Recent Submissions

  • Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study.

    Efe, Cumali; Dhanasekaran, Renumathy; Lammert, Craig; Ebik, Berat; Higuera-de la Tijera, Fatima; Aloman, Costica; Rıza Calışkan, Ali; Peralta, Mirta; Gerussi, Alessio; Massoumi, Hatef; et al. (Wiley, 2021-06)
    Background and aims: Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking. Approach and results: We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score-matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 × the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19. Conclusions: This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19.
  • Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks' Gestational Age: The CORSAD Randomized Clinical Trial.

    Donaldsson, Snorri; Drevhammar, Thomas; Li, Yinghua; Bartocci, Marco; Rettedal, Siren Irene; Lundberg, Fredrik; Odelberg-Johnson, Per; Szczapa, Tomasz; Thordarson, Thordur; Pilypiene, Ingrida; et al. (American Medical Association, 2021-09)
    Importance: Establishing stable breathing is a key event for preterm infants after birth. Delivery of pressure-stable continuous positive airway pressure and avoiding face mask use could be of importance in the delivery room. Objective: To determine whether using a new respiratory support system with low imposed work of breathing and short binasal prongs decreases delivery room intubations or death compared with a standard T-piece system with a face mask. Design, setting, and participants: In this unblinded randomized clinical trial, mothers threatening preterm delivery before week 28 of gestation were screened. A total of 365 mothers were enrolled, and 250 infants were randomized before birth and 246 liveborn infants were treated. The trial was conducted in 7 neonatal intensive care units in 5 European countries from March 2016 to May 2020. The follow-up period was 72 hours after intervention. Interventions: Infants were randomized to either the new respiratory support system with short binasal prongs (n = 124 infants) or the standard T-piece system with face mask (n = 122 infants). The intervention was providing continuous positive airway pressure for 10 to 30 minutes and positive pressure ventilation, if needed, with the randomized system. Main outcomes and measures: The primary outcome was delivery room intubation or death within 30 minutes of birth. Secondary outcomes included respiratory and safety variables. Results: Of 246 liveborn infants treated, the mean (SD) gestational age was 25.9 (1.3) weeks, and 127 (51.6%) were female. A total of 41 infants (33.1%) receiving the new respiratory support system were intubated or died in the delivery room compared with 55 infants (45.1%) receiving standard care. The adjusted odds ratio was statistically significant after adjusting for stratification variables (adjusted odds ratio, 0.53; 95% CI, 0.30-0.94; P = .03). No significant differences were seen in secondary outcomes or safety variables. Conclusions and relevance: In this study, using the new respiratory support system reduced delivery room intubation in extremely preterm infants. Stabilizing preterm infants with a system that has low imposed work of breathing and binasal prongs as interface is safe and feasible.
  • NANS-CDG: Delineation of the Genetic, Biochemical, and Clinical Spectrum.

    den Hollander, Bibiche; Rasing, Anne; Post, Merel A; Klein, Willemijn M; Oud, Machteld M; Brands, Marion M; de Boer, Lonneke; Engelke, Udo F H; van Essen, Peter; Fuchs, Sabine A; et al. (Frontiers Research Foundation, 2021-06-07)
    Background: NANS-CDG is a recently described congenital disorder of glycosylation caused by biallelic genetic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. Sialic acid at the end of glycoconjugates plays a key role in biological processes such as brain and skeletal development. Here, we present an observational cohort study to delineate the genetic, biochemical, and clinical phenotype and assess possible correlations. Methods: Medical and laboratory records were reviewed with retrospective extraction and analysis of genetic, biochemical, and clinical data (2016-2020). Results: Nine NANS-CDG patients (nine families, six countries) referred to the Radboudumc CDG Center of Expertise were included. Phenotyping confirmed the hallmark features including intellectual developmental disorder (IDD) (n = 9/9; 100%), facial dysmorphisms (n = 9/9; 100%), neurologic impairment (n = 9/9; 100%), short stature (n = 8/9; 89%), skeletal dysplasia (n = 8/9; 89%), and short limbs (n = 8/9; 89%). Newly identified features include ophthalmological abnormalities (n = 6/9; 67%), an abnormal septum pellucidum (n = 6/9; 67%), (progressive) cerebral atrophy and ventricular dilatation (n = 5/9; 56%), gastrointestinal dysfunction (n = 5/9; 56%), thrombocytopenia (n = 5/9; 56%), and hypo-low-density lipoprotein cholesterol (n = 4/9; 44%). Biochemically, elevated urinary excretion of N-acetylmannosamine (ManNAc) is pathognomonic, the concentrations of which show a significant correlation with clinical severity. Genotypically, eight novel NANS variants were identified. Three severely affected patients harbored identical compound heterozygous pathogenic variants, one of whom was initiated on experimental prenatal and postnatal treatment with oral sialic acid. This patient showed markedly better psychomotor development than the other two genotypically identical males. Conclusions: ManNAc screening should be considered in all patients with IDD, short stature with short limbs, facial dysmorphisms, neurologic impairment, and an abnormal septum pellucidum +/- congenital and neurodegenerative lesions on brain imaging, to establish a precise diagnosis and contribute to prognostication. Personalized management includes accurate genetic counseling and access to proper supports and tailored care for gastrointestinal symptoms, thrombocytopenia, and epilepsy, as well as rehabilitation services for cognitive and physical impairments. Motivated by the short-term positive effects of experimental treatment with oral sialic, we have initiated this intervention with protocolized follow-up of neurologic, systemic, and growth outcomes in four patients. Research is ongoing to unravel pathophysiology and identify novel therapeutic targets.
  • Recommendation for validation and quality assurance of non-invasive prenatal testing for foetal blood groups and implications for IVD risk classification according to EU regulations.

    Clausen, Frederik Banch; Hellberg, Åsa; Bein, Gregor; Bugert, Peter; Schwartz, Dieter; Drnovsek, Tadeja Dovc; Finning, Kirstin; Guz, Katarzyna; Haimila, Katri; Henny, Christine; et al. (Wiley, 2021-06-21)
    Background and objectives: Non-invasive assays for predicting foetal blood group status in pregnancy serve as valuable clinical tools in the management of pregnancies at risk of detrimental consequences due to blood group antigen incompatibility. To secure clinical applicability, assays for non-invasive prenatal testing of foetal blood groups need to follow strict rules for validation and quality assurance. Here, we present a multi-national position paper with specific recommendations for validation and quality assurance for such assays and discuss their risk classification according to EU regulations. Materials and methods: We reviewed the literature covering validation for in-vitro diagnostic (IVD) assays in general and for non-invasive foetal RHD genotyping in particular. Recommendations were based on the result of discussions between co-authors. Results: In relation to Annex VIII of the In-Vitro-Diagnostic Medical Device Regulation 2017/746 of the European Parliament and the Council, assays for non-invasive prenatal testing of foetal blood groups are risk class D devices. In our opinion, screening for targeted anti-D prophylaxis for non-immunized RhD negative women should be placed under risk class C. To ensure high quality of non-invasive foetal blood group assays within and beyond the European Union, we present specific recommendations for validation and quality assurance in terms of analytical detection limit, range and linearity, precision, robustness, pre-analytics and use of controls in routine testing. With respect to immunized women, different requirements for validation and IVD risk classification are discussed. Conclusion: These recommendations should be followed to ensure appropriate assay performance and applicability for clinical use of both commercial and in-house assays. Keywords: EU; HDFN; blood group; cell-free DNA; foetal RHD genotyping; quality assurance; validation.
  • Prevalence and Population Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

    Burney, Peter; Patel, Jaymini; Minelli, Cosetta; Gnatiuc, Louisa; Amaral, André F S; Kocabaş, Ali; Cherkaski, Hamid Hacene; Gulsvik, Amund; Nielsen, Rune; Bateman, Eric; et al. (American Thoracic Society, 2020-11-10)
    Rationale: The Global Burden of Disease programme identified smoking, and ambient and household air pollution as the main drivers of death and disability from Chronic Obstructive Pulmonary Disease (COPD). Objective: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a post-bronchodilator one-second forced expiratory volume to forced vital capacity ratio < lower limit of normal, and the relative risks associated with different risk factors. Local RR were estimated using a Bayesian hierarchical model borrowing information from across sites. From these RR and the prevalence of risk factors, we estimated local Population Attributable Risks (PAR). Measurements and Main Results: Mean prevalence of CAO was 11.2% in men and 8.6% in women. Mean PAR for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index (BMI), and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: While smoking remains the most important risk factor for CAO, in some areas poor education, low BMI and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.
  • Evaluation of a Novel Teleradiology Technology for Image-Based Distant Consultations: Applications in Neurosurgery.

    Cewe, Paulina; Burström, Gustav; Drnasin, Ivan; Ohlsson, Marcus; Skulason, Halldor; Vucica, Stanislav; Elmi-Terander, Adrian; Edström, Erik; 1Department of Trauma and Musculoskeletal Radiology, Karolinska University Hospital, 171 64 Stockholm, Sweden. 2Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden. 3Department of Neurosurgery, Karolinska University Hospital, 171 64 Stockholm, Sweden. 4Image Over Globe, 21000 Split, Croatia. 5Department of Neuroradiology, Karolinska University Hospital, 171 64 Stockholm, Sweden. 6Department of Neurosurgery, Landspitali University Hospital, 101 Reykjavik, Iceland. (MDPI, 2021-08-04)
    In emergency settings, fast access to medical imaging for diagnostic is pivotal for clinical decision making. Hence, a need has emerged for solutions that allow rapid access to images on small mobile devices (SMD) without local data storage. Our objective was to evaluate access times to full quality anonymized DICOM datasets, comparing standard access through an authorized hospital computer (AHC) to a zero-footprint teleradiology technology (ZTT) used on a personal computer (PC) or SMD using national and international networks at a regional neurosurgical center. Image datasets were sent to a senior neurosurgeon, outside the hospital network using either an AHC and a VPN connection or a ZTT (Image Over Globe (IOG)), on a PC or an SMD. Time to access DICOM images was measured using both solutions. The mean time using AHC and VPN was 250 ± 10 s (median 249 s (233-274)) while the same procedure using IOG took 50 ± 8 s (median 49 s (42-60)) on a PC and 47 ± 20 s (median 39 (33-88)) on a SMD. Similarly, an international consultation was performed requiring 23 ± 5 s (median 21 (16-33)) and 27 ± 1 s (median 27 (25-29)) for PC and SMD respectively. IOG is a secure, rapid and easy to use telemedicine technology facilitating efficient clinical decision making and remote consultations. Keywords: clinical decision-making; neurosurgery; remote consultation; telemedicine; teleradiology.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Metformin is associated with decreased risk of basal cell carcinoma: A whole-population case-control study from Iceland.

    Adalsteinsson, Jonas A; Muzumdar, Sonal; Waldman, Reid; Wu, Rong; Ratner, Désirée; Feng, Hao; Ungar, Jonathan; Silverberg, Jonathan I; Olafsdottir, Gudridur H; Kristjansson, Arni Kjalar; et al. (Elsevier, 2021-02-19)
    Background: Metformin has anticarcinogenic properties and is also known to inhibit the sonic hedgehog pathway, but population-based studies analyzing the potential protective effect for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are needed. Objectives: To delineate the association between metformin use and invasive SCC, SCC in situ (SCCis), and BCC. Methods: A population-based case-control study design was employed using all 6880 patients diagnosed in Iceland between 2003-2017 with first-time BCC, SCCis, or invasive SCC, and 69,620 population controls. Multivariate odds ratios (ORs) were calculated using conditional logistic regression. Results: Metformin was associated with a lower risk of developing BCC (OR, 0.71; 95% confidence interval [CI], 0.61-0.83), even at low doses. No increased risk of developing SCC was observed. SCCis risk was mildly elevated in the 501-1500 daily dose unit category (OR, 1.40; 95% CI, 1.00-1.96). Limitations: This study was retrospective in nature with the inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities. Conclusion: Metformin is associated with decreased risk of BCC development, even at low doses. Metformin might have potential as a chemoprotective agent for patients at high risk of BCC, although this will need confirmation in future studies. Keywords: basal cell carcinoma; keratinocyte carcinoma; metformin; squamous cell carcinoma; squamous cell carcinoma in situ.
  • 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.

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