Recent Submissions

  • The first wave of COVID-19 and concurrent social restrictions were not associated with a negative impact on mental health and psychiatric well-being.

    Love, Thorvardur Jon; Wessman, Inga; Gislason, Gauti Kjartan; Rognvaldsson, Saemundur; Thorsteinsdottir, Sigrun; Sigurdardottir, Gudrun Asta; Thordardottir, Asdis Rosa; Eythorsson, Elias; Asgeirsdottir, Tinna Laufey; Aspelund, Thor; et al. (Wiley, 2022-02-02)
    Background: The coronavirus disease 2019 (COVID-19) pandemic and efforts to contain it have substantially affected the daily lives of most of the world's population. Objective: We describe the impact of the first COVID-19 wave and associated social restrictions on the mental health of a large adult population. Methods: We performed a cohort study nested in a prospective randomized clinical trial, comparing responses during the first COVID-19 wave to previous responses. We calculated the odds ratio (OR) of the population moving up one severity category on validated instruments used to measure stress (PSS-10), anxiety (GAD-7), depression (PHQ-9), and Satisfaction With Life Scale (SWLS). Responses were linked to inpatient and outpatient ICD-10 codes from registries. Models were adjusted for age, sex, comorbidities, and pre-existing diagnoses of mental illness. Results: Of 63,848 invited participants, 42,253 (66%) responded. The median age was 60 (inter-quartile range 53-68) and 19,032 (45%) were male. Responses during the first wave of COVID-19 did not suggest increased stress (OR 0.97; 95% confidence interval [CI], 0.93-1.01; p = 0.28) or anxiety (OR 1.01; 95% CI, 0.96 to 1.05; p = 0.61), but were associated with decreased depression (OR 0.89; 95% CI, 0.85-0.93, p < 0.0001) and increased satisfaction with life (OR 1.12; 95% CI, 1.08-1.16, p < 0.0001). A secondary analysis of repeated measures data showed similar results. Conclusions: Social restrictions were sufficient to contain the pandemic but did not negatively impact validated measures of mental illness or psychiatric well-being. However, responses to individual questions showed signs of fear and stress. This may represent a normal, rather than pathological, population response to a stressful situation. Keywords: COVID-19; mental health; pandemics.
  • International links between Streptococcus pneumoniae vaccine serotype 4 sequence type (ST) 801 in Northern European shipyard outbreaks of invasive pneumococcal disease.

    Gladstone, R A; Siira, L; Brynildsrud, O B; Vestrheim, D F; Turner, P; Clarke, S C; Srifuengfung, S; Ford, R; Lehmann, D; Egorova, E; et al. (Elsevier, 2022-01-05)
    Background: Pneumococcal disease outbreaks of vaccine preventable serotype 4 sequence type (ST)801 in shipyards have been reported in several countries. We aimed to use genomics to establish any international links between them. Methods: Sequence data from ST801-related outbreak isolates from Norway (n = 17), Finland (n = 11) and Northern Ireland (n = 2) were combined with invasive pneumococcal disease surveillance from the respective countries, and ST801-related genomes from an international collection (n = 41 of > 40,000), totalling 106 genomes. Raw data were mapped and recombination excluded before phylogenetic dating. Results: Outbreak isolates were relatively diverse, with up to 100 SNPs (single nucleotide polymorphisms) and a common ancestor estimated around the year 2000. However, 19 Norwegian and Finnish isolates were nearly indistinguishable (0-2 SNPs) with the common ancestor dated around 2017. Conclusion: The total diversity of ST801 within the outbreaks could not be explained by recent transmission alone, suggesting that harsh environmental and associated living conditions reported in the shipyards may facilitate invasion of colonising pneumococci. However, near identical strains in the Norwegian and Finnish outbreaks does suggest that transmission between international shipyards also contributed to those outbreaks. This indicates the need for improved preventative measures in this working population including pneumococcal vaccination. Keywords: Molecular epidemiology; Outbreak; PCVs; PPV23; Pneumococcal; ST801; Serotype 4; Streptococcus pneumoniae; Whole genome sequencing.
  • Do patient-reported measures of disease activity in rheumatoid arthritis vary between countries? Results from a Nordic collaboration.

    Delcoigne, Bénédicte; Provan, Sella Aarrestad; Hammer, Hilde Berner; Di Giuseppe, Daniela; Frisell, Thomas; Glintborg, Bente; Grondal, Gerdur; Gudbjornson, Bjorn; Hetland, Merete Lund; Michelsen, Brigitte; et al. (Oxford University Press, 2022-02-09)
    Objectives: To investigate whether patient-reported outcomes vary across countries and are influenced by cultural/contextual factors. Specifically, we aimed to assess inter-country differences in tender joint count (TJC), pain and patient's global health assessment (PGA), and their impact on disease activity (DAS28-CRP) in rheumatoid arthritis (RA) patients from five Nordic countries. Methods: We collected data (baseline, 3- and 12-months) from rheumatology registers in the five countries comprising RA patients starting a first-ever methotrexate or a first-ever tumor necrosis factor inhibitor (TNFi). In order to assess the role of context (=country), we separately modelled TJC, pain and PGA as functions of objective variables (C-reactive protein, swollen joint count, age, sex, calendar period and disease duration) with linear models. Analyses were performed at each time point and for both treatments. We further assessed the impact of inter-country differences on DAS28-CRP. Results: 27 645 RA patients started methotrexate and 19 733 started a TNFi. Crude inter-country differences at methotrexate start amounted to up to 4 points (28 points scale) for TJC, 10 and 27 points (0-100 scale) for pain and PGA, respectively. Corresponding numbers at TNFi start were 3 (TJC), 27 (pain) and 24 (PGA) points. All differences were reduced at 3- and 12-months, and attenuated when adjusting for the objective variables. The variation in predicted DAS28-CRP across countries amounted to < 0.5 units. Conclusions: Inter-country differences in TJC, pain and PGA are greater than expected based on differences in objective measures, but have a small clinical impact on DAS28-CRP across countries. Keywords: Patient-reported outcome (PRO); disease activity; inter-country comparison; pain; rheumatoid arthritis.
  • Dili is rare amongst patients without liver metastases receiving cancer treatment in Iceland: a population-based cohort study.

    Björnsson, H K; Sverrisdottir, A; Björnsson, E S; 1Division of Gastroenterology and Hepatology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 2Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden. 3Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 4Department of Oncology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2022-02-09)
    Background: There is limited information on the frequency of idiosyncratic drug-liver injury (DILI) among cancer patients. The aim of the study was to evaluate the frequency of DILI due to cancer treatment in a population-based setting. Material and methods: All patients diagnosed with genitourinary cancer, breast cancer or metastatic malignant melanoma in 2007-2018 were matched with a database containing laboratory results for all major hospitals in Iceland. Medical chart review was performed for cases with ALT/AST ≥5× upper limit of normal (ULN), ALP ≥2× ULN or bilirubin ≥2× ULN. Patients with liver-, and/or bone metastases and isolated elevations of ALP and patients with other etiologies of liver enzyme elevations were excluded. Cases with a RUCAM score of probable or highly probable were included. Results: Among 4956 patients, 840 patients had liver enzyme elevations. Overall, nine (0.2%) cases of DILI were identified, seven women (78%), median age 59 years (IQR 52-66). Four patients had kidney cancer, four breast cancer and one metastatic prostate cancer. In eight cases, a single agent was implicated: Pazopanib (n = 3), axitinib, docetaxel, gemcitabine, letrozole and paclitaxel. In all cases, the treatment was interrupted or discontinued due to the liver injury. No patient developed jaundice or liver failure and no death was linked to DILI. Time to normalization of liver enzymes was 17 days (IQR 25-120). Conclusion: DILI was found to be rare and no cases of severe liver injury occurred. However, approximately 90% of patients switched to another treatment which might have affected prognosis. Keywords: DILI; RUCAM; hepatotoxicity; liver enzymes; malignancy.
  • Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene.

    Arnadottir, Gudny A; Oddsson, Asmundur; Jensson, Brynjar O; Gisladottir, Svanborg; Simon, Mariella T; Arnthorsson, Asgeir O; Katrinardottir, Hildigunnur; Fridriksdottir, Run; Ivarsdottir, Erna V; Jonasdottir, Adalbjorg; et al. (Nature Publishing Group, 2022-02-04)
    Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.
  • Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.

    Hautakangas, Heidi; Winsvold, Bendik S; Ruotsalainen, Sanni E; Bjornsdottir, Gyda; Harder, Aster V E; Kogelman, Lisette J A; Thomas, Laurent F; Noordam, Raymond; Benner, Christian; Gormley, Padhraig; et al. (Nature Publishing Group, 2022-02-03)
    Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
  • Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology.

    Bjornsdottir, Gyda; Stefansdottir, Lilja; Thorleifsson, Gudmar; Sulem, Patrick; Norland, Kristjan; Ferkingstad, Egil; Oddsson, Asmundur; Zink, Florian; Lund, Sigrun H; Nawaz, Muhammad S; et al. (Nature Publishing Group, 2022-02-02)
    Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.
  • Lower Intake of Saturated Fatty Acids Is Associated with Improved Lipid Profile in a 6-Year-Old Nationally Representative Population.

    Helgadottir, Hafdis; Thorisdottir, Birna; Gunnarsdottir, Ingibjorg; Halldorsson, Thorhallur I; Palsson, Gestur; Thorsdottir, Inga; 1Unit for Nutrition Research, Health Science Institute, School of Health Sciences, University of Iceland, 102 Reykjavik, Iceland. 2Faculty of Sociology, Anthropology and Folkloristics, School of Social Sciences, University of Iceland, 102 Reykjavik, Iceland. 3Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland, 102 Reykjavik, Iceland. 4Children's Hospital, Landspitali University Hospital, 101 Reykjavik, Iceland. (MDPI Publishing, 2022-02-05)
    To strengthen the organization of new national dietary surveys and interventions in childhood, our aim was to study macronutrient intake and blood lipid profile at 6 years of age by comparing results from two earlier population-based cohorts. Subjects were n = 131 and n = 162 in the years 2001-2002 and 2011-2012, respectively. Three-day weighed food records were used to estimate diet and calculate nutrient intake. Total cholesterol, HDL-cholesterol and triacylglycerol were measured in serum and LDL-cholesterol was calculated. The average intake of saturated fatty acids (SFA) and trans FA was lower in 2011-2012 than 2001-2002 (13.3E% vs. 14.7E%, p &lt; 0.001, and 0.8E% vs. 1.4E%, p &lt; 0.001, respectively), replaced by a higher intake of unsaturated fatty acids. Total cholesterol and LDL-cholesterol were significantly lower in 2011-2012 than 2001-2002 (4.6 vs. 4.4 mmol/L, p = 0.003 and 2.8 vs. 2.5 mmol/L, p &lt; 0.001, respectively). In a multiple linear regression model, one E% increase in SFA intake was related to a 0.03 mmol/L increase in LDL cholesterol (p = 0.04). A lower intake of saturated and trans fatty acids, replaced by unsaturated fatty acids, may have contributed to an improved lipid profile in a healthy 6-year-old population. Biological data for analysis of blood lipids are important in national dietary surveys in healthy children to monitor important health outcomes of interventions.
  • Long-term sequelae of drug-induced liver injury.

    Björnsson, Einar S; Andrade, Raul J; 1Faculty of Medicine, University of Iceland, Iceland; Department of Gastroenterology, Landspitali University Hospital Reykjavik, Iceland. Electronic address: einarsb@landspitali.is. 2Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. Electronic address: andrade@uma.es. (Elsevier, 2021-10-22)
    Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life-threatening liver failure. Chronic injury has also been reported to occur at a variable frequency, ranging from 3.4% to 39%, 6-12 months after discontinuing the implicated agent. This wide range is probably related to various definitions of chronic liver injury and variable selection of patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear, although rare vanishing bile duct syndrome is associated with an unfavourable prognosis, with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and, as a common final stage, the development of cirrhosis, portal hypertension and its complications. Immune checkpoint inhibitors, which can cause an autoimmune-like phenotype have also recently been shown to cause sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have a significant impact on health-related quality of life but very little is known about its psychological consequences in the long-term. Further investigations with structured long-term follow-up and periodic quality of life surveys are needed to assess the impact of DILI on psychological outcomes, particularly in those with chronic sequelae. Keywords: DILI; cirrhosis; drug-induced autoimmune hepatitis; hepatotoxicity; psychological disability; secondary sclerosing cholangitis; sinusoidal obstruction syndrome; vanishing bile duct syndrome.
  • Universal prediction of cell-cycle position using transfer learning.

    Zheng, Shijie C; Stein-O'Brien, Genevieve; Augustin, Jonathan J; Slosberg, Jared; Carosso, Giovanni A; Winer, Briana; Shin, Gloria; Bjornsson, Hans T; Goff, Loyal A; Hansen, Kasper D; et al. (BioMed Central, 2022-01-31)
    Background: The cell cycle is a highly conserved, continuous process which controls faithful replication and division of cells. Single-cell technologies have enabled increasingly precise measurements of the cell cycle both as a biological process of interest and as a possible confounding factor. Despite its importance and conservation, there is no universally applicable approach to infer position in the cell cycle with high-resolution from single-cell RNA-seq data. Results: Here, we present tricycle, an R/Bioconductor package, to address this challenge by leveraging key features of the biology of the cell cycle, the mathematical properties of principal component analysis of periodic functions, and the use of transfer learning. We estimate a cell-cycle embedding using a fixed reference dataset and project new data into this reference embedding, an approach that overcomes key limitations of learning a dataset-dependent embedding. Tricycle then predicts a cell-specific position in the cell cycle based on the data projection. The accuracy of tricycle compares favorably to gold-standard experimental assays, which generally require specialized measurements in specifically constructed in vitro systems. Using internal controls which are available for any dataset, we show that tricycle predictions generalize to datasets with multiple cell types, across tissues, species, and even sequencing assays. Conclusions: Tricycle generalizes across datasets and is highly scalable and applicable to atlas-level single-cell RNA-seq data. Keywords: Cell cycle; Single-cell RNA-sequencing; Transfer learning.
  • A Patients' Perspective Towards the Injection Devices for Humira® and Imraldi® in a Nationwide Switching Program.

    Karlsdottir, Kristin; Gunnarsdottir, Anna I; Grondal, Gerdur; Love, Thorvardur J; Stefansdottir, Elinborg; Davidsdottir, Loa G; Thorleifsdottir, Ragna H; Gudbjornsson, Bjorn; 1Hospital Pharmacy, Landspitali University Hospital, Reykjavik, Iceland. 2School of Health Sciences, University of Iceland, Reykjavik, Iceland. 3Centre for Rheumatology Research, Landspitali University Hospital, Reykjavik, Iceland. 4Department of Rheumatology, Landspitali University Hospital, Reykjavik, Iceland. 5Science and Research, Landspitali University Hospital, Reykjavik, Iceland. 6Department of Gastroenterology, Landspitali University Hospital, Reykjavik, Iceland. 7The Dermatology Center, Reykjavik, Iceland. (Frontiers Media S.A., 2022-01-27)
    Objective: Due to a tender process in Iceland, all patients on Humira® were switched nationwide to its biosimilar Imraldi® in March 2019. The study aimed to explore the patient's perspective of the Humira® and Imraldi® injection devices. Methods: A standard telephone interview was carried out among patients with inflammatory arthritis, inflammatory bowel disease and psoriasis, who underwent this nationwide switching program a few months earlier. Results: The response rate was 84.5% (n = 198). The average age was 50.8 years, and 53.5% were female. The patients self-administered the drugs in 96% of the cases. The majority (90.5%) stated that they received individualized instruction on using the Humira® pen, compared to 18.2% who accepted instruction in the case of the Imraldi® pen. Almost half (46.6%) of the patients found it more difficult to use the Imraldi® pen than the Humira® pen, while only 12.5% found the Imraldi® pen easier to use. Firstly, these differences were due to more painful insertion of the needle (62.2%) and secondly, due to the experience, the injection process was different (63.0%). Conclusion: Patients with inflammatory disorders who have been treated regularly with adalimumab preferred the Humira® injection device over the Imraldi® device, according to our results. After all, these injection devices' structure and content are not the same, although both contain the same active ingredient, i.e. adalimumab. Our results highlight the importance of thorough information, not only with an information letter but also with the possibilities for individualized introduction in planning switching to biosimilars. Keywords: Humira; Imraldi; adalimumab; injection devices; medicine administration at home.
  • Graduating nurse students' interest in older people nursing-A cross-sectional survey in six European countries.

    Koskinen, Sanna; Burke, Eimear; Fatkulina, Natalja; Fuster, Pilar; Löyttyniemi, Eliisa; Salminen, Leena; Stubner, Juliane; Thorsteinsson, Hrund Scheving; Leino-Kilpi, Helena; 1Department of the Nursing Science, University of Turku, Turku, Finland. 2School of Nursing and Midwifery, National University of Ireland, Galway, Ireland. 3Institute of Health Sciences, Vilnius University, Vilnius, Lithuania. 4Nursing Department, Universitat Internacional de Catalunya, Sant Cugat del Valles, Spain. 5Unit of Biostatistics, University of Turku, Turku, Finland. 6Turku University Hospital, Turku, Finland. 7Institute of Health and Nursing Science, Martin Luther University Halle-Wittenberg, Halle, Germany. 8Department of Development and Education, Landspitali University Hospital, Reykjavik, Iceland. (Wiley, 2022-01-26)
    Background: Countries vary in the number of qualified nurses employed in older adult services. Moreover, students' views of older people nursing as a career differ internationally. Studying future nurses and their career intentions for the field is warranted to meet the increased nurse workforce expectations in terms of quantity and competence. Aim: To analyse graduating nurse students' interest in older people nursing and the factors associated with it. Methods: A cross-sectional multicountry survey design was applied. Data were collected between May 2018 and March 2019 from several educational institutions in Finland, Germany, Iceland, Ireland, Lithuania and Spain. Non-probability convenience sampling was used to recruit graduating nurse students (n = 1796). The data were collected with a structured questionnaire comprising background factors and the Willingness sub-scale (six items) of the Students' Interest in Nursing Older People Scale. Data were analysed using a linear mixed model including relevant background variables. Results: Overall, students' interest in older people nursing was low (score 20.5, on a 0-100 scale). Among the studied countries, Spanish students scored the highest (38.8) and German students the lowest (3.6). Students' interest in older people nursing was associated with country (p < .001), the length of work experience (p = .006), plans for further study (p = .007), competence (p < .001) and the extent that nursing is valued by society (p < .001). The students who were most interested in older people nursing had higher self-reported competence level (p < .001). Conclusion: In the studied sample of future nurse professionals, interest in older people nursing is low at a time when the field suffers from workforce shortage. As for quality workforce, it was promising that the students who considered working in the field also evaluated themselves as competent. Implications for practice: Multidimensional actions are required to promote interest in the field, including continued development of competence in both undergraduate education and workplaces, and investing in various career pathways to envisage potential opportunities. Keywords: Europe; career choice; cross-sectional studies; nursing; older people nursing; self report; students.
  • Topical noninvasive retinal drug delivery of a tyrosine kinase inhibitor: 3% cediranib maleate cyclodextrin nanoparticle eye drops in the rabbit eye.

    Lorenzo-Soler, Laura; Praphanwittaya, Pitsiree; Olafsdottir, Olof Birna; Kristinsdottir, Iris Myrdal; Asgrimsdottir, Gudrun Marta; Loftsson, Thorsteinn; Stefansson, Einar; 1Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 2Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavík, Iceland. 3Department of Ophthalmology, Landspitali University Hospital, Reykjavík, Iceland. 4Oculis ehf., Reykjavík, Iceland. (Wiley, 2022-01-26)
    Purpose: Tyrosine kinase inhibitors inhibit VEGF receptors. If delivered to the retina, they might inhibit oedema and neovascularization such as in age-related macular degeneration and diabetic retinopathy. The aim of this study was to formulate cediranib maleate, a potent VEGF inhibitor, as γ-cyclodextrin nanoparticle eye drops and measure the retinal delivery and overall ocular pharmacokinetics after a single-dose administration in rabbits. Methods: A novel formulation technology with 3% cediranib maleate as γ-cyclodextrin micro-suspension was prepared by autoclaving method. Suitable stabilizers were tested for heat-stable eye drops. The ophthalmic formulation was topically applied to one eye in rabbits. The pharmacokinetics in ocular tissues, tear film and blood samples were studied at 1, 3 and 6 hr after administration. Results: γ-cyclodextrin formed complex with cediranib maleate. The formation of γ-cyclodextrin nanoparticles occurred in concentrated complexing media. Combined stabilizers prevented the degradation of drug during the autoclaving process. Three hours after administration of the eye drops, treated eyes showed cediranib levels of 737 ± 460 nM (mean ± SD) in the retina and 10 ± 6 nM in the vitreous humour. Conclusions: Cediranib maleate in γ-cyclodextrin nanoparticles were stable to heat in presence of stabilizers. The drug as eye drops reached the retina in concentrations that are more than 100 times higher than the 0.4 nM IC50 value reported for the VEGF type-II receptor and thus, presumably, above therapeutic level. These results suggest that γ-cyclodextrin-based cediranib maleate eye drops deliver effective drug concentrations to the retina in rabbits after a single-dose administration. Keywords: cediranib; cyclodextrins; drug delivery; in vivo; neovascularization; pharmacokinetics; topical administration.
  • Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs.

    Framme, Jenny Lingman; Lundqvist, Christina; Lundell, Anna-Carin; van Schouwenburg, Pauline A; Lemarquis, Andri L; Thörn, Karolina; Lindgren, Susanne; Gudmundsdottir, Judith; Lundberg, Vanja; Degerman, Sofie; et al. (Springer, 2022-01-26)
    Background: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS). Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed. Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells. Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring. Clinical implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices. Keywords: 22q11.2 deletion syndrome; DiGeorge syndrome; T lymphopenia; TREC; long-term outcome; newborn screening; severe combined immunodeficiency.
  • Creativity, leisure activities, social engagement and cognitive impairment: the AGES-Reykjavík study.

    Hansdottir, Helga; Jonsdottir, María K; Fisher, Diana E; Eiriksdottir, Gudny; Jonsson, Palmi V; Gudnason, Vilmundur; 1Mörkin and Grund Nursing Homes, Reykjavík, Iceland. helga.hansdottir@morkin.is. 2Department of Psychology, Reykjavík University, Reykjavik, Iceland. 3Office of Vision, Health and Population Sciences, Intramural Research Program, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. 4Icelandic Heart Association, Reykjavik, Iceland. 5Department of Geriatrics, Faculty of Medicine, Landspitali University Hospital, University of Iceland, Reykjavik, Iceland. 6Faculty of Medicine, University of Iceland, Icelandic Heart Association, Reykjavik, Iceland. (Springer, 2022-01-25)
    Background: Participation in leisure activities and extensive social network have been associated with lower risk of cognitive impairment (CI) and dementia. Aims: We examined whether leisure activities (cognitive solitary, cognitive group, social, physical, or creative activities) and social involvement are associated with less incidence of CI or dementia. Methods: Analyses were performed from data of 2933 cognitively intact individuals at baseline included in the AGES-REYKJAVIK study. Odds ratios (OR) were calculated for incident CI and dementia in relation to cognitive individual, cognitive group, social, physical, and creative leisure activities as well as social networks. Models were adjusted for a number of known risk factors for cognitive decline. Results: In 5 years, 12% of the cohort were diagnosed with CI or dementia. All leisure activities were associated with reduced likelihood of cognitive decline in the raw model, but in adjusted models, cognitive solitary [OR 0.49 (Confidence Interval (CI) 0.38-0.64)], cognitive group [OR 0.50 (CI 0.30-0.82)], and creative activities [OR 0.53 (CI 0.35-0.83)] were significantly associated with less cognitive decline. Analyses examining creative leisure activities independently, controlling for all other activities, suggested individuals participating in creative activities exhibited less CI [OR 0.64 (CI 0.41-0.98)]. Among social networks variables, frequency of meeting with friends and relatives was associated with reduced likelihood of CI [OR 0.49 (CI 0.31-0.75)]. Discussion: Cognitive and creative leisure activities and frequent gatherings with friends and relatives are associated with reduced incidence of CI in this older cohort. Conclusion: Creative leisure activities might have special benefit for cognitive ability. Keywords: Cognitive impairment; Creativity; Dementia; Elderly; Leisure activities; Social relations.
  • Effectiveness of Nursing Interventions for Patients With Cancer and their Family Members: A Systematic Review.

    Alfaro-Díaz, Cristina; Svavarsdottir, Erla Kolbrun; Esandi, Nuria; Klinke, Marianne E; Canga-Armayor, Ana; 1Universidad de Navarra, Pamplona, Spain. 2Navarra Institute for Health Research, Pamplona, Spain. 3University of Iceland, Reykjavik, Iceland. 4Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. (Sage Publications, 2022-01-21)
    Cancer diagnosis poses enormous physical and psychosocial challenges for both the affected person and their families. This systematic review identifies the characteristics and effectiveness of nursing interventions offered to adult patients with cancer and their families. Five databases were searched, and 19 studies published from 2009 to 2020 were included. Interventions were categorized as follows: (a) interventions with supporting and cognitive components (n = 3), (b) interventions that included skills training for the caregiver (n = 3), (c) interventions to enhance care through managing symptoms (n = 8), (d) interventions focusing on the dyad or family-patient relationship (n = 4), and (e) interventions targeted to the patient's condition (n = 1). The results of this review offer an overview from which to carry out new studies and are useful for providing future directions within family nursing practice, taking into account the impact that the family has on the disease and the consequences the condition may bring to the whole family.
  • Opioids for Treatment of Pre-hospital Acute Pain: A Systematic Review.

    Friesgaard, Kristian Dahl; Vist, Gunn Elisabeth; Hyldmo, Per Kristian; Raatiniemi, Lasse; Kurola, Jouni; Larsen, Robert; Kongstad, Poul; Magnusson, Vidar; Sandberg, Mårten; Rehn, Marius; et al. (Springer, 2022-01-18)
    Introduction: Acute pain is a frequent symptom among patients in the pre-hospital setting, and opioids are the most widely used class of drugs for the relief of pain in these patients. However, the evidence base for opioid use in this setting appears to be weak. The aim of this systematic review was to explore the efficacy and safety of opioid analgesics in the pre-hospital setting and to assess potential alternative therapies. Methods: The PubMed, EMBASE, Cochrane Library, Centre for Reviews and Dissemination, Scopus, and Epistemonikos databases were searched for studies investigating adult patients with acute pain prior to their arrival at hospital. Outcomes on efficacy and safety were assessed. Risk of bias for each included study was assessed according to the Cochrane approach, and confidence in the evidence was assessed using the GRADE method. Results: A total of 3453 papers were screened, of which the full text of 125 was assessed. Twelve studies were ultimately included in this systematic review. Meta-analysis was not undertaken due to substantial clinical heterogeneity among the included studies. Several studies had high risk of bias resulting in low or very low quality of evidence for most of the outcomes. No pre-hospital studies compared opioids with placebo, and no studies assessed the risk of opioid administration for subgroups of frail patients. The competency level of the attending healthcare provider did not seem to affect the efficacy or safety of opioids in two observational studies of very low quality. Intranasal opioids had a similar effect and safety profile as intravenous opioids. Moderate quality evidence supported a similar efficacy and safety of synthetic opioid compared to morphine. Conclusions: Available evidence for pre-hospital opioid administration to relieve acute pain is scarce and the overall quality of evidence is low. Intravenous administration of synthetic, fast-acting opioids may be as effective and safe as intravenous administration of morphine. More controlled studies are needed on alternative routes for opioid administration and pre-hospital pain management for potentially more frail patient subgroups. Keywords: Acute pain; Emergency medicine; Opioids; Pre-hospital.
  • Temporal trends in the epidemiology, management, and outcome of sepsis-A nationwide observational study.

    Vesteinsdottir, Edda; Sigurdsson, Martin Ingi; Gottfredsson, Magnus; Blondal, Asbjorn; Karason, Sigurbergur; 1Department of Anaesthesia and Intensive Care, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3Department of Infectious Diseases, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 4Department of Anaesthesia and Intensive Care, Akureyri Hospital, Akureyri, Iceland. (Wiley, 2022-01-11)
    Background: Registry-based studies have shown increasing incidence of sepsis and declining mortality rates in recent years, but are inherently at risk of bias. The objectives of this study were to describe 11-year trends in the incidence, treatment and outcome of sepsis using clinical criteria with chart review. Methods: This was a retrospective, observational study. All adult admissions to Icelandic ICUs during years 2006, 2008, 2010, 2012, 2014, and 2016 were screened for severe sepsis or septic shock by ACCP/SCCM criteria (sepsis-2). Incidence, patient characteristics, treatment and outcome were compared across the study years. Results: During the six study years, 9166 patients were admitted to Icelandic ICUs, 971 (10.6%) because of severe sepsis or septic shock. The crude incidence of sepsis requiring admission to ICU remained stable between 0.55 and 0.75 per 1000 inhabitants. No statistically significant trends were observed over time in median patient age (67 years), APACHE II score (21), SOFA score (8) or Charlson Comorbidity Index (4). The time to antibiotic administration (median 1.8 h) in the emergency departments was stable over the study period but the time to lactate measurements decreased from 4.1 h in 2006 to 1.2 h in 2016, p < .001. The 28-day mortality was 25% and 1-year mortality 41%, both with no observed change with time. Conclusions: In a nationwide cohort, diagnosed with clinical criteria, the incidence of sepsis requiring intensive care did not change over an 11-year period. Mortality remained stable and only minimal changes were observed in initial resuscitation in the emergency departments. Keywords: critical care; epidemiology; mortality; sepsis; septic shock; surviving sepsis campaign.
  • Epidemiology of trauma in the subarctic regions of the Nordic countries.

    Steinvik, Tine; Raatiniemi, Lasse; Mogensen, Brynjólfur; Steingrímsdóttir, Guðrún B; Beer, Torfinn; Eriksson, Anders; Dehli, Trond; Wisborg, Torben; Bakke, Håkon Kvåle; 1Anaesthesia and Critical Care Research Group, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. tine_m_s@hotmail.com. 2Centre for prehospital emergency medicine, Oulu university hospital, Oulu, Finland. 3Department of Anaesthesia and Intensive Care, Hammerfest Hospital, Finnmark Health Trust, Hammerfest, Norway. 4University Hospital of Iceland Hringbraut 101, 101, Reykjavík, Iceland. 5University of Iceland, Sæmundargata 4, 102, Reykjavík, Iceland. 6Department of Emergency Medicine, Landspítali University Hospital, Fossvogur, 108, Reykjavík, Iceland. 7Unit of Forensic Medicine, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden. 8The National Board of Forensic Medicine, Stockholm, Sweden. 9Department of Gastrointestinal Surgery, University Hospital of North Norway, Tromsø, Norway. 10Anaesthesia and Critical Care Research Group, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. 11Norwegian National Advisory Unit on Trauma, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway. 12Department of Anaesthesiology and Intensive Care, University Hospital of North Norway, Tromsø, Norway. 13Trauma section, Department of Cardiothoracic and Vascular Surgery, University Hospital of North Norway, Tromsø, Norway. 14Department of Health and Care Sciences, Faculty of Health Science, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. (BioMed Central, 2022-01-11)
    Background: The northern regions of the Nordic countries have common challenges of sparsely populated areas, long distances, and an arctic climate. The aim of this study was to compare the cause and rate of fatal injuries in the northernmost area of the Nordic countries over a 5-year period. Methods: In this retrospective cohort, we used the Cause of Death Registries to collate all deaths from 2007 to 2011 due to an external cause of death. The study area was the three northernmost counties in Norway, the four northernmost counties in Finland and Sweden, and the whole of Iceland. Results: A total of 4308 deaths were included in the analysis. Low energy trauma comprised 24% of deaths and high energy trauma 76% of deaths. Northern Finland had the highest incidence of both high and low energy trauma deaths. Iceland had the lowest incidence of high and low energy trauma deaths. Iceland had the lowest prehospital share of deaths (74%) and the lowest incidence of injuries leading to death in a rural location. The incidence rates for high energy trauma death were 36.1/100000/year in Northern Finland, 15.6/100000/year in Iceland, 27.0/100000/year in Northern Norway, and 23.0/100000/year in Northern Sweden. Conclusion: We found unexpected differences in the epidemiology of trauma death between the countries. The differences suggest that a comparison of the trauma care systems and preventive strategies in the four countries is required. Keywords: Epidemiology; Injury; Rural; Trauma.
  • Low dose rabbit antithymocyte globulin is non-inferior to higher dose in low-risk pediatric kidney transplant recipients.

    Sigurjonsdottir, Vaka K; Maestretti, Lynn; McGrath, Anne; Concepcion, Waldo; Gallo, Amy; Jonsdottir, Urdur; Grimm, Paul C; Chaudhuri, Abanti; 1Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, CA, USA. vakaks@gmail.com. 2Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. vakaks@gmail.com. 3Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. vakaks@gmail.com. 4Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, CA, USA. 5Transplantation Services, Mohamed Bin Rashid University, Dubai, UAE. 6Division of Abdominal Transplantation, Department of Surgery, Stanford University, Palo Alto, CA, USA. 7Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. (Springer, 2022-01-10)
    Background: Currently, there is no consensus among pediatric kidney transplant centers regarding the use and regimen for immunosuppressive induction therapy. Methods: In this single center, retrospective cohort study, pediatric kidney transplant recipients transplanted between 1 May 2013 and 1 May 2018 with rabbit antithymocyte globulin (rATG) induction were included. We stratified patients based on immunological risk, with high risk defined as those with repeat transplant, preformed donor specific antibody, current panel-reactive antibodies > 20%, 0 antigen match and/or African-American heritage. Outcome of interest was the incidence of biopsy proven acute rejection by 1 year. Results: A total of 166 patients met inclusion criteria. Age of patients was 12 years (11 mo-21 y), (median, range), 21.5% received a living donor transplant and 50.6% were female. Low-immunologic-risk patients were divided into 2 groups, those who received the lower cumulative rATG dose of ≤ 3.5 mg/kg (n = 52) versus the higher cumulative dose of > 3.5 mg/kg (n = 47). The median total dose in the lower dose group was 3.1 (IQR 0.3) and 4.4 (IQR 0.8) in the higher dose group, P < 0.001. Rejection rate did not differ significantly between the 2 treatment groups (7/52 vs. 6/47). None in the lower dose group developed BK nephropathy versus 3 in the higher dose group. Graft loss due to BK nephropathy occurred in 1 patient in the higher dose group. Graft loss in the whole cohort at 12 months was a rare event (n = 1) with 99.5% graft survival and 100% patient survival. Conclusions: Reduced rATG dosing (≤ 3.5 mg/kg) when compared to higher dosing (> 3.5 mg/kg) is safe and effective in low-risk pediatric kidney transplant recipients without increasing risk of rejection. A higher resolution version of the Graphical abstract is available as Supplementary information. Keywords: Acute allograft rejection; Immunosuppression; Induction therapy; Thymoglobulin; Transplantation.

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