• Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland.

      Ingimarsson, Oddur; MacCabe, James H; Haraldsson, Magnús; Jónsdóttir, Halldóra; Sigurdsson, Engilbert; 1 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavík, Iceland. 2 Landspitali University Hospital, Mental Health Services, Hringbraut, 101, Reykjavik, Iceland. 3 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College, London, UK. 4National Psychosis Unit, Bethlem Royal Hospital, South London and Maudsley NHS Foundation Trust, London, UK. 5 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavík, Iceland. 6 Landspitali University Hospital, Mental Health Services, Hringbraut, 101, Reykjavik, Iceland. (BioMed Central, 2016-12-12)
      Data on the haematological outcomes of patients who continue clozapine treatment following neutropenia are very rare as even mild neutropenia results in mandatory discontinuation of clozapine in most countries. However, in Iceland where clozapine monitoring is less stringent allows an observational study to be done on the risk of agranulocytosis and neutropenia during treatment with clozapine compared with other antipsychotics among patients with schizophrenia.
    • Biomarkers defining the metabolic age of red blood cells during cold storage.

      Paglia, Giuseppe; D'Alessandro, Angelo; Rolfsson, Óttar; Sigurjónsson, Ólafur E; Bordbar, Aarash; Palsson, Sirus; Nemkov, Travis; Hansen, Kirk C; Gudmundsson, Sveinn; Palsson, Bernhard O; et al. (Amer Soc Hematology, 2016-09-29)
      Metabolomic investigations of packed red blood cells (RBCs) stored under refrigerated conditions in saline adenine glucose mannitol (SAGM) additives have revealed the presence of 3 distinct metabolic phases, occurring on days 0-10, 10-18, and after day 18 of storage. Here we used receiving operating characteristics curve analysis to identify biomarkers that can differentiate between the 3 metabolic states. We first recruited 24 donors and analyzed 308 samples coming from RBC concentrates stored in SAGM and additive solution 3. We found that 8 extracellular compounds (lactic acid, nicotinamide, 5-oxoproline, xanthine, hypoxanthine, glucose, malic acid, and adenine) form the basis for an accurate classification/regression model and are able to differentiate among the metabolic phases. This model was then validated by analyzing an additional 49 samples obtained by preparing 7 new RBC concentrates in SAGM. Despite the technical variability associated with RBC processing strategies, verification of these markers was independently confirmed in 2 separate laboratories with different analytical setups and different sample sets. The 8 compounds proposed here highly correlate with the metabolic age of packed RBCs, and can be prospectively validated as biomarkers of the RBC metabolic lesion.
    • Clozapine treatment and discontinuation in Iceland: A national longitudinal study using electronic patient records.

      Ingimarsson, Oddur; MacCabe, James H; Haraldsson, Magnús; Jónsdóttir, Halldóra; Sigurdsson, Engilbert; [ 1 ] Univ Iceland, Sch Hlth Sci, Fac Med, Reykjavik, Iceland [ 2 ] Landspitali Univ Hosp, Mental Hlth Serv, IS-101 Reykjavik, Iceland   Organization-Enhanced Name(s)      Landspitali National University Hospital [ 3 ] Kings Coll London, London WC2R 2LS, England [ 4 ] South London & Maudsley NHS Fdn Trust, Bethlem Royal Hosp, Natl Psychosis Unit, London, England (Taylor & Francis Ltd, 2016-08)
      Clozapine is the only drug approved for treatment-resistant schizophrenia. There is evidence that clozapine is underutilized.
    • Variations in rates of severe perineal tears and episiotomies in 20 European countries: a study based on routine national data in Euro-Peristat Project.

      Blondel, Béatrice; Alexander, Sophie; Bjarnadóttir, Ragnheiður I; Gissler, Mika; Langhoff-Roos, Jens; Novak-Antolič, Živa; Prunet, Caroline; Zhang, Wei-Hong; Hindori-Mohangoo, Ashna D; Zeitlin, Jennifer; et al. (Wiley, 2016-07)
      Rates of severe perineal tears and episiotomies are indicators of obstetrical quality of care, but their use for international comparisons is complicated by difficulties with accurate ascertainment of tears and uncertainties regarding the optimal rate of episiotomies. We compared rates of severe perineal tears and episiotomies in European countries and analysed the association between these two indicators.
    • Acute phase inflammation is characterized by rapid changes in plasma/peritoneal fluid N-glycosylation in mice.

      Rombouts, Yoann; Jónasdóttir, Hulda S; Hipgrave Ederveen, Agnes L; Reiding, Karli R; Jansen, Bas C; Freysdottir, Jona; Hardardottir, Ingibjörg; Ioan-Facsinay, Andreea; Giera, Martin; Wuhrer, Manfred; et al. (Springer, 2016-06)
      Murine zymosan-induced peritonitis is a widely used model for studying the molecular and cellular events responsible for the initiation, persistence and/or resolution of inflammation. Among these events, it is becoming increasingly evident that changes in glycosylation of proteins, especially in the plasma and at the site of inflammation, play an important role in the inflammatory response. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS)-based glycosylation profiling, we investigated the qualitative and quantitative effect of zymosan-induced peritonitis on N-glycosylation in mouse plasma and peritoneal fluid. Our results show that both N-glycomes exhibit highly similar glycosylation patterns, consisting mainly of diantennary and triantennary complex type N-glycans with high levels (>95 %) of galactosylation and sialylation (mostly NeuGc) and a medium degree of core fucosylation (30 %). Moreover, MS/MS structural analysis, assisted by linkage-specific derivatization of sialic acids, revealed the presence of O-acetylated sialic acids as well as disialylated antennae ("branching sialylation") characterized by the presence of α2-6-linked NeuGc on the GlcNAc of the NeuGcα2-3-Galβ1-3-GlcNAc terminal motif. A significant decrease of (core) fucosylation together with an increase of both α2-3-linked NeuGc and "branching sialylation" were observed in N-glycomes of mice challenged with zymosan, but not in control mice injected with PBS. Importantly, substantial changes in glycosylation were already observed 12 h after induction of peritonitis, thereby demonstrating an unexpected velocity of the biological mechanisms involved.
    • No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

      Hollestelle, Antoinette; van der Baan, Frederieke H; Berchuck, Andrew; Johnatty, Sharon E; Aben, Katja K; Agnarsson, Bjarni A; Aittomäki, Kristiina; Alducci, Elisa; Andrulis, Irene L; Anton-Culver, Hoda; et al. (Academic Press Inc Elsevier Science, 2016-05)
      Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
    • Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

      Dunning, Alison M; Michailidou, Kyriaki; Kuchenbaecker, Karoline B; Thompson, Deborah; French, Juliet D; Beesley, Jonathan; Healey, Catherine S; Kar, Siddhartha; Pooley, Karen A; Lopez-Knowles, Elena; et al. (Nature Publishing Group, 2016-04)
      We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
    • Substantial between-country differences in organising community care for older people in Europe-a review.

      Van Eenoo, Liza; Declercq, Anja; Onder, Graziano; Finne-Soveri, Harriet; Garms-Homolová, Vjenka; Jónsson, Pálmi V; Dix, Olivia H M; Smit, Johannes H; van Hout, Hein P J; van der Roest, Henriëtte G; et al. (Oxford Univ Press, 2016-04)
      The European population is aging. The main drivers of public spending on health care for people of 65 years and older are hospital admission and admission to long-term care facilities. High quality community care can be a cost-effective and quality solution to respond to the impact of ageing populations on health-care systems. It is unclear how well countries are equipped to provide affordable and quality community care. The aim of this article is to describe and compare community care delivery with care-dependent older people in Europe. 
    • Wide differences in mode of delivery within Europe: risk-stratified analyses of aggregated routine data from the Euro-Peristat study.

      Macfarlane, A J; Blondel, B; Mohangoo, A D; Cuttini, M; Nijhuis, J; Novak, Z; Ólafsdóttir, H S; Zeitlin, J; [ 1 ] City Univ London, Ctr Maternal & Child Hlth Res, London EC1V 0HB, England [ 2 ] Paris Descartes Univ, INSERM, Obstet Perinatal & Paediat Epidemiol Res Team, Ctr Epidemiol & Biostat U1153, Paris, France [ 3 ] TNO, Netherlands Org Appl Sci Res, Dept Child Hlth, Leiden, Netherlands [ 4 ] Bambino Gesu Pediat Hosp, Res Unit Perinatal Epidemiol, Rome, Italy [ 5 ] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Dept Obstet & Gynaecol, Maastricht, Netherlands [ 6 ] Llubjana Univ, Univ Med Ctr, Perinatol Unit, Llubjana, Slovenia [ 7 ] Landspitali Univ Hosp, Dept Obstet & Gynaecol, Reykjavik, Iceland   Organization-Enhanced Name(s)      Landspitali National University Hospital (Wiley-Blackwell, 2016-03)
      To use data from routine sources to compare rates of obstetric intervention in Europe both overall and for subgroups at higher risk of intervention.
    • HLA class II sequence variants influence tuberculosis risk in populations of European ancestry

      Sveinbjornsson, Gardar; Gudbjartsson, Daniel F; Halldorsson, Bjarni V; Kristinsson, Karl G; Gottfredsson, Magnus; Barrett, Jeffrey C; Gudmundsson, Larus J; Blondal, Kai; Gylfason, Arnaldur; Gudjonsson, Sigurjon Axel; et al. (Nature Publishing Group, 2016-02-01)
      Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually. To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10(-13)) and PTB (OR = 1.25, P = 5.8 × 10(-12)), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10(-12))-both located between HLA-DQA1 and HLA-DRB1-and a missense variant encoding p.Ala210Thr in HLA-DQA1 (MAF = 19.1%, rs9272785), associated with M. tuberculosis infection (P = 9.3 × 10(-9), OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia (P < 5.9 × 10(-4)). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.
    • GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

      Ibrahim-Verbaas, C A; Bressler, J; Debette, S; Schuur, M; Smith, A V; Bis, J C; Davies, G; Trompet, S; Smith, J A; Wolf, C; et al. (Nature Publishing Group, 2016-02)
      To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
    • Ensuring Effective Prevention of Iodine Deficiency Disorders.

      Völzke, Henry; Caron, Philippe; Dahl, Lisbeth; de Castro, João J; Erlund, Iris; Gaberšček, Simona; Gunnarsdottir, Ingibjörg; Hubalewska-Dydejczyk, Alicja; Ittermann, Till; Ivanova, Ludmila; et al. (Mary Ann Liebert, 2016-02)
      Programs initiated to prevent iodine deficiency disorders (IDD) may not remain effective due to changes in government policies, commercial factors, and human behavior that may affect the efficacy of IDD prevention programs in unpredictable directions. Monitoring and outcome studies are needed to optimize the effectiveness of IDD prevention.
    • Translational research—the need of a new bioethics approach

      Hostiuc, Sorin; Moldoveanu, Alin; Dascălu, Maria-Iuliana; Unnthorsson, Runar; Jóhannesson, Ómar I.; Marcus, Ioan; [ 1 ] Carol Davila Univ, Dept Legal Med & Bioeth, Bucharest, Romania [ 2 ] Natl Inst Legal Med, Bucharest, Romania [ 3 ] Univ Politehn Bucuresti, Fac Automat Control & Comp, Bucharest, Romania [ 4 ] Univ Politehn Bucuresti, Dept Engn Foreign Languages, Bucharest, Romania [ 5 ] Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykjavik, Iceland [ 6 ] Univ Iceland, Dept Psychol, Reykjavik, Iceland [ 7 ] Univ Agr Sci & Vet Med, Fac Vet Med, Dept Pathophysiol, Cluj Napoca, Romania (BioMed Central Ltd, 2016-01-15)
      Translational research tries to apply findings from basic science to enhance human health and well-being. Many phases of the translational research may include non-medical tasks (information technology, engineering, nanotechnology, biochemistry, animal research, economy, sociology, psychology, politics, and so on). Using common bioethics principles to these areas might sometimes be not feasible, or even impossible. However, the whole process must respect some fundamental, moral principles. The purpose of this paper is to argument the need for a different approach to the morality in translational bioethics, and to suggest some directions that might be followed when constructing such a bioethics. We will show that a new approach is needed and present a few ethical issues that are specific to the translational research.
    • Variations in Multiple Birth Rates and Impact on Perinatal Outcomes in Europe.

      Heino, Anna; Gissler, Mika; Hindori-Mohangoo, Ashna D; Blondel, Béatrice; Klungsøyr, Kari; Verdenik, Ivan; Mierzejewska, Ewa; Velebil, Petr; Sól Ólafsdóttir, Helga; Macfarlane, Alison; et al. (Public Library Science, 2016)
      Infants from multiple pregnancies have higher rates of preterm birth, stillbirth and neonatal death and differences in multiple birth rates (MBR) exist between countries. We aimed to describe differences in MBR in Europe and to investigate the impact of these differences on adverse perinatal outcomes at a population level.
    • Convergent validity of the interRAI-HC for societal costs estimates in comparison with the RUD Lite instrument in community dwelling older adults.

      van Lier, Lisanne I; van der Roest, Henriëtte G; van Hout, Hein P J; van Eenoo, Liza; Declercq, Anja; Garms-Homolová, Vjenka; Onder, Graziano; Finne-Soveri, Harriet; Jónsson, Pálmi V; Hertogh, Cees M P M; et al. (BioMed Central, 2016)
      The interRAI-Home Care (interRAI-HC) instrument is commonly used in routine care to assess care and service needs, resource utilisation and health outcomes of community dwelling home care clients. Potentially, the interRAI-HC can also be used to calculate societal costs in economic evaluations. The purpose of this study was to assess the convergent validity of the interRAI-HC instrument in comparison with the RUD Lite instrument for the calculation of societal costs among care-dependent community dwelling older adults.
    • Socioeconomic inequalities in stillbirth rates in Europe: measuring the gap using routine data from the Euro-Peristat Project.

      Zeitlin, Jennifer; Mortensen, Laust; Prunet, Caroline; Macfarlane, Alison; Hindori-Mohangoo, Ashna D; Gissler, Mika; Szamotulska, Katarzyna; van der Pal, Karin; Bolumar, Francisco; Andersen, Anne-Marie Nybo; et al. (BioMed Central Ltd, 2016)
      Previous studies have shown that socioeconomic position is inversely associated with stillbirth risk, but the impact on national rates in Europe is not known. We aimed to assess the magnitude of social inequalities in stillbirth rates in European countries using indicators generated from routine monitoring systems.
    • A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.

      Rivas, Manuel A; Graham, Daniel; Sulem, Patrick; Stevens, Christine; Desch, A Nicole; Goyette, Philippe; Gudbjartsson, Daniel; Jonsdottir, Ingileif; Thorsteinsdottir, Unnur; Degenhardt, Frauke; et al. (Nature, 2016)
      Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
    • Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

      Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji; Raimondo, Anne; Mägi, Reedik; Reschen, Michael E; Mahajan, Anubha; Locke, Adam; William Rayner, N; Robertson, Neil; et al. (Nature Publishing Group, 2015-12)
      We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
    • Kinetic analysis of gluconate phosphorylation by human gluconokinase using isothermal titration calorimetry.

      Rohatgi, Neha; Guðmundsson, Steinn; Rolfsson, Óttar; Univ Iceland, Ctr Syst Biol, IS-101 Reykjavik, Iceland, Univ Iceland, Biomed Ctr, IS-101 Reykjavik, Iceland (Elsevier Science BV, 2015-11-30)
      Gluconate is a commonly encountered nutrient, which is degraded by the enzyme gluconokinase to generate 6-phosphogluconate. Here we used isothermal titration calorimetry to study the properties of this reaction. ΔH, KM and kcat are reported along with substrate binding data. We propose that the reaction follows a ternary complex mechanism, with ATP binding first. The reaction is inhibited by gluconate, as it binds to an Enzyme-ADP complex forming a dead-end complex. The study exemplifies that ITC can be used to determine mechanisms of enzyme catalyzed reactions, for which it is currently not commonly applied.
    • The effect of fontanel on scalp EEG potentials in the neonate.

      Gargiulo, P; Belfiore, P; Friðgeirsson, E A; Vanhatalo, S; Ramon, C; [ 1 ] Reykjavik Univ, Inst Biomed & Neural Engn, Reykjavik, Iceland [ 2 ] Landspitali Univ Hosp, Dept Sci, Reykjavik, Iceland [ 3 ] Univ Naples Federico II, Dept Biomed Elect & Telecommun Engn, Naples, Italy [ 4 ] Landspitali Univ Hosp, Dept Dev CE & IT, Reykjavik, Iceland [ 5 ] Univ Helsinki, Cent Hosp, HUS Med Imaging Ctr, Dept Childrens Clin Neurophysiol, Helsinki, Finland [ 6 ] Univ Helsinki, Cent Hosp, Childrens Hosp, Helsinki, Finland [ 7 ] Univ Helsinki, Helsinki, Finland [ 8 ] Univ Washington, Dept Elect Engn, Seattle, WA 98195 USA (Elsevier, 2015-09)
      To define how fontanels affect scalp EEG potentials in neonates.