    Jonsson Henningsson, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Division of Clinical Microbiology, Laboratory Medicine, Jönköping Region Jönköping County, Sweden.
    Tveitnes, Dag
    Stavanger Univ Hosp, Norway.
    Ushakova, Anastasia
    Stavanger Univ Hosp, Norway.
    Noraas, Solvi
    Hosp Southern Norway Trust, Norway.
    Ask, Ingvild S.
    Hosp Southern Norway Trust, Norway; Oslo Univ Hosp, Norway.
    Bosse, Franziskus J.
    Haukeland Hosp, Norway.
    Oymar, Knut
    Stavanger Univ Hosp, Norway.
    Cerebrospinal fluid cytokines and chemokines in children with Lyme neuroborreliosis; pattern and diagnostic utility2020In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 130, article id 155023Article in journal (Refereed)
    Abstract [en]

    Background: Lyme neuroborreliosis (LNB) is characterized by cerebrospinal fluid (CSF) inflammation with several cytokines/chemokines and B-lymphocytes. Clinically, LNB in children may be difficult to discriminate from non-Lyme aseptic meningitis (NLAM). We aimed to identify CSF cytokine/chemokine patterns in children with LNB, NLAM and controls and elucidate the diagnostic value of these cytokines/chemokines alone or in combination to discriminate between LNB and NLAM. Methods: Children with symptoms suggestive of LNB were included prospectively and categorized as LNB, NLAM or controls (no pleocytosis). Cytokines/chemokines in CSF were measured by multiplex bead assays and levels were compared between the three groups by nonparametric statistical tests. Previous results from the same children on the established biomarker, CXCL13, were included in the statistical analyses. The diagnostic properties of cytokines/chemokines to discriminate between LNB and NLAM were determined by receiver operating characteristic curve analyses with estimates of area under curve (AUC). To explore diagnostic properties of combinations of cytokines/chemokines, prediction models based on logistic regression were used. Results: We included 195 children with LNB (n = 77), NLAM (n = 12) and controls (n = 106). Children with LNB had higher CSF levels of CCL19, CCL22 and CXCL13 compared to NLAM and controls, whereas INF. was higher in NLAM than in LNB and controls. CXCL13 was the superior single cytokine/chemokine to discriminate LNB from NLAM (AUC 0.978). The combination CXCL13/CCL19 (AUC 0.992) may possibly improve the specificity for LNB, especially for children with moderate CXCL13 levels. Conclusions: The intrathecal immune reaction in LNB is characterized by B cell associated chemokines. Whether the combination CXCL13/CCL19 further improves discrimination between LNB and NLAM beyond the diagnostic improvements by CXCL13 alone needs to be tested in new studies.

  • 46.
    Baunwall, Simon Mark Dahl
    et al.
    Aarhus Univ Hosp, Denmark.
    Terveer, Elisabeth M.
    Leiden Univ Med Ctr, Netherlands; Leiden Univ Med Ctr, Netherlands.
    Dahlerup, Jens Frederik
    Aarhus Univ Hosp, Denmark.
    Erikstrup, Christian
    Aarhus Univ Hosp, Denmark.
    Arkkila, Perttu
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Vehreschild, Maria J. G. T.
    Univ Hosp Frankfurt, Germany; ESCMID Study Grp Host & Microbiota Interact ESGHA, Switzerland; Univ Cologne, Germany; German Ctr Infect Res DZIF, Germany.
    Ianiro, Gianluca
    Fdn Policlin Univ Gemelli IRCCS, Italy.
    Gasbarrini, Antonio
    Fdn Policlin Univ Gemelli IRCCS, Italy.
    Sokol, Harry
    Sorbonne Univ, France; AgroParisTech, France; French Grp Faecal Microbiota Transplantat GFTF, France.
    Kump, Patrizia K.
    Med Univ Graz, Austria.
    Satokari, Reetta
    Univ Helsinki, Finland.
    De Looze, Danny
    Ghent Univ Hosp, Belgium.
    Vermeire, Severine
    Katholieke Univ Leuven, Belgium; Katholieke Univ Leuven, Belgium.
    Nakov, Radislav
    Tsaritsa Yoanna Univ Hosp, Bulgaria.
    Brezina, Jan
    Inst Clin & Expt Med, Czech Republic.
    Helms, Morten
    Copenhagen Univ Hosp Hvidovre, Denmark.
    Kjeldsen, Jens
    Odense Univ Hosp, Denmark; Univ Southern Denmark, Denmark.
    Rode, Anne A.
    Zealand Univ Hosp, Denmark.
    Kousgaard, Sabrina Just
    Aalborg Univ Hosp, Denmark.
    Alric, Laurent
    IRD Toulouse 3 Univ, France.
    Trang-Poisson, Caroline
    Hop Hotel Dieu, France.
    Scanzi, Julien
    French Grp Faecal Microbiota Transplantat GFTF, France; Ctr Hosp Thiers, France.
    Link, Alexander
    Otto von Guericke Univ, Germany.
    Stallmach, Andreas
    Jena Univ Hosp, Germany.
    Kupcinskas, Juozas
    Lithuanian Univ Hlth Sci, Lithuania; Lithuanian Univ Hlth Sci, Lithuania.
    Johnsen, Peter Holger
    Univ Hosp North Norway Harstad, Norway.
    Garborg, Kjetil
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Rodriguez, Eugenia Sanchez
    Hosp Univ Ramon y Cajal, Spain.
    Serrander, Lena
    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 Microbiology.
    Brummer, Robert J.
    Orebro Univ, Sweden.
    Galperine, Katerina Tatiana
    French Grp Faecal Microbiota Transplantat GFTF, France; Univ Lausanne, Switzerland.
    Goldenberg, Simon D.
    Kings Coll London, England; Guys & St Thomas NHS Fdn Trust, England.
    Mullish, Benjamin H.
    Imperial Coll London, England.
    Williams, Horace Rt
    Imperial Coll London, England.
    Iqbal, Tariq H.
    Univ Birmingham, England.
    Ponsioen, Cyriel
    Amsterdam Univ Med Ctr, Netherlands.
    Kuijper, Ed J.
    Leiden Univ Med Ctr, Netherlands; ESCMID Study Grp Host & Microbiota Interact ESGHA, Switzerland; Leiden Univ Med Ctr, Netherlands; Leiden Univ Med Ctr, Netherlands; Natl Inst Publ Hlth & Environm, Netherlands.
    Cammarota, Giovanni
    Fdn Policlin Univ Gemelli IRCCS, Italy.
    Keller, Josbert J.
    Leiden Univ Med Ctr, Netherlands; Haaglanden Med Ctr, Netherlands; Leiden Univ Med Ctr, Netherlands.
    Hvas, Christian Lodberg
    Aarhus Univ Hosp, Denmark.
    The use of Faecal Microbiota Transplantation (FMT) in Europe: A Europe-wide survey2021In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 9, article id 100181Article in journal (Refereed)
    Abstract [en]

    Background: Faecal microbiota transplantation (FMT) is an emerging treatment modality, but its current clinical use and organisation are unknown. We aimed to describe the clinical use, conduct, and potential for FMT in Europe. Methods: We invited all hospital-based FMT centres within the European Council member states to answer a web-based questionnaire covering their clinical activities, organisation, and regulation of FMT in 2019. Responders were identified from trials registered at clinicaltrials.gov and from the United European Gastroenterology (UEG) working group for stool banking and FMT. Findings: In 2019, 31 FMT centres from 17 countries reported a total of 1,874 (median 25, quartile 10.64) FMT procedures; 1,077 (57%) with Clostridioides difficile infection (CDI) as indication, 791 (42%) with experimental indications, and 6 (0.3%) unaccounted for. Adjusted to population size, 0.257 per 100,000 population received FMT for CDI and 0-189 per 100,000 population for experimental indications. With estimated 12,400 (6,100-8,500) annual cases of multiple, recurrent CDI and indication for FMT in Europe, the current European FMT activity covers approximately 10% of the patients with indication. The participating centres demonstrated high safety standards and adherence to international consensus guidelines. Formal or informal regulation from health authorities was present at 21 (68%) centres. Interpretation: FMT is a widespread routine treatment for multiple, recurrent CDI and an experimental treatment. Embedded within hospital settings, FMT centres operate with high standards across Europe to provide safe FMT. A significant gap in FMT coverage suggests the need to raise clinical awareness and increase the FMT activity in Europe by at least 10-fold to meet the true, indicated need. (C) 2021 The Authors. Published by Elsevier Ltd.

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  • 47.
    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 &lt; 0.05) and increased transepithelial resistance (TER) over time (p &lt; 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 &lt; 0.05) and placebo (p &lt; 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 &lt; 0.05) and placebo-treated (p &lt; 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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  • 48.
    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.

  • 49.
    Berglin, Ewa
    et al.
    Umea Univ, Sweden.
    Mohammad, Aladdin J.
    Lund Univ, Sweden; Univ Cambridge, England.
    Dahlqvist, Johanna
    Uppsala Univ, Sweden.
    Johansson, Linda
    Umea Univ, Sweden.
    Eriksson, Catharina
    Umea Univ, Sweden.
    Sjöwall, Johanna
    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 Infectious Diseases.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Anti-neutrophil cytoplasmic antibodies predate symptom onset of ANCA-associated vasculitis: A case-control study2021In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 117, article id 102579Article in journal (Refereed)
    Abstract [en]

    Objectives: Anti-neutrophil cytoplasmic autoantibodies [ANCA) are important for diagnosis of ANCA-associated vasculitides (AAV). The timing of antibody development is not well established. To investigate the development of proteinase 3 (PR3)and myeloperoxidase (MPO)-ANCA, blood samples collected before onset of symptoms of AAV were analysed. Methods: To identify AAV patients with blood samples predating symptoms, the National Patient Register and Cause of Death register were scrutinized for ICD codes for AAV and linked to the registers of five biobanks. Diagnoses of AAV and time point for symptom onset were confirmed by reviewing 504 case-record. Eighty-five AAV cases (34 males, 51 females) with samples 1 month &lt; 10 years from AAV symptom onset and two controls matched for sex, age, and sampling time for each case were included. Samples were screened using ELISAs for ANCA and further analysed for PR3-or MPO- specificities. Results: In ANCA-screen 35.7% of the pre-symptomatic cases and 3.5% of controls tested positive (p &lt; 0.01). 26.2% of the cases were PR3-ANCA+ and 10.7% MPO-ANCA+. Median (Q1-Q3) predating time for PR3-ANCA+ was 2.7 (0.3-7.7) years and MPO-ANCA+ 2.0 (0.9-3.5) years. PR3-ANCA was demonstrated in samples up to nine years before symptom onset. At symptom onset predating PR3-ANCA+ cases were younger than PR3-ANCA(P &lt; 0.01), and MPO-ANCA+ were older than MPO-ANCA(p &lt; 0.05). Predating MPO-ANCA+ cases vs. MPO ANCAand vs. PR3-ANCA+ cases had more often at symptoms onset manifestations from lungs, kidneys or peripheral nervous system (p &lt; 0.01 and p &lt; 0.05, respectively). Conclusion: The PR3-and MPO-ANCAs are present years before AAV symptom onset and represent distinct diseases.

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  • 50.
    Berglund, Björn
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Hoang, Ngoc Thi Bich
    Vietnam Natl Childrens Hosp, Vietnam.
    Lundberg, Ludwig
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Swedish Univ Agr Sci, Sweden.
    Le, Ngai Kien
    Vietnam Natl Childrens Hosp, Vietnam.
    Tärnberg, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Services and Infrastructure. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Maud
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Bornefall, Elin
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Khu, Dung Thi Khanh
    Vietnam Natl Childrens Hosp, Vietnam; Training & Res Acad Collaborat TRAC Sweden Vietna, Vietnam.
    Welander, 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 Diagnostics, Department of Clinical Microbiology.
    Le, Hai Thanh
    Vietnam Natl Childrens Hosp, Vietnam; Training & Res Acad Collaborat TRAC Sweden Vietna, Vietnam.
    Olson, Linus
    Training & Res Acad Collaborat TRAC Sweden Vietna, Vietnam; Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Dien, Tran Minh
    Vietnam Natl Childrens Hosp, Vietnam.
    Nilsson, Lennart E
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Mattias
    Training & Res Acad Collaborat TRAC Sweden Vietna, Vietnam; Karolinska Inst, Sweden.
    Hanberger, Håkan
    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 Infectious Diseases. Training & Res Acad Collaborat TRAC Sweden Vietna, Vietnam.
    Clonal spread of carbapenem-resistant Klebsiella pneumoniae among patients at admission and discharge at a Vietnamese neonatal intensive care unit2021In: Antimicrobial Resistance and Infection Control, E-ISSN 2047-2994, Vol. 10, no 1, article id 162Article in journal (Refereed)
    Abstract [en]

    Background The increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) is a growing problem globally, particularly in low- to middle-income countries (LMICs). Previous studies have shown high rates of CRE colonisation among patients at hospitals in LMICs, with increased risk of hospital-acquired infections. Methods We isolated carbapenem-resistant Klebsiella pneumoniae (CRKP) from faecal samples collected in 2017 from patients at admission and discharge at a Vietnamese neonatal intensive care unit (NICU). 126 CRKP were whole-genome sequenced. The phylogenetic relationship between the isolates and between clinical CRKP isolates collected in 2012-2018 at the same hospital were investigated. Results NDM-type carbapenemase-(61%) and KPC-2-encoding genes (41%) were the most common carbapenem resistance genes observed among the admission and discharge isolates. Most isolates (56%) belonged to three distinct clonal clusters of ST15, carrying bla(KPC-2), bla(NDM-1) and bla(NDM-4), respectively. Each cluster also comprised clinical isolates from blood collected at the study hospital. The most dominant ST15 clone was shown to be related to isolates collected from the same hospital as far back as in 2012. Conclusions Highly resistant CRKP were found colonising admission and discharge patients at a Vietnamese NICU, emphasising the importance of continued monitoring. Whole-genome sequencing revealed a population of CRKP consisting mostly of ST15 isolates in three clonally related clusters, each related to blood isolates collected from the same hospital. Furthermore, clinical isolates collected from previous years (dating back to 2012) were shown to likely be clonally descended from ST15 isolates in the largest cluster, suggesting a successful hospital strain which can colonise inpatients.

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