• Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

      Boer, Cindy G; Hatzikotoulas, Konstantinos; Southam, Lorraine; Stefánsdóttir, Lilja; Zhang, Yanfei; Coutinho de Almeida, Rodrigo; Wu, Tian T; Zheng, Jie; Hartley, April; Teder-Laving, Maris; et al. (Cell Press, 2021-08-26)
      Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
    • Endothelial dysfunction and thromboembolism in children, adolescents, and young adults with acute lymphoblastic leukemia.

      Andrés-Jensen, Liv; Grell, Kathrine; Rank, Cecilie Utke; Albertsen, Birgitte Klug; Tuckuviene, Ruta; Linnemann Nielsen, Rikke; Lynggaard, Line Stensig; Jarvis, Kirsten Brunsvig; Quist-Paulsen, Petter; Trakymiene, Sonata Saulyte; et al. (Nature Publishing Group, 2021-08-13)
      Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P < 0.0001] and OR 1.21 per 100 pg/mL [95% CI 1.02‒1.21, P = 0.005], respectively). These associations remained significant when including only samples drawn >30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P < 0.0001). Among single nucleotide variants located in or neighboring coding genes for the three biomarkers, none were significantly associated with odds of thromboembolism. If results are validated in another cohort, thrombomodulin and VEGFR-1 could serve as predictive biomarkers, identifying patients in need of preemptive antithrombotic prophylaxis.
    • The Future of Sleep Measurements: A Review and Perspective.

      Arnardottir, Erna Sif; Islind, Anna Sigridur; Óskarsdóttir, María; 1Reykjavik University Sleep Institute, School of Technology, Reykjavik University, Menntavegi 1, 102 Reykjavik, Iceland; Internal Medicine Services, Landspitali University Hospital, E7 Fossvogi, 108 Reykjavik, Iceland. Electronic address: ernasifa@ru.is. 2Reykjavik University Sleep Institute, School of Technology, Reykjavik University, Menntavegi 1, 102 Reykjavik, Iceland; Department of Computer Science, Reykjavik University, Menntavegi 1, 102 Reykjavik, Iceland. (Elsevier, 2021-07-06)
      This article provides an overview of the current use, limitations, and future directions of the variety of subjective and objective sleep assessments available. This article argues for various ways and sources of collecting, combining, and using data to enlighten clinical practice and the sleep research of the future. It highlights the prospects of digital management platforms to store and present the data, and the importance of codesign when developing such platforms and other new instruments. It also discusses the abundance of opportunities that data science and machine learning open for the analysis of data. Keywords: Codesign; Data management platform; Data science; Machine learning; Objective data; Sleep diary; Sleep measurement; Subjective data.
    • Clinical management of patients with drug‐induced liver injury (DILI)

      Björnsson, Einar S.; 1 Univ Iceland, Fac Med, Reykjavik, Iceland 2 Natl Univ Hosp Iceland, Dept Internal Med, Div Gastroenterol & Hepatol, Reykjavik, Iceland (Wiley, 2021-06-28)
      Drug-induced liver injury (DILI) should be considered in all patients with recent elevation of liver tests without obvious etiology and normal hepatobiliary imaging. There is currently no biomarker that is helpful in diagnosis which relies on clinical and laboratory findings. Diagnosis is dependent on temporal relationship with a recently started drug or herbal and dietary supplement and elevated liver tests with exclusion of competing etiologies. The implicated agent should be discontinued and the patient should be observed closely. This is particularly important in patients with jaundice who have approximately 10% risk of liver related mortality and/or need for liver transplantation. There is no specific therapy for DILI which is only symptomatic such as for itching. Patients with jaundice and coagulopathy usually require hospitalization.
    • Cesarean birth, obstetric emergencies, and adverse neonatal outcomes in Iceland during a period of increasing labor induction.

      Gunnarsdóttir, Jóhanna; Swift, Emma M; Jakobsdóttir, Jóhanna; Smárason, Alexander; Thorkelsson, Thordur; Einarsdóttir, Kristjana; 1Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Obstetrics and Gynecology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 3Faculty of Nursing - Department of Midwifery, University of Iceland, Reykjavik, Iceland. 4Institution of Health Science Research, University of Akureyri and Akureyri Hospital, Akureyri, Iceland. 5Division of Neonatal Intensive Care, Children's Medical Center, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. (Wiley, 2021-06-16)
      Background: The rate of labor induction has risen steeply throughout the world. This project aimed to estimate changes in the rates of adverse maternal and neonatal outcomes in Iceland between 1997 and 2018, and to assess whether the changes can be explained by an increased rate of labor induction. Methods: Singleton live births, occurring between 1997 and 2018, that did not start by prelabor cesarean, were identified from the Icelandic Medical Birth Register (n = 85 971). Rates of intrapartum cesarean birth (CB), obstetric emergencies, and neonatal outcomes were calculated, and adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) were estimated with log-binomial regression (reference: 1997-2001). Adjustments were made for: (a) maternal characteristics, and (b) labor induction and gestational age. Results: The rate of labor induction increased from 13.6% in the period 1997-2001 to 28.1% in the period 2014-2018. The rate of intrapartum CB decreased between the periods of 1997-2001 and 2014-2018 for both primiparous (aRR 0.76, 95% CI: 0.69 to 0.84) and multiparous women (aRR 0.55, 95% CI: 0.49 to 0.63). The rate of obstetric emergencies and adverse neonatal outcomes also decreased between these time periods. Adjusting for labor induction did not attenuate these associations. Conclusions: The rates of adverse maternal outcomes and adverse neonatal outcomes decreased over the study period. However, there was no evidence that this decrease could be explained by the increased rate of labor induction. Keywords: cesarean; labor induction; neonatal outcome; obstetric emergencies.
    • Factor D Inhibition Blocks Complement Activation Induced by Mutant Factor B Associated With Atypical Hemolytic Uremic Syndrome and Membranoproliferative Glomerulonephritis.

      Aradottir, Sigridur Sunna; Kristoffersson, Ann-Charlotte; Roumenina, Lubka T; Bjerre, Anna; Kashioulis, Pavlos; Palsson, Runolfur; Karpman, Diana; 1Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden. 2Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France. 3Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway. 4Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 5Department of Molecular and Clinical Medicine/Nephrology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 6Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 7Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavík, Iceland. (Frontiers Research Foundation, 2021-06-10)
      Complement factor B (FB) mutant variants are associated with excessive complement activation in kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN). Patients with aHUS are currently treated with eculizumab while there is no specific treatment for other complement-mediated renal diseases. In this study the phenotype of three FB missense variants, detected in patients with aHUS (D371G and E601K) and MPGN (I242L), was investigated. Patient sera with the D371G and I242L mutations induced hemolysis of sheep erythrocytes. Mutagenesis was performed to study the effect of factor D (FD) inhibition on C3 convertase-induced FB cleavage, complement-mediated hemolysis, and the release of soluble C5b-9 from glomerular endothelial cells. The FD inhibitor danicopan abrogated C3 convertase-associated FB cleavage to the Bb fragment in patient serum, and of the FB constructs, D371G, E601K, I242L, the gain-of-function mutation D279G, and the wild-type construct, in FB-depleted serum. Furthermore, the FD-inhibitor blocked hemolysis induced by the D371G and D279G gain-of-function mutants. In FB-depleted serum the D371G and D279G mutants induced release of C5b-9 from glomerular endothelial cells that was reduced by the FD-inhibitor. These results suggest that FD inhibition can effectively block complement overactivation induced by FB gain-of-function mutations. Keywords: C3 glomerulopathy; atypical hemolytic uremic syndrome; complement; danicopan; factor B; factor D.
    • Detailed Multiplex Analysis of SARS-CoV-2 Specific Antibodies in COVID-19 Disease.

      Brynjolfsson, Siggeir F; Sigurgrimsdottir, Hildur; Einarsdottir, Elin D; Bjornsdottir, Gudrun A; Armannsdottir, Brynja; Baldvinsdottir, Gudrun E; Bjarnason, Agnar; Gudlaugsson, Olafur; Gudmundsson, Sveinn; Sigurdardottir, Sigurveig T; et al. (Frontiers Research Foundation, 2021-06-10)
      A detailed understanding of the antibody response against SARS-CoV-2 is of high importance, especially with the emergence of novel vaccines. A multiplex-based assay, analyzing IgG, IgM, and IgA antibodies against the receptor binding domain (RBD), spike 1 (S1), and nucleocapsid proteins of the SARS-CoV-2 virus was set up. The multiplex-based analysis was calibrated against the Elecsys® Anti-SARS-CoV-2 assay on a Roche Cobas® instrument, using positive and negative samples. The calibration of the multiplex based assay yielded a sensitivity of 100% and a specificity of 97.7%. SARS-CoV-2 specific antibody levels were analyzed by multiplex in 251 samples from 221 patients. A significant increase in all antibody types (IgM, IgG, and IgA) against RBD was observed between the first and the third weeks of disease. Additionally, the S1 IgG antibody response increased significantly between weeks 1, 2, and 3 of disease. Class switching appeared to occur earlier for IgA than for IgG. Patients requiring hospital admission and intensive care had higher levels of SARS-CoV-2 specific IgA levels than outpatients. These findings describe the initial antibody response during the first weeks of disease and demonstrate the importance of analyzing different antibody isotypes against multiple antigens and include IgA when examining the immunological response to COVID-19.
    • Prevalence and early-life risk factors of school-age allergic multimorbidity: The EuroPrevall-iFAAM birth cohort.

      Sigurdardottir, Sigurveig T; Jonasson, Kristjan; Clausen, Michael; Lilja Bjornsdottir, Kristin; Sigurdardottir, Sigridur Erla; Roberts, Graham; Grimshaw, Kate; Papadopoulos, Nikolaos G; Xepapadaki, Paraskevi; Fiandor, Ana; et al. (Wiley, 2021-06-08)
      Background: Coexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan-European, population-based birth cohort study have been lacking. This study compares the prevalence and early-life risk factors of these diseases in European primary school children. Methods: In the prospective multicentre observational EuroPrevall-iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC-based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these. Results: From 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family-allergy-score, odds ratio (OR) 1.50 (95% CI 1.32-1.70) per standard deviation; early-life allergy symptoms, OR 2.72 (2.34-3.16) for each symptom; and caesarean birth, OR 1.35 (1.04-1.76). Female gender, OR 0.72 (0.58-0.90); older siblings, OR 0.79 (0.63-0.99); and day care, OR 0.81 (0.63-1.06) were protective factors. Conclusion: Allergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early-life factors are modifiable and may be considered for prevention strategies. Keywords: allergic multimorbidity; allergic rhinitis; asthma; children; eczema.
    • Medication calculation skills of graduating nursing students within European context.

      Elonen, Imane; Salminen, Leena; Brasaitė-Abromė, Indrė; Fuster, Pilar; Kukkonen, Pia; Leino-Kilpi, Helena; Löyttyniemi, Eliisa; Noonan, Brendan; Stubner, Juliane; Svavarsdóttir, Margrét H; et al. (Wiley, 2021-06-08)
      Aim: The aim of this study is to evaluate the medication calculation skills of graduating nursing students in six European countries and analyse the associated factors. Background: Medication calculation skills are fundamental to medication safety, which is a substantial part of patient safety. Previous studies have raised concerns about the medication calculation skills of nurses and nursing students. Design: As part of a broader research project, this study applies a multinational cross-sectional survey design with three populations: graduating nursing students, nurse managers and patients. Methods: The students performed two calculations (tablet and fluid) testing medication calculation skills requiring different levels of conceptual understanding and arithmetic. The managers and patients answered one question about the students' medication kills. In total, 1,796 students, 538 managers and 1,327 patients participated the study. The data were analysed statistically. The STROBE guideline for cross-sectional studies was applied. Results: Almost all (99%) of the students performed the tablet calculation correctly, and the majority (71%) answered the fluid calculation correctly. Older age, a previous degree in health care and satisfaction with their current degree programme was positively associated with correct fluid calculations. The patients evaluated the students' medication skills higher than the nurse managers did and the evaluations were not systematically aligned with the calculation skills tested. Conclusions: Nursing students have the skills to perform simple medication calculations, but a significant number of students have difficulties with calculations involving multiple operations and a higher level of conceptual understanding. Due to the variation in students' medication calculation skills and the unalignment between the managers' and patients' evaluations and the calculation tests, further research is needed. Relevance to clinical practice: Graduating nursing students enter clinical field as qualified professionals, but there is still room for improvement in their medication calculation skills. This calls for attention in the fields of clinical nursing, education and research. Keywords: drug dosage calculations; graduating nursing students; medication calculation skills; nurse managers; patients.
    • Effect of replacing ambulance physicians with paramedics on outcome of resuscitation for prehospital cardiac arrest.

      Bjornsson, Hjalti Mar; Bjornsdottir, Gudrun G; Olafsdottir, Hronn; Mogensen, Brynjolfur Arni; Mogensen, Brynjolfur; Thorgeirsson, Gestur; 1Department of Emergency Medicine, Faculty of Medicine, University of Iceland, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 2Department of Aneaesthesia, Glasgow Royal Infirmary, Scotland, UK. 3Department of Orthopedic Surgery, Drammen Hospital, Norway. 4Department of Cardiology. 5Faculty of Medicine, University of Iceland, Research Institute in Emergency Medicine. 6Department of Cardiology, Landspitali-The National University Hospital of Iceland. Reykjavik, Iceland. (Lippincott Williams & Wilkins, 2021-06)
      Introduction: Limited evidence suggests that the presence of a prehospital physician improves survival from cardiac arrest. A retrospective study is undertaken to examine this question. In Reykjavik, Iceland, prehospital physicians on ambulances were replaced by emergency medical technicians (EMTs) in 2007. The aim of this study is to compare the outcome of prehospital resuscitation from cardiac arrest during periods of time with and without prehospital physician involvement. Methods: All cardiac arrests that underwent prehospital resuscitation by emergency medical systems between 2004 and 2014 were included. The primary outcome was survival to hospital discharge, and the secondary outcome was return of spontaneous circulation (ROSC). Subgroup analyses were performed according to the type of cardiac arrest. Results: A total of 471 cardiac arrests were included for analysis, 200 treated by prehospital physicians from 2004 to 2007 and 271 treated by EMTs from 2008 to 2014. The overall rate of survival to hospital discharge and ROSC was 23 and 50% during the study period. No significant difference was observed in the rate of survival to hospital discharge [25 vs 22%, difference 3% (95% confidence interval (CI): 11-5%)] or ROSC [53 vs 47%, difference -6% (95% CI: 15-3%)] between these two time periods. In the subgroup of patients with pulseless electrical activity, survival to hospital discharge did not differ between the two periods, but the rate of ROSC was higher in the 'physician period' [50 vs 30%, difference -20% (95% CI: -40 to -1%)]. Conclusions: The presence of a prehospital physician on the ambulance was not found to result in a significant improvement in survival or ROSC after cardiac arrest compared to care by EMTs. Patients with pulseless electrical activity experienced an increase in ROSC when a physician was present but without improvement in survival to hospital discharge.
    • Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.

      Brueggemann, Angela B; Jansen van Rensburg, Melissa J; Shaw, David; McCarthy, Noel D; Jolley, Keith A; Maiden, Martin C J; van der Linden, Mark P G; Amin-Chowdhury, Zahin; Bennett, Désirée E; Borrow, Ray; et al. (Elsevier, 2021-06)
      Background Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. Methods In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. Findings 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0.32 [95% CI 0.27-0.37]) and 82% at 8 weeks (0.18 [0.14-0.23]) following the week in which significant changes in population movements were recorded. Interpretation The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide.
    • Molecular Epidemiology and Evolutionary Trajectory of Emerging Echovirus 30, Europe.

      Benschop, Kimberley S M; Broberg, Eeva K; Hodcroft, Emma; Schmitz, Dennis; Albert, Jan; Baicus, Anda; Bailly, Jean-Luc; Baldvinsdottir, Gudrun; Berginc, Natasa; Blomqvist, Soile; et al. (Centers for Disease Control and Prevention (CDC), 2021-06)
      In 2018, an upsurge in echovirus 30 (E30) infections was reported in Europe. We conducted a large-scale epidemiologic and evolutionary study of 1,329 E30 strains collected in 22 countries in Europe during 2016-2018. Most E30 cases affected persons 0-4 years of age (29%) and 25-34 years of age (27%). Sequences were divided into 6 genetic clades (G1-G6). Most (53%) sequences belonged to G1, followed by G6 (23%), G2 (17%), G4 (4%), G3 (0.3%), and G5 (0.2%). Each clade encompassed unique individual recombinant forms; G1 and G4 displayed >2 unique recombinant forms. Rapid turnover of new clades and recombinant forms occurred over time. Clades G1 and G6 dominated in 2018, suggesting the E30 upsurge was caused by emergence of 2 distinct clades circulating in Europe. Investigation into the mechanisms behind the rapid turnover of E30 is crucial for clarifying the epidemiology and evolution of these enterovirus infections.
    • Reliability and Validity of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Portuguese Version.

      Marques, Cristiana Campos; Matos, Ana Paula; do Céu Salvador, Maria; Arnarson, Eiríkur Örn; Craighead, W Edward; 1Center for Research in Neuropsychology and Cognitive Behavioural Intervention (CINEICC), Faculty of Psychology and Educational Sciences, University of Coimbra, Rua do Colégio Novo, 3000-115, Coimbra, Portugal. cristiana.marques@uc.pt. 2Center for Research in Neuropsychology and Cognitive Behavioural Intervention (CINEICC), Faculty of Psychology and Educational Sciences, University of Coimbra, Rua do Colégio Novo, 3000-115, Coimbra, Portugal. 3School of Health Sciences, Faculty of Medicine, University of Iceland, Landspítali -University Hospital, 101, Reykjavik, Iceland. 4Department of Psychiatry and Behavioral Sciences, Department of Psychology, Emory University, Atlanta, GA, USA. (Springer, 2021-05-28)
      This study examined the test-retest reliability, consensual, convergent and divergent validities, sensitivity, specificity, positive and negative predictive values, and accuracy of the Portuguese version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). Eighty-nine children/adolescents (65 psychiatric outpatients and 24 healthy controls) were interviewed with K-SADS-PL and completed measures of depressive and anxiety symptoms. The child's parent/caretaker completed the Child Behavior Checklist. Good to excellent values were obtained for test-retest reliability and consensual validity. For the convergent validity, moderate correlations between the K-SADS-PL and the corresponding self-report measures were observed. Divergent validity was acceptable for the K-SADS-PL diagnoses. The lowest values of sensitivity, specificity, and accuracy of the K-SADS-PL were 88, 88, and 91, respectively. The Portuguese version of K-SADS-PL proved to be a valid and reliable assessment instrument for children and adolescents, and was sensitive, specific and accurate when diagnosing mood, anxiety, adjustment, and attention-deficit/hyperactivity disorders. Keywords: Children/adolescents; K-SADS-PL; Portuguese version; Reliability; Validity.
    • Detection mode of childhood acute lymphoblastic leukaemia relapse and its effect on survival: a Nordic population-based cohort study.

      Jensen, Karen S; Oskarsson, Trausti; Lähteenmäki, Päivi M; Flaegstad, Trond; Schmiegelow, Kjeld; Vedsted, Peter; Albertsen, Birgitte K; Schrøder, Henrik; 1Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark. 2Department of Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden. 3Childhood Cancer Research Unit, Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden. 4Children's Hospital, Landspitali University Hospital, Reykjavik, Iceland. 5Department of Paediatric and Adolescent Haematology/Oncology, Turku University Hospital, FICAN-West, Turku University, Turku, Finland. 6Department of Paediatrics, University of Tromsø and University Hospital of North Norway, Tromsø, Norway. 7Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark. 8Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 9Research Unit for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark. (Wiley, 2021-05-27)
      Relapse constitutes the greatest threat to event-free survival after completion of treatment for childhood acute lymphoblastic leukaemia (ALL). However, evidence on optimal follow-up schedules is limited. The aims of the present population-based cohort study were to assess the value of current follow-up schedules after completion of Nordic Society of Paediatric Haematology and Oncology ALL protocol treatment and to estimate the impact of relapse detection mode on overall survival (OS). Among 3262 patients diagnosed between 1992 and 2014 and who completed treatment, 338 developed a relapse. Relapse detection was equally distributed between extra visits (50·8%) and scheduled follow-up visits (49·2%). All cases detected at an extra visit and 64·3% of cases detected at a scheduled visit presented with symptoms or objective findings. Neither the mode of detection {adjusted hazard ratio 0·95, [95% confidence interval (CI) 0·61-1·48] for scheduled visits} nor the duration of symptoms was an independent risk factor for OS after relapse. The estimated number of scheduled blood samples needed to diagnose one subclinical relapse during the first 5 years after treatment cessation was 1269 (95% CI 902-1637). In conclusion, based on OS data, scheduled visits after cessation of therapy seem to yield no extra benefit. These results should frame future follow-up strategies. Keywords: acute lymphoblastic leukaemia; cancer survivors; childhood leukaemia; recurrence; surveillance.
    • Validation of the Hospital Frailty Risk Score in older surgical patients: A population-based retrospective cohort study.

      Gunnarsdottir, Gudrun M; Helgadottir, Solveig; Einarsson, Sveinn G; Hreinsson, Kari; Whittle, John; Karason, Sigurbergur; Sigurdsson, Martin I; 1Division of Anaesthesia and Intensive Care Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, Uppsala University, Uppsala, Sweden. 4Centre for Perioperative Medicine, Division of Surgery and Interventional Science, University College London, London, UK. (Wiley, 2021-05-18)
      Background: There is a need for standardized and cost-effective identification of frailty risk. The objective was to validate the Hospital Frailty Risk Score which utilizes International Classification Diagnoses in a cohort of older surgical patients, assess the score as an independent risk factor for adverse outcomes and compare discrimination properties of the frailty risk score with other risk stratification scores. Methods: Data were analysed from all patients ≥65 years undergoing primary surgical procedures from 2006-2018. Patients were categorized based on the frailty risk score. The primary outcomes were 30-day mortality and 180-day risk of readmission. Results: Of 16 793 patients evaluated, 7480 (45%), 7605 (45%) and 1708 (10%) had a low, intermediate and high risk of frailty. There was a higher incidence of 30-day mortality for individuals with intermediate (2.9%) and high (8.3%) compared with low (1.4%) risk of frailty (P < .001 for both comparisons). Similarly, the hazard of readmission within the first 180 days was higher for intermediate (HR 1.25; 95% CI: 1.16-1.34) and high (HR 1.84; 95% CI: 1.66-2.03) compared with low (HR 1.00, P < .001 for both comparisons) risk of frailty. The hazard of long-term mortality was higher for intermediate (HR 1.70; 95% CI: 1.61-1.80) and high (HR 4.16; 95% CI: 3.84-4.49) compared with low (HR 1.00, P < .001 for both comparisons) risk of frailty. Finally, long length of primary hospitalization occurred for 9.3%, 15.0% and 27.3% of individuals with low, intermediate and high frailty risk (P < .001 for all comparisons). A model including age and ASA classification had the best discrimination for 30-day mortality (AUC 0.862; 95% CI: 0.847-0.877). Conclusion: Our findings suggest that the Hospital Frailty Risk Score might be used to screen older surgical patients for risk of frailty. While only slightly improving prediction of 30-day mortality using the ASA classification, the Hospital Frailty Risk Score can be used to independently classify older patients for the risk of important outcomes using pre-existing readily available electronic data.
    • Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.

      Rögnvaldsson, Sæmundur; Love, Thorvardur Jon; Thorsteinsdottir, Sigrun; Reed, Elín Ruth; Óskarsson, Jón Þórir; Pétursdóttir, Íris; Sigurðardóttir, Guðrún Ásta; Viðarsson, Brynjar; Önundarson, Páll Torfi; Agnarsson, Bjarni A; et al. (Nature Publishing Group, 2021-05-17)
      Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.
    • Paracetamol poisoning: a population-based study from Iceland.

      Friðriksdóttir, Þorbjörg Andrea; Jónsdóttir, Freyja; Snook, Curtis P; Líndal, Helena; Björnsson, Einar S; 1Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland. 2Hospital Pharmacy, Landspítali University Hospital, Reykjavik, Iceland. 3Emergency Department, Landspítali University Hospital, Reykjavik, Iceland. 4Poison Information Centre, Landspítali University Hospital, Reykjavik, Iceland. 5Division of Gastroenterology and Hepatology of the Landspítali, University Hospital, Reykjavik, Iceland. 6Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2021-05-11)
      Objective: To examine the incidence and severity of paracetamol poisoning in a population-based cohort in Iceland. A previous study showed a decrease in the incidence during a financial crisis in Iceland, by approximately half (16/100,000 annually). The aims of the study were to assess the incidence and nature of paracetamol poisoning after economic recovery in Iceland and to compare intentional and accidental poisoning. Methods: Paracetamol serum concentrations were used to identify patients in this retrospective study from 2010-2017. A search was undertaken in laboratory databases for patients with serum paracetamol concentrations, which were grouped by <66 µmol/L (below detection limit) and ≥66 µmol/L. Medical records were reviewed and relevant laboratory and clinical information obtained to determine whether paracetamol poisoning had occurred. Results: Altogether 542 cases of paracetamol poisoning were identified. The mean annual incidence was 27/100,000 (range 22-33). Intentional poisoning was observed in 437/542 (81%) cases, most frequently among females 16-25 years of age. Males ≥65 years were more likely to overdose by accident, which was associated with worse outcomes. Twenty-five (4.6%) patients developed severe paracetamol-induced liver injury and coagulopathy. Overall, six (1.1%) cases were fatal in which paracetamol contributed to the cause of death, with accidental poisoning found in 67% (4/6). Conclusions: The incidence of paracetamol poisoning has increased in recent years associated with economic recovery in Iceland. Most patients had favourable outcomes. Intentional overdose was most common in young females, whereas accidental overdose was more common in older males and more frequently associated with a fatal outcome. Keywords: Accidental; acute liver failure; epidemiology; incidence; intentional; liver injury; overdose; paracetamol (acetaminophen); poisoning.
    • Antibiotic resistance among major pathogens compared to hospital treatment guidelines and antibiotic use in Nordic hospitals 2010-2018.

      Möller, Vidar; Östholm-Balkhed, Åse; Berild, Dag; Fredriksson, Mats; Gottfredsson, Magnus; Holmbom, Martin; Järvinen, Asko; Kristjansson, Mar; Rydell, Ulf; Sönksen, Ute Wolff; et al. (Taylor & Francis, 2021-05-10)
      Antibiotic resistance levels among Escherichia coli and Klebsiella pneumoniae were similar in all Nordic countries in 2018 and low compared to the European mean. Guidelines for acute pyelonephritis varied; 2nd generation cephalosporin (Finland), 3rd generation cephalosporins (Sweden, Norway), ampicillin with an aminoglycoside or aminoglycoside monotherapy (Denmark, Iceland and Norway). Corresponding guidelines for sepsis of unknown origin were 2nd (Finland) or 3rd (Sweden, Norway, Iceland) generation cephalosporins, carbapenems, (Sweden) combinations of penicillin with an aminoglycoside (Norway, Denmark), or piperacillin-tazobactam (all Nordic countries). Methicillin-resistant Staphylococcus aureus rates were 0-2% and empirical treatment with anti-MRSA antibiotics was not recommended in any country. Rates of penicillin non-susceptibility among Streptococcus pneumoniae were low (<10%) except in Finland and Iceland (<15%), but benzylpenicillin was recommended for community-acquired pneumonia in all countries.
    • Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits.

      Beyter, Doruk; Ingimundardottir, Helga; Oddsson, Asmundur; Eggertsson, Hannes P; Bjornsson, Eythor; Jonsson, Hakon; Atlason, Bjarni A; Kristmundsdottir, Snaedis; Mehringer, Svenja; Hardarson, Marteinn T; et al. (Nature Pub. Co, 2021-05-10)
      Long-read sequencing (LRS) promises to improve the characterization of structural variants (SVs). We generated LRS data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions). We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association of a rare deletion in PCSK9 with lower low-density lipoprotein (LDL) cholesterol levels, compared to the population average. We also discovered an association of a multiallelic SV in ACAN with height; we found 11 alleles that differed in the number of a 57-bp-motif repeat and observed a linear relationship between the number of repeats carried and height. These results show that SVs can be accurately characterized at the population scale using LRS data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.
    • Molecular genetics of inherited retinal degenerations in Icelandic patients.

      Thorsteinsson, Daniel A; Stefansdottir, Vigdis; Eysteinsson, Thor; Thorisdottir, Sigridur; Jonsson, Jon J; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Genetics and Molecular Medicine, Landspitali - National University Hospital of Iceland, Reykjavik, Iceland. 3Department of Physiology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 4Department of Ophthalmology, Landspitali - National University Hospital of Iceland, Reykjavik, Iceland. 5Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Wiley, 2021-05-07)
      The study objective was to delineate the genetics of inherited retinal degenerations (IRDs) in Iceland, a small nation of 364.000 and a genetic isolate. Benefits include delineating novel pathogenic genetic variants and defining genetically homogenous patients as potential investigative molecular therapy candidates. The study sample comprised patients with IRD in Iceland ascertained through national centralized genetic and ophthalmological services at Landspitali, a national social support institute, and the Icelandic patient association. Information on patients' disease, syndrome, and genetic testing was collected in a clinical registry. Variants were reevaluated according to ACMG/AMP guidelines. Overall, 140 IRD patients were identified (point prevalence of 1/2.600), of which 70 patients had a genetic evaluation where two-thirds had an identified genetic cause. Thirteen disease genes were found in patients with retinitis pigmentosa, with the RLBP1 gene most common (n = 4). The c.1073 + 5G > A variant in the PRPF31 gene was homozygous in two RP patients. All tested patients with X-linked retinoschisis (XLRS) had the same possibly unique RS1 pathogenic variant, c.441G > A (p.Trp147X). Pathologic variants and genes for IRDs in Iceland did not resemble those described in ancestral North-Western European nations. Four variants were reclassified as likely pathogenic. One novel pathogenic variant defined a genetically homogenous XLRS patient group. Keywords: Iceland; eye diseases; genetics; hereditary; human genetics; population; retinitis pigmentosa.