Recent Submissions

  • Accelerated decline in quadriceps area and Timed Up and Go test performance are associated with hip fracture risk in older adults with impaired kidney function.

    Marques, Elisa A; Elbejjani, Martine; Viana, João L; Gudnason, Vilmundur; Sigurdsson, Gunnar; Lang, Thomas; Sigurdsson, Sigurdur; Aspelund, Thor; Siggeirsdottir, Kristin; Launer, Lenore; et al. (Elsevier, 2021-03-16)
    Objective: This study aimed to examine whether an accelerated decline in quadriceps cross-sectional area (CSA), attenuation (a surrogate of quality), and strength, as well as lower limb muscular function, are associated with hip fractures in older adults with impaired kidney function. Design: Prospective population-based study. Setting: Community-dwelling old population in Reykjavik, Iceland. Subjects: A total of 875 older adults (mean baseline age 76 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study with impaired kidney function. Methods: Quadriceps CSA and density were determined using computed tomography (CT), knee extension strength was measured with an isometric dynamometer chair, and muscular function was assessed using the Timed Up and Go (TUG) test. All muscle-related measurements were assessed twice over a mean follow-up of 5.2 years. Data on hip fracture incidence was obtained from medical records during a maximum of 8.4 years of follow-up time. Results: Fully adjusted cox-proportional hazard regression models showed that a faster decline in quadriceps CSA and TUG test performance were significantly associated with increased hip fracture risk (HR = 1.55, 95% CI = 1.02-2.36, and HR = 1.80, 95% CI = 1.19-2.72, respectively). A faster decrease in quadriceps density and isometric knee extension strength were not associated with fracture risk. Conclusions: Accelerated decline in CT-derived quadriceps CSA and muscular function, as measured by the TUG test's performance, are predictive of hip fracture risk in older adults with impaired kidney function. TUG test is a simple measure and easily included in routine medical examinations, compared to CT scans, which seems to be useful for identifying a subgroup of individuals with high risk of fracture. Keywords: Chronic kidney disease; Computed tomography; Estimated glomerular filtration rate; Fracture; Muscular function.
  • Computed tomography-based skeletal muscle and adipose tissue attenuation: Variations by age, sex, and muscle.

    Figueiredo, Pedro; Marques, Elisa A; Gudnason, Vilmundur; Lang, Thomas; Sigurdsson, Sigurdur; Jonsson, Palmi V; Aspelund, Thor; Siggeirsdottir, Kristin; Launer, Lenore; Eiriksdottir, Gudny; et al. (Elsevier, 2021-03-10)
    Objective: This study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age. Design: Population-based cross-sectional study. Setting: Community-dwelling old population in Reykjavik, Iceland. Subjects: A total of 5331 older adults (42.8% women), aged 66-96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied. Methods: Muscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable. Results: Muscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle. Conclusions: Our data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles. Keywords: Computed tomography; Fat; Thigh muscles; Tissue density; Trunk muscles.
  • 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.
  • 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.
  • 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.
  • The Impact of Histological Subtype on the Incidence, Timing, and Patterns of Recurrence in Patients with Renal Cell Carcinoma After Surgery-Results from RECUR Consortium.

    Abu-Ghanem, Yasmin; Powles, Thomas; Capitanio, Umberto; Beisland, Christian; Järvinen, Petrus; Stewart, Grant D; Gudmundsson, Eiríkur Orri; Lam, Thomas B; Marconi, Lorenzo; Fernandéz-Pello, Sergio; et al. (Elsevier, 2020-10-24)
    Background: Current follow-up strategies for patients with renal cell carcinoma (RCC) after curative surgery rely mainly on risk models and the treatment delivered, regardless of the histological subtype. Objective: To determine the impact of RCC histological subtype on recurrence and to examine the incidence, pattern, and timing of recurrences to improve follow-up recommendations. Design, setting, and participants: This study included consecutive patients treated surgically with curative intention (ie, radical and partial nephrectomy) for nonmetastatic RCC (cT1-4, M0) between January 2006 and December 2011 across 15 centres from 10 countries, as part of the euRopEan association of urology renal cell carcinoma guidelines panel Collaborative multicenter consortium for the studies of follow-Up and recurrence patterns in Radically treated renal cell carcinoma patients (RECUR) database project. Outcome measurements and statistical analysis: The impact of histological subtype (ie, clear cell RCC [ccRCC], papillary RCC [pRCC], and chromophobe RCC [chRCC]) on recurrence-free survival (RFS) was assessed via univariate and multivariate analyses, adjusting for potential interactions with important variables (stage, grade, risk score, etc.) Patterns of recurrence for all histological subtypes were compared according to recurrence site and risk criteria. Results and limitations: Of the 3331 patients, 62.2% underwent radical nephrectomy and 37.8% partial nephrectomy. A total of 2565 patients (77.0%) had ccRCC, 535 (16.1%) had pRCC, and 231 (6.9%) had chRCC. The median postoperative follow-up period was 61.7 (interquartile range: 47-83) mo. Patients with ccRCC had significantly poorer 5-yr RFS than patients with pRCC and chRCC (78% vs 86% vs 91%, p = 0.001). The most common sites of recurrence for ccRCC were the lung and bone. Intermediate-/high-risk pRCC patients had an increased rate of lymphatic recurrence, both mediastinal and retroperitoneal, while recurrence in chRCC was rare (8.2%), associated with higher stage and positive margins, and predominantly in the liver and bone. Limitations include the retrospective nature of the study. Conclusions: The main histological subtypes of RCC exhibit a distinct pattern and dynamics of recurrence. Results suggest that intermediate- to high-risk pRCC may benefit from cross-sectional abdominal imaging every 6 mo until 2 yr after surgery, while routine imaging might be abandoned for chRCC except for abdominal computed tomography in patients with advanced tumour stage or positive margins. Patient summary: In this analysis of a large database from 15 countries around Europe, we found that the main histological subtypes of renal cell carcinoma have a distinct pattern and dynamics of recurrence. Patients should be followed differently according to subtype and risk score. Keywords: Chromophobe; Clear cell; Follow-up; Papillary; RECUR database; Recurrence-free survival; Renal cell carcinoma.
  • A nationwide population-based prospective study of cirrhosis in Iceland.

    Olafsson, Sigurdur; Rögnvaldsson, Sigurjon; Bergmann, Ottar M; Jonasson, Jon G; Benitez Hernandez, Ubaldo; Björnsson, Einar S; 1Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali-National University Hospital of Iceland, Reykjavik, Iceland. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3Department of Surgery, Landspitali-National University Hospital of Iceland, Reykjavik, Iceland. 4Department of Pathology, Landspitali-National University Hospital of Iceland, Reykjavik, Iceland. 5Department of Science/Biostatistics, Landspitali-National University Hospital of Iceland, Reykjavik, Iceland. (Elsevier, 2021-03-31)
    Background & aims: The incidence of cirrhosis in Iceland has been the lowest in the world with only 3 cases per 100,000 inhabitants. Alcohol consumption has almost doubled in Iceland from 1980 to 2016. Obesity has also risen and hepatitis C virus has spread among people who inject drugs in Iceland. The aim of this study was to evaluate the effects of these risk factors on the incidence and aetiology of cirrhosis in Iceland. Methods: The study included all patients diagnosed with cirrhosis for the first time during 2010-2015. Diagnosis was based on liver histology or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, and/or elevated INR. Results: Overall, 157 patients were diagnosed, 105 (67%) males, mean age 61 years. The overall incidence was 9.7 cases per 100,000 inhabitants annually. Alcohol was the only underlying cause in 48/157 (31%), non-alcoholic fatty liver disease (NAFLD) in 34/157(22%), and alcohol and hepatitis C together in 23/157(15%) were the most common causes. Only 6% of patients had an unknown cause of cirrhosis. Upon diagnosis, the median model for end-stage liver disease score was 11 (IQR 8-15), 53% were of Child-Pugh class A whereas 61 (39%) had ascites, 11% encephalopathy, and 8% variceal bleeding. In all, 25% of deaths were from HCC and 25% from liver failure. Conclusion: A major increase in incidence of cirrhosis has occurred in Iceland associated with increases in alcohol consumption, obesity, and hepatitis C. In a high proportion NAFLD was the aetiology and very few had unknown cause of cirrhosis. The highest death rate was from HCC. Lay summary: In a nationwide population-based study from Iceland, including all patients diagnosed with cirrhosis of the liver over a period of 5 years, we found the incidence of new cases had increased 3-fold compared with a previous study 20 years ago. The increase is attributable to increased alcohol consumption, an epidemic of diabetes and obesity, and infection with the hepatitis C virus. Furthermore, we found that with thorough investigations, a specific cause for cirrhosis could be found in 94% of patients. Patients with cirrhosis frequently die of liver cancer and other complications related to their liver disease. Keywords: AIH, autoimmune hepatitis; ALD, alcoholic liver disease; Aetiology of cirrhosis; Alcohol; CIF, cumulative incidence function; CRR, competing-risks regression; Cirrhosis; HCC, hepatocellular carcinoma; Hepatitis C; Incidence of cirrhosis; MELD, model for end-stage liver disease; NAFLD; NAFLD, non-alcoholic fatty liver disease; NALD, non-alcoholic liver disease; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SHRs, subhazard ratios.
  • 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.
  • 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. 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.
  • Genetic insight into sick sinus syndrome.

    Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Aegisdottir, Hildur M; Benonisdottir, Stefania; Stefansdottir, Lilja; Ivarsdottir, Erna V; Halldorsson, Gisli H; Sigurdsson, Jon K; Torp-Pedersen, Christian; Weeke, Peter E; et al. (Oxford University Press, 2021-05)
    Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS. Keywords: KRT8; Atrial fibrillation; GWAS; Mendelian randomization; Sick sinus syndrome.
  • 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.
  • 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.
  • COVID-19 in pregnancy-characteristics and outcomes of pregnant women admitted to hospital because of SARS-CoV-2 infection in the Nordic countries.

    Engjom, Hilde; Aabakke, Anna J M; Klungsøyr, Kari; Svanvik, Teresia; Äyräs, Outi; Jonasdottir, Eva; Thurn, Lars; Jones, Elin; Pettersson, Karin; Nyfløt, Lill T; et al. (Wiley, 2021-05-07)
    Introduction: Population-based studies about the consequences of SARS-CoV-2 infection (COVID-19) in pregnancy are few and have limited generalizability to the Nordic population and healthcare systems. Material and methods: This study examines pregnant women with COVID-19 in the five Nordic countries. Pregnant women were included if they were admitted to hospital between 1 March and 30 June 2020 and had a positive SARS-CoV-2 PCR test ≤14 days prior to admission. Cause of admission was classified as obstetric or COVID-19-related. Results: In the study areas, 214 pregnant women with a positive test were admitted to hospital, of which 56 women required hospital care due to COVID-19. The risk of admission due to COVID-19 was 0.4/1000 deliveries in Denmark, Finland and Norway, and 3.8/1000 deliveries in the Swedish regions. Women hospitalized because of COVID-19 were more frequently obese (p < 0.001) and had a migrant background (p < 0.001) compared with the total population of women who delivered in 2018. Twelve women (21.4%) needed intensive care. Among the 56 women admitted due to COVID-19, 48 women delivered 51 infants. Preterm delivery (n = 12, 25%, p < 0.001) and cesarean delivery (n = 21, 43.8%, p < 0.001) were more frequent in women with COVID-19 compared with women who delivered in 2018. No maternal deaths, stillbirths or neonatal deaths were reported. Conclusions: The risk of admission due to COVID-19 disease in pregnancy was low in the Nordic countries. A fifth of the women required intensive care and we observed higher rates of preterm and cesarean deliveries. National public health policies appear to have had an impact on the risk of admission due to severe COVID-19 disease in pregnancy. Nordic collaboration is important in collecting robust data and assessing rare outcomes. Keywords: COVID-19; cohort studies; obstetric delivery; pregnancy; pregnancy complications; pregnancy outcome; prospective studies; severe acute respiratory syndrome coronavirus 2.
  • Heart rate variability during wakefulness as a marker of obstructive sleep apnea severity.

    Qin, Hua; Keenan, Brendan T; Mazzotti, Diego R; Vaquerizo-Villar, Fernando; Kraemer, Jan F; Wessel, Niels; Tufik, Sergio; Bittencourt, Lia; Cistulli, Peter A; de Chazal, Philip; et al. (Oxford University Press, 2021-05)
    Study objectives: Patients with obstructive sleep apnea (OSA) exhibit heterogeneous heart rate variability (HRV) during wakefulness and sleep. We investigated the influence of OSA severity on HRV parameters during wakefulness in a large international clinical sample. Methods: 1247 subjects (426 without OSA and 821 patients with OSA) were enrolled from the Sleep Apnea Global Interdisciplinary Consortium. HRV parameters were calculated during a 5-minute wakefulness period with spontaneous breathing prior to the sleep study, using time-domain, frequency-domain and nonlinear methods. Differences in HRV were evaluated among groups using analysis of covariance, controlling for relevant covariates. Results: Patients with OSA showed significantly lower time-domain variations and less complexity of heartbeats compared to individuals without OSA. Those with severe OSA had remarkably reduced HRV compared to all other groups. Compared to non-OSA patients, those with severe OSA had lower HRV based on SDNN (adjusted mean: 37.4 vs. 46.2 ms; p < 0.0001), RMSSD (21.5 vs. 27.9 ms; p < 0.0001), ShanEn (1.83 vs. 2.01; p < 0.0001), and Forbword (36.7 vs. 33.0; p = 0.0001). While no differences were found in frequency-domain measures overall, among obese patients there was a shift to sympathetic dominance in severe OSA, with a higher LF/HF ratio compared to obese non-OSA patients (4.2 vs. 2.7; p = 0.009). Conclusions: Time-domain and nonlinear HRV measures during wakefulness are associated with OSA severity, with severe patients having remarkably reduced and less complex HRV. Frequency-domain measures show a shift to sympathetic dominance only in obese OSA patients. Thus, HRV during wakefulness could provide additional information about cardiovascular physiology in OSA patients. Clinical trial information: A Prospective Observational Cohort to Study the Genetics of Obstructive Sleep Apnea and Associated Co-Morbidities (German Clinical Trials Register - DKRS, DRKS00003966) Keywords: autonomic nervous activity; frequency domain analysis; heart rate variability; nonlinear dynamic analysis; obstructive sleep apnea; time domain analysis; wakefulness.
  • When does fetal head rotation occur in spontaneous labor at term: results of an ultrasound-based longitudinal study in nulliparous women.

    Hjartardóttir, Hulda; Lund, Sigrún H; Benediktsdóttir, Sigurlaug; Geirsson, Reynir T; Eggebø, Torbjørn M; 1Department of Obstetrics and Gynecology, Landspitali - The National University Hospital of Iceland, Reykjavík, Iceland; Faculty of Medicine, University of Iceland, Reykjavík, Iceland. Electronic address: 2deCODE genetics, Reykjavík, Iceland. 3Department of Obstetrics and Gynecology, Landspitali - The National University Hospital of Iceland, Reykjavík, Iceland; Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 4National Center for Fetal Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Obstetrics and Gynecology, Stavanger University Hospital, Stavanger, Norway; Institute of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. (Elsevier, 2020-11-15)
    Background: Improved information about the evolution of fetal head rotation during labor is required. Ultrasound methods have the potential to provide reliable new knowledge about fetal head position. Objective: The aim of the study was to describe fetal head rotation in women in spontaneous labor at term using ultrasound longitudinally throughout the active phase. Study design: This was a single center, prospective cohort study at Landspitali - The National University Hospital of Iceland, Reykjavík, Iceland, from January 2016 to April 2018. Nulliparous women with a single fetus in cephalic presentation and spontaneous labor onset at ≥37 weeks' gestation were eligible. Inclusion occurred when the active phase could be clinically established by labor ward staff. Cervical dilatation was clinically examined. Fetal head position and subsequent rotation were determined using both transabdominal and transperineal ultrasound. Occiput positions were marked on a clockface graph with 24 half-hour divisions and categorized into occiput anterior (≥10- and ≤2-o'clock positions), left occiput transverse (>2- and <4-o'clock positions), occiput posterior (≥4- and ≤8 o'clock positions), and right occiput transverse positions (>8- and <10-o'clock positions). Head descent was measured with ultrasound as head-perineum distance and angle of progression. Clinical vaginal and ultrasound examinations were performed by separate examiners not revealing the results to each other. Results: We followed the fetal head rotation relative to the initial position in the pelvis in 99 women, of whom 75 delivered spontaneously, 16 with instrumental assistance, and 8 needed cesarean delivery. At inclusion, the cervix was dilated 4 cm in 26 women, 5 cm in 30 women, and ≥6 cm in 43 women. Furthermore, 4 women were examined once, 93 women twice, 60 women 3 times, 47 women 4 times, 20 women 5 times, 15 women 6 times, and 3 women 8 times. Occiput posterior was the most frequent position at the first examination (52 of 99), but of those classified as posterior, most were at 4- or 8-o'clock position. Occiput posterior positions persisted in >50% of cases throughout the first stage of labor but were anterior in 53 of 80 women (66%) examined by and after full dilatation. The occiput position was anterior in 75% of cases at a head-perineum distance of ≤30 mm and in 73% of cases at an angle of progression of ≥125° (corresponding to a clinical station of +1). All initial occiput anterior (19), 77% of occiput posterior (40 of 52), and 93% of occiput transverse positions (26 of 28) were thereafter delivered in an occiput anterior position. In 6 cases, the fetal head had rotated over the 6-o'clock position from an occiput posterior or transverse position, resulting in a rotation of >180°. In addition, 6 of the 8 women ending with cesarean delivery had the fetus in occiput posterior position throughout the active phase of labor. Conclusion: We investigated the rotation of the fetal head in the active phase of labor in nulliparous women in spontaneous labor at term, using ultrasound to provide accurate and objective results. The occiput posterior position was the most common fetal position throughout the active phase of the first stage of labor. Occiput anterior only became the most frequent position at full dilatation and after the head had descended below the midpelvic plane. Keywords: active phase; angle of progression; cesarean delivery; fetal head position; head-perineum distance; progress of labor; transabdominal ultrasound; transperineal ultrasound.
  • Inter-Visit Reliability of Smooth Pursuit Neck Torsion Test in Patients with Chronic Neck Pain and Healthy Individuals.

    Majcen Rosker, Ziva; Vodicar, Miha; Kristjansson, Eythor; 1Faculty of Sport, University of Ljubljana, 1000 Ljubljana, Slovenia. 2Department of Orthopaedic Surgery, University Medical Centre, 1000 Ljubljana, Slovenia. 3Landspitali University Hospital, 101 Reykjavik, Iceland. (MDPI, 2021-04-22)
    Visual disturbances are commonly reported in patients with neck pain. Smooth pursuit neck torsion (SPNT) test performed in neutral position and with trunk rotated under the stationary head has been used to discriminate between those with cervical component and those without. However, no studies investigated the reliability of the SPNT-test in patients with chronic neck pain and healthy controls. The aim of this study was to assess inter-visit reliability of the SPNT-test while applying different amplitudes and velocities of target movement. Thirty-two controls and thirty-one patients were enrolled in the study. The SPNT-test was performed in neutral position and through 45° torsion positions. The test was performed at 20°/s, 30°/s and 40°/s velocities and at 30°, 40° and 50° amplitudes of cyclic sinusoidal target movements. Interclass correlation coefficient and smallest detectable change were calculated for parameters of gain and SPNT-differences. In patients, moderate to good reliability was observed for gain at 40° and 50° amplitudes and for 20°/s and 30°/s velocities, while moderate to excellent reliability for gain was observed in controls. Both groups presented with moderate to good reliability for SPNT-difference. Our findings imply that amplitudes of 40° and 50° and velocities of 20°/s and 30°/s are the most reliable and should be applied in future studies assessing oculomotor functions during the SPNT test. Keywords: neck pain; oculomotor functions; reliability; smooth pursuit neck torsion test.
  • Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia.

    Gottschalk Højfeldt, Sofie; Grell, Kathrine; Abrahamsson, Jonas; Lund, Bendik; Vettenranta, Kim; Jónsson, Ólafur G; Frandsen, Thomas L; Wolthers, Benjamin O; Marquart, Hanne Vibeke; Vaitkeviciene, Goda; et al. (Elsevier, 2021-04)
    Truncation of asparaginase treatment due to asparaginase-related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1 to 17 years, diagnosed with ALL between July 2008 and February 2016, treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (including extended asparaginase exposure [1000 IU/m2 intramuscularly weeks 5-33]). Patients were included with delayed entry at their last administered asparaginase treatment, or detection of SI, and followed until relapse, death, secondary malignancy, or end of follow-up (median, 5.71 years; interquartile range, 4.02-7.64). In a multiple Cox model comparing patients with (n = 358) and without (n = 1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (HR; aHR) was 1.33 (95% confidence interval [CI], 0.86-2.06; P = .20). In a substudy including only patients with information on enzyme activity (n = 1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI, 6.9-15.4) vs 6.7% (95% CI, 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI, 1.05-2.74, P=.03). The unadjusted bone marrow relapse-specific HR was 1.83 (95% CI, 1.07-3.14, P=.03) and 1.86 (95% CI, 0.90- 3.87, P=.095) for any central nervous system relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible. This trial was registered at as #NCT03987542.
  • The impact and cost-effectiveness of introducing the 10-valent pneumococcal conjugate vaccine into the paediatric immunisation programme in Iceland-A population-based time series analysis.

    Eythorsson, Elias; Ásgeirsdóttir, Tinna L; Erlendsdóttir, Helga; Hrafnkelsson, Birgir; Kristinsson, Karl G; Haraldsson, Ásgeir; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Faculty of Economics, University of Iceland, Reykjavik, Iceland. 3Department of Clinical Microbiology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 4Department of Mathematics, University of Iceland, Reykjavik, Iceland. 5Children's Hospital Iceland, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. (Public Library of Science, 2021-04-08)
    Introduction: Streptococcus pneumoniae is a cause of infections that range in severity from acute otitis media (AOM) to pneumonia and invasive pneumococcal disease (IPD). The 10-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced into the Icelandic paediatric immunisation programme in 2011. The aim was to estimate the population impact and cost-effectiveness of PHiD-CV10 introduction. Methods: Data on primary care visits from 2005-2015 and hospitalisations from 2005-2017 were obtained from population-based registries. A Bayesian time series analysis with synthetic controls was employed to estimate the number of cases of AOM, pneumonia and IPD that would have occurred between 2013-2017, had PHiD-CV10 not been introduced. Prevented cases were calculated by subtracting the observed number of cases from this estimate. The cost of the programme was calculated accounting for cost-savings due to prevented cases. Results: The introduction of PHiD-CV10 prevented 13,767 (95% credible interval [CI] 2,511-29,410) visits for AOM from 2013-2015, and prevented 1,814 (95%CI -523-4,512) hospitalisations for pneumonia and 53 (95%CI -17-177) admissions for IPD from 2013-2017. Visits for AOM decreased both among young children and among children 4-19 years of age, with rate ratios between 0.72-0.89. Decreases were observed in both pneumonia hospitalisations (rate ratios between 0.67-0.92) and IPD (rate ratios between 0.27-0.94). The total cost of implementing PHiD-CV10 in Iceland was -7,463,176 United States Dollars (USD) (95%CI -16,159,551-582,135) with 2.1 USD (95%CI 0.2-4.7) saved for every 1 USD spent. Conclusions: The introduction of PHiD-CV10 was associated with large decreases in visits and hospitalisations for infections commonly caused by pneumococcus and was cost-saving during the first five years of the immunisation programme.
  • Alzheimer's disease neuropathology in the hippocampus and brainstem of people with obstructive sleep apnea.

    Owen, Jessica E; Benediktsdottir, Bryndis; Cook, Elizabeth; Olafsson, Isleifur; Gislason, Thorarinn; Robinson, Stephen R; 1School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3Department of Sleep Medicine, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 4Department of Clinical Biochemistry, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 5Institute for Breathing and Sleep (IBAS), Austin Health, Heidelberg, Victoria, Australia. (Owen JE, Benediktsdottir B, Cook E, Olafsson I, Gislason T, Robinson SR. Alzheimer's disease neuropathology in the hippocampus and brainstem of people with obstructive sleep apnea. Sleep. 2021 Mar 12;44(3):zsaa195. doi: 10.1093/sleep/zsaa195., 2021-03)
    Obstructive sleep apnea (OSA) involves intermittent cessations of breathing during sleep. People with OSA can experience memory deficits and have reduced hippocampal volume; these features are also characteristic of Alzheimer's disease (AD), where they are accompanied by neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques in the hippocampus and brainstem. We have recently shown reduced hippocampal volume to be related to OSA severity, and although OSA may be a risk factor for AD, the hippocampus and brainstems of clinically verified OSA cases have not yet been examined for NFTs and Aβ plaques. The present study used quantitative immunohistochemistry to investigate postmortem hippocampi of 34 people with OSA (18 females, 16 males; mean age 67 years) and brainstems of 24 people with OSA for the presence of NFTs and Aβ plaques. OSA severity was a significant predictor of Aβ plaque burden in the hippocampus after controlling for age, sex, body mass index (BMI), and continuous positive airway pressure (CPAP) use. OSA severity also predicted NFT burden in the hippocampus, but not after controlling for age. Although 71% of brainstems contained NFTs and 21% contained Aβ plaques, their burdens were not correlated with OSA severity. These results indicate that OSA accounts for some of the "cognitively normal" individuals who have been found to have substantial Aβ burdens, and are currently considered to be at a prodromal stage of AD. Keywords: Alzheimer’s disease; amyloid beta; continuous positive airway pressure; neurofibrillary tangles; tau.

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