• Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes.

      Gudbjartsson, Daniel F; Thorgeirsson, Gudmundur; Sulem, Patrick; Helgadottir, Anna; Gylfason, Arnaldur; Saemundsdottir, Jona; Bjornsson, Eythor; Norddahl, Gudmundur L; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; et al. (Elsevier Science, 2019-12-17)
      Background: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). Objectives: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. Methods: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. Results: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. Conclusions: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk. Keywords: Lp(a); Mendelian randomization; coronary artery disease; genetics; type 2 diabetes.
    • Immediate and long-term need for permanent cardiac pacing following aortic valve replacement.

      Viktorsson, Sindri A; Orrason, Andri W; Vidisson, Kristjan O; Gunnarsdottir, Anna G; Johnsen, Arni; Helgason, Dadi; Arnar, David O; Geirsson, Arnar; Gudbjartsson, Tomas; 1 Division of Cardiothoracic Surgery, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 2 Internal Medicine Services, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 3 Division of Cardiology, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 4 Division of Cardiac Surgery, Yale School of Medicine, New Haven, CT, USA. 5 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2019-12-06)
      Introduction: Atrioventricular (AV) node conduction disturbances are common following surgical aortic valve replacement (SAVR), and in some cases the patient needs a permanent pacemaker (PPM) implantation before discharge from hospital. Little is known about the long-term need for PPM and the PPM dependency of these individuals. We determined the incidence of PPM implantation before and after discharge in SAVR patients. Methods: We studied 557 consecutive patients who underwent SAVR for aortic stenosis in Iceland between 2002 and 2016. Timing and indication for PPM were registered, with a new concept, ventricular pacing proportion (VPP), defined as ventricular pacing ≥90% of the time, being used to approximate pacemaker dependency. The median follow-up time was 73 months. We plotted the cumulative incidence of pacemaker implantation, treating death as a competing risk. Results: Of the 557 patients, 22 (3.9%) received PPM in the first 30 days after surgery, most commonly for complete AV block (n = 14) or symptomatic bradycardia (n = 8); Thirty-eight other patients (6.8%) had a PPM implanted >30 days postoperatively, at a median of 43 months after surgery (range 0‒181), most often for AV block (n = 13) or sick-sinus syndrome (n = 10). The cumulative incidence of PPM implantation at 1, 5, and 10 years postoperatively was 5.0%, 9.2%, and 12.3%, respectively. During follow-up, 45.0% of the 60 patients had VPP ≥90%. Conclusion: The cumulative incidence of permanent pacemaker implantation following SAVR was about 12% at 10 years, with every other patient having VPP ≥90% during follow-up. This suggests that AV node conduction disturbances extend significantly beyond the perioperative period.
    • Metabolomics study of platelet concentrates photochemically treated with amotosalen and UVA light for pathogen inactivation.

      Jóhannsson, Freyr; Árnason, Níels Á; Landrö, Ragna; Guðmundsson, Sveinn; Sigurjonsson, Ólafur E; Rolfsson, Óttar; 1 Center for Systems Biology, University of Iceland, Sturlugata 8, Reykjavik, Iceland. 2 Medical Department, University of Iceland, Sturlugata 8, Reykjavik, Iceland. 3 The Blood Bank, Landspitali-University Hospital, Snorrabraut 60, Reykjavik, Iceland. 4 School of Science and Engineering, Reykjavik University, Menntavegur 1, Reykjavik, Iceland. (Wiley, 2019-12-05)
      BACKGROUND: The risk of bacterial contamination and the deterioration of platelet (PLT) quality limit the shelf-life of platelet concentrates (PCs). The INTERCEPT pathogen inactivation system reduces the risk of pathogen transmission by inhibiting nucleic acid replication using a combination of a photo-reactive compound and UVA illumination. The goal of this study was to investigate the effects the INTERCEPT system has on the PLT metabolome and metabolic activity. STUDY DESIGN AND METHODS: Paired units of buffy coat-derived PCs were generated using a pool and split strategy (n = 8). The paired PCs were either treated with the INTERCEPT system or left untreated. Samples were collected on Days 1, 2, 4, and 7 of storage. Ultra-performance chromatography coupled with time-of-flight mass spectrometry was used to analyze the extra- and intracellular metabolomes. Constraint-based metabolic modeling was then used to predict the metabolic activity of the stored PLTs. RESULTS: A relatively large number of metabolites in the extracellular environment were depleted during the processing steps of the INTERCEPT system, in particular, metabolites with hydrophobic functional groups, including acylcarnitines and lysophosphatidylcholines. In the intracellular environment, alterations in glucose and glycerophospholipid metabolism and decreased levels of 2-hydroxyglutarate were observed following the INTERCEPT treatment. Untargeted metabolomics analysis revealed residual amotosalen dimers present in the treated PCs. Systems-level analysis of PLT metabolism indicated that the INTERCEPT system does not have a significant impact on the PLT energy metabolism and nutrient utilization. CONCLUSIONS: The INTERCEPT system significantly alters the metabolome of the stored PCs without significantly influencing PLT energy metabolism.
    • Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study.

      Jarvis, Kirsten Brunsvig; LeBlanc, Marissa; Tulstrup, Morten; Nielsen, Rikke Linnemann; Albertsen, Birgitte Klug; Gupta, Ramneek; Huttunen, Pasi; Jónsson, Ólafur Gisli; Rank, Cecilie Utke; Ranta, Susanna; et al. (Pergamon Press, 2019-12)
      1 Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Postbok 4950, Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072, Blindern, 0316 Oslo, Norway. Electronic address: kirjar@ous-hf.no. 2 Oslo Center for Biostatistics and Epidemiology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway. 3 Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark. 4 Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark; Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, 380 Huaibeizhuang, Huairou district, Beijing, China. 5 Children and Adolescent Health, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark. 6 Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark. 7 Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, New Children's Hospital, Helsinki University Hospital, Stenbäckinkatu 9, 00290 Helsinki, Finland. 8 Children's Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Hringbraut 101, 101 Reykjavik, Iceland. 9 Department of hematology, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Pediatric Oncology Research Laboratory, Rigshospitalet, University of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark. 10 Department of Women's and Children's Health, Karolinska University Hospital, Eugeniavägen 3, 171 76 Solna, Sweden; Childhood Cancer Research Unit, Women's and Children's Health, Karolinska Insitutet, Solnavägen 1, 171 77 Solna, Sweden. 11 Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Postbok 4950, Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072, Blindern, 0316 Oslo, Norway. 12 Department of Hematology and Oncology, Tallinn Children's Hospital, 13419 Tallinn, Estonia. 13 Center for Pediatric Oncology and Hematology, Children's Hospital, Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius 08410, Lithuania. 14 Department of Pediatrics, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark. 15 Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Nørregade 10, 1165 Copenhagen, Denmark.
    • YKL-40/CHI3L1 facilitates migration and invasion in HER2 overexpressing breast epithelial progenitor cells and generates a niche for capillary-like network formation.

      Morera, Erika; Steinhäuser, Sarah Sophie; Budkova, Zuzana; Ingthorsson, Saevar; Kricker, Jennifer; Krueger, Aileen; Traustadottir, Gunnhildur Asta; Gudjonsson, Thorarinn; 1 Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Vatnsmyrarvegi 16, 101, Reykjavik, Iceland. 2 Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany. 3 Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Vatnsmyrarvegi 16, 101, Reykjavik, Iceland. tgudjons@hi.is. 4 Department of Laboratory Hematology, Landspitali - University Hospital, Reykjavik, Iceland. tgudjons@hi.is. (Springer, 2019-12)
      Epithelial to mesenchymal transition (EMT) is a developmental event that is hijacked in some diseases such as fibrosis and cancer. In cancer, EMT has been linked to increased invasion and metastasis and is generally associated with a poor prognosis. In this study, we have compared phenotypic and functional differences between two isogenic cell lines with an EMT profile: D492M and D492HER2 that are both derived from D492, a breast epithelial cell line with stem cell properties. D492M is non-tumorigenic while D492HER2 is tumorigenic. Thus, the aim of this study was to analyze the expression profile of these cell lines, identify potential oncogenes, and evaluate their effects on cellular phenotype. We performed transcriptome and secretome analyses of D492M and D492HER2 and verified expression of selected genes at the RNA and protein level. One candidate, YKL-40 (also known as CHI3L1), was selected for further studies due to its differential expression between D492M and D492HER2, being considerably higher in D492HER2. YKL-40 has been linked to chronic inflammation diseases and cancer, yet its function is not fully understood. Knock-down experiments of YKL-40 in D492HER2 resulted in reduced migration and invasion as well as reduced ability to induce angiogenesis in an in vitro assay, plus changes in the EMT-phenotype. In summary, our data suggest that YKL-40 may provide D492HER2 with increased aggressiveness, supporting cancer progression and facilitating angiogenesis.
    • Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

      Hobbs, Brian D; Putman, Rachel K; Araki, Tetsuro; Nishino, Mizuki; Gudmundsson, Gunnar; Gudnason, Vilmundur; Eiriksdottir, Gudny; Zilhao Nogueira, Nuno Rodrigues; Dupuis, Josée; Xu, Hanfei; et al. (American Thoracic Society, 2019-12)
      Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.
    • Post cholecystectomy bile duct injury: early, intermediate or late repair with hepaticojejunostomy - an E-AHPBA multi-center study.

      Rystedt, Jenny M. L.; Kleeff, Joerg; Salvia, Roberto; Besselink, Mark G.; Prasad, Raj; Lesurtel, Mickael; Sturesson, Christian; Abu Hilal, M.; Aljaiuossi, A.; Antonucci, A.; et al. (Elsevier Science, 2019-12)
      BACKGROUND: Treatment of bile duct injuries (BDI) during cholecystectomy depends on the severity of injury and the timing of diagnosis. Standard of care for severe BDIs is hepaticojejunostomy. The aim of this retrospective multi-center study was to assess the optimal timing for repair of BDI with hepaticojejunostomy. METHODS: Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients with hepaticojejunostomy after BDI from January 2000 to June 2016. Patients were stratified according to the timing of biliary reconstruction with hepaticojejunostomy: early (day 0-7), intermediate (1-6 weeks) and late (6 weeks-6 months). Primary endpoint was re-intervention >90 days after the hepaticojejunostomy and secondary endpoints were severe 90-day complications and liver-related mortality. RESULTS: In total 913 patients from 48 centers were included in the analysis. In 401 patients (44%) the bile duct injury was diagnosed intraoperatively, and 126 patients (14%) suffered from concomitant vascular injury. In multivariable analysis the timing of hepaticojejunostomy had no impact on postoperative complications, the need for re-intervention after 90 days nor liver-related mortality. The rate of re-intervention more than 90 days after the hepaticojejunostomy was significantly increased in male patients but decreased in older patients. Severe co-morbidity increased the risk for liver-related mortality (HR 3.439; CI 1.37-8.65; p = 0.009). CONCLUSION: After BDI occurring during cholecystectomy, the timing of biliary reconstruction with hepaticojejunostomy did not have any impact on severe postoperative complications, the need for re-intervention or liver-related mortality. Individualised treatment after iatrogenic bile duct injury is still advisable.
    • Definition of excessive daytime sleepiness in the general population: Feeling sleepy relates better to sleep-related symptoms and quality of life than the Epworth Sleepiness Scale score. Results from an epidemiological study.

      Thorarinsdottir, Elin H; Bjornsdottir, Erla; Benediktsdottir, Bryndis; Janson, Christer; Gislason, Thorarinn; Aspelund, Thor; Kuna, Samuel T; Pack, Allan I; Arnardottir, Erna S; 1 Department of Medicine, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 2 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3 Sleep Department, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 4 School of Science and Engineering, Reykjavik University, Reykjavik, Iceland. 5 Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden. 6 Icelandic Heart Association, Kopavogur, Iceland. 7 Department of Medicine and Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 8 Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA. 9 Internal Medicine Services, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. (Wiley, 2019-12)
      Many different subjective tools are being used to measure excessive daytime sleepiness (EDS) but the most widely used is the Epworth Sleepiness Scale (ESS). However, it is unclear if using the ESS is adequate on its own when assessing EDS. The aim of this study was to estimate the characteristics and prevalence of EDS using the ESS and the Basic Nordic Sleep Questionnaire (BNSQ) in general population samples. Participants aged 40 years and older answered questions about sleepiness, health, sleep-related symptoms and quality of life. Two groups were defined as suffering from EDS: those who scored >10 on the ESS (with increased risk of dozing off) and those reporting feeling sleepy during the day ≥3 times per week on the BNSQ. In total, 1,338 subjects (53% male, 74.1% response rate) participated, 13.1% reported an increased risk of dozing off, 23.2% reported feeling sleepy and 6.4% reported both. The prevalence of restless leg syndrome, nocturnal gastroesophageal reflux, difficulties initiating and maintaining sleep and nocturnal sweating was higher among subjects reporting feeling sleepy compared to non-sleepy subjects. Also, subjects reporting feeling sleepy had poorer quality of life and reported more often feeling unrested during the day than non-sleepy subjects. However, subjects reporting increased risk of dozing off (ESS > 10) without feeling sleepy had a similar symptom profile as the non-sleepy subjects. Therefore, reporting only risk of dozing off without feeling sleepy may not reflect problematic sleepiness and more instruments in addition to ESS are needed when evaluating daytime sleepiness.
    • 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery.

      Kunst, Gudrun; Milojevic, Milan; Boer, Christa; De Somer, Filip M J J; Gudbjartsson, Tomas; van den Goor, Jenny; Jones, Timothy J; Lomivorotov, Vladimir; Merkle, Frank; Ranucci, Marco; et al. (Elsevier Science, 2019-12)
      Disclaimer 2019: The EACTS/EACTA/EBCP Guidelines represent the views of the EACTS, the EACTA and EBCP and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The EACTS, EACTA and EBCP are not responsible in the event of any contradiction, discrepancy and/or ambiguity between the EACTS, EACTA and EBCP Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the EACTS, EACTA and EBCP Guidelines fully into account when exercising their clinical judgement as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the EACTS, EACTA and EBCP Guidelines do not, in any way whatsoever, override the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and, where appropriate and/or necessary, in consultation with that patient and the patient's care provider. Nor do the EACTS, EACTA and EBCP Guidelines exempt health professionals from giving full and careful consideration to the relevant official, updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription. The article has been co-published with permission in the British Journal of Anaesthesia, the European Journal of Cardio-Thoracic Surgery and the Interactive CardioVascular and Thoracic Surgery. All rights reserved in respect of the European Journal of Cardio-Thoracic Surgery and the Interactive CardioVascular and Thoracic Surgery. (C) European Association for Cardio-Thoracic Surgery 2019, published by Oxford University Press, and in respect of the British Journal of Anaesthesia (C) 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
    • Rhesus D alloimmunization in pregnancy from 1996 to 2015 in Iceland: a nation-wide population study prior to routine antenatal anti-D prophylaxis.

      Gudlaugsson, Brynjar; Hjartardottir, Hulda; Svansdottir, Gudrun; Gudmundsdottir, Gudny; Kjartansson, Sveinn; Jonsson, Thorbjorn; Gudmundsson, Sveinn; Halldorsdottir, Anna M; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Obstetrics and Gynecology, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 3Blood Bank, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 4Department of Pediatrics, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. (Wiley, 2019-12)
      Background: Rhesus D (RhD) incompatibility is still the most important cause of hemolytic disease of the fetus and newborn (HDFN) worldwide. The aim of this study was to investigate the incidence, causes, and consequences of anti-D alloimmunizations in pregnancy in Iceland, prior to implementation of targeted routine antenatal anti-D prophylaxis (RAADP) in 2018. Study design and methods: This was a nation-wide cohort study of 130 pregnancies affected by RhD alloimmunization in Iceland in the period from 1996 through 2015. Data were collected from transfusion medicine databases, medical records, and the Icelandic Medical Birth Register. Results: Of 130 RhD alloimmunizations, 80 cases (61.5%) represented new RhD immunization in the current pregnancy. Sensitization was discovered in the third trimester in 41 (51.3%) and occurred in the first pregnancy in 14 cases (17.5%). The most likely causative immunization event was the index pregnancy for 45 (56.25%), a previous pregnancy/birth for 26 (32.5%), abortion for 3 (3.75%), and unknown for 6 women (7.5%). Higher anti-D titers were associated with shorter gestational length, cesarean sections, positive direct antiglobulin test (DAT), and severe HDFN. Intrauterine transfusion (IUT) was performed in five pregnancies (3.8%), and 35 of 132 (26.5%) live-born neonates received treatment for HDFN; 32 received phototherapy (24.2%), 13 exchange transfusion (9.8%), and seven simple blood transfusion (5.3%). Conclusion: In about half of cases, RhD alloimmunization was caused by the index pregnancy and discovered in the third trimester. Thus, the newly implemented RAADP protocol should be effective in reducing the incidence of RhD immunization in Iceland in the future.
    • Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

      Page, Elizabeth C; Bancroft, Elizabeth K; Brook, Mark N; Assel, Melissa; Hassan Al Battat, Mona; Thomas, Sarah; Taylor, Natalie; Chamberlain, Anthony; Pope, Jennifer; Raghallaigh, Holly Ni; et al. (Elsevier, 2019-12)
      BACKGROUND: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. OBJECTIVE: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. DESIGN, SETTING, AND PARTICIPANTS: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. RESULTS AND LIMITATIONS: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). CONCLUSIONS: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. PATIENT SUMMARY: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.
    • Meðferð með hreyfiseðli í kjölfar meðgöngusykursýki

      Þórunn Jóhanna Júlíusdóttir; Hannes Hrafnkelsson; Ragnheiður I. Bjarnadóttir; Sesselja Guðmundsdóttir; Ragnheiður Bachmann; Karitas Ívarsdóttir; Jón Steinar Jónsson; 1 Heilsugæslu höfuðborgarsvæðisins, 2 Háskóla Íslands, 3 Þróunarmiðstöð íslenskrar heilsugæslu (Læknafélag Íslands, Læknafélag Reykjavíkur, 2019-12)
      TILGANGUR Algengi meðgöngusykursýki fer hratt vaxandi og tæplega 19% kvenna sem fæddu á Landspítala á árinu 2018 höfðu þessa greiningu. Þær konur sem fá meðgöngusykursýki eru í aukinni hættu að fá hana aftur á síðari meðgöngum og einnig í aukinni áhættu á að þróa sykursýki tegund 2 síðar á ævinni. Ofþyngd og hreyfingarleysi eru sterkir áhættuþættir. Hreyfiseðill er meðferðarúrræði sem stendur til boða á öllum heilbrigðisstofnunum. Markmið rannsóknarinnar var að kanna áhrif meðferðar með hreyfiseðli eftir fæðingu hjá konum sem höfðu meðgöngusykursýki, á virkni þeirra, líðan og þætti sem tengjast efnaskiptavillu. EFNIVIÐUR OG AÐFERÐIR Konur sem fæddu börn frá 1. janúar 2016 til 30. júní 2017, voru í mæðravernd hjá Heilsugæslu höfuðborgarsvæðisins og greindust með meðgöngusykursýki var boðin þátttaka. Þátttakendum var skipt tilviljanakennt í tvo hópa þar sem annar hópurinn fékk meðferð með hreyfiseðli í 5 mánuði en viðmiðunarhópurinn hefðbundna meðferð. Mælingar á blóðgildum, hæð, þyngd, virkni og líðan voru gerðar þremur mánuðum og 8 mánuðum eftir fæðingu. NIÐURSTÖÐUR Áttatíu og fjórar konur tóku þátt, 45 í íhlutunarhópi og 39 í viðmiðunarhópi. Virkni jókst marktækt í íhlutunarhópi en ekki urðu marktækar breytingar á blóðmælingum. Viss áhrif en ekki marktæk mældust á þyngd, líkamsþyngdarstuðli og lífsgæðum. Þær konur sem voru með barn sitt á brjósti voru með marktækt lægra insúlín en þær konur sem ekki voru með barn sitt á brjósti. Sterkari fylgni var á milli þyngdar og insúlíns en á milli fastandi blóðsykurs og insúlíns. ÁLYKTUN Meðferð með hreyfiseðli eftir fæðingu jók marktækt virkni kvenna sem höfðu meðgöngusykursýki. Brjóstagjöf hefur mögulega áhrif til lækkunar insúlíns.
    • Pulmonary carcinoid tumours: incidence, histology, and surgical outcome. A population-based study.

      Petursdottir, Astridur; Sigurdardottir, Johanna; Fridriksson, Bjorn M; Johnsen, Arni; Isaksson, Helgi J; Hardardottir, Hronn; Jonsson, Steinn; Gudbjartsson, Tomas; 1 Department of Cardiothoracic Surgery, Landspitali University Hospital, IS-101, Reykjavik, Iceland. 2 Department of Surgery, Vasteras County Hospital, Reykjavik, Iceland. 3 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 4 Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland. 5 Department of Pulmonology, Landspitali University Hospital, Reykjavik, Iceland. 6 Department of Cardiothoracic Surgery, Landspitali University Hospital, IS-101, Reykjavik, Iceland. tomasgud@landspitali.is. 7 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. tomasgud@landspitali.is. (Springer Japan, 2019-11-28)
      BACKGROUND: Pulmonary carcinoids (PCs) represent only a minority of all primary pulmonary malignancies but they are the most common type of pulmonary malignancy diagnosed in children and adolescents. In this nationwide study, we analyzed data on all PC tumours in the Icelandic population over a 60-year period and concentrated especially on incidence and patient outcomes. METHODS: We studied all cases of PCs diagnosed in Iceland in the period 1955‒2015. Histological specimens were re-evaluated and the tumours were staged according to the TNM system (seventh edition). Survival was estimated using the Kaplan-Meier method, with a mean follow-up of 15.7 years. RESULTS: Altogether, 88 patients (median age 51.0 years, 65.9% women) were diagnosed with PCs in the study period. The incidence increased from 0.19/100,000/year in the first decade (1955‒1964) to 0.58/100,000/year in the last decade (2005‒2015), with a mean increase of 29.0% per decade of the study period (p < 0.001). The rise in incidental detection was, however, not significant. The median tumour diameter was 2.2 cm (range 0.4‒7.0) and typical histology was seen in 74 patients (84.1%). The other 14 patients (15.9%) had atypical histology. In all, 90.9% of the patients underwent pulmonary resection, 81.2% of them with lobectomy, with all of them surviving at least 30 days postoperatively. Most patients (n = 52, 62.7%) were stage IA at diagnosis, 15 (18.1%) were stage IB, nine (10.8%) were stage IIA, and three were stage IIIA (3.6%). Four patients (4.8%) had distant metastases (stage IV), two of whom had typical histology. Five-year survival was 89.8% for all patients: 93.2% for patients with typical histology and 70.7% for those with atypical histology. CONCLUSION: The incidence of PCs in Iceland has increased significantly over the last six decades, which cannot be explained by a rise in incidental detection at chest imaging. Most patients have localized disease and a favourable histology, where the long-term outcome is excellent.
    • The majority of early term elective cesarean sections can be postponed.

      Hardardottir, Hildur; Thorkelsson, Thordur; Rikhardsdottir, Johanna Vigdis; 1 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2 Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavík, Iceland. 3 Department of Neonatology, Children's Hospital Iceland, Landspitali University Hospital, Reykjavik, Iceland. (Taylor & Francis, 2019-11-21)
      Introduction: To minimize the risk of neonatal respiratory morbidity it is recommended that elective cesarean sections should not be done before 39-week gestation unless medically indicated. However, elective cesarean sections are still being performed at early term (at 370-386 weeks gestation) without sound medical indications. In this study, we evaluated the indications for elective cesarean sections performed at early term to assess the proportion of procedures that could possibly have been postponed until ≥39 weeks to avoid neonatal respiratory morbidity.Material and methods: Maternal and neonatal information was collected from medical records on all elective cesarean sections performed in singleton pregnancies at ≥370 weeks gestation over a 20-year period in a population with secure ultrasound gestational age assignment. Indications were grouped and uterine scar, breech, or transverse presentation and maternal request classified as nonurgent.Results: There were 3411 elective cesarean sections performed at ≥37-week gestation, of which 790 (23.2%) were at 370-386 weeks. Medical indications were present for 34% (272/790), but 65.6% (518/790) could possibly have been postponed until ≥390 weeks. Of the neonates 5.7% developed respiratory morbidity if delivery was at 370-386 weeks gestation compared to 2.4% at 390-421 weeks gestation (p < .001).Conclusion: Of elective cesarean sections before 39-week gestation two-thirds were done without a clear medical indication, thereby exposing the newborn to an increased risk of respiratory morbidity. Scheduling elective cesarean sections at ≥39-week gestation is important to minimize the risk of neonatal respiratory morbidity, unless a clear medical indication dictates earlier delivery.
    • Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects.

      Fahrner, Jill A; Bjornsson, Hans T; 1 McKusick-Nathans Institute of Genetic Medicine, 21205. 2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 3 Landspitali University Hospital, Reykjavik 101, Iceland. 4 Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland. (Oxford University Press, 2019-11-21)
      he epigenetic machinery in conjunction with the transcriptional machinery is responsible for maintaining genome-wide chromatin states and dynamically regulating gene expression. Mendelian disorders of the epigenetic machinery (MDEMs) are genetic disorders resulting from mutations in components of the epigenetic apparatus. Though individually rare, MDEMs have emerged as a collectively common etiology for intellectual disability (ID) and growth disruption. Studies in model organisms and humans have demonstrated dosage sensitivity of this gene group with haploinsufficiency as a predominant disease mechanism. The epigenetic machinery consists of three enzymatic components (writers, erasers and chromatin remodelers) as well as one non-enzymatic group (readers). A tally of the entire census of such factors revealed that although multiple enzymatic activities never coexist within a single component, individual enzymatic activities often coexist with a reader domain. This group of disorders disrupts both the chromatin and transcription states of target genes downstream of the given component but also DNA methylation on a global scale. Elucidation of these global epigenetic changes may inform our understanding of disease pathogenesis and have diagnostic utility. Moreover, many therapies targeting epigenetic marks already exist, and some have proven successful in treating cancer. This, along with the recent observation that neurological dysfunction in these disorders may in fact be treatable in postnatal life, suggests that the scientific community should prioritize this group as a potentially treatable cause of ID. Here we summarize the recent expansion and major characteristics of MDEMs, as well as the unique therapeutic prospects for this group of disorders.
    • Clinical epigenetics: a primer for the practitioner.

      Aygun, Deniz; Bjornsson, Hans T; 1 School of Arts and Sciences, Tufts University, Medford, MA, USA. 2 McKusick-Nathans Institute of Genetic Medicine, Baltimore, MD, USA. 3 Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA. 4 Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland. 5 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Wiley, 2019-11-20)
      Disruption of epigenetic modifications and the factors that maintain these modifications is rapidly emerging as a cause of developmental disorders. Here we summarize some of the major principles of epigenetics including how epigenetic modifications are: (1) normally reset in the germ line, (2) form an additional layer of interindividual variation, (3) are environmentally sensitive, and (4) change over time in humans. We also briefly discuss the disruption of growth and intellect associated with the Mendelian disorders of the epigenetic machinery and the classical imprinting disorders (such as Beckwith-Wiedemann syndrome, Silver-Russell syndrome, Prader-Willi syndrome, and Angelman syndrome), as well as suggesting some diagnostic considerations for the clinicians taking care of these patients. Finally, we discuss novel therapeutic strategies targeting epigenetic modifications, which may offer a safe alternative to up and coming genome editing strategies for the treatment of genetic diseases. This review provides a starting point for clinicians interested in epigenetics and the role epigenetic disruption plays in human disease.
    • Preterm births in Iceland 1997-2016: Preterm birth rates by gestational age groups and type of preterm birth.

      Grétarsdóttir, Áslaug Salka; Aspelund, Thor; Steingrímsdóttir, Þóra; Bjarnadóttir, Ragnheiður Ingibjörg; Einarsdóttir, Kristjana; 1 Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2 Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 3 Department of Obstetrics and Gynaecology, Landspítali University Hospital, Reykjavík, Iceland. (Wiley, 2019-11-19)
      BACKGROUND: The frequency of preterm births has been increasing globally, mainly due to a rise in iatrogenic late preterm births. The aim of this study was to assess the prevalence of preterm births in Iceland during 1997-2016 by type of preterm birth. METHODS: This study included all live births in Iceland during 1997-2016 identified from the Icelandic Medical Birth Registry. Risk of preterm birth by time period was assessed with Poisson regression models adjusted for demographic variables and indications for iatrogenic births. RESULTS: The study population included 87 076 infants, of which 4986 (5.7%) were preterm. The preterm birth rate increased from 5.3% to 6.1% (adjusted rate ratio [ARR] = 1.16, confidence interval [CI] = 1.07-1.26) between 1997-2001 and 2012-2016 overall. The increase was only evident in multiples (ARR 1.41, 95% CI 1.21-1.65), not singletons (1.07, 0.97-1.19). The rate of late preterm births (34-36 weeks) increased significantly (1.24, 1.14-1.40), and the rate of iatrogenic preterm births more than doubled during this period even after adjustment for identified medical indications (2.40, 2.00-2.88). The rate of spontaneous preterm births decreased during the study period (0.63, 0.55-0.73), and the rate of PPROM increased (1.31, 1.09-1.57). The most common contributing indications for iatrogenic births were fetal distress (26.2%), hypertensive disorders (18.2%), and severe preeclampsia (16.9%). CONCLUSIONS: Preterm birth rates increased in multiples in Iceland between 1997 and 2016, and late and iatrogenic preterm births increased overall. The increase in iatrogenic preterm births remained significant after adjusting for medical indications, suggesting that other factors might be affecting the rise.
    • Prevalence of allergic sensitization to storage mites in Northern Europe.

      Jõgi, Nils Oskar; Kleppe Olsen, Robin; Svanes, Cecilie; Gislason, David; Gislason, Thorarinn; Schlünssen, Vivi; Sigsgaard, Torben; Sundbom, Fredrik; Storaas, Torgeir; Bertelsen, Randi Jacobsen; et al. (Wiley, 2019-11-19)
      BACKGROUND: Allergic sensitization to storage mites has mostly been related to occupational exposures like farming, grain/cattle handling, whereas for non-occupational settings, storage mite sensitization has been attributed to cross-reactivity with house dust mite (HDM) allergens. OBJECTIVE: We aimed to describe the prevalence of allergic sensitization to storage mites, co-sensitization to HDM allergens and respiratory symptoms in Denmark, Iceland, Norway and Sweden. METHODS: The population comprised of 1180 participants born 1945-1972 of the third follow-up of the population-based cohort European Community Respiratory Health Survey (ECRHS) in Aarhus, Bergen, Reykjavik and Uppsala. A clinical examination included skin prick tests (SPT) to Lepidoglyphus destructor, Tyrophagus putrescentiae, Acarus siro and common inhalant allergens, as well as standardized interviews. RESULTS: 8% were sensitized to HDM and 10% to storage mite, with some variation by study centre: Reykjavik 13%, Bergen 8% and Aarhus 7%. In Uppsala, only L destructor (3%) was measured. Storage mite sensitization was higher among men (11%) than women (8%). Among storage mite sensitized, 44% were also sensitized to HDM. Storage mite sensitization was associated with asthma and nasal allergies, but not with age, education, pet keeping or place of upbringing. CONCLUSIONS AND CLINICAL RELEVANCE: In this Northern European population-based study, allergic sensitization to storage mite was as common as HDM sensitization. Storage mite sensitization was, independently of HDM sensitization, associated with respiratory symptoms and asthma. Our findings suggest that storage mite sensitization should be evaluated with regard to inclusion into the common inhalant allergen panel in Northern Europe.
    • Effectiveness of cognitive behavioral therapy (CBT) for child and adolescent anxiety disorders across different CBT modalities and comparisons: a systematic review and meta-analysis.

      Sigurvinsdóttir, Anna Lilja; Jensínudóttir, Kolbrún Björk; Baldvinsdóttir, Karen Dögg; Smárason, Orri; Skarphedinsson, Gudmundur; 1 The Health Care Institution of North Iceland, Akureyri, Iceland. 2 Faculty of Psychology, University of Iceland, Reykjavik, Iceland. 3 Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2019-11-18)
      Aim: Pediatric Anxiety Disorders (AD) are common. Cognitive behavioral therapy (CBT) is one of two first-line treatments of youth AD and it has previously been shown to be superior to wait-list but not placebo therapy. This study consists of a systematic review and meta-analysis of the literature to assess the efficacy of CBT modalities in comparison to control contingencies for pediatric anxiety disorders.Methods: Studies were included if they were randomized controlled trials, and if CBT was manualized or modular, alone or in combination with medication. CBT was required to include behavioral treatment, exposure treatment, or cognitive elements. Eligible studies included participants aged 18 years or younger.Results: Eighty-one studies were included, with 3386 CBT participants and 2527 control participants. The overall results indicated that CBT is an effective treatment for childhood AD. The results showed that individual-based CBT is superior to wait-list and attention control. Group-based CBT is superior to wait-list control and treatment as usual. Remote-based CBT was superior to attention control and wait-list control. Family-based CBT was superior to treatment as usual, wait-list control, and attention control. Selective serotonin reuptake inhibitors were no more effective than individual-based CBT. Combination treatment was, however, more effective than individual-based CBT.Conclusion: To the best of our knowledge, no meta-analysis has thus far disentangled the effects of CBT modalities across various comparisons. This meta-analysis hence provides an important update to the literature on the efficacy of CBT for treating anxiety disorders in young people.
    • A standalone bioreactor system to deliver compressive load under perfusion flow to hBMSC-seeded 3D chitosan-graphene templates.

      Lovecchio, Joseph; Gargiulo, Paolo; Vargas Luna, Jose Luis; Giordano, Emanuele; Sigurjónsson, Ólafur Eysteinn; 1 Institute of Biomedical and Neural Engineering, Reykjavík University, Menntavegur 1, 101, Reykiavík, Iceland. joseph.lovecchio@unibo.it. 2 Laboratory of Cellular and Molecular Engineering "Silvio Cavalcanti" - Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi" (DEI), University of Bologna, Via Cesare Pavese 50, 47522, Cesena, FC, Italy. joseph.lovecchio@unibo.it. 3 Advanced Research Center on Electronic Systems (ARCES), University of Bologna, Via Vincenzo Toffano 2/2, 40125, Bologna, Italy. joseph.lovecchio@unibo.it. 4 Institute of Biomedical and Neural Engineering, Reykjavík University, Menntavegur 1, 101, Reykiavík, Iceland. 5 Department of Science, Reykjavík University, Menntavegur 1, 101, Reykiavík, Iceland. 6 Center of Medical Physics and Biomedical Engineering, Medical University of Vienna, Waehringer Guertel 18-20/4L, 1090, Wien, Austria. 7 Laboratory of Cellular and Molecular Engineering "Silvio Cavalcanti" - Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi" (DEI), University of Bologna, Via Cesare Pavese 50, 47522, Cesena, FC, Italy. 8 Advanced Research Center on Electronic Systems (ARCES), University of Bologna, Via Vincenzo Toffano 2/2, 40125, Bologna, Italy. 9 Health Sciences and Technologies - Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, 40064, Ozzano dell'Emilia, BO, Italy. 10 The Blood Bank, The Landspitali University Hospital, Snorrabraut 60, 105, Reykjavík, Iceland. (Nature Publishing Group, 2019-11-14)
      The availability of engineered biological tissues holds great potential for both clinical applications and basic research in a life science laboratory. A prototype standalone perfusion/compression bioreactor system was proposed to address the osteogenic commitment of stem cells seeded onboard of 3D chitosan-graphene (CHT/G) templates. Testing involved the coordinated administration of a 1 mL/min medium flow rate together with dynamic compression (1% strain at 1 Hz; applied twice daily for 30 min) for one week. When compared to traditional static culture conditions, the application of perfusion and compression stimuli to human bone marrow stem cells using the 3D CHT/G template scaffold induced a sizable effect. After using the dynamic culture protocol, there was evidence of a larger number of viable cells within the inner core of the scaffold and of enhanced extracellular matrix mineralization. These observations show that our novel device would be suitable for addressing and investigating the osteogenic phenotype commitment of stem cells, for both potential clinical applications and basic research.