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Hirsla is an open access repository, designed as a place to store, index, preserve and redistribute in digital format scholarly work of Landspitali employees. (A/H1N1)

  • Increased use of cross-sectional imaging for follow-up does not improve post-recurrence survival of surgically treated initially localized R.C.C.: results from a European multicenter database (R.E.C.U.R.).

    Dabestani, Saeed; Beisland, Christian; Stewart, Grant D; Bensalah, Karim; Gudmundsson, Eirikur; Lam, Thomas B; Gietzmann, William; Zakikhani, Paimaun; Marconi, Lorenzo; Fernandéz-Pello, Sergio; Monagas, Serenella; Williams, Samuel P; Powles, Thomas; Van Werkhoven, Erik; Meijer, Richard; Volpe, Alessandro; Staehler, Michael; Ljungberg, Börje; Bex, Axel; 1 a Department of Clinical Sciences Lund , Lund University, Skane University Hospital , Lund , Sweden. 2 b Department of Urology , Haukeland University Hospital , Bergen , Norway. 3 c Department of Clinical Medicine , University of Bergen , Bergen , Norway. 4 d Department of Surgery , Academic Urology Group, University of Cambridge , Cambridge , United Kingdom. 5 e Department of Urology , University of Rennes , Rennes , France. 6 f Department of Urology , Landspitali University Hospital , Reykjavik , Iceland. 7 g Academic Urology Unit , University of Aberdeen , Aberdeen , United Kingdom. 8 h Department of Urology , Aberdeen Royal Infirmary , Aberdeen , United Kingdom. 9 i Department of Urology , Coimbra University Hospital , Coimbra , Portugal. 10 j Department of Urology , Cabueñes University Hospital , Gijón , Spain. 11 k Department of Urology , San Agustin University Hospital , Aviles , Spain. 12 l Medical School , University of Edinburgh , Edinburgh , United Kingdom. 13 m Barts Cancer Institute , Queen Mary University of London , London , United Kingdom. 14 n Department of Bioinformatics and Statistics , The Netherlands Cancer Institute , Amsterdam , The Netherlands. 15 o Department of Urology , University Medical Center Utrecht , Utrecht , The Netherlands. 16 p Department of Urology , University of Eastern Piedmont , Novara , Italy. 17 q Department of Urology , Klinikum Grosshadern, Ludwig Maximilians University of Munich , Munich , Germany. 18 r Department of Surgical and Perioperative Sciences , Umeå University , Umeå , Sweden. 19 s Division of Surgical Oncology, Department of Urology , The Netherlands Cancer Institute , Amsterdam , The Netherlands. (Taylor & Francis, 2019-03-25)
    Modality and frequency of image-based renal cell carcinoma (R.C.C.) follow-up strategies are based on risk of recurrence. Using the R.E.C.U.R.-database, frequency of imaging was studied in regard to prognostic risk groups. Furthermore, it was investigated whether imaging modality utilized in contemporary follow-up were associated with outcome after detection of recurrence. Moreover, outcome was compared based on whether the assessment of potential curability was a pre-defined set of criteria's (per-protocol) or stated by the investigator. Consecutive non-metastatic R.C.C. patients (n = 1,612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Leibovich or U.I.S.S. risk group, recurrence characteristics, imaging modality, frequency and survival were recorded. Primary endpoints were overall survival (O.S.) after detection of recurrence and frequency of features associated with favourable outcome (non-symptomatic recurrences and detection within the follow-up-programme). Recurrence occurred in 336 patients. Within low, intermediate and high risk for recurrence groups, the frequency of follow-up imaging was highest in the early phase of follow-up and decreased significantly over time (p < 0.001). However, neither the image modality for detection nor ≥ 50% cross-sectional imaging during follow-up were associated with improved O.S. after recurrence. Differences between per protocol and investigator based assessment of curability did not translate into differences in O.S. As expected, the frequency of imaging was highest during early follow-up. Cross-sectional imaging use for detection of recurrences following surgery for localized R.C.C. did not improve O.S. post-recurrence. Prospective studies are needed to determine the value of imaging in follow-up.
  • Sequence variation at ANAPC1 accounts for 24% of the variability in corneal endothelial cell density.

    Ivarsdottir, Erna V; Benonisdottir, Stefania; Thorleifsson, Gudmar; Sulem, Patrick; Oddsson, Asmundur; Styrkarsdottir, Unnur; Kristmundsdottir, Snaedis; Arnadottir, Gudny A; Thorgeirsson, Gudmundur; Jonsdottir, Ingileif; Zoega, Gunnar M; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F; Jonasson, Fridbert; Holm, Hilma; Stefansson, Kari; 1 deCODE genetics/Amgen, Reykjavik, Iceland. 2 School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. 3 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 4 Division of Cardiology, Department of Internal Medicine, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland. 5 Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland. 6 Department of Ophthalmology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland. 7 deCODE genetics/Amgen, Reykjavik, Iceland. hilma.holm@decode.is. 8 deCODE genetics/Amgen, Reykjavik, Iceland. kari.stefansson@decode.is. 9 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. kari.stefansson@decode.is. (Nature Publishing Group, 2019-03-20)
    The corneal endothelium is vital for transparency and proper hydration of the cornea. Here, we conduct a genome-wide association study of corneal endothelial cell density (cells/mm2), coefficient of cell size variation (CV), percentage of hexagonal cells (HEX) and central corneal thickness (CCT) in 6,125 Icelanders and find associations at 10 loci, including 7 novel. We assess the effects of these variants on various ocular biomechanics such as corneal hysteresis (CH), as well as eye diseases such as glaucoma and corneal dystrophies. Most notably, an intergenic variant close to ANAPC1 (rs78658973[A], frequency = 28.3%) strongly associates with decreased cell density and accounts for 24% of the population variance in cell density (β = -0.77 SD, P = 1.8 × 10-314) and associates with increased CH (β = 0.19 SD, P = 2.6 × 10-19) without affecting risk of corneal diseases and glaucoma. Our findings indicate that despite correlations between cell density and eye diseases, low cell density does not increase the risk of disease.
  • Mapping of Signaling Pathways Linked to sIgAD Reveals Impaired IL-21 Driven STAT3 B-Cell Activation.

    Lemarquis, Andri L; Theodors, Fannar; Einarsdottir, Helga K; Ludviksson, Bjorn R; 1 Department of Immunology, Landspítali-The National University Hospital of Iceland, Reykjavík, Iceland. 2 Faculty of Medicine, University of Iceland, Reykjavík, Iceland. (Frontiers Research Foundation, 2019-03)
    Objectives: It has recently been shown that individuals with selective IgA deficiency (sIgAD) have defective B cell responses both to T cell dependent and independent mimicking stimulations. The complex intracellular signaling pathways from different stimuli leading to IgA isotype switching have not been fully elucidated. Thus, the main objective of this study was to delineate these pathways and their potential role in the immunopathology linked to sIgAD. Materials and Methods: PBMCs from 10 individuals with sIgAD and 10 healthy controls (HC) were activated in vitro via either a T cell dependent or independent mimicking stimulation. Intracellular phosphorylation of pSTAT3, pSTAT5, pSTAT6, and as pERK1/2 was evaluated in T and B cells using phosphoflow cytometry. Results: By evaluating T cell dependent cytokine driven pathways linked to IgA isotype induction we identified a defect involving an IL-21 driven STAT3 activation isolated to B cells in sIgAD individuals. However, all other signaling pathways studied were found to be normal compared to HC. In T cell dependent cytokine driven stimulations linked to IgA isotype induction the following patterns emerged: (i) IL-10 led to significant STAT3 activation in both T- and B cells; (ii) IL-4 stimulation was predominantly confined to STAT6 activation in both T- and B cells, with some effects on STAT3 activation in T-cells; (iii) as expected, of tested stimuli, IL-2 alone activated STAT5 and some STAT3 activation though in both cases only in T-cells; (iv) IL-21 induced significant activation of STAT3 in both T- and B cells, with some effects on STAT5 activation in T-cells; and finally (v) synergistic effects were noted of IL-4+IL-10 on STAT5 activation in T-cells, and possibly STAT6 in both T- and B cells. On the other hand, CPG induced T cell independent activation was confined to ERK1/2 activation in B cells. Conclusion: Our results indicate a diminished STAT3 phosphorylation following IL-21 stimulation solely in B cells from sIgAD individuals. This can represent aberrant germinal center reactions or developmental halt. Thus, our work provides further insight into the unraveling of the previously hypothesized role of IL-21 to reconstitute immunoglobulin production in primary antibody deficiencies.
  • Integrative cognitive remediation for early psychosis: Results from a randomized controlled trial

    Vidarsdottir, Olina G; Roberts, David L; Twamley, Elizabeth W; Gudmundsdottir, Berglind; Sigurdsson, Engilbert; Magnusdottir, Brynja B; [ 1 ] Natl Univ Hosp Reykjavik, Landspitali, Dept Psychiat, Reykjavik, Iceland Show more [ 2 ] Univ Iceland, Fac Med, Sch Hlth Sci, Vatnsmyrarvegur 16, IS-101 Reykjavik, Iceland Show more [ 3 ] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, Div Community Recovery Res & Training, San Antonio, TX 78229 USA Show more [ 4 ] Univ Calif, Dept Psychiat, La Jolla, CA USA Show more [ 5 ] VA San Diego Healthcare Syst, Ctr Excellence Stress & Mental Hlth & Res Serv, San Diego, CA USA Show more [ 6 ] Reykjavik Univ, Dept Psychol, Menntavegur 1, IS-101 Reykjavik, Iceland (ELSEVIER IRELAND, 2019-03)
    Early application of cognitive remediation may help prevent the development of long-term functional impairments that characterize psychotic disorders. Interventions that encompass both neurocognitive and social-cognitive training may work synergistically to bridge the gap between cognitive gains and functional outcomes in early psychosis. We integrated three cognitive remediation approaches: Neuropsychological Educational Approach to Remediation (NEAR), Compensatory Cognitive Training (CCT), and Social Cognition and Interaction Training (SCIT), and evaluated the effects on cognition, clinical symptoms, self-assessed and informant-assessed social functioning in early psychosis. A total of 49 patients diagnosed with primary psychotic disorder seeking service at an early-intervention service in Iceland were randomized to either a waiting-list control group (n = 24) or a 12-week group-based integrative cognitive remediation (n = 25). Neurocognition, social cognition, community functioning and clinical symptoms were assessed at baseline and post-treatment. The intervention group showed significant improvements in verbal memory, cognitive flexibility, working memory, ToM and a significant reduction in hostile attributions, compared to those receiving standard treatment alone, but there were no differences between groups on measures of social functioning or clinical symptoms. The intervention was well tolerated and received high treatment satisfaction ratings. Findings indicate that integrated cognitive remediation has potential to improve neurocognition and social cognition in early psychosis.
  • Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis.

    Kachroo, Priyanka; Eraso, Jesus M; Beres, Stephen B; Olsen, Randall J; Zhu, Luchang; Nasser, Waleed; Bernard, Paul E; Cantu, Concepcion C; Saavedra, Matthew Ojeda; Arredondo, María José; Strope, Benjamin; Do, Hackwon; Kumaraswami, Muthiah; Vuopio, Jaana; Gröndahl-Yli-Hannuksela, Kirsi; Kristinsson, Karl G; Gottfredsson, Magnus; Pesonen, Maiju; Pensar, Johan; Davenport, Emily R; Clark, Andrew G; Corander, Jukka; Caugant, Dominique A; Gaini, Shahin; Magnussen, Marita Debess; Kubiak, Samantha L; Nguyen, Hoang A T; Long, S Wesley; Porter, Adeline R; DeLeo, Frank R; Musser, James M; 1 Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, TX, USA. 2 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. 3 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA. 4 Institute of Biomedicine, Medical Microbiology and Immunology, University of Turku, Turku, Finland. 5 National Institute for Health and Welfare, Helsinki, Finland. 6 Department of Clinical Microbiology, Landspitali University Hospital, Reykjavik, Iceland. 7 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 8 Department of Infectious Diseases, Landspitali University Hospital, Reykjavik, Iceland. 9 Helsinki Institute of Information Technology, Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. 10 Department of Computer Science, Aalto University, Espoo, Finland. 11 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA. 12 Department of Biostatistics, University of Oslo, Oslo, Norway. 13 Division for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway. 14 Medical Department, Infectious Diseases Division, National Hospital of the Faroe Islands, Tórshavn, Denmark. 15 Department of Infectious Diseases, Odense University Hospital, Odense, Denmark. 16 Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 17 Department of Science and Technology, Centre of Health Research, University of the Faroe Islands, Tórshavn, Denmark. 18 Thetis, Food and Environmental Laboratory, Torshavn, Denmark. 19 Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA. 20 Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, TX, USA. JMMusser@houstonmethodist.org. 21 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. JMMusser@houstonmethodist.org. 22 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA. JMMusser@houstonmethodist.org. (Nature Publishing Group, 2019-03)
    Streptococcus pyogenes causes 700 million human infections annually worldwide, yet, despite a century of intensive effort, there is no licensed vaccine against this bacterium. Although a number of large-scale genomic studies of bacterial pathogens have been published, the relationships among the genome, transcriptome, and virulence in large bacterial populations remain poorly understood. We sequenced the genomes of 2,101 emm28 S. pyogenes invasive strains, from which we selected 492 phylogenetically diverse strains for transcriptome analysis and 50 strains for virulence assessment. Data integration provided a novel understanding of the virulence mechanisms of this model organism. Genome-wide association study, expression quantitative trait loci analysis, machine learning, and isogenic mutant strains identified and confirmed a one-nucleotide indel in an intergenic region that significantly alters global transcript profiles and ultimately virulence. The integrative strategy that we used is generally applicable to any microbe and may lead to new therapeutics for many human pathogens.

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