Recent Submissions

  • Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia.

    Modvig, S; Madsen, H O; Siitonen, S M; Rosthøj, S; Tierens, A; Juvonen, V; Osnes, L T N; Vålerhaugen, H; Hultdin, M; Thörn, I; Matuzeviciene, R; Stoskus, M; Marincevic, M; Fogelstrand, L; Lilleorg, A; Toft, N; Jónsson, O G; Pruunsild, K; Vaitkeviciene, G; Vettenranta, K; Lund, B; Abrahamsson, J; Schmiegelow, K; Marquart, H V; 1 Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 2 Helsinki University Ctrl. Hospital, Helsinki, Finland. 3 Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark. 4 Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, ON, Canada. 5 Department of Pathology, University Hospital of Oslo, Oslo, Norway. 6 Department of Clinical Chemistry and Laboratory Division, University of Turku and Turku University Hospital, Turku, Finland. 7 Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. 8 Department of Pathology, Laboratory of Molecular Pathology, Oslo University Hospital, Oslo, Norway. 9 Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden. 10 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 11 Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania. 12 Centre of Laboratory Medicine, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania. 13 Hematology, Oncology and Transfusion Medicine Centre, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania. 14 Department of Clinical Chemistry, Sahlgrenska University Hospital, and Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. 15 Department of Clinical Immunology, North Estonia Medical Centre, Tallinn, Estonia. 16 Department of Hematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 17 Children's Hospital, Landspitali University Hospital, Reykjavik, Iceland. 18 Tallinn Children's Hospital, Tallinn, Estonia. 19 Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania. 20 Department of Pediatrics, Helsinki University Children's Hospital and University of Helsinki, Helsinki, Finland. 21 Department of Pediatrics, St. Olavs University Hospital and Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway. 22 Institution of Clinical Sciences, Department of Pediatrics, Sahlgrenska University Hospital, Gothenburg, Sweden. 23 Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 24 The Institute of Clinical medicine, The Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark. 25 Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. hanne.marquart@regionh.dk. (Nature Publishing Group, 2019-06)
    Minimal residual disease (MRD) measured by PCR of clonal IgH/TCR rearrangements predicts relapse in T-cell acute lymphoblastic leukemia (T-ALL) and serves as risk stratification tool. Since 10% of patients have no suitable PCR-marker, we evaluated flowcytometry (FCM)-based MRD for risk stratification. We included 274 T-ALL patients treated in the NOPHO-ALL2008 protocol. MRD was measured by six-color FCM and real-time quantitative PCR. Day 29 PCR-MRD (cut-off 10-3) was used for risk stratification. At diagnosis, 93% had an FCM-marker for MRD monitoring, 84% a PCR-marker, and 99.3% (272/274) had a marker when combining the two. Adjusted for age and WBC, the hazard ratio for relapse was 3.55 (95% CI 1.4-9.0, p = 0.008) for day 29 FCM-MRD ≥ 10-3 and 5.6 (95% CI 2.0-16, p = 0.001) for PCR-MRD ≥ 10-3 compared with MRD < 10-3. Patients stratified to intermediate-risk therapy on day 29 with MRD 10-4-<10-3 had a 5-year event-free survival similar to intermediate-risk patients with MRD < 10-4 or undetectable, regardless of method for monitoring. Patients with day 15 FCM-MRD < 10-4 had a cumulative incidence of relapse of 2.3% (95% CI 0-6.8, n = 59). Thus, FCM-MRD allows early identification of patients eligible for reduced intensity therapy, but this needs further studies. In conclusion, FCM-MRD provides reliable risk prediction for T-ALL and can be used for stratification when no PCR-marker is available.
  • Biochemical response to ursodeoxycholic acid among PBC patients: a nationwide population-based study.

    Örnolfsson, Kristjan T; Lund, Sigrun H; Olafsson, Sigurdur; Bergmann, Ottar M; Björnsson, Einar S; 1 a Faculty of Medicine , University of Iceland, Reykjavík, Iceland. 2 b Division of Gastroenterology and Hepatology , Landspitali The National University Hospital of Iceland , Reykjavík , Iceland. (Taylor & Francis, 2019-05)
    Objective: To assess the proportion of PBC patients with a biochemical response to ursodeoxycholic acid (UDCA) in a population-based cohort and the association of biochemical response with outcomes. Methods: All patients diagnosed with PBC in Iceland from 1991-2015 were identified. Patients taking UDCA for an adequate period of time were analyzed for treatment response according to the Barcelona, Paris I, Paris II and Toronto criteria and outcomes. Results: Overall 182 females and 40 males were diagnosed with PBC and 135 patients were treated with UDCA. Overall 99 (73%) patients had adequate data on UDCA treatment and results of liver tests to assess biochemical response according to the Barcelona criteria, 95 (70%) according to the Toronto criterion and 85 (63%) according to the Paris I and II criteria. In all 74% (n = 63), 67% (n = 64), 54% (n = 53) and 46% (n = 39) responded to treatment according to the Paris I, Toronto, Barcelona and Paris II criteria. Among nonresponders according to the Paris I, Toronto, Paris II and Barcelona criteria, 50%, 39%, 33% and 30% developed cirrhosis versus 10%, 6%, 5% and 11% of responders, HR 5.36 (p = .002), 6.61 (p = .002), 10.94 (p = .003) and 2.21(p = .11), respectively. Age-adjusted mortality was significantly lower among responders according to the Paris I and Paris II criteria, HR 0.33 (p = .02) and 0.31 (p = .02), respectively. Conclusion: Development of cirrhosis and higher mortality was significantly associated with a lack of biochemical response to UDCA. Frequent development of cirrhosis and increased mortality in nonresponders underlines the need for a more effective therapy than UDCA for this sizeable subgroup of patients.
  • Reducing recurrence in non-muscle-invasive bladder cancer by systematically implementing guideline-based recommendations: effect of a prospective intervention in primary bladder cancer patients.

    Sörenby, Anne; Baseckas, Gediminas; Bendahl, Pär-Ola; Brändstedt, Johan; Håkansson, Ulf; Nilsson, Stefan; Patschan, Oliver; Tinzl, Martina; Wokander, Mats; Liedberg, Fredrik; Gudjonsson, Sigurdur; 1 a Department of Urology , Skåne University Hospital , Malmö , Sweden. 2 b Department of Translational Medicine , Lund University , Malmö , Sweden. 3 c Division of Oncology and Pathology, Department of Clinical Sciences Lund , Lund University, Medicon Village , Lund , Sweden. 4 d Department of Urology , Landspitali University Hospital , Reykjavik , Iceland. (Taylor & Francis, 2019-05-08)
    OBJECTIVE: In non-muscle-invasive bladder cancer (NMIBC), local recurrence after transurethral resection of the bladder (TURB) is common. Outcomes vary between urological centres, partly due to the sub-optimal surgical technique and insufficient application of measures recommended in the guidelines. This study evaluated early recurrence rates after primary TURB for NMIBC before and after introducing a standardized treatment protocol. METHODS: Medical records of all patients undergoing primary TURB for NMIBC in 2010 at Skåne University Hospital, Malmö, Sweden, were reviewed. A new treatment protocol for NMIBC was defined and introduced in 2013, and results documented during the first year thereafter were compared with those recorded in 2010 prior to the intervention. The primary endpoint was early recurrence at first control cystoscopy. Comparisons were made by Chi-square analysis and Fisher's exact test. Recurrence-free survival (RFS) in the two cohorts was also investigated. RESULTS: TURB was performed on 116 and 159 patients before and after the intervention, respectively. The early recurrence rate decreased from 22% to 9.6% (p = 0.005) at the first control cystoscopy after treatment. Residual/Recurrent tumour at the first control cystoscopy after the primary TURB (i.e. at second-look resection or first control cystoscopy) decreased from 31% to 20% (p = 0.038). The proportion of specimens containing muscle in T1 tumours increased from 55% to 94% (p < 0.001). RFS was improved in the intervention group (HR = 0.65, CI = 0.43-1.0; p = 0.05). CONCLUSIONS: Introduction of a standardized protocol and reducing the number of surgeons for primary treatment of NMIBC decreased the early recurrence rate from 22% to 9.6% and lowered the recurrence incidence by 35%.
  • Dampness, mould, onset and remission of adult respiratory symptoms, asthma and rhinitis.

    Wang, Juan; Pindus, Mihkel; Janson, Christer; Sigsgaard, Torben; Kim, Jeong-Lim; Holm, Mathias; Sommar, Johan; Orru, Hans; Gislason, Thorarinn; Johannessen, Ane; Bertelsen, Randi J; Norbäck, Dan; 1 Dept of Medical Sciences, Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden. 2 These authors contributed equally to this work. 3 Institute of Family Medicine and Public Health, University of Tartu, Tartu, Estonia. 4 Dept of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden. 5 Dept of Public Health, Section for Environment, Occupation and Health, Aarhus University, Danish Ramazzini Centre, Aarhus, Denmark. 6 Occupational and Environmental Medicine, Gothenburg University, Gothenburg, Sweden. 7 Occupational and Environmental Medicine, Dept of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden. 8 Landspitali University Hospital (E7), Reykjavik, Iceland. 9 Centre for International Health, Dept of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. 10 Dept of Occupational Medicine, Haukeland University Hospital, Bergen, Norway. 11 Dept of Clinical Science, University of Bergen, Bergen, Norway. (European Respiratory Society, 2019-05-23)
    STUDY QUESTION: Is dampness and indoor mould associated with onset and remission of respiratory symptoms, asthma and rhinitis among adults? MATERIALS AND METHODS: Associations between dampness, mould and mould odour at home and at work and respiratory health were investigated in a cohort of 11 506 adults from Iceland, Norway, Sweden, Denmark and Estonia. They answered a questionnaire at baseline and 10 years later, with questions on respiratory health, home and work environment. RESULTS: Baseline water damage, floor dampness, mould and mould odour at home were associated with onset of respiratory symptoms and asthma (OR 1.23-2.24). Dampness at home during follow-up was associated with onset of respiratory symptoms, asthma and rhinitis (OR 1.21-1.52). Dampness at work during follow-up was associated with onset of respiratory symptoms, asthma and rhinitis (OR 1.31-1.50). Combined dampness at home and at work increased the risk of onset of respiratory symptoms and rhinitis. Dampness and mould at home and at work decreased remission of respiratory symptoms and rhinitis. THE ANSWER TO THE QUESTION: Dampness and mould at home and at work can increase onset of respiratory symptoms, asthma and rhinitis, and decrease remission.
  • Do female elite athletes experience more complicated childbirth than non-athletes? A case-control study.

    Sigurdardottir, Thorgerdur; Steingrimsdottir, Thora; Geirsson, Reynir Tomas; Halldorsson, Thorhallur Ingi; Aspelund, Thor; Bø, Kari; 1 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 2 Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland. 3 Faculty of Food Sciences and Nutrition, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 4 Department of Sports Medicine, Norwegian School of Sports Sciences, Oslo, Norway. 5 Department of Obstetrics and Gynecology, Akershus University Hospital, Lørenskog, Norway. (BMJ Publishing Group, 2019-03)
    OBJECTIVE: Previous studies have suggested that female athletes might be at higher risk of experiencing complications such as caesarean sections and perineal tears during labour than non-athletes. Our aim was to study delivery outcomes, including emergency caesarean section rates, length of the first and second stages of labour and severe perineal tears, in first-time pregnant elite athletes compared with non-athletes. METHODS: This is a retrospective case-control study comparing birth outcomes of primiparous female elite athletes engaging in high-impact and low-impact sports compared with non-athletic controls. The athletes had prior to birth competed at a national team level or equivalent. Participant characteristics and frequency of training for at least 3 years before a first pregnancy were collected via a self-administered questionnaire. Information on delivery outcome was retrieved from the Icelandic Medical Birth Registry. RESULTS: In total, 248 participated, 118 controls, 41 low-impact and 89 high-impact elite athletes. No significant differences were found between the groups with regard to incidence of emergency caesarean section or length of the first and second stages of labour. The incidence of third-degree to fourth-degree perineal tears was significantly higher (23.7%) among low-impact athletes than in the high-impact group (5.1%, p=0.01), but no significant differences were seen when the athletes were compared with the controls (12%; p=0.09 for low-impact and p=0.12 for high-impact athletes). CONCLUSION: Participation in competitive sports at the elite level was not related to adverse delivery outcome, including length of labour, the need for caesarean section during delivery and severe perineal tears.
  • Oral nutrition supplements and between-meal snacks for nutrition therapy in patients with COPD identified as at nutritional risk: a randomised feasibility trial.

    Ingadottir, Arora Ros; Beck, Anne Marie; Baldwin, Christine; Weekes, Christine Elizabeth; Geirsdottir, Olof Gudny; Ramel, Alfons; Gislason, Thorarinn; Gunnarsdottir, Ingibjorg; 1 Unit for Nutrition Research, Landspitali University Hospital and Faculty of Food Science and Nutrition, University of Iceland, Reykjavik, Iceland. 2 Department of Clinical Nutrition, Landspitali University Hospital, Reykjavik, Iceland. 3 Faculty of Health, Copenhagen University College, Copenhagen, Denmark. 4 Research Unit for Nutrition, Herlev and Gentofte Hospital, Copenhagen, Denmark. 5 Department of Nutritional Sciences, King's College London, London, UK. 6 The Icelandic Gerontological Research Institute, Landspitali University Hospital and University of Iceland, Reykjavik, Iceland. 7 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 8 Department of Sleep, Landspitali University Hospital, Reykjavik, Iceland. (BMJ Publishing Group, 2019-01-03)
    INTRODUCTION: Intervention studies have mainly used oral nutritional supplements (ONS) for the management of patients with chronic obstructive pulmonary disease (COPD) identified as at nutritional risk. In this 12-month randomised feasibility trial, we assessed the (1) feasibility of the recruitment, retention and provision of two interventions: ONS and between-meal snacks (snacks) and (2) the potential impact of the provision of snacks and ONS on body weight and quality of life in patients with COPD. METHODS : Hospitalised patients with COPD, at nutritional risk, were randomised to ONS (n=19) or snacks (n=15) providing 600 kcal and 22 g protein a day in addition to regular daily diet. The intervention started in hospital and was continued for 12 months after discharge from the hospital. RESULTS : Study recruitment rate was n=34 (45%) and retention rate at 12 months was similar for both groups: n=13 (68%) in the ONS group and n=10 (67%) in the Snacks group. Both groups gained weight from baseline to 12 months (2.3±4.6 kg (p=0.060) in the ONS group and 4.4±6.4 kg (p=0.030) in the Snacks group). The St George's Respiratory Questionnaire total score improved from baseline to 12 months in both groups (score 3.9±11.0 (p=0.176) in the ONS group and score 8.9±14.1 (p=0.041) in the Snacks group). DISCUSSION : In patients with COPD who are at nutritional risk snacks are at least as feasible and effective as ONS, however, adequately powered trials that take account of the difficulties in recruiting this patient group are required to confirm this effect.
  • Incidence of diverticular bleeding: a population-based study.

    Olafsson, G D; Hreinsson, J P; Björnsson, E S; 1 a Faculty of Medicine , University of Iceland , Reykjavik , Iceland. 2 b Division of Gastroenterology and Hepatology, Department of Internal Medicine , The National University Hospital of Iceland , Reykjavik , Iceland. (Taylor & Francis, 2019-02)
    OBJECTIVE: To determine the incidence of diverticular bleeding (DB) and examine the time trend of the incidence. Furthermore to study prognosis with regard to therapy and rebleeding. METHODS: A retrospective, population-based study of patients with DB in a National University Hospital from 2006 to 2016. Patients were identified in an electronically stored colonoscopy database. Definite diverticular bleeding was defined as active bleeding, a nonbleeding visible vessel or adherent clot. Presumptive diverticular bleeding was defined as acute painless rectal bleeding leading to hospitalization with visible diverticula but no evidence of bleeding and no other colonic lesions or bleeding sites identified on endoscopy. A 30-day re-bleeding was determined after discharge. RESULTS: A total of 3683 colonoscopy reports were reviewed, including 345 patients (males 51%) with presumptive 95% (n = 327) or definitive 5% (n = 18) diverticular bleeding. Overall 96% were treated conservatively, 3% endoscopically and 0.3% surgically. Only 5.8% of patients had a 30-day rebleed. After exclusion, 315 patients were included in the incidence calculations. The mean cumulative incidence of diverticular bleeding was 14/100,000 inhabitants per year. A time trend analysis of the incidence of DB revealed no significant change in incidence during the study period. CONCLUSIONS: The mean incidence of colonic diverticular bleeding was found to be approximately 14 cases per 100,000 inhabitants and year. The incidence does not seem to have changed in the past decade. The vast majority of patients with diverticular bleeding did not require endoscopic therapy and could be managed with conservative treatment.
  • Group B Streptococcal Neonatal and Early Infancy Infections in Iceland, 1976-2015.

    Björnsdóttir, Erla S; Martins, Elisabete R; Erlendsdóttir, Helga; Haraldsson, Gunnsteinn; Melo-Cristino, José; Ramirez, Mário; Kristinsson, Karl G; 1 From the Department of Clinical Microbiology, Landspitali University Hospital, Reykjavik, Iceland. 2 BioMedical Centre of the University of Iceland, Reykjavik, Iceland. 3 Instituto de Microbiologia, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. (Lippincott Williams & Wilkins, 2019-06)
    BACKGROUND: Despite a risk-based peripartum chemoprophylaxis approach in Iceland since 1996, Streptococcus agalactiae [group B streptococci (GBS)] remains an important cause of early-onset [<7 days, early-onset disease (EOD)] and late-onset disease (LOD; 7 days to 3 months). METHODS: We studied GBS invasive disease in children <1 year in Iceland in 1976-2015. Bacteria (n = 98) were characterized by susceptibility to a panel of antimicrobials, capsular serotyping, resistance genes, surface protein and pilus-locus profiling and multilocus sequence typing. RESULTS: Both EOD and LOD increased during the early years, but while EOD subsequently decreased from 0.7/1000 live births in 1991-1995 to 0.2/1000 in 2011-2015, LOD showed a nonsignificant decrease from its peak value of 0.6/1000 in 2001-2005 to 0.4/1000 in 2006-2015. Serotype III was the most frequently found (n = 48), represented mostly by the hypervirulent lineage CC17/III/rib/PI-1+PI-2b (62%), but also by CC19/III/rib/PI-1+PI-2a (35%) frequently associated with colonization. Serotype Ia (n = 22) was represented by CC23/Ia/eps/PI-2a (68%) and CC7/Ia/bca/PI-1+PI-2b (23%) of possible zoonotic origin. Resistance to erythromycin and clindamycin was increasingly detected in the last years of the study (5 of the 9 cases were isolated after 2013), including representatives of a multiresistant CC17/III/rib/PI-2b sublineage described recently in other countries and expressing resistance to erythromycin, clindamycin and streptomycin. CONCLUSIONS: The risk-based chemoprophylaxis adopted in Iceland possibly contributed to the decline of EOD but has had limited effect on LOD. GBS causing neonatal and early infancy invasive infections in Iceland are genetically diverse, and the recent emergence of antimicrobial resistant lineages may reduce the choices for prophylaxis and therapy of these infections.
  • A worldwide perspective of sepsis epidemiology and survival according to age: Observational data from the ICON audit.

    Kotfis, Katarzyna; Wittebole, Xavier; Jaschinski, Ulrich; Solé-Violán, Jordi; Kashyap, Rahul; Leone, Marc; Nanchal, Rahul; Fontes, Luis E; Sakr, Yasser; Vincent, Jean-Louis; 1 Dept of Anaesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University, Szczecin, Poland. 2 Dept of Critical Care, Cliniques Universitaires St Luc, UCL, Brussels, Belgium. 3 Klinik für Anästhesiologie und Operative Intensivmedizin, Klinikum Augsburg, Augsburg, Germany. 4 Dept of Intensive Care, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain. 5 Dept of Anesthesia & Perioperative Medicine, Mayo Clinic, Rochester, MN, USA. 6 Service d'Anesthésie et de Réanimation, Aix Marseille Université, APHM, Hôpital Nord, Marseille, France. 7 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. 8 Department of Intensive Care and Evidence-Based Medicine, Hospital Alcides Carneiro, Petrópolis Medical School, Petrópolis, Brazil. 9 Department of Anesthesiology and Intensive Care, Uniklinikum Jena, Jena, Germany. 10 Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: jlvincent@intensive.org. (W.B. Saunders, 2019-06)
    PURPOSE: To investigate age-related differences in outcomes of critically ill patients with sepsis around the world. METHODS: We performed a secondary analysis of data from the prospective ICON audit, in which all adult (>16 years) patients admitted to participating ICUs between May 8 and 18, 2012, were included, except admissions for routine postoperative observation. For this sub-analysis, the 10,012 patients with completed age data were included. They were divided into five age groups - ≤50, 51-60, 61-70, 71-80, >80 years. Sepsis was defined as infection plus at least one organ failure. RESULTS: A total of 2963 patients had sepsis, with similar proportions across the age groups (≤50 = 25.2%; 51-60 = 30.3%; 61-70 = 32.8%; 71-80 = 30.7%; >80 = 30.9%). Hospital mortality increased with age and in patients >80 years was almost twice that of patients ≤50 years (49.3% vs 25.2%, p < .05). The maximum rate of increase in mortality was about 0.75% per year, occurring between the ages of 71 and 77 years. In multilevel analysis, age > 70 years was independently associated with increased risk of dying. CONCLUSIONS: The odds for death in ICU patients with sepsis increased with age with the maximal rate of increase occurring between the ages of 71 and 77 years.
  • Effects of an intervention program for reducing severe perineal trauma during the second stage of labor.

    Sveinsdottir, Edda; Gottfredsdottir, Helga; Vernhardsdottir, Anna S; Tryggvadottir, Gudny B; Geirsson, Reynir T; 1 Midwifery Division, Faculty of Nursing, University of Iceland, Reykjavik, Iceland. 2 Department of Obstetrics and Gynecology, Women's Clinic, Landspítali University Hospital, Reykjavik, Iceland. 3 Department of Social Sciences, University of Iceland, Reykjavik, Iceland. 4 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Wiley, 2019-06)
    BACKGROUND: Obstetric anal sphincter injuries lead frequently to short- and long-term consequences for the mother, including perineal pain, genital prolapse, and sexual problems. The aim of the study was to evaluate whether the implementation of an intervention program in the second stage of labor involving altered perineal support techniques reduced severe perineal trauma. METHODS: All women reaching the second stage of labor and giving birth vaginally to singleton babies at Landspítali University Hospital (comprising 76% of births in Iceland in 2013) were enrolled in a cohort study. Data were recorded retrospectively for 2008-2010 and prospectively in 2012-2014, for a total of 16 336 births. During 2011, an intervention program was implemented, involving all midwives and obstetricians working in the labor wards. Two professionals assessed and agreed on classification of every perineal tear. RESULTS: The prevalence of obstetric anal sphincter injuries decreased from 5.9% to 3.7% after the implementation (P < 0.001). Third-degree tears decreased by 40%, and fourth-degree tears decreased by 56% (P < 0.001). The prevalence of first-degree tears increased from 25.8% to 33.1%, whereas second-degree tears decreased from 44.7% to 36.6% between the before and after study periods. Severe perineal trauma was linked to birthweight, and this did not change despite the new intervention. CONCLUSIONS: Active intervention to reduce perineal trauma was associated with an overall significant decrease in obstetric anal sphincter injuries. Good perineal visualization, manual perineal support, and controlled delivery of the fetal head were essential components for reducing perineal trauma.
  • The Robson 10-group classification in Iceland: Obstetric interventions and outcomes.

    Einarsdóttir, Kristjana; Sigurðardóttir, Hekla; Ingibjörg Bjarnadóttir, Ragnheiður; Steingrímsdóttir, Þóra; Smárason, Alexander K; 1 Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 2 Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 3 Centre of Development, Primary Health Care of the Capital Area, Reykjavík, Iceland. 4 Department of Obstetrics and Gynaecology, Landspítali University Hospital, Reykjavík, Iceland. 5 Institution of Health Science Research, University of Akureyri and Akureyri Hospital, Akureyri, Iceland. (Wiley, 2019-06)
    BACKGROUND: Rising cesarean rates call for studies on which subgroups of women contribute to the rising rates, both in countries with high and low rates. This study investigated the cesarean rates and contributing groups in Iceland using the Robson 10-group classification system. METHODS: This study included all births in Iceland from 1997 to 2015, identified from the Icelandic Medical Birth Registry (81 839). The Robson distribution, cesarean rate, and contribution of each Robson group were analyzed for each year, and the distribution of other outcomes was calculated for each Robson group. RESULTS: The overall cesarean rate in the population was 16.4%. Robson groups 1 (28.7%) and 3 (38.0%) (spontaneous term births) were the largest groups, and groups 2b (0.4%) and 4b (0.7%) (prelabor cesareans) were small. The cesarean rate in group 5 (prior cesarean) was 55.5%. Group 5 was the largest contributing group to the overall cesarean rate (31.2%), followed by groups 1 (17.1%) and 2a (11.0%). The size of groups 2a (RR 1.04 [95% CI 1.01-1.08]) and 4a (RR 1.04 [95% CI 1.01-1.07]) (induced labors) increased over time, whereas their cesarean rates were stable (group 2a: P = 0.08) or decreased (group 4a: RR 0.95 [95% CI 0.91-0.98]). CONCLUSIONS: In comparison with countries with high cesarean rates, the prelabor cesarean groups (singleton term pregnancies) in Iceland were small, and in women with a previous cesarean, the cesarean rate was low. The size of the labor induction group increased, yet the cesarean rate in this group did not increase.
  • Asthma and selective migration from farming environments in a three-generation cohort study.

    Timm, Signe; Frydenberg, Morten; Abramson, Michael J; Bertelsen, Randi J; Bråbäck, Lennart; Benediktsdottir, Bryndis; Gislason, Thorarinn; Holm, Mathias; Janson, Christer; Jogi, Rain; Johannessen, Ane; Kim, Jeong-Lim; Malinovschi, Andrei; Mishra, Gita; Moratalla, Jesús; Sigsgaard, Torben; Svanes, Cecilie; Schlünssen, Vivi; 1 Department of Public Health, Danish Ramazzini Centre, Aarhus University, Bartholins Alle 2, Building 1260, 8000, Aarhus C, Denmark. signe.timm@ph.au.dk. 2 Department of Public Health, Danish Ramazzini Centre, Aarhus University, Bartholins Alle 2, Building 1260, 8000, Aarhus C, Denmark. 3 School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. 4 Institute of Clinical Science, University of Bergen, Bergen, Norway. 5 Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden. 6 Medical Faculty, University of Iceland, Reykjavík, Iceland. 7 Primary Health Care Center, Gardabaer, Iceland. 8 Department of Sleep, Landspitali University Hospital, Reykjavík, Iceland. 9 Section of Occupational and Environmental Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. 10 Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden. 11 Department of Pulmonology (ARKS), University of Tartu, Tartu, Estonia. 12 Department of Global Public Health and Primary Care, Centre for International Health, University of Bergen, Bergen, Norway. 13 Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway. 14 Section of Occupational and Environmental Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 15 Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden. 16 School of Public Health, The University of Queensland, Brisbane, QLD, 4006, Australia. 17 Department of Internal Medicine, Albacete University Hospital, Albacete, Spain. 18 National Research Centre for The Working Environment, Copenhagen, Denmark. (Springer, 2019-06)
    Individuals raised on a farm appear to have less asthma than individual raised elsewhere. However, selective migration might contribute to this as may also the suggested protection from farm environment. This study investigated if parents with asthma are less likely to raise their children on a farm. This study involved three generations: 6045 participants in ECRHS/RHINE cohorts (born 1945-1973, denoted G1), their 10,121 parents (denoted G0) and their 8260 offspring participating in RHINESSA (born 1963-1998, denoted G2). G2-offspring provided information on parents not participating in ECRHS/RHINE. Asthma status and place of upbringing for all three generations were reported in questionnaires by G1 in 2010-2012 and by G2 in 2013-2016. Binary regressions with farm upbringing as outcome were performed to explore associations between parental asthma and offspring farm upbringing in G0-G1 and G1-G2. Having at least one parent with asthma was not associated with offspring farm upbringing, either in G1-G2 (RR 1.11, 95% CI 0.81-1.52) or in G0-G1 (RR 0.99, 0.85-1.15). G1 parents with asthma born in a city tended to move and raise their G2 offspring on a farm (RR 2.00, 1.12-3.55), while G1 parents with asthma born on a farm were less likely to raise their G2 offspring on a farm (RR 0.34, 0.11-1.06). This pattern was not observed in analyses of G0-G1. This study suggests that the protective effect from farm upbringing on subsequent asthma development could not be explained by selective migration. Intriguingly, asthmatic parents appeared to change environment when having children.
  • Molecularly confirmed Kabuki (Niikawa-Kuroki) syndrome patients demonstrate a specific cognitive profile with extensive visuospatial abnormalities.

    Harris, J; Mahone, E M; Bjornsson, H T; 1 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA. 2 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA. 3 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4 Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, MD, USA. 5 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 6 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 7 Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland. (Wiley, 2019-06)
    BACKGROUND: Kabuki (Niikawa-Kuroki) syndrome (KS) is caused by disease-causing variants in either of two components (KMT2D and KDM6A) of the histone methylation machinery. Nearly all individuals with KS have cognitive difficulties, and most have intellectual disability. Recent studies on a mouse model of KS suggest disruption of normal adult neurogenesis in the granule cell layer of the dentate gyrus of the hippocampus. These mutant mice also demonstrate hippocampal memory defects compared with littermates, but this phenotype is rescued postnatally with agents that target the epigenetic machinery. If these findings are relevant to humans with KS, we would expect significant and disproportionate disruption of visuospatial functioning in these individuals. METHODS: To test this hypothesis, we have compiled a battery to robustly explore visuospatial function. We prospectively recruited 22 patients with molecularly confirmed KS and 22 IQ-matched patients with intellectual disability. RESULTS: We observed significant deficiencies in visual motor, visual perception and visual motor memory in the KS group compared with the IQ-matched group on several measures. In contrast, language function appeared to be marginally better in the KS group compared with the IQ-matched group in a sentence comprehension task. CONCLUSIONS: Together, our data suggest specific disruption of visuospatial function, likely linked to the dentate gyrus, in individuals with KS and provide the groundwork for a novel and specific outcome measure for a clinical trial in a KS population.
  • Development of a novel benchmark method to identify and characterize best practices in home care across six European countries: design, baseline, and rationale of the IBenC project.

    van der Roest, Henriëtte G; van Eenoo, Liza; van Lier, Lisanne I; Onder, Graziano; Garms-Homolová, Vjenka; Smit, Johannes H; Finne-Soveri, Harriet; Jónsson, Pálmi V; Draisma, Stasja; Declercq, Anja; Bosmans, Judith E; van Hout, Hein P J; 1 Department of General Practice and Elderly Care Medicine, Amsterdam Public Health research institute, Amsterdam UMC, VU University medical center, Van der Boechorststraat 7, 1081, BT, Amsterdam, The Netherlands. hg.vanderroest@gmail.com. 2 LUCAS Centre for Care Research and Consultancy, KU Leuven, Leuven, Belgium. 3 Department of General Practice and Elderly Care Medicine, Amsterdam Public Health research institute, Amsterdam UMC, VU University medical center, Van der Boechorststraat 7, 1081, BT, Amsterdam, The Netherlands. 4 Department of Geriatrics, Neuroscience and Orthopedics, Agostino Gemelli University Hospital, Università Cattolica del Sacro Cuore, Rome, Italy. 5 Department of Economics and Law, HTW Berlin, University of Applied Sciences, Berlin, Germany. 6 Department of Psychiatry, Amsterdam Public Health research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands & GGZ inGeest Specialized Mental Health Care, Research and Innovation, Amsterdam, The Netherlands. 7 Department of Wellbeing, National Institute for Health and Welfare, Helsinki, Finland. 8 Department of Geriatrics, Landspitali University Hospital, and Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 9 Department of Health Sciences, Faculty of Science, Amsterdam Public Health research institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. (BioMed Central, 2019-05-15)
    BACKGROUND: Europe's ageing society leads to an increased demand for long-term care, thereby putting a strain on the sustainability of health care systems. The 'Identifying best practices for care-dependent elderly by Benchmarking Costs and outcomes of Community Care' (IBenC) project aims to develop a new benchmark methodology based on quality of care and cost of care utilization to identify best practices in home care. The study's baseline data, methodology, and rationale are reported. METHODS: Home care organizations in Belgium, Finland, Germany, Iceland, Italy, and the Netherlands, home care clients of 65 years and over receiving home care, and professionals working in these organizations were included. Client data were collected according to a prospective longitudinal design with the interRAI Home Care instrument. Assessments were performed at baseline, after six and 12 months by trained (research) nurses. Characteristics of home care organizations and professionals were collected cross-sectionally with online surveys. RESULTS: Thirty-eight home care organizations, 2884 home care clients, and 1067 professionals were enrolled. Home care clients were mainly female (66.9%), on average 82.9 years (± 7.3). Extensive support in activities of daily living was needed for 41.6% of the sample, and 17.6% suffered cognitive decline. Care professionals were mainly female (93.4%), and over 45 years (52.8%). Considerable country differences were found. CONCLUSION: A unique, international, comprehensive database is established, containing in-depth information on home care organizations, their clients and staff members. The variety of data enables the development of a novel cost-quality benchmark method, based on interRAI-HC data. This benchmark can be used to explore relevant links between organizational efficiency and organizational and staff characteristics.
  • GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

    Rongve, Arvid; Witoelar, Aree; Ruiz, Agustín; Athanasiu, Lavinia; Abdelnour, Carla; Clarimon, Jordi; Heilmann-Heimbach, Stefanie; Hernández, Isabel; Moreno-Grau, Sonia; de Rojas, Itziar; Morenas-Rodríguez, Estrella; Fladby, Tormod; Sando, Sigrid B; Bråthen, Geir; Blanc, Frédéric; Bousiges, Olivier; Lemstra, Afina W; van Steenoven, Inger; Londos, Elisabet; Almdahl, Ina S; Pålhaugen, Lene; Eriksen, Jon A; Djurovic, Srdjan; Stordal, Eystein; Saltvedt, Ingvild; Ulstein, Ingun D; Bettella, Francesco; Desikan, Rahul S; Idland, Ane-Victoria; Toft, Mathias; Pihlstrøm, Lasse; Snaedal, Jon; Tárraga, Lluís; Boada, Mercè; Lleó, Alberto; Stefánsson, Hreinn; Stefánsson, Kári; Ramírez, Alfredo; Aarsland, Dag; Andreassen, Ole A; 1 Haugesund Hospital, Helse Fonna, Department of Research and Innovation, Haugesund, Norway. arvid.rongve@helse-fonna.no. 2 The University of Bergen, Department of Clinical Medicine (K1), Bergen, Norway. arvid.rongve@helse-fonna.no. 3 NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 4 Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 5 Memory Clinic and Research Center of Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain. 6 Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 7 Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid and Barcelona, Spain. 8 Institute of Human Genetics, University of Bonn, Bonn, Germany. 9 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. 10 Department of Neurology, Akershus University Hospital, Lørenskog, Norway. 11 University of Oslo, AHUS Campus, Oslo, Norway. 12 Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway. 13 Department of Neurology, St Olav's Hospital, Trondheim, Norway. 14 University Hospital of Strasbourg, CMRR (Memory Resources and Research Centre), Geriatrics Department, Strasbourg, France. 15 University of Strasbourg and CNRS, ICube laboratory and FMTS, team IMIS/Neurocrypto, Strasbourg, France. 16 University Hospital of Strasbourg, CMRR (Memory Resources and Research Centre), Laboratory of Biochemistry and Molecular Biology, Strasbourg, France. 17 University of Strasbourg and CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364, 67000, Strasbourg, France. 18 Alzheimercenter & Department of Neurology VU University Medical Center, Amsterdam, the Netherlands. 19 Lund University, Skane University Hospital, Institute of Clinical Sciences, Malmö, Sweden. 20 Department of Geriatric Psychiatry, Oslo University Hospital, Oslo, Norway. 21 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 22 NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway. 23 Department of Psychiatry, Namsos Hospital, Namsos, Norway. 24 Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway. 25 Department of Geriatrics, St. Olav's Hospital, Trondheim, Norway. 26 Departments of Radiology and Biomedical Imaging, Neurology and Pediatrics, UCSF, San Francisco, USA. 27 Oslo Delirium Research Group, Department of Geriatric Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 28 Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway. 29 Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. 30 Department of Neurology, Oslo University Hospital, Oslo, Norway. 31 Landspitali University Hospital, Reykjavik, Iceland. 32 DeCODE genetics, Reykjavik, Iceland. 33 Division for Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, 50924, Cologne, Germany. 34 Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, 53127, Bonn, Germany. 35 Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. daarsland@gmail.com. 36 Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway. daarsland@gmail.com. 37 NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. ole.andreassen@medisin.uio.no. 38 Institute of Clinical Medicine, University of Oslo, Oslo, Norway. ole.andreassen@medisin.uio.no. (Nature Publishing Group, 2019-05-07)
    Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10-8). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10-6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.
  • Cardiovascular risk factors and incident giant cell arteritis: a population-based cohort study.

    Tomasson, G; Bjornsson, J; Zhang, Y; Gudnason, V; Merkel, P A; 1 a Department of Epidemiology and Biostatistics, Faculty of Medicine , University of Iceland , Reykjavik , Iceland. 2 b Department of Rheumatology , University Hospital , Reykjavik , Iceland. 3 c Centre for Rheumatology Research , University Hospital , Reykjavik , Iceland. 4 d Department of Pathology , Akureyri Regional Hospital , Akureyri , Iceland. 5 e Clinical Epidemiology Research and Training Unit , Boston University School of Medicine , Boston , MA , USA. 6 f Faculty of Medicine , University of Iceland , Reykjavik , Iceland. 7 g Icelandic Heart Association , Kopavogur , Iceland. 8 h Division of Rheumatology , University of Pennsylvania , Philadelphia , PA , USA. 9 i Department of Biostatistics, Epidemiology, and Informatics , University of Pennsylvania , Philadelphia , PA , USA. (Taylor & Francis, 2019-05)
    OBJECTIVE: To assess the strength of the effect of cardiovascular risk factors on the incidence of giant cell arteritis (GCA) in a general population context. METHOD: Data from the Reykjavik Study (RS), a population-based cohort study focusing on cardiovascular disease, were used. Everyone born in 1907-1935 living in Reykjavik, Iceland, or adjacent communities on 1 December 1967 were invited to participate. Subjects attended a study visit in 1967-1996 and information on cardiovascular risk factors [smoking habits, blood pressure, diabetes, body mass index (BMI), and serum cholesterol] was obtained. All temporal artery biopsies obtained from members of the RS cohort were re-examined by a single pathologist with expertise in vascular pathology. Effects of risk factors on GCA occurrence are expressed as incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: Altogether, 19 241 subjects contributed a median of 23.1 (interquartile range 17.6-29.4) years after the age of 50 to this analysis. During 444 126 person-years of follow-up, 194 subjects developed GCA, corresponding to an incidence rate of 43.6 (95% CI 37.8-50.2) per 100 000 person-years. Being overweight or obese were inversely associated with GCA, especially in women [IRRs 0.70 (0.48-1.02) and 0.31 (0.14-0.71), respectively]. There was a weaker association between BMI and incident GCA in men. Smoking was inversely associated with GCA in men [IRR 0.47 (0.27-0.81)], but not in women. CONCLUSIONS: The incidence of GCA in Iceland is very high. High BMI protects against the occurrence of GCA, and smoking may protect against GCA in men.
  • Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.

    Styrkarsdottir, Unnur; Stefansson, Olafur A; Gunnarsdottir, Kristbjorg; Thorleifsson, Gudmar; Lund, Sigrun H; Stefansdottir, Lilja; Juliusson, Kristinn; Agustsdottir, Arna B; Zink, Florian; Halldorsson, Gisli H; Ivarsdottir, Erna V; Benonisdottir, Stefania; Jonsson, Hakon; Gylfason, Arnaldur; Norland, Kristjan; Trajanoska, Katerina; Boer, Cindy G; Southam, Lorraine; Leung, Jason C S; Tang, Nelson L S; Kwok, Timothy C Y; Lee, Jenny S W; Ho, Suzanne C; Byrjalsen, Inger; Center, Jacqueline R; Lee, Seung Hun; Koh, Jung-Min; Lohmander, L Stefan; Ho-Pham, Lan T; Nguyen, Tuan V; Eisman, John A; Woo, Jean; Leung, Ping-C; Loughlin, John; Zeggini, Eleftheria; Christiansen, Claus; Rivadeneira, Fernando; van Meurs, Joyce; Uitterlinden, Andre G; Mogensen, Brynjolfur; Jonsson, Helgi; Ingvarsson, Thorvaldur; Sigurdsson, Gunnar; Benediktsson, Rafn; Sulem, Patrick; Jonsdottir, Ingileif; Masson, Gisli; Holm, Hilma; Norddahl, Gudmundur L; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F; Stefansson, Kari; 1 deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. unnur.styrkarsdottir@decode.is. 2 deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. 3 Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. 4 Department of Epidemiology, ErasmusMC, 3015 GD, Rotterdam, The Netherlands. 5 Department of Internal Medicine, ErasmusMC, 3015 GD, Rotterdam, The Netherlands. 6 Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. 7 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. 8 Jockey Club Centre for Osteoporosis Care and Control, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 9 Faculty of Medicine, Department of Chemical Pathology and Laboratory for Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. 10 CUHK Shenzhen Research Institute, Shenzhen, 518000, China. 11 Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China. 12 Faculty of Medicine, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. 13 Department of Medicine, Alice Ho Miu Ling Nethersole Hospital and Tai Po Hospital, Hong Kong, China. 14 JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 15 Nordic Bioscience A/S, 2730, Herlev, Denmark. 16 Bone Biology Division, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia. 17 School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, 2010, Australia. 18 St Vincent's Clinical School, University of New South Wales, Sydney, NSW, 2010, Australia. 19 Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea. 20 Orthopaedics, Department of Clinical Sciences Lund, Lund University, SE-22 100, Lund, Sweden. 21 Bone and Muscle Research Lab, Ton Duc Thang University, Ho Chi Minh City, 700000, Vietnam. 22 School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia. 23 Clinical Translation and Advanced Education, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia. 24 Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China. 25 Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 7RU, UK. 26 Institute of Translational Genomics, Helmholtz Zentrum München, 85764, München, Germany. 27 Department of Emergengy Medicine, Landspitali, The National University Hospital of Iceland, 101, Reykjavik, Iceland. 28 Research Institute in Emergency Medicine, Landspitali, The National University Hospital of Iceland, and University of Iceland, 101, Reykjavik, Iceland. 29 Department of Medicine, Landspitali-The National University Hospital of Iceland, 101, Reykjavik, Iceland. 30 Department of Orthopedic Surgery, Akureyri Hospital, 600, Akureyri, Iceland. 31 Institution of Health Science, University of Akureyri, 600, Akureyri, Iceland. 32 Research Service Center, Reykjavik, 201, Iceland. 33 Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, 101, Reykjavik, Iceland. 34 Department of Immunology, Landspitali-The National University Hospital of Iceland, 101, Reykjavik, Iceland. 35 School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 107, Iceland. 36 deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. kstefans@decode.is. 37 Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. kstefans@decode.is. (Nature Publishing Group, 2019-05-24)
    The original HTML version of this Article was updated shortly after publication to add links to the Peer Review file.In addition, affiliations 16 and 17 incorrectly read 'School of Medicine Sydney, University of Notre Dame Australia, Sydney, WA, 6160, Australia' and 'St Vincent's Clinical School, University of New South Wales Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.' This has now been corrected in both the PDF and HTML versions of the Article.
  • GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.

    Styrkarsdottir, Unnur; Stefansson, Olafur A; Gunnarsdottir, Kristbjorg; Thorleifsson, Gudmar; Lund, Sigrun H; Stefansdottir, Lilja; Juliusson, Kristinn; Agustsdottir, Arna B; Zink, Florian; Halldorsson, Gisli H; Ivarsdottir, Erna V; Benonisdottir, Stefania; Jonsson, Hakon; Gylfason, Arnaldur; Norland, Kristjan; Trajanoska, Katerina; Boer, Cindy G; Southam, Lorraine; Leung, Jason C S; Tang, Nelson L S; Kwok, Timothy C Y; Lee, Jenny S W; Ho, Suzanne C; Byrjalsen, Inger; Center, Jacqueline R; Lee, Seung Hun; Koh, Jung-Min; Lohmander, L Stefan; Ho-Pham, Lan T; Nguyen, Tuan V; Eisman, John A; Woo, Jean; Leung, Ping-C; Loughlin, John; Zeggini, Eleftheria; Christiansen, Claus; Rivadeneira, Fernando; van Meurs, Joyce; Uitterlinden, Andre G; Mogensen, Brynjolfur; Jonsson, Helgi; Ingvarsson, Thorvaldur; Sigurdsson, Gunnar; Benediktsson, Rafn; Sulem, Patrick; Jonsdottir, Ingileif; Masson, Gisli; Holm, Hilma; Norddahl, Gudmundur L; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F; Stefansson, Kari; 1 deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. unnur.styrkarsdottir@decode.is. 2 deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. 3 Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. 4 Department of Epidemiology, ErasmusMC, 3015 GD, Rotterdam, The Netherlands. 5 Department of Internal Medicine, ErasmusMC, 3015 GD, Rotterdam, the Netherlands. 6 Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. 7 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. 8 Jockey Club Centre for Osteoporosis Care and Control, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 9 Faculty of Medicine, Department of Chemical Pathology and Laboratory for Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences,, The Chinese University of Hong Kong, Hong Kong, China. 10 CUHK Shenzhen Research Institute, Shenzhen, 518000, China. 11 Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China. 12 Faculty of Medicine, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. 13 Department of Medicine, Alice Ho Miu Ling Nethersole Hospital and Tai Po Hospital, Hong Kong, China. 14 JC School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 15 Nordic Bioscience A/S, 2730, Herlev, Denmark. 16 Bone Biology Division, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia. 17 School of Medicine Sydney, University of Notre Dame Australia, Sydney, NSW, 2010, Australia. 18 St Vincent's Clinical School, University of New South Wales, Sydney, NSW, 2010, Australia. 19 Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea. 20 Orthopaedics, Department of Clinical Sciences Lund, Lund University, SE-22 100, Lund, Sweden. 21 Bone and Muscle Research Lab, Ton Duc Thang University, Ho Chi Minh City, 700000, Vietnam. 22 School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia. 23 Clinical Translation and Advanced Education, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia. 24 Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China. 25 Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 7RU, UK. 26 Institute of Translational Genomics, Helmholtz Zentrum München, 85764, München, Germany. 27 Department of Emergengy Medicine, Landspitali, The National University Hospital of Iceland, 101, Reykjavik, Iceland. 28 Research Institute in Emergency Medicine, Landspitali, The National University Hospital of Iceland, and University of Iceland, 101, Reykjavik, Iceland. 29 Department of Medicine, Landspitali-The National University Hospital of Iceland, 101, Reykjavik, Iceland. 30 Department of Orthopedic Surgery, Akureyri Hospital, 600, Akureyri, Iceland. 31 Institution of Health Science, University of Akureyri, 600, Akureyri, Iceland. 32 Research Service Center, Reykjavik, 201, Iceland. 33 Department of Endocrinology and Metabolism, Landspitali, The National University Hospital of Iceland, 101, Reykjavik, Iceland. 34 Department of Immunology, Landspitali-The National University Hospital of Iceland, 101, Reykjavik, Iceland. 35 School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 107, Iceland. 36 deCODE genetics/Amgen Inc., Reykjavik, 101, Iceland. kstefans@decode.is. 37 Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. kstefans@decode.is. (Nature Publishing Group, 2019-05-03)
    Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10-42, β = -0.090) and confers risk of hip fracture (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.
  • A comparative brief on conducted electrical weapon safety.

    Kunz, Sebastian N; Adamec, Jiri; 1 Department of Forensic Pathology, Landspítali University Hospital Reykjavik, v/Barónsstíg 101, Reykjavik, Iceland. sebastian@landspitali.is. 2 Institute of Forensic Medicine, Ludwigs-Maximilians University Munich, Munich, Germany. (Springer Verlag, 2019-05)
    The variety and high number of published research articles on conducted electrical weapons (CEW) provides a detailed, yet in some parts inconclusive overview of medical aspects of CEW. Due to different research approaches and the use of dissimilar test subjects, an assessment of possible health risks of CEW is limited. The present work provides a brief on CEW safety based on currently available animal, computer and human research data. Using the medical database PubMed, articles published on this topic are critically evaluated and compared with each other. Special focuses are the differences and similarities of human and animal research as well as computer simulation programs. The authors explain why some studies are more reliable than others and give their expert opinion on the safety of CEW. The body of data that have been reviewed provides reasonable support for the safety of CEW.
  • Oral anticoagulant monitoring: Are we on the right track?

    Onundarson, Pall T; Flygenring, Bjorn; 1 Landspitali/The National University Hospital of Iceland, Reykjavik, Iceland. 2 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Wiley, 2019-05-01)
    Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran-related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.

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