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  • 1.
    Aaseth, Jan
    et al.
    Innlandet Hosp Trust, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Alehagen, Urban
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Coenzyme Q(10) supplementation - In ageing and disease2021In: Mechanisms of Ageing and Development, ISSN 0047-6374, E-ISSN 1872-6216, Vol. 197, article id 111521Article in journal (Refereed)
    Abstract [en]

    Coenzyme Q(10) (CoQ(10)) is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ(10) by a specialized cytoplasmatic-mitochondrial pathway. CoQ(10) deficiency can result from genetic failure or ageing. Some drugs including statins, widely used by inter alia elderly, may inhibit endogenous CoQ(10) synthesis. There are also chronic diseases with lower levels of CoQ(10) in tissues and organs. High doses of CoQ(10) may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Here, we review the current knowledge of CoQ(10) biosynthesis and primary and acquired CoQ(10) deficiency, and results from clinical trials based on CoQ(10) supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ(10). There is a need for further studies and well-designed clinical trials, with CoQ(10) in a formulation of proven bioavailability, involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ(10) treatment in neurodegenerative disorders, as well as in metabolic syndrome and its complications.

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  • 2.
    Aaseth, Jan
    et al.
    Innlandet Hosp, Norway; Inland Norway Univ Appl Sci, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Alehagen, Urban
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Tinkov, Alexey
    Yaroslavl State Univ, Russia; IM Sechenov First Moscow State Med Univ Sechenov, Russia.
    Skalny, Anatoly
    IM Sechenov First Moscow State Med Univ Sechenov, Russia; KG Razumovsky Moscow State Univ Technol & Managem, Russia.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Crisponi, Guido
    Univ Cagliari, Italy.
    Nurchi, Valeria Marina
    Univ Cagliari, Italy.
    The Aging Kidney - As Influenced by Heavy Metal Exposure and Selenium Supplementation2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 8, article id 1078Article, review/survey (Refereed)
    Abstract [en]

    The aging process in the kidneys has been well studied. It is known that the glomerular filtration rate (GFR) declines with age in subjects older than 50-60 years. However, there is still insufficient knowledge regarding the response of the aged kidney to environmental toxicants such as mercury, cadmium, and lead. Here, we present a review on the functional decline and proposed mechanisms in the aging kidney as influenced by metal pollutants. Due to the prevalence of these toxicants in the environment, human exposure is nearly unavoidable. Further, it is well known that acute and chronic exposures to toxic metals may be detrimental to kidneys of normal adults, thus it may be hypothesized that exposure of individuals with reduced GFR will result in additional reductions in renal function. Individuals with compromised renal function, either from aging or from a combination of aging and disease, may be particularly susceptible to environmental toxicants. The available data appear to show an association between exposure to mercury, cadmium and/or lead and an increase in incidence and severity of renal disease in elderly individuals. Furthermore, some physiological thiols, as well as adequate selenium status, appear to exert a protective action. Further studies providing improved insight into the mechanisms by which nephrotoxic metals are handled by aging kidneys, as well as possibilities of therapeutic protection, are of utmost importance.

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  • 3.
    Aaseth, Jan
    et al.
    Innlandet Hosp, Norway; Inland Norway Univ Appl Sci, Norway.
    Ellefsen, Stian
    Inland Norway Univ Appl Sci, Norway.
    Alehagen, Urban
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sundfor, Tine M.
    Oslo Univ Hosp, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Diets and drugs for weight loss and health in obesity: An update2021In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 140, article id 111789Article, review/survey (Refereed)
    Abstract [en]

    Numerous combinations of diets and pharmacological agents, including lifestyle changes, have been launched to treat obesity. There are still ambiguities regarding the efficacies of different approaches despite many clinical trials and the use of animal models to study physiological mechanisms in weight management and obesity comorbidities, Here, we present an update on promising diets and pharmacological aids. Literature published after the year 2005 was searched in PubMed, Medline and Google scholar. Among recommended diets are low-fat (LF) and low-carbohydrate (LC) diets, in addition to the Mediterranean diet and the intermittent fasting approach, all of which presumably being optimized by adequate contents of dietary fibers. A basic point for weight loss is to adopt a diet that creates a permanently negative and acceptable energy balance, and prolonged dietary adherence is a crucial factor. As for pharmacological aids, obese patients with type 2 diabetes or insulin resistance seem to benefit from LC diet combined with a GLP-1 agonist, e.g. semaglutide, which may improve glycemic control, stimulate satiety, and suppress appetite. The lipase inhibitor orlistat is still used to maintain a low-fat approach, which may be favorable e.g. in hypercholesterolemia. The bupropion-naltrexone-combination appears promising for interruption of the vicious cycle of addictive over-eating. Successful weight loss seems to improve almost all biomarkers of obesity comorbidities. Until more support for specific strategies is available, clinicians should recommend an adapted lifestyle, and when necessary, a drug combination tailored to individual needs and comorbidities. Different diets may change hormonal secretion, gut-brain signaling, and influence hunger, satiety and energy expenditure. Further research is needed to clarify mechanisms and how such knowledge can be used in weight management.

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  • 4.
    Aaseth, Jan O.
    et al.
    Innlandet Hosp Trust, Norway; Inland Norway Univ Appl Sci, Norway.
    Alehagen, Urban
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Opstad, Trine Baur
    Oslo Univ Hosp Ullevaal, Norway; Univ Oslo, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Vitamin K and Calcium Chelation in Vascular Health2023In: Biomedicines, E-ISSN 2227-9059, Vol. 11, no 12, article id 3154Article, review/survey (Refereed)
    Abstract [en]

    The observation that the extent of artery calcification correlates with the degree of atherosclerosis was the background for the alternative treatment of cardiovascular disease with chelator ethylenediamine tetraacetate (EDTA). Recent studies have indicated that such chelation treatment has only marginal impact on the course of vascular disease. In contrast, endogenous calcium chelation with removal of calcium from the cardiovascular system paralleled by improved bone mineralization exerted, i.e., by matrix Gla protein (MGP) and osteocalcin, appears to significantly delay the development of cardiovascular diseases. After post-translational vitamin-K-dependent carboxylation of glutamic acid residues, MGP and other vitamin-K-dependent proteins (VKDPs) can chelate calcium through vicinal carboxyl groups. Dietary vitamin K is mainly provided in the form of phylloquinone from green leafy vegetables and as menaquinones from fermented foods. Here, we provide a review of clinical studies, addressing the role of vitamin K in cardiovascular diseases, and an overview of vitamin K kinetics and biological actions, including vitamin-K-dependent carboxylation and calcium chelation, as compared with the action of the exogenous (therapeutic) chelator EDTA. Consumption of vitamin-K-rich foods and/or use of vitamin K supplements appear to be a better preventive strategy than EDTA chelation for maintaining vascular health.

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

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

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  • 6.
    Abramian, David
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Blystad, Ida
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    Eklund, Anders
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Computer and Information Science, The Division of Statistics and Machine Learning. Division of Medical Informatics, Department of Biomedical Engineering Linköping University Linköping Sweden;Center for Medical Image Science and Visualization (CMIV) Linköping University Linköping Sweden;Division of Statistics & Machine Learning, Department of Computer and Information Science Linköping University Linköping Sweden.
    Evaluation of inverse treatment planning for gamma knife radiosurgery using fMRI brain activation maps as organs at risk2023In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 50, no 9, p. 5297-5311Article in journal (Refereed)
    Abstract [en]

    Background: Stereotactic radiosurgery (SRS) can be an effective primary or adjuvant treatment option for intracranial tumors. However, it carries risks of various radiation toxicities, which can lead to functional deficits for the patients. Current inverse planning algorithms for SRS provide an efficient way for sparing organs at risk (OARs) by setting maximum radiation dose constraints in the treatment planning process.Purpose: We propose using activation maps from functional MRI (fMRI) to map the eloquent regions of the brain and define functional OARs (fOARs) for Gamma Knife SRS treatment planning.Methods: We implemented a pipeline for analyzing patient fMRI data, generating fOARs from the resulting activation maps, and loading them onto the GammaPlan treatment planning software. We used the Lightning inverse planner to generate multiple treatment plans from open MRI data of five subjects, and evaluated the effects of incorporating the proposed fOARs.Results: The Lightning optimizer designs treatment plans with high conformity to the specified parameters. Setting maximum dose constraints on fOARs successfully limits the radiation dose incident on them, but can have a negative impact on treatment plan quality metrics. By masking out fOAR voxels surrounding the tumor target it is possible to achieve high quality treatment plans while controlling the radiation dose on fOARs.Conclusions: The proposed method can effectively reduce the radiation dose incident on the eloquent brain areas during Gamma Knife SRS of brain tumors.

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  • 7.
    Abtahi, Jahan
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
    Klintström, Benjamin
    Department of Biomedical Engineering and Health Systems, KTH Royal Institute of Technology, Stockholm, Sweden.
    Klintström, Eva
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Ibandronate Reduces the Surface Bone Resorption of Mandibular Bone Grafts: A Randomized Trial With Internal Controls2021In: JBMR Plus, E-ISSN 2473-4039, Vol. 5, no 3, article id e10468Article in journal (Refereed)
    Abstract [en]

    ABSTRACT Autologous bone grafts are considered the gold standard for reconstruction of the edentulous alveolar ridges. However, this procedure is associated with unpredictable bone loss caused by physiological bone resorption. Bisphosphonates are antiresorptive drugs that act specifically on osteoclasts, thereby maintaining bone density, volume, and strength. It was hypothesized that the resorption of bone grafts treated with an ibandronate solution would be less advanced than bone grafts treated with saline. Ten patients who underwent bilateral sagittal split osteotomy were included in a randomized double-blind trial with internal controls. Each patient received a bone graft treated with a solution of ibandronate on one side and a graft treated with saline (controls) contralaterally. Radiographs for the measurement of bone volume were obtained at 2 weeks and at 6 months after surgery. The primary endpoint was the difference in the change of bone volume between the control and the ibandronate bone grafts 6 months after surgery. All of the bone grafts healed without complications. One patient was excluded because of reoperation. In eight of the nine patients, the ibandronate bone grafts showed an increase in bone volume compared with baseline, with an average gain of 126 mm3 (40% more than baseline) with a range of +27 to +218 mm3. Only one ibandronate-treated graft had a decrease in bone volume (8%). In the controls, an average bone volume loss of −146 mm3 (58% of baseline) with a range of −29 to −301 mm3 was seen. In the maxillofacial field, the reconstructions of atrophic alveolar ridges, especially in the esthetical zones, are challenging. These results show that bone grafts locally treated with ibandronate solution increases the remaining bone volume. This might lead to new possibilities for the maxillofacial surgeons in the preservation of bone graft volumes and for dental implant installations. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

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  • 8.
    Adoberg, Annika
    et al.
    North Estonia Med Ctr, Estonia.
    Paats, Joosep
    Tallinn Univ Technol, Estonia.
    Arund, Jurgen
    Tallinn Univ Technol, Estonia.
    Dhondt, Annemieke
    Ghent Univ Hosp, Belgium.
    Fridolin, Ivo
    Tallinn Univ Technol, Estonia.
    Glorieux, Griet
    Ghent Univ Hosp, Belgium.
    Holmar, Jana
    Tallinn Univ Technol, Estonia.
    Lauri, Kai
    Synlab Eesti OU, Estonia.
    Leis, Liisi
    North Estonia Med Ctr, Estonia.
    Luman, Merike
    North Estonia Med Ctr, Estonia; Tallinn Univ Technol, Estonia.
    Pilt, Kristjan
    Tallinn Univ Technol, Estonia.
    Uhlin, Fredrik
    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 Nephrology. Tallinn Univ Technol, Estonia.
    Tanner, Risto
    Tallinn Univ Technol, Estonia.
    Treatment with Paracetamol Can Interfere with the Intradialytic Optical Estimation in Spent Dialysate of Uric Acid but Not of Indoxyl Sulfate2022In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 14, no 9, article id 610Article in journal (Refereed)
    Abstract [en]

    Optical online methods are used to monitor the haemodialysis treatment efficiency of end stage kidney disease (ESKD) patients. The aim of this study was to analyse the effect of the administration of UV-absorbing drugs, such as paracetamol (Par), on the accuracy of optical monitoring the removal of uremic toxins uric acid (UA) and indoxyl sulfate (IS) during standard haemodialysis (HD) and haemodiafiltration (HDF) treatments. Nine patients received Par in daily dosages 1-4 g for 30 sessions. For 137 sessions, in 36 patients the total daily dosage of UV-absorbing drugs was less than 500 mg, and for 6 sessions 3 patients received additional UV-absorbing drugs. Par administration slightly affected the accuracy of optically assessed removal of UA expressed as bias between optically and laboratory-assessed reduction ratios (RR) during HD but not HDF employing UV absorbance of spent dialysate (p < 0.05) at 295 nm wavelength with the strongest correlation between the concentration of UA and absorbance. Corresponding removal of IS based on fluorescence at Ex280/Em400 nm during HD and HDF was not affected. Administration of UV-absorbing drugs may in some settings influence the accuracy of optical assessments in spent dialysate of the removal of uremic solutes during haemodialysis treatment of ESKD patients.

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  • 9.
    Adolfsson, Emma
    et al.
    Orebro Univ, Sweden.
    Kling, Daniel
    Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Gunnarsson, Cecilia
    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, Clinical genetics.
    Jonasson, Jon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Green, Anna
    Orebro Univ, Sweden.
    Whole exome sequencing of FFPE samples - expanding the horizon of forensic molecular autopsies2023In: International journal of legal medicine, ISSN 0937-9827, E-ISSN 1437-1596, Vol. 137, p. 1215-1234Article in journal (Refereed)
    Abstract [en]

    Forensic molecular autopsies have emerged as a tool for medical examiners to establish the cause of death. It is particularly useful in sudden unexplained deaths where the cause of death cannot be determined with a regular medical autopsy. We provide the first study of exome data from formalin-fixed paraffin-embedded samples (FFPE) paired with data from high-quality blood samples in forensic applications. The approach allows exploration of the potential to use FFPE samples for molecular autopsies and identify variants in extensive exome data. We leverage the high uniformity of the hybridization capture approach provided by Twist Bioscience to target the complete exome and sequence the libraries on a NextSeq 550. Our findings suggest that exome sequencing is feasible for 24 out of a total of 35 included FFPE samples. When successful, the coverage across the exome is comparatively high (> 90% covered to 20X) and uniform (fold80 below 1.5). Detailed variant comparisons for matched FFPE and blood samples show high concordance with few false variants (positive predictive value of 0.98 and a sensitivity of 0.97) with no distinct FFPE artefacts. Ultimately, we apply carefully constructed forensic gene panels in a stepwise manner to find genetic variants associated with the clinical phenotype and with relevance to the sudden unexplained death.

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  • 10.
    Adolfsson, Emma
    et al.
    Orebro Univ Hosp, Sweden; Orebro Univ, Sweden.
    Qvick, Alvida
    Orebro Univ Hosp, Sweden; Orebro Univ, Sweden.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Kling, Daniel
    Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Gunnarsson, Cecilia
    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, Clinical genetics. Region Östergötland, Regionledningskontoret, Övr Regionledningskontoret.
    Jonasson, Jon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Orebro Univ Hosp, Sweden.
    Green, Anna
    Orebro Univ Hosp, Sweden; Orebro Univ, Sweden.
    Technical in-depth comparison of two massive parallel DNA-sequencing methods for formalin-fixed paraffin-embedded tissue from victims of sudden cardiac death2021In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 53, article id 102522Article in journal (Refereed)
    Abstract [en]

    Sudden cardiac death (SCD) is a tragic and traumatic event. SCD is often associated with hereditary genetic disease and in such cases, sequencing of stored formalin fixed paraffin embedded (FFPE) tissue is often crucial in trying to find a causal genetic variant. This study was designed to compare two massive parallel sequencing assays for differences in sensitivity and precision regarding variants related to SCD in FFPE material. From eight cases of SCD where DNA from blood had been sequenced using HaloPlex, corresponding FFPE samples were collected six years later. DNA from FFPE samples were amplified using HaloPlex HS, sequenced on MiSeq, representing the first method, as well as amplified using modified Twist and sequenced on NextSeq, representing the second method. Molecular barcodes were included to distinguish artefacts from true variants. In both approaches, read coverage, uniformity and variant detection were compared using genomic DNA isolated from blood and corresponding FFPE tissue, respectively. In terms of coverage uniformity, Twist performed better than HaloPlex HS for FFPE samples. Despite higher overall coverage, amplicon-based HaloPlex technologies, both for blood and FFPE tissue, suffered from design and/or performance issues resulting in genes lacking complete coverage. Although Twist had considerably lower overall mean coverage, high uniformity resulted in equal or higher fraction of genes covered at >= 20X. By comparing variants found in the matched samples in a pre-defined cardiodiagnostic gene panel, HaloPlex HS for FFPE material resulted in high sensitivity, 98.0% (range 96.6-100%), and high precision, 99.9% (range 99.5-100%) for moderately fragmented samples, but suffered from reduced sensitivity (range 74.2-91.1%) in more severely fragmented samples due to lack of coverage. Twist had high sensitivity, 97.8% (range 96.8-98.7%) and high precision, 99.9% (range 99.3-100%) in all analyzed samples, including the severely fragmented samples.

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  • 11.
    Aengerud, Karin Hellstroem
    et al.
    Umea Univ, Sweden.
    Ericsson, Maria
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Brannstrom, Margareta
    Umea Univ, Sweden.
    Sederholm Lawesson, Sofia
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Strömberg, Anna
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Thylén, Ingela
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Symptoms of Acute Myocardial Infarction as Described in Calls to Tele-Nurses and in Questionnaires A Mixed-Methods Study2023In: Journal of Cardiovascular Nursing, ISSN 0889-4655, E-ISSN 1550-5049, Vol. 38, no 2, p. 150-157Article in journal (Refereed)
    Abstract [en]

    BackgroundPatient-reported symptoms of acute myocardial infarction (MI) may be affected by recall bias depending on when and where symptoms are assessed.AimThe aim of this study was to gain an understanding of patients symptom description in more detail before and within 24 hours after a confirmed MI diagnosis.MethodsA convergent parallel mixed-methods design was used to examine symptoms described in calls between the tele-nurse and the patient compared with symptoms selected by the patient from a questionnaire less than 24 hours after hospital admission. Quantitative and qualitative data were analyzed separately and then merged into a final interpretation.ResultsThirty patients (median age, 67.5 years; 20 men) were included. Chest pain was the most commonly reported symptom in questionnaires (24/30). Likewise, in 19 of 30 calls, chest pain was the first complaint mentioned, usually described together with the symptom onset. Expressions used to describe symptom quality were pain, pressure, discomfort, ache, cramp, tension, and soreness. Associated symptoms commonly described were pain or numbness in the arms, cold sweat, dyspnea, weakness, and nausea. Bodily sensations, such as feeling unwell or weak, were also described. Fear and tiredness were described in calls significantly less often than reported in questionnaires (P = .01 and P = .02), whereas "other" symptoms were more often mentioned in calls compared with answers given in the questionnaire (P = .02). Some symptoms expressed in the calls were not listed in the questionnaire, which expands the understanding of acute MI symptoms. The results showed no major inconsistencies between datasets.ConclusionPatients MI symptom descriptions in tele-calls and those reported in questionnaires after diagnosis are comparable and convergent.

  • 12.
    af Geijerstam, Peder
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Engvall, Jan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Östgren, Carl Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Primary Care Center, Primary Health Care Center Ekholmen.
    Nyström, Fredrik
    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, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Rådholm, Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Kärna. The George Institute for Global Health, University of New South Wales, Sydney, Australia.
    Home Blood Pressure Compared With Office Blood Pressure in Relation to Dysglycemia2022In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 35, no 9, p. 810-819Article in journal (Refereed)
    Abstract [en]

    Background: Masked hypertension is more common in individuals with type 2 diabetes than in individuals with normoglycemia. We aimed to explore if there is a discrepancy between office blood pressure (office BP) and home blood pressure monitoring (HBPM) in relation to HbA1c as well as glycemic status in 5,029 middle-aged individuals.

    Methods: HBPM was measured in a subsample of 5,029 participants in The Swedish CardioPulmonary BioImage Study (SCAPIS), a population-based cohort of 50–64 years old participants. Both office BP and HBPM were obtained after 5 minutes’ rest using the semiautomatic Omron M10-IT oscillometric device. White coat effect was calculated by subtracting systolic HBPM from systolic office BP. Participants were classified according to glycemic status: Normoglycemia, prediabetes, or diabetes based on fasting glucose, HbA1c value, and self-reported diabetes diagnosis.

    Results: Of the included 5,025 participants, 947 (18.8%) had sustained hypertension, 907 (18.0%) reported taking antihypertensive treatment, and 370 (7.4%) had diabetes mellitus. Both systolic office BP and HBPM increased according to worsened glycemic status (P for trend 0.002 and 0.002, respectively). Masked hypertension was more prevalent in participants with dysglycemia compared with normoglycemia (P = 0.036). The systolic white coat effect was reversely associated with HbA1c (P = 0.012).

    Conclusions: The systolic white coat effect was reversely associated with HbA1c, and the prevalence of masked hypertension increased with dysglycemia.

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  • 13.
    af Geijerstam, Peder
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Engvall, Jan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Östgren, Carl Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Primary Care Center, Primary Health Care Center Ekholmen.
    Rådholm, Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Kärna.
    Nyström, Fredrik
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    Masked hypertension in a middle-aged population and its relation to manifestations of vascular disease2023In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 41, no 7, p. 1084-1091Article in journal (Refereed)
    Abstract [en]

    Background: Masked hypertension is associated with cardiovascular disease (CVD). However, previous large studies have not used the same device to measure office and home blood pressure (BP) and adhered to current home BP measurement recommendations of the European Society of Hypertension. We aimed to characterize masked hypertension and explore its relation to manifestations of CVD.

    Methods: A randomly selected cohort of 5057 participants aged 50–64 years from the Swedish CardioPulmonary BioImage Study (SCAPIS) was evaluated with office and home BP using the semi-automatic Omron M10-IT oscillometric device. Additional analyses included pulse wave velocity (PWV) and coronary artery calcium score (CACS).

    Results: Of participants, 4122 did not have current antihypertensive treatment, and were thus included in our analyses. Of these, 2634 (63.9%) had sustained normotension, and 172 (4.2%) had masked hypertension. Participants with masked hypertension vs. sustained normotension were more often men (66.9 vs. 46.2%, P < 0.001). Those with masked hypertension had higher mean PWV [9.3 (95% confidence interval, 95% CI 9.1–9.5) vs. 8.3 (95% CI 8.2–8.4) m/s, P < 0.001] and odds ratio for CACS at least 100 [1.65 (95% CI 1.02–2.68), P = 0.040]. These associations were similar in a posthoc analysis of masked hypertension and sustained normotension, matched for age, sex and systolic office BP.

    Conclusion: Masked hypertension was associated with markers of CVD. This suggests that home BP is a better predictor of risk, even when the recordings are performed with the same measurement device, in a population-based setting with randomized recruitment.

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  • 14.
    af Geijerstam, Peder
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Janryd, Fredrik
    Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Nyström, Fredrik
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    Smoking and cardiovascular disease in patients with type 2 diabetes: a prospective observational study2023In: Journal of Cardiovascular Disease, ISSN 2330-4596, E-ISSN 2330-460X, Vol. 24, no 11, p. 802-807Article in journal (Refereed)
    Abstract [en]

    Background

    Cigarette smoking is a major risk factor for cardiovascular disease. In type 2 diabetes mellitus (T2D), medications such as antihypertensives and statins can reduce the increased cardiovascular risk. The aim of this study was to evaluate the impact of cigarette smoking on major adverse cardiovascular event (MACE) and all-cause mortality in patients with T2D in a relatively well treated Swedish cohort.

    Methods

    Seven hundred and sixty-one patients with T2D aged 55–66 years were followed in the prospective observational CArdiovascular Risk factors in patients with DIabetes – a Prospective study in Primary care (CARDIPP) study. Baseline data included blood samples of markers of dysglycemia and inflammation, blood pressure as well as questionnaire responses regarding cigarette smoking. Participants were followed for incidence of MACE and all-cause mortality.

    Results

    Of the included 663 participants, the mean age was 60.6 (SD 3.1) years and 423 (63.8%) were men. Levels of C-reactive protein and vitamin D, as well as the proportion of participants treated with antihypertensives, acetylic salicylic acid, statins, and diabetes medications, were similar between smokers and nonsmokers. Median follow-up time was 11.9 (Q1–Q3 10.8–12.7) years. Cigarette smoking was associated with all-cause mortality [hazard ratio 2.24 (95% confidence interval, 95% CI 1.40–3.56), P < 0.001], but not MACE [hazard ratio 1.30 (95% CI 0.77–2.18), P = 0.328].

    Conclusion

    In patients with T2D, cigarette smoking was not associated with an increased risk of MACE. This raises the question of whether cardioprotective drugs in individuals with T2D to some degree mitigate the cardiovascular harm of smoking, even though they do not affect other dire consequences of smoking.

  • 15.
    af Geijerstam, Peder
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Joelsson, Annelie
    Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Rådholm, Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Kärna.
    Nyström, Fredrik H
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    A low dose of daily licorice intake affects renin, aldosterone, and home blood pressure in a randomized crossover trial2024In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207Article in journal (Refereed)
    Abstract [en]

    BackgroundLicorice, through the effects of glycyrrhizic acid (GA), raises blood pressure (BP). The World Health Organization has suggested that 100 mg GA/d would be unlikely to cause adverse effects, but of 13 previously published studies none have been randomized and controlled and independently quantified the GA content.

    Objective

    Our aim was to analyze the effects on home BP of a daily licorice intake containing 100 mg GA.

    Methods

    Healthy volunteers were randomly assigned to start with either licorice or a control product in a nonblinded, 2 × 2 crossover study. Home BP was measured daily, and blood samples were collected at the end of each 2-wk period.

    Results

    There were 28 participants and no dropouts. The median age was 24.0 y (interquartile range 22.8–27.0 y). During the licorice compared with control intake period, the systolic home BP increased [mean difference: 3.1 mm Hg (95% confidence interval [CI]: 0.8, 5.4 mm Hg) compared with −0.3 mm Hg (95% CI: −1.8, 1.3 mm Hg); P = 0.018] and renin and aldosterone were suppressed [mean change: −30.0% (95% CI: −56.7%, −3.3%) compared with 15.8% (95% CI: −12.8%, 44.4%); P = 0.003; and −45.1% (95% CI: −61.5%, −28.7%) compared with 8.2% (95% CI: −14.7%, 31.1%); P <0.001, respectively]. In the quartile of participants with the most pronounced suppression of renin and aldosterone, N-terminal prohormone of brain natriuretic peptide concentration increased during the licorice compared with control period [mean change: 204.1% (95% CI: −11.6%, 419.7%) compared with 72.4% (95% CI: −52.2%, 197.1%); P = 0.016].

    Conclusions

    We found licorice to be more potent than previously known, with significant increases in BP, after a daily intake of only 100 mg GA. Thus, the safe limit of intake of this substance might need to be reconsidered.

  • 16.
    Ahlander, B. M.
    et al.
    Ryhov County Hospital, Jönköping, Sweden.
    Engvall, Jan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Ericsson, E.
    Faculty of Medicine and Health, School of Health Science, Örebro University, Örebro, Sweden.
    Anxiety during magnetic resonance imaging of the spine in relation to scanner design and size2020In: Radiography, ISSN 1078-8174, E-ISSN 1532-2831, Vol. 26, no 2, p. 110-116Article in journal (Refereed)
    Abstract [en]

    Introduction: Magnetic resonance imaging in closed-bore scanners sometimes provokes anxiety but closed-bore designs have gradually become wider and shorter. Open scanners may be easier to tolerate. The aim was to compare patient anxiety during MRI between bore diameters of 60 cm and 70 cm, and to determine the current level of patient anxiety and experience in open scanners in a clinical setrting. Methods: Consecutive patients referred for examination of the spine in 60 cm and 70 cm bores and one open scanner participated. Four established/validated questionnaires, answered before, directly after (N = 155) and one week after (N = 109) the MRI-examination were used, measuring anxiety, fear and depression. Results: No difference was found in the patient scores of anxiety between the 60 cm and the 70 cm scanners on the examination day. At follow-up, patients in the 70 cm bore rated their examination experience better (p &lt; 0.025), compared to patients in the 60 cm bore. Patients in the open scanner rated higher levels of anxiety (p &lt; 0.001) before, directly after and one week after the examination, compared to the closed bore scanners. Conclusion: Scanners with a 70 cm diameter bore seem more tolerable than those with a 60 cm bore. Patients referred to the open scanner had on average a higher tendency to express anxiety. Still, patient anxiety in MRI is challenging and further research required. Implications for practice: Patients prefer to be examined in 70 cm bore scanners compared with 60 cm. If open scanners arent available extended support may be necessary for the most anxious patients. (c) 2019 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.

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  • 17.
    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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  • 18.
    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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  • 19.
    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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  • 20.
    Akbari, Camilla
    et al.
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Dodd, Maja
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Stål, Per
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Nasr, Patrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. epartment of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Vessby, Johan
    Uppsala University Hospital, Uppsala, Sweden.
    Rorsman, Fredrik
    Uppsala University Hospital, Uppsala, Sweden.
    Zhang, Xiao
    Merck & Co., Inc., Rahway, NJ, USA.
    Wang, Tongtong
    Merck & Co., Inc., Rahway, NJ, USA.
    Jemielita, Thomas
    Merck & Co., Inc., Rahway, NJ, USA.
    Fernandes, Gail
    Merck & Co., Inc., Rahway, NJ, USA.
    Engel, Samuel S.
    Merck & Co., Inc., Rahway, NJ, USA.
    Hagström, Hannes
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Shang, Ying
    Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD2024In: JHEP Reports, ISSN 2589-5559, Vol. 6, no 2, article id 100915Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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  • 21.
    Akerstrom, Finn
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Hutter, Julie
    Kerckhoff Heart & Thorax Ctr, Germany.
    Charitakis, Emmanouil
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Tabrizi, Fariborz
    Arrhythm Ctr, Sweden.
    Asaad, Fahd
    Karolinska Univ Hosp, Sweden.
    Bastani, Hamid
    Karolinska Univ Hosp, Sweden.
    Bourke, Tara
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Braunschweig, Frieder
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Drca, Nikola
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Englund, Anders
    Arrhythm Ctr, Sweden.
    Friberg, Leif
    Karolinska Inst, Sweden.
    Insulander, Per
    Karolinska Inst, Sweden.
    Jonsson, Anders Hassel
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Kenneback, Goran
    Karolinska Univ Hosp, Sweden.
    Paul-Nordin, Astrid
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Sadigh, Bita
    Karolinska Univ Hosp, Sweden.
    Saluveer, Ott
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Saygi, Serkan
    Karolinska Univ Hosp, Sweden.
    Schwieler, Jonas
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Svennberg, Emma
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Tapanainen, Jari
    Danderyd Hosp, Sweden.
    Turkmen, Yusuf
    Karolinska Univ Hosp, Sweden.
    Jensen-Urstad, Mats
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Association between catheter ablation of atrial fibrillation and mortality or stroke2024In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 110, p. 163-169Article in journal (Refereed)
    Abstract [en]

    Objective Catheter ablation of atrial fibrillation effectively reduces symptomatic burden. However, its long-term effect on mortality and stroke is unclear. We investigated if patients with atrial fibrillation who undergo catheter ablation have lower risk for all-cause mortality or stroke than patients who are managed medically. Methods We retrospectively included 5628 consecutive patients who underwent first-time catheter ablation for atrial fibrillation between 2008 and 2018 at three major Swedish electrophysiology units. Control individuals with an atrial fibrillation diagnosis but without previous stroke were selected from the Swedish National Patient Register, resulting in a control group of 48 676 patients. Propensity score matching was performed to produce two cohorts of equal size (n=3955) with similar baseline characteristics. The primary endpoint was a composite of all-cause mortality or stroke. Results Patients who underwent catheter ablation were healthier (mean CHA(2)DS(2)-VASc score 1.4 +/- 1.4 vs 1.6 +/- 1.5, p&lt;0.001), had a higher median income (288 vs 212 1000 Swedish krona [KSEK]/year, p&lt;0.001) and had more frequently received university education (45.1% vs 28.9%, p&lt;0.001). Mean follow-up was 4.5 +/- 2.8 years. After propensity score matching, catheter ablation was associated with lower risk for the combined primary endpoint (HR 0.58, 95% CI 0.48 to 0.69). The result was mainly driven by a decrease in all-cause mortality (HR 0.51, 95% CI 0.41 to 0.63), with stroke reduction showing a trend in favour of catheter ablation (HR 0.75, 95% CI 0.53 to 1.07). Conclusions Catheter ablation of atrial fibrillation was associated with a reduction in the primary endpoint of all-cause mortality or stroke. This result was driven by a marked reduction in all-cause mortality.

  • 22.
    Alehagen, Urban
    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.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Brismar, Kerstin
    Karolinska Univ Hosp, Sweden.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Selenium and Coenzyme Q10 Supplementation Improves Renal Function in Elderly Deficient in Selenium: Observational Results and Results from a Subgroup Analysis of a Prospective Randomised Double-Blind Placebo-Controlled Trial2020In: Nutrients, E-ISSN 2072-6643, Vol. 12, no 12, article id 3780Article in journal (Refereed)
    Abstract [en]

    A low selenium intake is found in European countries, and is associated with increased cardiovascular mortality. There is an association between selenium level and the severity of kidney disease. An association between inflammation and selenium intake is also reported. The coenzyme Q10 level is decreased in kidney disease. The aim of this study was to examine a possible association between selenium and renal function in an elderly population low in selenium and coenzyme Q(10), and the impact of intervention with selenium and coenzyme Q(10) on the renal function. The association between selenium status and creatinine was studied in 589 elderly persons. In 215 of these (mean age 71 years) a randomised double-blind placebo-controlled prospective trial with selenium yeast (200 mu g/day) and coenzyme Q(10) (200 mg/day) (n = 117) or placebo (n = 98) was conducted. Renal function was determined using measures of glomerular function at the start and after 48 months. The follow-up time was 5.1 years. All individuals were low on selenium (mean 67 mu g/L (SD 16.8)). The changes in renal function were evaluated by measurement of creatinine, cystatin-C, and the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm, and by the use of T-tests, repeated measures of variance and ANCOVA analyses. An association between low selenium status and impaired renal function was observed. Intervention causes a significantly lower serum creatinine, and cystatin-C concentration in the active treatment group compared with those on placebo (p = 0.0002 and p = 0.001 resp.). The evaluation with CKD-EPI based on both creatinine and cystatin-C showed a corresponding significant difference (p &lt; 0.0001). All validations showed corresponding significant differences. In individuals with a deficiency of selenium and coenzyme Q(10,) low selenium status is related to impaired renal function, and thus supplementation with selenium and coenzyme Q10 results in significantly improved renal function as seen from creatinine and cystatin-C and through the CKD-EPI algorithm. The explanation could be related to positive effects on inflammation and oxidative stress as a result of the supplementation.

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  • 23.
    Alehagen, Urban
    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.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Johansson, Peter
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Supplemental selenium and coenzyme Q10 reduce glycation along with cardiovascular mortality in an elderly population with low selenium status - A four-year, prospective, randomised, double-blind placebo-controlled trial2020In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 61, article id UNSP 126541Article in journal (Refereed)
    Abstract [en]

    Background: A low intake of selenium has been shown to increase the risk of cardiovascular mortality, and supplementation of selenium and coenzyme Q10 influences this. The mechanism behind is unclear although effects on inflammation, oxidative stress and microRNA expression have been reported. Fructosamine, a marker of long-term glycaemic control, is also a marker of increased risk of heart disease and death, even in non-diabetics. Objective: To analyse the impact of selenium and coenzyme Q10 supplementation on the concentration of fructosamine. Also, the relation between pre-intervention serum selenium concentration and the effect on fructosamine of the intervention was studied. Methods: Fructosamine plasma concentration was determined in 219 participants after six and 42 months of intervention with selenium yeast (200 mu g/day) and coenzyme Q10 (200 mg/ day) (n = 118 of which 20 had diabetes at inclusion), or placebo (n = 101 of which 18 had diabetes at inclusion). Pre-intervention, the serum selenium levels were 67 mu g/L (active treatment group: 66.6 mu g/L; placebo group: 67.4 mu g/L), corresponding to an estimated intake of 35 mu g/day. Changes in concentrations of fructosamine following intervention were assessed by the use of T-tests, repeated measures of variance, and ANCOVA analyses. Results: Post-intervention selenium concentrations were 210 mu g/L in the active group and 72 mu g/L in the placebo group. A lower concentration of fructosamine could be seen as a result of the intervention in the total population (P = 0.001) in both the males (P = 0.04) and in the females (P = 0.01) in the non-diabetic population (P = 0.002), and in both the younger ( &lt; 76 years) (P = 0.01) and the older (&gt;= 6 years) participants (P = 0.03). No difference could be demonstrated in fructosamine concentration in the diabetic patients, but the total sample was small (n = 38). In subjects with a low pre-intervention level of serum selenium the intervention gave a more pronounced decrease in fructosamine compared with those with a higher baseline selenium level. Conclusion: A significantly lower concentration of fructosamine was observed in the elderly community-living participants supplemented with selenium and coenzyme Q10 for 42 months compared to those on the placebo. As oxidative mechanisms are involved in the glycation of proteins, less glycoxidation could be a result of the supplementation of selenium and coenzyme Q10, which could have contributed to lower cardiac mortality and less inflammation, as has earlier been reported.

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  • 24.
    Alehagen, Urban
    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.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Decreased Concentration of Fibroblast Growth Factor 23 (FGF-23) as a Result of Supplementation with Selenium and Coenzyme Q(10) in an Elderly Swedish Population: A Sub-Analysis2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 3, article id 509Article in journal (Refereed)
    Abstract [en]

    There is a reduced intake of selenium in many countries due to low levels of selenium in the soil. This results in an increased cardiovascular risk. Fibroblast growth factor 23 (FGF-23) is active mainly in the metabolism of vitamin D and phosphorus. However, there are indications that FGF-23 may also provide information both on cardiovascular function and prognosis. The aim of the study was to evaluate the effect of supplementation with selenium and coenzyme Q(10) on the FGF-23 concentration in an elderly population with low concentrations of both selenium and coenzyme Q(10) and in which the supplementation improved cardiac function and mortality. In a randomised double-blind placebo-controlled trial, FGF-23 was measured in 219 individuals at the start and after 48 months. Selenium yeast (200 mu g/day) and coenzyme Q(10) (200 mg/day) (n = 118) or placebo (n = 101) were given as a dietary supplement. The intervention time was 48 months. t-Tests, repeated measures of variance, and ANCOVA analyses were used to evaluate the differences in FGF-23 concentration. Following supplementation with selenium and coenzyme Q(10), a significantly lower level of FGF-23 could be seen (p = 0.01). Applying 10 years of follow-up, those who later died a cardiovascular death had a significantly higher FGF-23 concentration after 48 months compared with those who survived (p = 0.036), and a significantly lower FGF-23 concentration could be seen in those with a normal renal function compared to those with an impaired renal function (p = 0.027). Supplementation with selenium and coenzyme Q(10) to an elderly community-living population low in both substances prevented an increase of FGF-23 and also provided a reduced cardiovascular risk.

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  • 25.
    Alehagen, Urban
    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.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway.
    Lindahl, Tomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Dietary Supplementation with Selenium and Coenzyme Q(10) Prevents Increase in Plasma D-Dimer While Lowering Cardiovascular Mortality in an Elderly Swedish Population2021In: Nutrients, E-ISSN 2072-6643, Vol. 13, no 4, article id 1344Article in journal (Refereed)
    Abstract [en]

    A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q(10). D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q(10) on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 mu g/day) and coenzyme Q(10) (200 mg/day) (n = 106) or placebo (n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 mu g/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly lower D-dimer concentration was observed in the active treatment group in comparison with those on placebo (p = 0.006). Although D-dimer values at baseline were weakly associated with high-sensitive CRP, while being more strongly associated with soluble tumour necrosis factor receptor 1 and sP-selectin, controlling for these in the analysis there was an independent effect on D-dimer. In participants with a D-dimer level above median at baseline, the supplementation resulted in significantly lower cardiovascular mortality compared to those on placebo (p = 0.014). All results were validated with a persisting significant difference between the two groups. Therefore, supplementation with selenium and coenzyme Q(10) in a group of elderly low in selenium and coenzyme Q(10) prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group. The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk.

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  • 26.
    Alehagen, Urban
    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.
    Alexander, J.
    Norwegian Inst Publ Hlth, Norway.
    Aaseth, J.
    Innlandet Hosp Trust, Norway.
    Larsson, A.
    Uppsala Univ, Sweden.
    Lindahl, Tomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Significant decrease of von Willebrand factor and plasminogen activator inhibitor-1 by providing supplementation with selenium and coenzyme Q10 to an elderly population with a low selenium status2020In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 59, p. 3581-3590Article in journal (Refereed)
    Abstract [en]

    Purpose Endothelial dysfunction and inflammation are conditions which fuel atherosclerosis and ischaemic heart disease. We have previously reported reduced cardiovascular (CV) mortality following supplementation with selenium and coenzyme Q10 to 443 elderly individuals with low selenium status (mean 67 mu g/L) for 4 years. Here, we wanted to evaluate a possible association between the supplementation and the plasma concentrations of the von Willebrand factor (vWf), and the plasminogen activator inhibitor-1 (PAI-1), as they, besides other functions, are also strongly associated with endothelial function. Methods In this sub-study, 308 individuals (active substance: 157, placebo: 151) were included. Blood samples were drawn after 6 and 36 months and vWf and PAI-1 were determined in plasma by ELISA. Changes in concentrations of the biomarkers were evaluated by the use of T tests, repeated measures of variance, and ANCOVA analyses. Results The active treatment group presented a lower level of vWf after 36 months compared with the placebo group (1.08 U/mL vs. 5.10 U/mL; p = 0.0007). The results were validated through the repeated measures of variance evaluation. The PAI-1 levels showed an equally significant decrease in the active group (26.2 ng/mL vs. 49.2 ng/mL; p = 0.0002) and were also validated through repeated measures of variance evaluation. Conclusion In this sub-study on elderly receiving selenium and coenzyme Q10, or placebo we found significantly lower levels of vWf and PAI-1 in the active treatment group as compared to the placebo group. We interpret this as a better endothelial function because of the intervention, which accords with a previous finding of reduced CV mortality.

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  • 27.
    Alehagen, Urban
    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.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Aaseth, Jan O.
    Innlandet Hosp Trust, Norway; Inland Norway Univ Appl Sci, Norway.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Svensson, Erland
    Swedish Def Res Agcy, Sweden.
    Opstad, Trine B.
    Oslo Univ Hosp Ulleval, Norway; Univ Oslo, Norway.
    Effects of an Intervention with Selenium and Coenzyme Q(10) on Five Selected Age-Related Biomarkers in Elderly Swedes Low in Selenium: Results That Point to an Anti-Ageing Effect-A Sub-Analysis of a Previous Prospective Double-Blind Placebo-Controlled Randomised Clinical Trial2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 13, article id 1773Article in journal (Refereed)
    Abstract [en]

    Background: Ageing is associated with cardiovascular disease (CVD). As no single biomarker reflects the full ageing process, we aimed to investigate five CVD- and age-related markers and the effects of selenium and coenzyme Q10 intervention to elucidate the mechanisms that may influence the course of ageing. Methods: This is a sub-study of a previous prospective double-blind placebo-controlled randomized clinical trial that included 441 subjects low in selenium (mean age 77, 49% women). The active treatment group (n = 220) received 200 & mu;g/day of selenium and 200 mg/day of coenzyme Q10, combined. Blood samples were collected at inclusion and after 48 months for measurements of the intercellular adhesion molecule (ICAM-1), adiponectin, leptin, stem cell factor (SCF) and osteoprotegerin (OPG), using ELISAs. Repeated measures of variance and ANCOVA evaluations were used to compare the two groups. In order to better understand and reduce the complexity of the relationship between the biomarkers and age, factor analyses and structural equation modelling (SEM) were performed, and a structural model is presented. Results: Correlation analyses of biomarker values at inclusion in relation to age, and relevant markers related to inflammation, endothelial dysfunction and fibrosis, demonstrated the biomarkers association with these pathological processes; however, only ICAM1 and adiponectin were directly correlated with age. SEM analyses showed, however, that the biomarkers ICAM-1, adiponectin, SCF and OPG, but not leptin, all had significant associations with age and formed two independent structural factors, both significantly related to age. While no difference was observed at inclusion, the biomarkers were differently changed in the active treatment and placebo groups (decreasing and increasing levels, respectively) at 48 months (p & LE; 0.02 in all, adjusted), and in the SEM model, they showed an anti-ageing impact. Conclusions: Supplementation with selenium/Q10 influenced the analysed biomarkers in ways indicating an anti-ageing effect, and by applying SEM methodology, the interrelationships between two independent structural factors and age were validated.

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  • 28.
    Alehagen, Urban
    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.
    Johansson, Peter
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Svensson, Erland
    Swedish Def Res Agcy, Sweden.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway; Inland Norway Univ Appl Sci, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Improved cardiovascular health by supplementation with selenium and coenzyme Q10: applying structural equation modelling (SEM) to clinical outcomes and biomarkers to explore underlying mechanisms in a prospective randomized double-blind placebo-controlled intervention project in Sweden2022In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 61, no 6, p. 3135-3148Article in journal (Refereed)
    Abstract [en]

    Purpose Selenium and coenzyme Q10 have synergistic antioxidant functions. In a four-year supplemental trial in elderly Swedes with a low selenium status, we found improved cardiac function, less cardiac wall tension and reduced cardiovascular mortality up to 12 years of follow-up. Here we briefly review the main results, including those from studies on biomarkers related to cardiovascular risk that were subsequently conducted. In an effort, to explain underlying mechanisms, we conducted a structured analysis of the inter-relationship between biomarkers. Methods Selenium yeast (200 mu g/day) and coenzyme Q10 (200 mg/ day), or placebo was given to 443 elderly community-living persons, for 48 months. Structural Equation Modelling (SEM) was used to investigate the statistical inter-relationships between biomarkers related to inflammation, oxidative stress, insulin-like growth factor 1, expression of microRNA, fibrosis, and endothelial dysfunction and their impact on the clinical effects. The main study was registered at Clinicaltrials.gov at 30th of September 2011, and has the identifier NCT01443780. Results In addition to positive clinical effects, the intervention with selenium and coenzyme Q10 was also associated with favourable effects on biomarkers of cardiovascular risk. Using these results in the SEM model, we showed that the weights of the first-order factors inflammation and oxidative stress were high, together forming a second-order factor inflammation/oxidative stress influencing the factors, fibrosis (beta = 0.74; p &lt; 0.001) and myocardium (beta = 0.65; p &lt; 0.001). According to the model, the intervention impacted fibrosis and myocardium through these factors, resulting in improved cardiac function and reduced CV mortality. Conclusion Selenium reduced inflammation and oxidative stress. According to the SEM analysis, these effects reduced fibrosis and improved myocardial function pointing to the importance of supplementation in those low on selenium and coenzyme Q10.

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  • 29.
    Alehagen, Urban
    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.
    Opstad, Trine B.
    Oslo Univ Hosp Ulleval, Norway; Univ Oslo, Norway.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway; Inland Norway Univ Appl Sci, Norway.
    Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 10, article id 1478Article, review/survey (Refereed)
    Abstract [en]

    Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.a., the enzymes thioredoxin reductases (TXNRD1-3), glutathione peroxidases (GPX1-4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.a., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1-4 and TXNRD1-3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.

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  • 30.
    Alehagen, Urban
    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.
    Shamoun, Levar
    Dept Lab Med, Sweden; Uppsala Univ, Sweden.
    Dimberg, Jan Ingvar
    Jonkoping Univ, Sweden.
    Wagsater, Dick
    Uppsala Univ, Sweden.
    Increased mortality in the A/A genotype of the SNP rs28372698 of interleukin 322021In: Experimental and Therapeutic Medicine, ISSN 1792-0981, E-ISSN 1792-1015, Vol. 21, no 2, article id 127Article in journal (Refereed)
    Abstract [en]

    One of the major causes of mortality in the western hemisphere is cardiovascular disease. Therefore, a variety of markers to identify those at risk are required. Interleukin-32 (IL-32) is a cytokine that is associated with inflammation. The aim of the current study was to investigate variations in single nucleotide polymorphisms (SNPs) of IL-32 and plasma expression, and their associations with mortality. A population of 486 elderly community-living persons were evaluated. The participants were followed for 7.1 years and underwent a clinical examination and blood sampling. SNP analyses of IL-32 rs28372698 using allelic discrimination and plasma measurement of IL-32, using ELISA, were performed. During the follow-up period, 140 (28.8%) all-cause and 87 (17.9%) cardiovascular deaths were registered. No significant difference between mortality and plasma concentration of IL-32 was observed. The A/A genotype group exhibited significantly higher all-cause mortality (P=0.036), and an almost two-fold increased risk in a multivariate Cox regression model for all-cause and cardiovascular mortality. A highly significant difference in all-cause and cardiovascular mortality between the A/A and the T/T groups was demonstrated (P=0.015 resp. P=0.014). In the present study, the cytokine IL-32 was demonstrated to have prognostic information, with an increased risk of all-cause and cardiovascular mortality for those with the A/A genotype rs28372698 of IL-32. The A/A genotype could therefore be regarded as a possible biomarker for mortality risk that may be used to offer optimized cardiovascular patient handling in the future. However, the present study sample was small, and the results should be regarded as hypothesis-generating.

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  • 31.
    Alehagen, Urban
    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.
    Shamoun, Levar
    Jonkoping Cty, Sweden; Uppsala Univ, Sweden.
    Wagsaeter, Dick
    Uppsala Univ, Sweden.
    Increased cardiovascular mortality in females with the a/a genotype of the SNPs rs1478604 and rs2228262 of thrombospondin-12020In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 21, no 1, article id 179Article in journal (Refereed)
    Abstract [en]

    BackgroundCardiovascular diseases are still the major cause of death in the Western world, with different outcomes between the two genders. Efforts to identify those at risk are therefore given priority in the handling of health resources. Thrombospondins (TSP) are extracellular matrix proteins associated with cardiovascular diseases. The aim of this study was to investigate variations in single nucleotide polymorphisms (SNPs) of TSP-1 and plasma expression, and associations with mortality from a gender perspective.MethodsA population of 470 community-living persons were invited to participate. The participants were followed for 7.9years and underwent a clinical examination and blood sampling. SNP analyses of TSP-1 rs1478604 and rs2228262 using allelic discrimination and plasma measurement of TSP-1 using ELISA were performed,ResultsDuring the follow-up period, 135 (28.7%) all-cause and 83 (17.7%) cardiovascular deaths were registered.In the female population, the A/A genotype of rs2228262 and the T/T genotype of rs1478604 exhibited significantly more cardiovascular deaths compared with the A/G and G/G, or the T/C and C/C genotypes amalgamated (rs2228262: 13.7% vs 2.0%; Chi(2):5.29; P=0.02; rs1478604:17.7% vs 4.7%; Chi(2):9.50; P=0.002). Applied in a risk evaluation, the A/A, or T/T genotypes exhibited an increased risk of cardiovascular mortality (rs2228262: HR: 7.1; 95%CI 1.11-45.8; P=0.04; rs1478604: HR: 3.18; 95%CI 1.35-7.50; p=0.008). No differences among the three genotypes could be seen in the male group.ConclusionIn this study the female group having the A/A genotype of rs2228262, or the T/T genotype of rs1478604 of TSP-1 exhibited higher cardiovascular mortality after a follow-up of almost 8 years. No corresponding genotype differences could be found in the male group. Genotype evaluations should be considered as one of the options to identify individuals at risk. However, this study should be regarded as hypothesis-generating, and more research in the field is needed.

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  • 32.
    Alehagen, Urban
    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.
    Shamoun, Levar
    Jonkoping Cty, Sweden; Uppsala Univ, Sweden.
    Wagsater, Dick
    Uppsala Univ, Sweden.
    Genetic variance and plasma concentration of CD93 is associated with cardiovascular mortality: Results from a 6.7-year follow-up of a healthy community-living elderly population2020In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 22, no 6, p. 4629-4636Article in journal (Refereed)
    Abstract [en]

    Inflammation is one of the fundamental processes in numerous diseases. Cluster of differentiation (CD) 93, a glycoprotein, has been reported to be associated with a number of these diseases. There are reports indicating that a high plasma level of CD93 is associated with adverse events in ischaemic heart disease. Additionally, there are reports indicating different cardiovascular risks between different single nucleotide polymorphisms (SNPs) of CD93. Therefore, the present study aimed to determine whether the plasma concentration of CD93 and polymorphism of rs2749812 in CD93 were associated with clinical conditions and mortality in an elderly population. In 470 healthy elderly community-living individuals a novel clinical examination involving echocardiography and blood sampling was performed. The population was followed for 6.7 years. Plasma levels of CD93 and SNP analyses of rs2749812 of CD93 using PCR methodology were used. During the follow-up period, 106 (22.6%) all-cause and 61 (13.0%) cardiovascular deaths were registered. Those with the highest plasma concentration had markedly higher all-cause mortality. Evaluating the A/A, A/G and G/G genotypes, the G/G group exhibited significantly higher cardiovascular mortality (P=0.026), and an almost two-fold increased risk in a multivariate Cox regression model compared with the A/G genotype. Evaluation of subgroups with respect to sex, diabetes and hypertension revealed markedly increased cardiovascular risk in the G/G genotype in all subgroups. All results persisted in the multiple models used. In the present study, the glycoprotein CD93 was demonstrated to have prognostic cardiovascular information, with increased risk for those with a high plasma concentration. Furthermore, the G/G genotype of rs2749812 of CD93 has a significantly higher cardiovascular risk, as demonstrated here, and could therefore be regarded as a possible cardiovascular risk biomarker that might in the future be used to offer optimised cardiovascular patient handling. However, this was a small study, and more research is required.

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  • 33.
    Alexander, Jan
    et al.
    Folkehelseinstituttet, Norway.
    Alehagen, Urban
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Aaseth, Jan Olav
    Sykehuset Innlandet, Sweden.
    Selenium - a trace element of clinical significance2020In: Tidsskrift for Den norske lægeforening, ISSN 0029-2001, E-ISSN 0807-7096, Vol. 140, no 17, p. 1784-1784Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 34.
    Alexander, Jan
    et al.
    Norwegian Inst Publ Hlth, Norway.
    Tinkov, Alexey
    Yaroslavl State Univ, Russia; Sechenov Univ, Russia.
    Strand, Tor A.
    Univ Bergen, Norway; Innlandet Hosp Trust, Norway.
    Alehagen, Urban
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Skalny, Anatoly
    Yaroslavl State Univ, Russia; Sechenov Univ, Russia.
    Aaseth, Jan
    Sechenov Univ, Russia.
    Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-192020In: Nutrients, E-ISSN 2072-6643, Vol. 12, no 8, article id 2358Article, review/survey (Refereed)
    Abstract [en]

    Objectives: The novel coronavirus infection (COVID-19) conveys a serious threat globally to health and economy because of a lack of vaccines and specific treatments. A common factor for conditions that predispose for serious progress is a low-grade inflammation, e.g., as seen in metabolic syndrome, diabetes, and heart failure, to which micronutrient deficiencies may contribute. The aim of the present article was to explore the usefulness of early micronutrient intervention, with focus on zinc, selenium, and vitamin D, to relieve escalation of COVID-19. Methods: We conducted an online search for articles published in the period 2010-2020 on zinc, selenium, and vitamin D, and corona and related virus infections. Results: There were a few studies providing direct evidence on associations between zinc, selenium, and vitamin D, and COVID-19. Adequate supply of zinc, selenium, and vitamin D is essential for resistance to other viral infections, immune function, and reduced inflammation. Hence, it is suggested that nutrition intervention securing an adequate status might protect against the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome - coronavirus-2) and mitigate the course of COVID-19. Conclusion: We recommended initiation of adequate supplementation in high-risk areas and/or soon after the time of suspected infection with SARS-CoV-2. Subjects in high-risk groups should have high priority as regards this nutritive adjuvant therapy, which should be started prior to administration of specific and supportive medical measures.

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  • 35.
    Alfredsson, Joakim
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Heart Center, Department of Cardiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    James, Stefan K.
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Erlinge, David
    Lund Univ, Sweden.
    Herlitz, Johan
    Univ Boras, Sweden.
    Frobert, Ole
    Orebro Univ, Sweden.
    Dworeck, Christian
    Univ Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Redfors, Bjorn
    Univ Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Arefalk, Gabriel
    Uppsala Univ, Sweden.
    Ostlund, Ollie
    Uppsala Univ, Sweden.
    Jernberg, Tomas
    Karolinska Inst, Sweden.
    Mars, Katarina
    Karolinska Inst, Sweden.
    Haaga, Urban
    Karlstad Cent Hosp, Sweden.
    Lindahl, Bertil
    Uppsala Univ, Sweden.
    Swahn, Eva
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Sederholm Lawesson, Sofia
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Hofmann, Robin
    Karolinska Inst, Sweden.
    Randomized comparison of early supplemental oxygen versus ambient air in patients with confirmed myocardial infarction: Sex-related outcomes from DETO2X-AMI2021In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 237, p. 13-24Article in journal (Refereed)
    Abstract [en]

    Background The purpose of this study is to investigate the impact of oxygen therapy on cardiovascular outcomes in relation to sex in patients with confirmed myocardial infarction (MI). Methods The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction trial randomized 6,629 patients to oxygen at 6 L/min for 6-12 hours or ambient air. In the present subgroup analysis including 5,010 patients (1,388 women and 3,622 men) with confirmed MI, we report the effect of supplemental oxygen on the composite of all-cause death, rehospitalization with MI, or heart failure at long-term follow-up, stratified according to sex. Results Event rate for the composite endpoint was 18.1% in women allocated to oxygen, compared to 21.4% in women allocated to ambient air (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.65-1.05). In men, the incidence was 13.6% in patients allocated to oxygen compared to 13.3% in patients allocated to ambient air (HR 1.03, 95% CI 0.86-1.23). No significant interaction in relation to sex was found ( P = .16). Irrespective of allocated treatment, the composite endpoint occurred more often in women compared to men (19.7 vs 13.4%, HR 1.51; 95% CI, 1.30-1.75). After adjustment for age alone, there was no difference between the sexes (HR 1.06, 95% CI 0.91-1.24), which remained consistent after multivariate adjustment. Conclusion Oxygen therapy in normoxemic MI patients did not significantly affect all-cause mortality or rehospitalization for MI or heart failure in women or men. The observed worse outcome in women was explained by differences in baseline characteristics, especially age. (Am Heart J 2021;237:13 & ndash;24.)

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  • 36.
    Alfredsson, Joakim
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Heart Center, Department of Cardiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Omar, Kime
    Vastmanland Cty Hosp, Sweden.
    Csog, Jozsef
    Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Venetsanos, Dimitrios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Janzon, Magnus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Bleeding complications with clopidogrel or ticagrelor in ST-elevation myocardial infarction patients: A real life cohort study of two treatment strategies2020In: IJC Heart & Vasculature, E-ISSN 2352-9067, Vol. 27, article id 100495Article in journal (Refereed)
    Abstract [en]

    Introduction

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

    Methods and Results

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

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

    Conclusions

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

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  • 37.
    Ali, Zaheer
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cui, Dongmei
    Sun Yat Sen Univ, Peoples R China.
    Yang, Yunlong
    Fudan Univ, Peoples R China.
    Tracey-White, Dhani
    UCL Inst Ophthalmol, England.
    Vazquez Rodriguez, Gabriela
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Moosajee, Mariya
    UCL Inst Ophthalmol, England.
    Ju, Rong
    Sun Yat Sen Univ, Peoples R China.
    Li, Xuri
    Sun Yat Sen Univ, Peoples R China.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Synchronized tissue-scale vasculogenesis and ubiquitous lateral sprouting underlie the unique architecture of the choriocapillaris2020In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 457, no 2, p. 206-214Article in journal (Refereed)
    Abstract [en]

    The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature.

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  • 38.
    Ali, Zaheer
    et al.
    BioReperia AB, Linkoping, Sweden.
    Vildevall, Malin
    BioReperia AB, Linkoping, Sweden.
    Rodriguez, Gabriela Vazquez
    BioReperia AB, Linkoping, Sweden.
    Tandiono, Decky
    BioReperia AB, Linkoping, Sweden.
    Vamvakaris, Ioannis
    Athens Chest Hosp Sotiria, Greece.
    Evangelou, Georgios
    Natl Kapodistrian Univ Athens, Greece.
    Lolas, Georgios
    Natl Kapodistrian Univ Athens, Greece; Catalan Inst Oncol ICO, Spain.
    Syrigos, Konstantinos N.
    Natl Kapodistrian Univ Athens, Greece.
    Villanueva, Alberto
    InCELLiA PC, Greece; Xenopat SL, Spain.
    Wick, Michael
    XenoSTART, TX USA.
    Omar, Shenga
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Erkstam, Anna
    BioReperia AB, Linkoping, Sweden.
    Schueler, Julia
    Charles River Labs, Germany.
    Fahlgren, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. BioReperia AB, Linkoping, Sweden.
    Jensen, Lasse
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. BioReperia AB, Linkoping, Sweden.
    Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer2022In: Journal of Experimental & Clinical Cancer Research, E-ISSN 1756-9966, Vol. 41, no 1, article id 58Article in journal (Refereed)
    Abstract [en]

    Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days. Conclusions We conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine.

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  • 39.
    Ali, Zaheer
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Zang, Jingjing
    Univ Zurich, Switzerland.
    Lagali, Neil S
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Schmitner, Nicole
    Univ Innsbruck, Austria.
    Salvenmoser, Willi
    Univ Innsbruck, Austria.
    Mukwaya, Anthony
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences.
    Neuhauss, Stephan C. F.
    Univ Zurich, Switzerland.
    Jensen, Lasse
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Kimmel, Robin A.
    Univ Innsbruck, Austria.
    Photoreceptor Degeneration Accompanies Vascular Changes in a Zebrafish Model of Diabetic Retinopathy2020In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 61, no 2, article id UNSP 43Article in journal (Refereed)
    Abstract [en]

    PURPOSE. Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness worldwide in the working-age population, and the incidence is rising. Until now it has been difficult to define initiating events and disease progression at the molecular level, as available diabetic rodent models do not present the full spectrum of neural and vascular pathologies. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 were previously shown to display a diabetic phenotype from larval stages through adulthood. In this study, pdx1 mutants were examined for retinal vascular and neuronal pathology to demonstrate suitability of these fish for modeling DR. METHODS. Vessel morphology was examined in pdx1 mutant and control fish expressing the fli1a:EGFP transgene. We further characterized vascular and retinal phenotypes in mutants and controls using immunohistochemistry, histology, and electron microscopy. Retinal function was assessed using electroretinography. RESULTS. Pdx1 mutants exhibit clear vascular phenotypes at 2 months of age, and disease progression, including arterial vasculopenia, capillary tortuosity, and hypersprouting, could be detected at stages extending over more than 1 year. Neural-retinal pathologies are consistent with photoreceptor dysfunction and loss, but do not progress to blindness. CONCLUSIONS. This study highlights pdx1 mutant zebrafish as a valuable complement to rodent and other mammalian models of DR, in particular for research into the mechanistic interplay of diabetes with vascular and neuroretinal disease. They are furthermore suited for molecular studies to identify new targets for treatment of early as well as late DR.

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  • 40.
    Almlöv, Karin
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
    Woisetschläger, Mischa
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Faculty of Medicine and Health Sciences.
    Loftås, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Hallböök, Olof
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sandström, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    MRI Lymph Node Evaluation for Prediction of Metastases in Rectal Cancer2020In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 40, no 5, p. 2757-2763Article in journal (Refereed)
    Abstract [en]

    Aim: To explore whether the size and characteristics of the largest regional lymph node in patients with rectal cancer, based on magnetic resonance imaging (MRI), following neoadjuvant therapy and before surgery, is able to identify patients at high risk of developing metachronous metastases.

    Patients and Methods: A retrospective case–control study with data from the Swedish Colo-Rectal Cancer Registry. Forty patients were identified with metachronous metastases (M+), and 40 patients without metastases (M0) were matched as controls.

    Results: Patients with M+ disease were more likely to have a regional lymph node measuring ≥5 mm than patients with M0. (87% vs. 65%, p=0.02). There was also a significant difference between the groups regarding the presence of an irregular border of the largest lymph node (68% vs. 40%, p=0.01).

    Conclusion: Lymph nodes measuring ≥5 mm with/without displaying irregular borders at MRI performed after neoadjuvant therapy emerged as risk factors for metachronous metastases in patients with rectal cancer. Intensified follow-up programmes may be indicated in these patients.

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  • 41.
    Al-Shamkhi, Nasrin
    et al.
    Orebro Univ Hosp, Sweden; Orebro Univ, Sweden; Uppsala Univ Hosp, Sweden; Akadem Sjukhuset, Sweden.
    Berinder, Katarina
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Borg, Henrik
    Lund Univ, Sweden.
    Burman, Pia
    Lund Univ, Sweden.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Hoybye, Charlotte
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Olsson, Daniel S.
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden; AstraZeneca, Sweden.
    Ragnarsson, Oskar
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Ekman, Bertil
    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.
    Engstrom, Britt Eden
    Uppsala Univ, Sweden.
    Pituitary function before and after surgery for nonfunctioning pituitary adenomas-data from the Swedish Pituitary Register2023In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 189, no 2, p. 217-224Article in journal (Refereed)
    Abstract [en]

    Objective Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA). Design and methods Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded. Results Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm(3). Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P &lt; .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively. Conclusions Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.

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  • 42.
    Altena, Renske
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp Stockholm, Sweden.
    Hübbert, Laila
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Norrköping.
    Kiani, Narsis A.
    Karolinska Inst, Sweden.
    Wengstrom, Yvonne
    Karolinska Inst, Sweden.
    Bergh, Jonas
    Karolinska Inst, Sweden; Karolinska Univ Hosp Stockholm, Sweden.
    Hedayati, Elham
    Karolinska Inst, Sweden; Karolinska Univ Hosp Stockholm, Sweden.
    Evidence-based prediction and prevention of cardiovascular morbidity in adults treated for cancer2021In: Cardio-Oncology, ISSN 2057-3804, Vol. 7, no 1, article id 20Article, review/survey (Refereed)
    Abstract [en]

    Background Cancer treatment-related morbidity relevantly compromises health status in cancer survivors, and efforts to optimise health-related outcomes in this population are vital to maximising healthy survivorship. A pre-treatment assessment - and possibly preventive management strategies - of cancer patients at increased risk for cardiovascular disease (CVD) seems a rational approach in this regard. Definitive evidence for such strategies is largely lacking, thereby impeding the formulation of firm recommendations. Results The current scoping review aims to summarise and grade the evidence regarding strategies for prediction and prevention of CVD in adults in relation to oncological treatments. We conducted a scoping literature search for different strategies for primary prevention, such as medical and lifestyle interventions, as well as the use of predictive risk scores. We identified studies with moderate to good strength and up to now limited evidence to recommend primary preventive strategies in unselected patients treated with potentially cardiotoxic oncologic therapies. Conclusion Efforts to minimize the CVD burden in cancer survivors are needed to accomplish healthy survivorship. This can be done by means of robust models predictive for CVD events or application of interventions during or after oncological treatments. Up to now there is insufficient evidence to implement preventive strategies in an unselected group of patients treated with potential cardiotoxic oncological treatments. We conclude that randomised controlled trials are needed that evaluate medical and lifestyle interventions in groups at increased risk for complications, in order to be able to influence chronic illness risks, such as cardiovascular complications, for cancer survivors.

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  • 43.
    Amgad, Mohamed
    et al.
    Emory Univ, GA USA.
    Stovgaard, Elisabeth Specht
    Univ Copenhagen, Denmark.
    Balslev, Eva
    Univ Copenhagen, Denmark.
    Thagaard, Jeppe
    Tech Univ Denmark, Denmark; Visiopharm AS, Denmark.
    Chen, Weijie
    FDA CDRH OSEL, MD USA.
    Dudgeon, Sarah
    FDA CDRH OSEL, MD USA.
    Sharma, Ashish
    Emory Univ, GA USA.
    Kerner, Jennifer K.
    PathAI, MA USA.
    Denkert, Carsten
    Philipps Univ Marburg, Germany; Philipps Univ Marburg, Germany; German Canc Consortium DKTK, Germany.
    Yuan, Yinyin
    Inst Canc Res, England.
    AbdulJabbar, Khalid
    Inst Canc Res, England.
    Wienert, Stephan
    Philipps Univ Marburg, Germany.
    Savas, Peter
    Univ Melbourne, Australia.
    Voorwerk, Leonie
    Netherlands Canc Inst, Netherlands.
    Beck, Andrew H.
    PathAI, MA USA.
    Madabhushi, Anant
    Case Western Reserve Univ, OH 44106 USA; Louis Stokes Cleveland Vet Adm Med Ctr, OH USA.
    Hartman, Johan
    Karolinska Inst, Sweden; Univ Hosp, Sweden.
    Sebastian, Manu M.
    Univ Texas MD Anderson Canc Ctr, TX 77030 USA.
    Horlings, Hugo M.
    Netherlands Canc Inst, Netherlands.
    Hudecek, Jan
    Netherlands Canc Inst, Netherlands.
    Ciompi, Francesco
    Radboud Univ Nijmegen, Netherlands.
    Moore, David A.
    UCL Canc Inst, England; Icahn Sch Med Mt Sinai, NY 10029 USA.
    Singh, Rajendra
    Icahn Sch Med Mt Sinai, NY 10029 USA.
    Roblin, Elvire
    Univ Paris Sud, France.
    Balancin, Marcelo Luiz
    Univ Sao Paulo, Brazil.
    Mathieu, Marie-Christine
    Gustave Roussy Canc Campus, France.
    Lennerz, Jochen K.
    Massachusetts Gen Hosp, MA 02114 USA.
    Kirtani, Pawan
    Manipal Hosp Dwarka, India.
    Chen, I-Chun
    Natl Taiwan Univ, Taiwan.
    Braybrooke, Jeremy P.
    Univ Oxford, England; Univ Hosp Bristol NHS Fdn Trust, England.
    Pruneri, Giancarlo
    Ist Nazl Tumori, Italy; Univ Milan, Italy.
    Demaria, Sandra
    Weill Cornell Med Coll, NY USA.
    Adams, Sylvia
    NYU Langone Med Ctr, NY USA.
    Schnitt, Stuart J.
    Brigham & Womens Hosp, MA 02115 USA.
    Lakhani, Sunil R.
    Univ Queensland, Australia.
    Rojo, Federico
    CIBERONC Inst Invest Sanitaria Fdn Jimenez Diaz I, Spain; GEICAM Spanish Breast Canc Res Grp, Spain.
    Comerma, Laura
    CIBERONC Inst Invest Sanitaria Fdn Jimenez Diaz I, Spain; GEICAM Spanish Breast Canc Res Grp, Spain.
    Badve, Sunil S.
    Indiana Univ Sch Med, IN 46202 USA.
    Khojasteh, Mehrnoush
    Roche Tissue Diagnost, CA USA.
    Symmans, W. Fraser
    Univ Texas MD Anderson Canc Ctr, TX 77030 USA.
    Sotiriou, Christos
    Univ Libre Bruxelles ULB, Belgium; Univ Libre Bruxelles, Belgium.
    Gonzalez-Ericsson, Paula
    Vanderbilt Univ, TN USA.
    Pogue-Geile, Katherine L.
    NRG Oncol NSABP, PA USA.
    Kim, Rim S.
    NRG Oncol NSABP, PA USA.
    Rimm, David L.
    Yale Univ, CT 06510 USA.
    Viale, Giuseppe
    European Inst Oncol IRCCS, Italy; State Univ Milan, Italy.
    Hewitt, Stephen M.
    NCI, MD 20892 USA.
    Bartlett, John M. S.
    Ontario Inst Canc Res, Canada; Western Gen Hosp, Scotland.
    Penault-Llorca, Frederique
    Ctr Jean Perrin, France; Univ Clermont Auvergne, France.
    Goel, Shom
    Peter MacCallum Canc Ctr, Australia.
    Lien, Huang-Chun
    Natl Taiwan Univ Hosp, Taiwan.
    Loibl, Sibylle
    GBG Forsch GmbH, Germany.
    Kos, Zuzana
    BC Canc, Canada.
    Loi, Sherene
    Univ Melbourne, Australia; Peter MacCallum Canc Ctr, Australia.
    Hanna, Matthew G.
    Mem Sloan Kettering Canc Ctr, NY 10021 USA.
    Michiels, Stefan
    Univ Paris Saclay, France; Univ Paris Sud, France.
    Kok, Marleen
    Netherlands Canc Inst, Netherlands; Netherlands Canc Inst, Netherlands.
    Nielsen, Torsten O.
    Univ British Columbia, Canada.
    Lazar, Alexander J.
    Univ Texas MD Anderson Canc Ctr, TX 77030 USA; Univ Texas MD Anderson Canc Ctr, TX 77030 USA; Univ Texas MD Anderson Canc Ctr, TX 77030 USA; Univ Texas MD Anderson Canc Ctr, TX 77030 USA.
    Bago-Horvath, Zsuzsanna
    Med Univ Vienna, Austria.
    Kooreman, Loes F. S.
    Maastricht Univ, Netherlands; Maastricht Univ, Netherlands.
    van der Laak, Jeroen
    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, Clinical pathology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Radboud Univ Nijmegen, Netherlands.
    Saltz, Joel
    SUNY Stony Brook, NY 11794 USA.
    Gallas, Brandon D.
    FDA CDRH OSEL, MD USA.
    Kurkure, Uday
    Roche Tissue Diagnost, CA USA.
    Barnes, Michael
    Roche Diagnost Informat Solut, CA USA.
    Salgado, Roberto
    Univ Melbourne, Australia; GZA ZNA Ziekenhuizen, Belgium.
    Cooper, Lee A. D.
    Northwestern Univ, IL 60611 USA.
    Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group2020In: npj Breast Cancer, E-ISSN 2374-4677, Vol. 6, no 1, article id 16Article, review/survey (Refereed)
    Abstract [en]

    Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

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  • 44.
    Amsallem, Myriam
    et al.
    Stanford Univ, CA 94305 USA.
    Tedford, Ryan J.
    Med Univ South Carolina, SC 29425 USA.
    Denault, Andre
    Univ Montreal, Canada.
    Sweatt, Andrew J.
    Stanford Univ, CA 94305 USA.
    Guihaire, Julien
    Paris Sud Univ, France.
    Hedman, Kristofer
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping. Stanford Univ, CA 94305 USA.
    Peighambari, Shadi
    Stanford Univ, CA 94305 USA.
    Kim, Juyong Brian
    Stanford Univ, CA 94305 USA.
    Li, Xiao
    Stanford Univ, CA 94305 USA.
    Miller, Robert J. H.
    Stanford Univ, CA 94305 USA.
    Mercier, Olaf
    Paris Sud Univ, France.
    Fadel, Elie
    Paris Sud Univ, France.
    Zamanian, Roham
    Stanford Univ, CA 94305 USA.
    Haddad, Francois
    Stanford Univ, CA 94305 USA.
    Quantifying the Influence of Wedge Pressure, Age, and Heart Rate on the Systolic Thresholds for Detection of Pulmonary Hypertension2020In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 9, no 11, article id e016265Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The strong linear relation between mean (MPAP) and systolic (SPAP) pulmonary arterial pressure (eg, SPAP=1.62xMPAP) has been mainly reported in precapillary pulmonary hypertension. This study sought to quantify the influence of pulmonary arterial wedge pressure (PAWP), heart rate, and age on the MPAP-SPAP relation. METHODS AND RESULTS: An allometric equation relating invasive MPAP and SPAP was developed in 1135 patients with pulmonary arterial hypertension, advanced lung disease, chronic thromboembolic pulmonary hypertension, or left heart failure. The equation was validated in 60 885 patients from the United Network for Organ Sharing (UNOS) database referred for heart and/or lung transplant. The MPAP/SPAP longitudinal stability was assessed in pulmonary arterial hypertension with repeated right heart catheterization. The equation obtained was SPAP=1.39xMPAPxPAWP(-0.07)x(60/heart rate)(0.12)xage(0.08) (P&lt;0.001). It was validated in the UNOS cohort (R-2=0.93, P&lt;0.001), regardless of the type of organ(s) patients were listed for (mean bias [-1.96 SD; 1.96 SD] was 0.94 [-8.00; 9.88] for heart, 1.34 [-7.81; 10.49] for lung and 0.25 [-16.74; 17.24] mm Hg for heart-lung recipients). Thresholds of SPAP for MPAP=25 and 20 mm Hg were lower in patients with higher PAWP (37.2 and 29.8 mm Hg) than in those with pulmonary arterial hypertension (40.1 and 32.0 mm Hg). In 186 patients with pulmonary arterial hypertension, the predicted MPAP/SPAP was stable over time (0.63 +/- 0.03 at baseline and follow-up catheterization, P=0.43). CONCLUSIONS: This study quantifies the impact of PAWP, and to a lesser extent heart rate and age, on the MPAP-SPAP relation, supporting lower SPAP thresholds for pulmonary hypertension diagnosis in patients with higher PAWP for echocardiography-based epidemiological studies.

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  • 45.
    Anders, Hans-Joachim
    et al.
    Klinikum Univ Munich, Germany.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Juarez, Gema Maria Fernandez
    Hosp Univ Fdn Alcorcon, Spain.
    Floege, Juergen
    RWTH Aachen Univ Hosp, Germany.
    Goumenos, Dimitrios
    Patras Univ Hosp, Greece.
    Turkmen, Kultigin
    Necmettin Erbakan Univ, Turkey.
    van Kooten, Cees
    Leiden Univ, Netherlands.
    Tesar, Vladimir
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    Segelmark, Mårten
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Recommendations for the management of patients with immune-mediated kidney disease during the severe acute respiratory syndrome coronavirus 2 pandemic2020In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 35, no 6, p. 920-925Article, review/survey (Refereed)
    Abstract [en]

    The coronavirus disease 2019 (COVID-19) pandemic has created major challenges for all countries around the globe. Retrospective studies have identified hypertension, cardiovascular disease, diabetes and older age as risk factors for high morbidity and mortality from COVID-19. There is a general concern that patients with immune-mediated kidney diseases, namely those on immunosuppressive therapies and/or those with more advanced kidney failure, could particularly be at risk for adverse outcomes due to a compromised antiviral immunity. Uncertainties exist on how management routines should be reorganized to minimize the risk of severe acute respiratory syndrome coronavirus 2 infection and what measures are necessary for infected patients. The aim of the present review of the Immunonephrology Working Group of the European Renal Association-European Dialysis and Transplant Association is to provide recommendations for the management of patients with immune-mediated kidney diseases based on the available evidence, similar circumstances with other infectious organisms and expert opinions from across Europe. Such recommendations may help to minimize the risk of encountering COVID-19 or developing complications during COVID-19 in patients with immune-mediated kidney disease.

  • 46.
    Anders, Hans-Joachim
    et al.
    Klinikum Univ, Germany.
    Loutan, Jerome
    Klinikum Univ, Germany.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Fernandez-Juarez, Gema M.
    Hosp Univ Fdn Alcorcon, Spain.
    Floege, Juergen
    RWTH Aachen Univ Hosp, Germany.
    Goumenos, Dimitrios
    Patras Univ Hosp, Greece.
    Turkmen, Kultigin
    Necmettin Erbakan Univ, Turkey.
    van Kooten, Cees
    Leiden Univ, Netherlands.
    Frangou, Eleni
    Limassol Gen Hosp, Cyprus.
    Stevens, Kate I
    Queen Elizabeth Univ Hosp, Scotland.
    Kronbichler, Andreas
    Univ Cambridge, England.
    Segelmark, Marten
    Karolinska Inst, Sweden; Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Tesar, Vladimir
    Charles Univ Prague, Czech Republic; Gen Univ Hosp, Czech Republic.
    The management of lupus nephritis as proposed by EULAR/ERA 2019 versus KDIGO 20212023In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 38, no 3, p. 551-561Article in journal (Refereed)
    Abstract [en]

    In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (+/- V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies.

  • 47.
    Andersson, Elisabeth
    et al.
    Skane Univ Hosp, Sweden.
    Dai Ydrefelt, Ying
    Skane Univ Hosp, Sweden.
    Johannesson, Marit
    Sahlgrens Univ Hosp, Sweden.
    Lundbäck, Maria
    Umea Univ, Sweden.
    Mannila, Maria
    Karolinska Univ Hosp, Sweden.
    Persson, Margaretha
    Lund Univ, Sweden.
    Swahn, Eva
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart Center, Department of Cardiology in Linköping.
    Bolejko, Anetta
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Surveillance of indeterminate pulmonary nodules detected with CT in a Swedish population-based study (SCAPIS): psychosocial consequences and impact on health-related quality of life-a multicentre prospective cross-sectional study2021In: BMJ Open, E-ISSN 2044-6055, Vol. 11, no 9, article id e048721Article in journal (Refereed)
    Abstract [en]

    Objectives To investigate whether surveillance of pulmonary nodules detected with low-dose CT (LDCT) impacted health-related quality of life and psychosocial consequences in the Swedish population-based study, Swedish CArdioPulmonary bioImage Study (SCAPIS). Design A prospective cross-sectional study. Settings and participants This multicentre (five sites) observational study, which included a cohort from SCAPIS, consisted of 632 participants with indeterminate pulmonary nodules detected with LDCT. These participants continued surveillance for up to 36 months, during which lung cancer was not detected (surveillance group). Additionally, 972 participants with a negative pulmonary LDCT scan were included as a control group. Matching criteria were LDCT date (+/- 2 weeks), gender and site. Outcome measures All participants completed a health-related quality of life questionnaire (RAND-36) and the Consequences of Screening (COS) questionnaire, an average of 3 years after LDCT was conducted at entry into SCAPIS. Results Participants were 51-70 years old at study commencement. Overall, the two groups did not differ in demographic or psychosocial variables, smoking habits or pulmonary medical history. Individuals from countries other than Sweden and those with low socioeconomic status were less likely to participate (p&lt;0.001). No effects on health-related quality of life were observed via RAND-36. In COS, the surveillance group demonstrated a higher OR for anxiety about lung cancer (OR 3.96, 95% CI 2.35 to 6.66, p&lt;0.001), experiencing a sense of dejection (OR 1.35, 95% CI 1.06 to 1.72, p=0.015) and thoughts about existential values (OR 1.30, 95% CI 1.04 to 1.60, p=0.018). Conclusions Lung surveillance with LDCT contributed to significant experiences of sense of dejection, anxiety about lung cancer and development of thoughts about existential values among participants in the surveillance group compared with the controls. The risk of side effects should be communicated for informed decision-making about (non-)attendance in lung cancer screening.

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  • 48.
    Andersson, Gerhard
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. 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 Otorhinolaryngology. Karolinska Inst, Sweden.
    Käll, Anton
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Juhlin, Simon
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Wahlstrom, Carl
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Licht, Edvard de Fine
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Färdeman, Simon
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Franck, Anna
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Tholcke, Anna
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences.
    Nachtweij, Karin
    Linnaeus Univ, Sweden.
    Fransson, Emma
    Linnaeus Univ, Sweden.
    Vernmark, Kristofer
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Ludvigsson, Mikael
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. 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, Psykiatricentrum, Psykiatriska kliniken i Linköping. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Berg, Matilda
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Free choice of treatment content, support on demand and supervision in internet-delivered CBT for adults with depression: A randomized factorial design trial2023In: Behaviour Research and Therapy, ISSN 0005-7967, E-ISSN 1873-622X, Vol. 162, article id 104265Article in journal (Refereed)
    Abstract [en]

    Even if much is known regarding the effects of internet-delivered cognitive behaviour therapy (ICBT) for depression there are several topics that have not been studied. In this factorial design trial with 197 participants we investigated if clients in ICBT could select treatment modules themselves based on a selection of 15 tailored treatment modules developed for use in ICBT for depression. We contrasted this against clinician-tailored module selection. We also investigated if support on demand (initiated by the client) could work as well as scheduled support. Finally, we tested if clients that were mentioned in supervision would improve more than clients not mentioned (with the exception of acute cases). The treatment period lasted for 10 weeks, and we measured effects at post-treatment and two-year follow-up. Measures of depression and secondary outcomes were collected at pre-treatment, post-treatment and two-year follow-up. Overall, within-group effects were large across con-ditions (e.g., d = 1.73 on the BDI-II). We also found a small but significant difference in favour of self-tailored treatment over clinician-tailored (d = 0.26). Within-group effects for the secondary measures were all moderate to large including a test of knowledge about CBT. The other two contrasts "support on demand" and "supervision" yielded mostly non-significant differences, with the exception of a larger dropout rate in the support on demand condition. There were few negative effects (2.2%). Effects were largely maintained at a two-year follow-up. We conclude that clients can choose treatment modules and that support on demand may work. The role of su-pervision is not yet clear as advice can be transferred across clients.

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  • 49.
    Anstee, Quentin M.
    et al.
    Newcastle Univ, England; Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Fdn Trust, England.
    Darlay, Rebecca
    Newcastle Univ, England.
    Cockell, Simon
    Newcastle Univ, England.
    Meroni, Marica
    Univ Milan, Italy.
    Govaere, Olivier
    Newcastle Univ, England.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Burt, Alastair D.
    Newcastle Univ, England; Univ Adelaide, Australia.
    Bedossa, Pierre
    Newcastle Univ, England.
    Palmer, Jeremy
    Newcastle Univ, England.
    Liu, Yang-Lin
    Newcastle Univ, England.
    Aithal, Guruprasad P.
    Univ Nottingham, England.
    Allison, Michael
    Cambridge Univ NHS Fdn Trust, England.
    Yki-Jarvinen, Hannele
    Univ Helsinki, Finland; Univ Cambridge, England; Univ Cambridge, England.
    Vacca, Michele
    Cambridge Univ NHS Fdn Trust, England; Helsinki Univ Hosp, Finland.
    Dufour, Jean-Francois
    Univ Bern, Switzerland.
    Invernizzi, Pietro
    Univ Milano Bicocca, Italy; Univ Milano Bicocca, Italy; San Gerardo Hosp, Italy.
    Prati, Daniele
    Univ Milan, Italy.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Francque, Sven
    Antwerp Univ Hosp, Belgium.
    Petta, Salvatore
    Univ Palermo, Italy.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Clement, Karine
    Sorbonne Univ, France.
    Ratziu, Vlad
    Sorbonne Univ, France.
    Schattenberg, Joern M.
    Johannes Gutenberg Univ Mainz, Germany.
    Valenti, Luca
    Univ Milan, Italy.
    Day, Christopher P.
    Newcastle Univ, England.
    Cordell, Heather J.
    Newcastle Univ, England.
    Daly, Ann K.
    Newcastle Univ, England; Newcastle Univ, England.
    Correction: Genome-wide association study of non- alcoholic fatty liver and steatohepatitis in a histologically characterised cohort ( vol 73, pp 505-515 , 2020 )2023In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 78, no 5, p. 1085-1086Article in journal (Other academic)
  • 50.
    Anstee, Quentin M.
    et al.
    Newcastle Univ, England; Newcastle Upon Tyne Hosp NHS Fdn Trust, England.
    Darlay, Rebecca
    Newcastle Univ, England.
    Cockell, Simon
    Newcastle Univ, England.
    Meroni, Marica
    Univ Milan, Italy.
    Govaere, Olivier
    Newcastle Univ, England.
    Tiniakos, Dina
    Newcastle Univ, England; Natl & Kapodistrian Univ Athens, Greece.
    Burt, Alastair D.
    Newcastle Univ, England; Univ Adelaide, Australia.
    Bedossa, Pierre
    Newcastle Univ, England.
    Palmer, Jeremy
    Newcastle Univ, England.
    Liu, Yang-Lin
    Newcastle Univ, England.
    Aithal, Guruprasad P.
    Nottingham Univ Hosp NHS Trust, England; Univ Nottingham, England.
    Allison, Michael
    Cambridge Univ NHS Fdn Trust, England.
    Yki-Jarvinen, Hannele
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Vacca, Michele
    Cambridge Univ NHS Fdn Trust, England; Univ Cambridge, England; Univ Cambridge, England.
    Dufour, Jean-Francois
    Univ Bern, Switzerland.
    Invernizzi, Pietro
    Univ Milano Bicocca, Italy; San Gerardo Hosp, Italy.
    Prati, Daniele
    Univ Milan, Italy.
    Ekstedt, Mattias
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Kechagias, Stergios
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken.
    Francque, Sven
    Antwerp Univ Hosp, Belgium.
    Petta, Salvatore
    Univ Palermo, Italy.
    Bugianesi, Elisabetta
    Univ Turin, Italy.
    Clement, Karine
    Sorbonne Univ, France.
    Ratziu, Vlad
    Sorbonne Univ, France.
    Schattenberg, Joern M.
    Johannes Gutenberg Univ Mainz, Germany.
    Valenti, Luca
    Univ Milan, Italy.
    Day, Christopher P.
    Newcastle Univ, England.
    Cordell, Heather J.
    Newcastle Univ, England.
    Daly, Ann K.
    Newcastle Univ, England.
    Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort2020In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 73, no 3, p. 505-515Article in journal (Refereed)
    Abstract [en]

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

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