• Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study.

      Skuladottir, S S; Ramel, A; Hjaltadottir, I; Launer, L J; Cotch, M F; Siggeirsdottir, K; Gudnason, V; Sigurdsson, G; Steingrimsdottir, L; Halldorsson, T; et al. (Springer, 2020-08-18)
      Poor physical function and body composition my partly predict the risk of falls leading to fracture regardless of bone mineral density. Introduction: To examine the relationship between body composition, physical function, and other markers of health with hip fractures in older community-dwelling Icelandic adults. Methods: A prospective cohort of 4782 older adults from the AGES-Reykjavik study. Baseline recruitment took place between 2002 and 2006, and information on hip fractures occurring through 2012 was extracted from clinical records. Using multivariate regression analyses, baseline measures of bone health, physical function, and body composition were compared between those who later experienced hip fractures and to those who did not. Associations with the risk of fractures were quantified using Cox regression. Results: Mean age was 76.3 years at baseline. After adjustment for age, regression showed that male hip fracture cases compared with non-cases had (mean (95% confidence interval)) significantly lower thigh muscle cross-sectional area - 5.6 cm2 (- 10.2, - 1.1), poorer leg strength - 28 N (- 49, - 7), and decreased physical function as measured by longer timed up and go test 1.1 s (0.5, 1.7). After adjustment for age, female cases had, compared with non-cases, lower body mass index - 1.5 kg/m2 (- 2.1, - 0.9), less lean mass - 1.6 kg (- 2.5, - 0.8), thigh muscle cross-sectional area - 4.4 cm2 (- 6.5, - 2.3), and worse leg strength - 16 N (- 25, - 6). These differences largely persisted after further adjustment for bone mineral density (BMD), suggesting that body composition may contribute to the risk of fracture independent of bone health. When examining the association between these same factors and hip fractures using Cox regression, the same conclusions were reached. Conclusions: After accounting for age and BMD, older adults who later experienced a hip fracture had poorer baseline measures of physical function and/or body composition, which may at least partly contribute to the risk of falls leading to fracture. Keywords: Aging; Biomarkers; Body composition; Hip fracture; Physical function.
    • GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

      Zhou, Wei; Brumpton, Ben; Kabil, Omer; Gudmundsson, Julius; Thorleifsson, Gudmar; Weinstock, Josh; Zawistowski, Matthew; Nielsen, Jonas B; Chaker, Layal; Medici, Marco; et al. (Nature Publishing Group, 2020-08-07)
      Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
    • Association of glial and neuronal degeneration markers with Alzheimer's disease cerebrospinal fluid profile and cognitive functions.

      Teitsdottir, Unnur D; Jonsdottir, Maria K; Lund, Sigrun H; Darreh-Shori, Taher; Snaedal, Jon; Petersen, Petur H; 1Faculty of Medicine, Department of Anatomy, Biomedical Center, University of Iceland, Reykjavik, Iceland. udt1@hi.is. 2Department of Psychology, Reykjavik University, Reykjavik, Iceland. 3Department of Psychiatry, Landspitali - National University Hospital, Reykjavik, Iceland. 4deCODE genetics/Amgen, Inc., Reykjavik, Iceland. 5Division of Clinical Geriatrics, Center for Alzheimer Research, NVS Department, Karolinska Institutet, Huddinge, Sweden. 6Memory clinic, Department of Geriatric Medicine, Landspitali - National University Hospital, Reykjavik, Iceland. 7Faculty of Medicine, Department of Anatomy, Biomedical Center, University of Iceland, Reykjavik, Iceland. (BioMed Central, 2020-08-04)
      Background: Neuroinflammation has gained increasing attention as a potential contributing factor in the onset and progression of Alzheimer's disease (AD). The objective of this study was to examine the association of selected cerebrospinal fluid (CSF) inflammatory and neuronal degeneration markers with signature CSF AD profile and cognitive functions among subjects at the symptomatic pre- and early dementia stages. Methods: In this cross-sectional study, 52 subjects were selected from an Icelandic memory clinic cohort. Subjects were classified as having AD (n = 28, age = 70, 39% female, Mini-Mental State Examination [MMSE] = 27) or non-AD (n = 24, age = 67, 33% female, MMSE = 28) profile based on the ratio between CSF total-tau (T-tau) and amyloid-β1-42 (Aβ42) values (cut-off point chosen as 0.52). Novel CSF biomarkers included neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP), measured with enzyme-linked immunosorbent assays (ELISAs). Subjects underwent neuropsychological assessment for evaluation of different cognitive domains, including verbal episodic memory, non-verbal episodic memory, language, processing speed, and executive functions. Results: Accuracy coefficient for distinguishing between the two CSF profiles was calculated for each CSF marker and test. Novel CSF markers performed poorly (area under curve [AUC] coefficients ranging from 0.61 to 0.64) compared to tests reflecting verbal episodic memory, which all performed fair (AUC > 70). LASSO regression with a stability approach was applied for the selection of CSF markers and demographic variables predicting performance on each cognitive domain, both among all subjects and only those with a CSF AD profile. Relationships between CSF markers and cognitive domains, where the CSF marker reached stability selection criteria of > 75%, were visualized with scatter plots. Before calculations of corresponding Pearson's correlations coefficients, composite scores for cognitive domains were adjusted for age and education. GFAP correlated with executive functions (r = - 0.37, p = 0.01) overall, while GFAP correlated with processing speed (r = - 0.68, p < 0.001) and NFL with verbal episodic memory (r = - 0.43, p = 0.02) among subjects with a CSF AD profile. Conclusions: The novel CSF markers NFL and GFAP show potential as markers for cognitive decline among individuals with core AD pathology at the symptomatic pre- and early stages of dementia. Keywords: AD biomarker profile; Alzheimer’s disease; Cerebrospinal fluid; Cognitive domains; Glial fibrillary acidic protein; Neurofilament light; S100 calcium-binding protein B; YKL-40.
    • A gene expression-based single sample predictor of lung adenocarcinoma molecular subtype and prognosis.

      Liljedahl, Helena; Karlsson, Anna; Oskarsdottir, Gudrun N; Salomonsson, Annette; Brunnström, Hans; Erlingsdottir, Gigja; Jönsson, Mats; Isaksson, Sofi; Arbajian, Elsa; Ortiz-Villalón, Cristian; et al. (Wiley, 2020-08-03)
      Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer. Keywords: gene expression; lung adenocarcinoma; molecular subtypes; prognosis; single sample predictor.
    • The Impact of Family Strengths Oriented Therapeutic Conversations on Parents of Children with a New Chronic Illness Diagnosis.

      Svavarsdottir, Erla Kolbrun; Kamban, Solrun W; Konradsdottir, Elísabet; Sigurdardottir, Anna Olafia; 1University of Iceland, Reykjavik, Iceland. 2Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. (Sage Publications, 2020-07-29)
      A growing number of families with children are dealing with a new diagnosis of chronic illnesses or health problems that are demanding. Nurses are in a prime position to provide support and empowerment to these families. The aim of the study was to evaluate the benefits of two sessions of a Family Strengths Oriented Therapeutic Conversation (FAM-SOTC) intervention, offered by advanced practice nurses (APNs) to mothers (N = 31) of children and adolescents in Iceland with newly diagnosed chronic illnesses/disorders. Families of children with Juvenile Idiopathic Arthritis (JIA), epilepsy, Type 1 diabetes (T1DM), or with sleep disturbance with attention-deficit/hyperactivity disorder (ADHD), reported significantly higher family support, greater conviction about their illness beliefs, increased quality of life, and greater satisfaction with health care services after receiving two sessions of the FAM-SOTC intervention (Time 2) compared to before the intervention (Time 1). The findings emphasize the importance of the APN's role and family nursing expertise in supporting families of children with a new diagnosis of chronic illnesses or disorders who are in active treatment.
    • Early diagnosis is associated with improved clinical outcomes in benign esophageal perforation: an individual patient data meta-analysis.

      Vermeulen, Bram D; van der Leeden, Britt; Ali, Jawad T; Gudbjartsson, Tomas; Hermansson, Michael; Low, Donald E; Adler, Douglas G; Botha, Abraham J; D'Journo, Xavier B; Eroglu, Atila; et al. (Springer, 2020-07-17)
      Background: Time of diagnosis (TOD) of benign esophageal perforation is regarded as an important risk factor for clinical outcome, although convincing evidence is lacking. The aim of this study is to assess whether time between onset of perforation and diagnosis is associated with clinical outcome in patients with iatrogenic esophageal perforation (IEP) and Boerhaave's syndrome (BS). Methods: We searched MEDLINE, Embase and Cochrane library through June 2018 to identify studies. Authors were invited to share individual patient data and a meta-analysis was performed (PROSPERO: CRD42018093473). Patients were subdivided in early (≤ 24 h) and late (> 24 h) TOD and compared with mixed effects multivariable analysis while adjusting age, gender, location of perforation, initial treatment and center. Primary outcome was overall mortality. Secondary outcomes were length of hospital stay, re-interventions and ICU admission. Results: Our meta-analysis included IPD of 25 studies including 576 patients with IEP and 384 with BS. In IEP, early TOD was not associated with overall mortality (8% vs. 13%, OR 2.1, 95% CI 0.8-5.1), but was associated with a 23% decrease in ICU admissions (46% vs. 69%, OR 3.0, 95% CI 1.2-7.2), a 22% decrease in re-interventions (23% vs. 45%, OR 2.8, 95% CI 1.2-6.7) and a 36% decrease in length of hospital stay (14 vs. 22 days, p < 0.001), compared with late TOD. In BS, no associations between TOD and outcomes were found. When combining IEP and BS, early TOD was associated with a 6% decrease in overall mortality (10% vs. 16%, OR 2.1, 95% CI 1.1-3.9), a 19% decrease in re-interventions (26% vs. 45%, OR 1.9, 95% CI 1.1-3.2) and a 35% decrease in mean length of hospital stay (16 vs. 22 days, p = 0.001), compared with late TOD. Conclusions: This individual patient data meta-analysis confirms the general opinion that an early (≤ 24 h) compared to a late diagnosis (> 24 h) in benign esophageal perforations, particularly in IEP, is associated with improved clinical outcome. Keywords: Esophageal rupture; Individual patient data meta-analysis; Time of diagnosis.
    • Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance.

      Schnappauf, Oskar; Zhou, Qing; Moura, Natalia Sampaio; Ombrello, Amanda K; Michael, Drew G; Deuitch, Natalie; Barron, Karyl; Stone, Deborah L; Hoffmann, Patrycja; Hershfield, Michael; et al. (Springer, 2020-07-08)
      Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder that manifests with fever, early-onset vasculitis, strokes, and hematologic dysfunction. This study aimed to identify disease-causing variants by conventional Sanger and whole exome sequencing in two families suspected to have DADA2 and non-confirmatory genotypes. ADA2 enzymatic assay confirmed the clinical diagnosis of DADA2. Molecular diagnosis was important to accurately identify other family members at risk. Methods: We used a variety of sequencing technologies, ADA2 enzymatic testing, and molecular methods including qRT-PCR and MLPA. Results: Exome sequencing identified heterozygosity for the known pathogenic variant ADA2: c.1358A>G, p.Tyr453Cys in a 14-year-old female with a history of ischemic strokes, livedo, and vasculitis. No second pathogenic variant could be identified. ADA2 enzymatic testing in combination with quantitative RT-PCR suggested a loss-of-function allele. Subsequent genome sequencing identified a canonical splice site variant, c.-47+2T>C, within the 5'UTR of ADA2. Two of her unaffected siblings were found to carry the same two pathogenic variants. A homozygous 800-bp duplication comprising exon 7 of ADA2 was identified in a 5-year-old female with features consistent with Diamond-Blackfan anemia (DBA). The duplication was missed by Sanger sequencing of ADA2, chromosomal microarray, and exome sequencing but was detected by MLPA in combination with long-read PCR sequencing. The exon 7 duplication was also identified in her non-symptomatic father and younger sister. Conclusions: ADA2 pathogenic variants may not be detected by conventional sequencing and genetic testing and may require the incorporation of additional diagnostic methods. A definitive molecular diagnosis is crucial for all family members to make informed treatment decisions. Keywords: Exome sequencing; deficiency of adenosine deaminase 2; genome sequencing; loss-of-function variants.
    • Parents' smoking onset before conception as related to body mass index and fat mass in adult offspring: Findings from the RHINESSA generation study.

      Knudsen, Gerd Toril Mørkve; Dharmage, Shyamali; Janson, Christer; Abramson, Michael J; Benediktsdóttir, Bryndís; Malinovschi, Andrei; Skulstad, Svein Magne; Bertelsen, Randi Jacobsen; Real, Francisco Gomez; Schlünssen, Vivi; et al. (Public Library of Science, 2020-07-06)
      Emerging evidence suggests that parents' preconception exposures may influence offspring health. We aimed to investigate maternal and paternal smoking onset in specific time windows in relation to offspring body mass index (BMI) and fat mass index (FMI). We investigated fathers (n = 2111) and mothers (n = 2569) aged 39-65 years, of the population based RHINE and ECRHS studies, and their offspring aged 18-49 years (n = 6487, mean age 29.6 years) who participated in the RHINESSA study. BMI was calculated from self-reported height and weight, and FMI was estimated from bioelectrical impedance measures in a subsample. Associations with parental smoking were analysed with generalized linear regression adjusting for parental education and clustering by study centre and family. Interactions between offspring sex were analysed, as was mediation by parental pack years, parental BMI, offspring smoking and offspring birthweight. Fathers' smoking onset before conception of the offspring (onset ≥15 years) was associated with higher BMI in the offspring when adult (β 0.551, 95%CI: 0.174-0.929, p = 0.004). Mothers' preconception and postnatal smoking onset was associated with higher offspring BMI (onset <15 years: β1.161, 95%CI 0.378-1.944; onset ≥15 years: β0.720, 95%CI 0.293-1.147; onset after offspring birth: β2.257, 95%CI 1.220-3.294). However, mediation analysis indicated that these effects were fully mediated by parents' postnatal pack years, and partially mediated by parents' BMI and offspring smoking. Regarding FMI, sons of smoking fathers also had higher fat mass (onset <15 years β1.604, 95%CI 0.269-2.939; onset ≥15 years β2.590, 95%CI 0.544-4.636; and onset after birth β2.736, 95%CI 0.621-4.851). There was no association between maternal smoking and offspring fat mass. We found that parents' smoking before conception was associated with higher BMI in offspring when they reached adulthood, but that these effects were mediated through parents' pack years, suggesting that cumulative smoking exposure during offspring's childhood may elicit long lasting effects on offspring BMI.
    • Association between lung function decline and obstructive sleep apnoea: the ALEC study.

      Emilsson, Össur Ingi; Sundbom, Fredrik; Ljunggren, Mirjam; Benediktsdottir, Bryndis; Garcia-Aymerich, Judith; Bui, Dinh Son; Jarvis, Deborah; Olin, Anna-Carin; Franklin, Karl A; Demoly, Pascal; et al. (Springer, 2020-07-06)
      Purpose: To study changes in lung function among individuals with a risk of obstructive sleep apnoea (OSA), and if asthma affected this relationship. Methods: We used data from the European Community Respiratory Health Survey II and III, a multicentre general population study. Participants answered questionnaires and performed spirometry at baseline and 10-year follow-up (n = 4,329 attended both visits). Subjects with high risk for OSA were identified from the multivariable apnoea prediction (MAP) index, calculated from BMI, age, gender, and OSA symptoms at follow-up. Asthma was defined as having doctor's diagnosed asthma at follow-up. Primary outcomes were changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) from baseline to follow-up. Results: Among 5108 participants at follow-up, 991 (19%) had a high risk of OSA based on the MAP index. Participants with high OSA risk more often had wheeze, cough, chest tightness, and breathlessness at follow-up than those with low OSA risk. Lung function declined more rapidly in subjects with high OSA risk (low vs high OSA risk [mean ± SD]: FEV1 = - 41.3 ± 24.3 ml/year vs - 50.8 ± 30.1 ml/year; FVC = - 30.5 ± 31.2 ml/year vs - 45.2 ± 36.3 ml/year). Lung function decline was primarily associated with higher BMI and OSA symptoms. OSA symptoms had a stronger association with lung function decline among asthmatics, compared to non-asthmatics. Conclusion: In the general population, a high probability of obstructive sleep apnoea was related to faster lung function decline in the previous decade. This was driven by a higher BMI and more OSA symptoms among these subjects. The association between OSA symptoms and lung function decline was stronger among asthmatics. Keywords: Asthma; Lung function; Lung function decline; Sleep apnoea.
    • Acute lymphoblastic leukemia and down syndrome: 6-mercaptopurine and methotrexate metabolites during maintenance therapy.

      Østergaard, Anna; Bohnstedt, Cathrine; Grell, Kathrine; Degn, Matilda; Zeller, Bernward; Taskinen, Mervi; Hafsteinsdottir, Solveig; Björgvinsdóttir, Helga; Heyman, Mats; Hoogerbrugge, Peter; et al. (Nature Publishing Group, 2020-07-04)
    • Zonulin-Dependent Intestinal Permeability in Children Diagnosed with Mental Disorders: A Systematic Review and Meta-Analysis.

      Asbjornsdottir, Birna; Snorradottir, Heiddis; Andresdottir, Edda; Fasano, Alessio; Lauth, Bertrand; Gudmundsson, Larus S; Gottfredsson, Magnus; Halldorsson, Thorhallur Ingi; Birgisdottir, Bryndis Eva; 1Unit for Nutrition Research, Faculty of Food and Nutritional Sciences, University of Iceland, 101 Reykjavik, Iceland. 2Faculty of Medicine, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. 3Children's and Adolescents Psychiatric Unit, Landspitali University Hospital, 101 Reykjavik, Iceland. 4Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, MassGeneral Hospital for Children, Boston, MA 02114, USA. 5Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland. 6Department of Scientific Affairs, Landspitali University Hospital, 101 Reykjavik, Iceland. (MDPI Publishing, 2020-07-03)
      Worldwide, up to 20% of children and adolescents experience mental disorders, which are the leading cause of disability in young people. Research shows that serum zonulin levels are associated with increased intestinal permeability (IP), affecting neural, hormonal, and immunological pathways. This systematic review and meta-analysis aimed to summarize evidence from observational studies on IP in children diagnosed with mental disorders. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of the Cochrane Library, PsycINFO, PubMed, and the Web of Science identified 833 records. Only non-intervention (i.e., observational) studies in children (<18 years) diagnosed with mental disorders, including a relevant marker of intestinal permeability, were included. Five studies were selected, with the risk of bias assessed according to the Newcastle-Ottawa scale (NOS). Four articles were identified as strong and one as moderate, representing altogether 402 participants providing evidence on IP in children diagnosed with attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). In ADHD, elevated serum zonulin levels were associated with impaired social functioning compared to controls. Children with ASD may be predisposed to impair intestinal barrier function, which may contribute to their symptoms and clinical outcome compared to controls. Children with ASD, who experience gastro-intestinal (GI) symptoms, seem to have an imbalance in their immune response. However, in children with OCD, serum zonulin levels were not significantly different compared to controls, but serum claudin-5, a transmembrane tight-junction protein, was significantly higher. A meta-analysis of mean zonulin plasma levels of patients and control groups revealed a significant difference between groups (p = 0.001), including the four studies evaluating the full spectrum of the zonulin peptide family. Therefore, further studies are required to better understand the complex role of barrier function, i.e., intestinal and blood-brain barrier, and of inflammation, to the pathophysiology in mental and neurodevelopmental disorders. This review was PROSPERO preregistered, (162208).
    • Retention and response rates in 14 261 PsA patients starting TNF inhibitor treatment-results from 12 countries in EuroSpA.

      Brahe, Cecilie Heegaard; Ørnbjerg, Lykke Midtbøll; Jacobsson, Lennart; Nissen, Michael J; Kristianslund, Eirik Klami; Mann, Herman; Santos, Maria José; Reino, Juan Gómez; Nordström, Dan; Rotar, Ziga; et al. (Oxford University Press, 2020-07)
      Objective: To investigate TNF inhibitor (TNFi) retention and response rates in European biologic-naïve patients with PsA. Methods: Prospectively collected data on PsA patients in routine care from 12 European registries were pooled. Heterogeneity in baseline characteristics between registries were explored (analysis of variance and pairwise comparison). Retention rates (Kaplan-Meier), clinical remission [28-joint count DAS (DAS28) <2.6; 28 joint Disease Activity index for Psoriatic Arthritis ⩽4] and ACR criteria for 20% improvement (ACR20)/ACR50/ACR70 were calculated, including LUNDEX adjustment. Results: Overall, 14 261 patients with PsA initiated a first TNFi. Considerable heterogeneity of baseline characteristics between registries was observed. The median 12-month retention rate (95% CI) was 77% (76, 78%), ranging from 68 to 90% across registries. Overall, DAS28/28 joint Disease Activity index for Psoriatic Arthritis remission rates at 6 months were 56%/27% (LUNDEX: 45%/22%). Six-month ACR20/50/70 responses were 53%/38%/22%, respectively. In patients initiating a first TNFi after 2009 with registered fulfilment of ClASsification for Psoriatic ARthritis (CASPAR) criteria (n = 1980) or registered one or more swollen joint at baseline (n = 5803), the retention rates and response rates were similar to those found overall. Conclusion: Approximately half of >14 000 patients with PsA who initiated first TNFi treatment in routine care were in DAS28 remission after 6 months, and three-quarters were still on the drug after 1 year. Considerable heterogeneity in baseline characteristics and outcomes across registries was observed. The feasibility of creating a large European database of PsA patients treated in routine care was demonstrated, offering unique opportunities for research with real-world data. Keywords: DAPSA28; DAS28; TNFi; drug survival; effectiveness; epidemiology; psoriatic arthritis; register; response; spondyloarthritis.
    • Effect of vaccination on the use of antimicrobial agents: a systematic literature review.

      Doherty, T Mark; Hausdorff, William P; Kristinsson, Karl G; 1Global Medical Affairs, GSK, Wavre, Belgium. 2PATH, Washington, DC, USA. 3Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. 4Department of Clinical Microbiology, Landspitali University Hospital, Reykjavík, Iceland. 5Faculty of Medicine, University of Iceland, Reykjavík, Iceland. (Taylor & Francis, 2020-06-29)
      Background: Antimicrobial resistance is a growing global health threat. To preserve the effectiveness of antimicrobials, it is important to reduce demand for antimicrobials. Objectives: The objective of the study was to screen the existing peer-reviewed literature to identify articles that addressed the potential impact of influenza or Pneumococcus vaccination on antibiotic usage. Data sources: PubMed, Embase Study eligibility criteria: Clinical studies where antimicrobial prescribing was assessed in both vaccinated and unvaccinated populations. Participants and interventions: All patient populations were included (infants, children, adults and elderly), where the effects of the intervention (vaccination) was assessed. Results: We identified unique 3638 publications, of which 26 were judged to be of sufficiently high quality to allow the calculation of the potential impact of vaccination. Of these studies 23/26 found a significant reduction in antibiotic use by at least one of the parameters assessed. Limitations: Different measures used to define anti-microbial use, studies typically focus on specific risk groups and most studies are from high-income countries. Conclusions and implications of key findings: Despite the limitations of the review, the evidence indicates that improved coverage with existing vaccines may significantly reduce antimicrobial demand. This suggests it may be a valuable tool for antimicrobial stewardship. Key messages While vaccines against a number of pathogens have been studied for their ability to reduce antimicrobial use, currently only vaccination against influenza or pneumococcus has generated sufficient data for analysis Vaccination against either influenza or pneumococcus significantly reduced overall antimicrobial prescribing rates, both in vaccinated individuals and at a population level Maintaining and expanding vaccination coverage thus appears to be a key tool for antimicrobial stewardship. Keywords: Vaccination; antimicrobial resistance; antimicrobial use; meta-analysis.
    • Does metabolomic profile differ with regard to birth weight?

      Vidarsdottir, Harpa; Thorkelsson, Thordur; Halldorsson, Thorhallur Ingi; Bjarnason, Ragnar; Geirsson, Reynir Tomas; Rinaldo, Piero; Franzson, Leifur; 1Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 2Astrid Lindgren Children´s Hospital, Karolinska University Hospital, Stockholm, Sweden. 3Children's Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 4Faculty for Food Science and Nutrition, School of Health Science, University of Iceland, Reykjavik, Iceland. 5Women's Clinic, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 6Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 7Faculty of Pharmaceutical Sciences, School of Health Science, Univeristy of Iceland, Reykjavik, Iceland. leifurfr@landspitali.is. 8Department of Genetics and Molecular Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. leifurfr@landspitali.is. (Nature Publishing Group, 2020-06-29)
      Background: Macrosomia and child obesity are growing health-care issues worldwide. The purpose of the study was to evaluate how extremely high or low birth weight affects metabolic markers evaluated in newborn screening. Methods: The study was register-based and included full-term singletons born in Iceland from 2009 to 2012 with newborn screening samples taken 72-96 h after birth. Three groups based on birth weight were compared: low birth weight (<2500 g), appropriate-for-gestational age, and extreme macrosomia (≥5000 g). The comparison was adjusted for possible confounding factors. Results: Compared to appropriate-for-gestational age neonates, both low birth weight and extreme macrosomia were associated with higher levels of glutamic acid. The amino acids alanine and threonine were increased in low birth weight neonates. Free carnitine and some medium- and long-chain acylcarnitines were higher in low birth weight infants. Hydroxybutyrylcarnitine was lower in low birth weight infants, but higher in extremely macrosomic neonates. Acetylcarnitine was higher in low birth weight and extremely macrosomic neonates. Succinylcarnitine was lower and hexadecenoylcarnitine higher in macrosomic newborns. Conclusion: Low birth weight and extremely macrosomic neonates show distinctive differences in their metabolomic profile compared to appropriate-for-gestational age newborns. The differences are not explained by gestational age. Impact: The key message of this article is that both low birth weight and extremely macrosomic newborns show dissimilar metabolomic profiles compared to appropriate-for-gestational age neonates.The article contributes to knowledge on what affects evaluation of results in newborn screening.The impact of this article is to provide information on metabolism at both ends of the birth weight range after accounting for confounding factors including gestational age.
    • Percutaneous coronary intervention in the very elderly with NSTE-ACS: the randomized 80+ study.

      Hirlekar, Geir; Libungan, Berglind; Karlsson, Thomas; Bäck, Maria; Herlitz, Johan; Albertsson, Per; 1Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden. 2Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. 3Department of Cardiology, University Hospital of Iceland, Reykjavik, Iceland. 4Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 5Department of Occupational Therapy and Physiotherapy, Sahlgrenska University Hospital, Gothenburg, Sweden. 6Centre for Pre-hospital Research, Faculty of Caring Science, Work Life and Social Welfare, University of Borås, Borås, Sweden. (Taylor & Francis, 2020-06-26)
      Objective: The treatment strategy in the very elderly with NSTE-ACS is debated, as they are often under-represented in clinical trials. The aim of this multicenter randomized controlled trial was to compare invasive and conservative strategies in the very elderly with NSTE-ACS.Methods: We randomly assigned patients ≥ 80 years of age with NSTE-ACS to an invasive strategy with coronary angiography and optimal medical treatment or a conservative strategy with only optimal medical treatment. The primary outcome was the combined endpoint of major adverse cardiac and cerebrovascular events (MACCE). Sample size was powered for a 50% reduction of event rate in MACCE with an invasive strategy. We used intention-to-treat analysis.Results: Altogether, 186 patients were included between 2009 and 2017. The study was terminated prematurely due to slow enrollment. At 12-month follow-up, the primary outcome occurred in 31 (33.3%) of the invasive treatment group and 34 (36.6%) of the conservative treatment group, with a hazard ratio (HR) of 0.90 (95% CI 0.55‒1.46; p = 0.66) for the invasive group relative to the conservative group. The corresponding HR value for urgent revascularization was 0.29 (95% CI 0.10‒0.85; p = 0.02), 0.56 (95% CI 0.27‒1.18; p = 0.13) for myocardial infarction, 0.70 (95% CI 0.31‒1.58; p = 0.40) for all-cause mortality, 1.35 (95% CI 0.23‒7.98; p = 0.74) for stroke, and 1.62 (95% CI 0.67‒3.90; p = 0.28) for recurrent hospitalization for cardiac reasons.Conclusion: In the very elderly with NSTE-ACS, we did not find any significant difference in MACCE between invasive and conservative treatment groups at 12-month follow-up, possibly due to small sample size. ClinicalTrials.gov: NCT02126202.
    • Feasibility of ActivABLES to promote home-based exercise and physical activity of community-dwelling stroke survivors with support from caregivers: A mixed methods study.

      Olafsdottir, Steinunn A; Jonsdottir, Helga; Bjartmarz, Ingibjörg; Magnusson, Charlotte; Caltenco, Héctor; Kytö, Mikko; Maye, Laura; McGookin, David; Arnadottir, Solveig Asa; Hjaltadottir, Ingibjörg; et al. (BioMed Central, 2020-06-22)
      Background: Technical applications can promote home-based exercise and physical activity of community-dwelling stroke survivors. Caregivers are often able and willing to assist with home-based exercise and physical activity but lack the knowledge and resources to do so. ActivABLES was established to promote home-based exercise and physical activity among community-dwelling stroke survivors, with support from their caregivers. The aim of our study is to investigate the feasibility of ActivABLES in terms of acceptability, demand, implementation and practicality. Methods: A convergent design of mixed methods research in which quantitative results were combined with personal experiences of a four-week use of ActivABLES by community-dwelling stroke survivors with support from their caregivers. Data collection before, during and after the four-week period included the Berg Balance Scale (BBS), Activities-Specific Balance Confidence Scale (ABC), Timed-Up-and-Go (TUG) and Five Times Sit to Stand Test (5xSST) and data from motion detectors. Semi-structured interviews were conducted with stroke survivors and caregivers after the four-week period. Descriptive statistics were used for quantitative data. Qualitative data was analysed with direct content analysis. Themes were identified related to the domains of feasibility: acceptability, demand, implementation and practicality. Data was integrated by examining any (dis)congruence in the quantitative and qualitative findings. Results: Ten stroke survivors aged 55-79 years participated with their informal caregivers. Functional improvements were shown in BBS (+ 2.5), ABC (+ 0.9), TUG (- 4.2) and 5xSST (- 2.7). More physical activity was detected with motion detectors (stand up/sit down + 2, number of steps + 227, standing + 0.3 h, hours sitting/lying - 0.3 h). The qualitative interviews identified themes for each feasibility domain: (i) acceptability: appreciation, functional improvements, self-initiated activities and expressed potential for future stroke survivors; (2) demand: reported use, interest in further use and need for follow-up; (3) implementation: importance of feedback, variety of exercises and progression of exercises and (4) practicality: need for support and technical problems. The quantitative and qualitative findings converged well with each other and supported the feasibility of ActivABLES. Conclusions: ActivABLES is feasible and can be a good asset for stroke survivors with slight or moderate disability to use in their homes. Further studies are needed with larger samples.
    • Beating the odds with systematic individualized care: Nationwide prospective follow-up of all patients with COVID-19 in Iceland.

      Helgason, D; Eythorsson, E; Olafsdottir, L B; Agustsson, T; Ingvarsdottir, S; Sverrisdottir, S; Ragnarsdottir, E D; Gottfredsson, M; Gudlaugsson, O; Palsson, R; et al. (Wiley, 2020-06-19)
      The current pandemic of a novel coronavirus disease 2019 (COVID‐19) began in December 2019 in Wuhan, China, and has since spread worldwide. Pandemic preparedness has been an ongoing project in Iceland since the Severe Acute Respiratory Syndrome (SARS) epidemic in 2003‐2004. In mid‐January 2020, The Directorate of Health (DOH) and The Department of Civil Protection and Emergency Management (DCPEM) revised the current pandemic preparedness response plan. The DOH and DCPEM, in close collaboration with the Department of Clinical Microbiology and Internal Medicine Services at Landspitali–The National University Hospital (LUH) and deCODE genetics, initiated a nationwide surveillance program for COVID‐19, including diagnostic testing which began on 31 January. A report on the extensive screening efforts in Iceland has recently been published.
    • COVID-19 highlights the need for universal adoption of standards of medical care for physicians in nursing homes in Europe.

      O'Neill, Desmond; Briggs, Robert; Holmerová, Iva; Samuelsson, Olafur; Gordon, Adam L; Martin, Finbarr C; 1Centre for Ageing, Neuroscience and the Humanities, Trinity College Dublin, Trinity Centre for Health Sciences, Tallaght University Hospital, Dublin, D24 NR0A, Ireland. doneill@tcd.ie. 2Trinity College Dublin, Dublin, Ireland. 3Charles University, Prague, Czech Republic. 4Landspitali University Hospital, Reykjavik, Iceland. 5Division of Medical Sciences and Graduate Entry Medicine, University of Nottingham, Nottingham, UK. 6Population Health Sciences, King's College London, London, UK. (Springer, 2020-06-17)
      The nursing home sector has seen a disproportionately high number of deaths as part of the COVID-19 pandemic. This reflects, in part, the frailty and vulnerability of older people living in care homes but has also, in part, been a consequence of the failure to include care homes in the systematic planning of a response to COVID, as well as a measure of neglect of standards and quality improvement in the sector. In response, the EUGMS published a set of medical standards of care developed in consultation with experts across its member national societies in 2015. The standards consisted of seven core principles of medical care for physicians working in nursing homes as a first step in developing a programme of clinical, academic and policy engagement in improving medical care for older people who are living and frequently also dying as residents in nursing homes. The gravity of the concerns arising for nursing home care from the COVID-19 pandemic, as well as emerging insights on care improvement in nursing homes indicate that an update of these medical standards is timely. This was performed by the writing group from the original 2015 guidelines and is intended as an interim measure pending a more formal review incorporating a systematic review of emerging literature and a Delphi process. Keywords: COVID-19; MeSH; Nursing home; Physicians; Standard of care.
    • Expression of ncRNAs on the DLK1-DIO3 Locus Is Associated With Basal and Mesenchymal Phenotype in Breast Epithelial Progenitor Cells.

      Budkova, Zuzana; Sigurdardottir, Anna Karen; Briem, Eirikur; Bergthorsson, Jon Thor; Sigurdsson, Snævar; Magnusson, Magnus Karl; Traustadottir, Gunnhildur Asta; Gudjonsson, Thorarinn; Hilmarsdottir, Bylgja; 1Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 2Department of Laboratory Hematology, Landspitali - University Hospital, Reykjavik, Iceland. 3Department of Pharmacology and Toxicology, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 4Department of Pathology, Landspitali - University Hospital, Reykjavik, Iceland. (Frontiers Media S.A., 2020-06-16)
      Epithelial-to-mesenchymal transition (EMT) and its reversed process mesenchymal-to-epithelial transition (MET) play a critical role in epithelial plasticity during development and cancer progression. Among important regulators of these cellular processes are non-coding RNAs (ncRNAs). The imprinted DLK1-DIO3 locus, containing numerous maternally expressed ncRNAs including the lncRNA maternally expressed gene 3 (MEG3) and a cluster of over 50 miRNAs, has been shown to be a modulator of stemness in embryonic stem cells and in cancer progression, potentially through the tumor suppressor role of MEG3. In this study we analyzed the expression pattern and functional role of ncRNAs from the DLK1-DIO3 locus in epithelial plasticity of the breast. We studied their expression in various cell types of breast tissue and revisit the role of the locus in EMT/MET using a breast epithelial progenitor cell line (D492) and its isogenic mesenchymal derivative (D492M). Marked upregulation of ncRNAs from the DLK1-DIO3 locus was seen after EMT induction in two cell line models of EMT. In addition, the expression of MEG3 and the maternally expressed ncRNAs was higher in stromal cells compared to epithelial cell types in primary breast tissue. We also show that expression of MEG3 is concomitant with the expression of the ncRNAs from the DLK1-DIO3 locus and its expression is therefore likely indicative of activation of all ncRNAs at the locus. MEG3 expression is correlated with stromal markers in normal tissue and breast cancer tissue and negatively correlated with the survival of breast cancer patients in two different cohorts. Overexpression of MEG3 using CRISPR activation in a breast epithelial cell line induced partial EMT and enriched for a basal-like phenotype. Conversely, knock down of MEG3 using CRISPR inhibition in a mesenchymal cell line reduced the mesenchymal and basal-like phenotype of the cell line. In summary our study shows that maternally expressed ncRNAs are markers of EMT and suggests that MEG3 is a novel regulator of EMT/MET in breast tissue. Nevertheless, further studies are needed to fully dissect the molecular pathways influenced by non-coding RNAs at the DLK1-DIO3 locus in breast tissue.