Recent Submissions

  • Larger head circumference in Icelandic children 0-4 years of age compared to the World Health Organization and Swedish growth charts.

    Juliusson, Petur B; Dagbjartsson, Atli; Roelants, Mathieu; Palsson, Gestur; Fridjonsdottir, Hildigunnur; Einarsdottir, Rosa; Thorsson, Arni V; 1Department of Clinical Science, University of Bergen, Bergen, Norway. 2Department of Paediatrics, Haukeland University Hospital, Bergen, Norway. 3Department of Health Registries, Norwegian Institute of Public Health, Bergen, Norway. 4Department of Paediatrics, Landspítalinn University Hospital, Reykjavik, Iceland. 5Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 6Environment and Health/Youth health Care, Department of Public Health and Primary Care, University of Leuven, KU Leuven, Belgium. (Wiley, 2019-12-05)
    Aim: The World Health Organization (WHO) published universal growth standards for children below five year of age in 2006. Traditionally, Swedish growth references have been used to monitor growth of children in Iceland, but it is not yet known how they compare with these reference charts. Methods: A total of 2128 longitudinal measurements of length or height, 2132 of weight and 2126 of head circumference between birth and four years of age were collected in 1996-2000 from 199 healthy children (53% boys) recruited at Landspitali University Hospital. Measurements were converted to z-scores using the WHO growth standards and Swedish growth references for further analysis with mixed-effects models. Results: Length or height, weight and in particular head circumference largely exceeded the WHO standards, with average z-scores that fluctuated between 0.5 and 1.5. Likewise, the proportion of children with a z-score larger than 2 SD increased about 10-fold. Icelandic children were longer and heavier than their Swedish peers during the first six months of life, but differences were less pronounced thereafter. Conclusion: The growth of Icelandic children deviated significantly from the WHO growth standards. Although more comparable to the Swedish references, significant differences were found, suggesting that a national growth reference would be more appropriate. Keywords: Growth anthropometry; Iceland; growth reference; growth standards; head circumference.
  • A retrospective cohort study on the association between elevated preoperative red cell distribution width and all-cause mortality after noncardiac surgery.

    Olafsson, Halldor B; Sigurdarson, Gissur A; Christopher, Kenneth B; Karason, Sigurbergur; Sigurdsson, Gisli H; Sigurdsson, Martin I; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. 3Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Division of Anaesthesia and Intensive Care Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. 4Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Division of Anaesthesia and Intensive Care Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland. Electronic address: (Elsevier Science, 2020-03-23)
    Background: Elevated red cell distribution width (RDW) has been associated with worse outcomes in several medical patient populations. The aim of this study was to investigate the association of increased preoperative RDW and short- and long-term mortality after noncardiac surgery. Methods: This investigation was a retrospective cohort study including all patients undergoing noncardiac surgery between 2005 and 2015 at Landspitali-the National University Hospital in Iceland. Patients were separated into five predefined groups based on preoperative RDW (≤13.3%, 13.4-14.0%, 14.1-14.7%, 14.8-15.8%, and >15.8%). The primary outcome was all-cause long-term mortality and secondary outcomes included 30-day mortality, length of stay, and readmissions within 30 days, compared with propensity score matched (PSM) cohort from patients with RDW ≤13.3%. Results: There was a higher hazard of long-term mortality for patients with RDW between 14.8% and 15.8% (hazard ratio=1.33; 95% confidence interval, 1.15-1.59; P<0.001) and above 15.8% (hazard ratio=1.66; 95% confidence interval, 1.41-1.95; P<0.001), compared with matched controls with RDW ≤13.3%. This association held in multiple patient subgroups. For secondary outcomes, there was no difference in 30-day mortality, length of stay, or risk of readmission within 30 days. Conclusions: Increased preoperative RDW is associated with increased long-term mortality after noncardiac surgery. RDW could be a composite biomarker of pre-existing chronic inflammation and poor nutritional status. Future studies should clarify if this is a modifiable risk factor for improved surgical outcomes. Keywords: inflammation; mortality; noncardiac surgery; perioperative outcome; propensity score matching; red cell distribution width.
  • Frequency of food allergy in school-aged children in eight European countries-The EuroPrevall-iFAAM birth cohort.

    Grabenhenrich, Linus; Trendelenburg, Valérie; Bellach, Johanna; Yürek, Songül; Reich, Andreas; Fiandor, Ana; Rivero, Daniela; Sigurdardottir, Sigurveig; Clausen, Michael; Papadopoulos, Nikolaos G; et al. (Wiley, 2020-03-27)
    Background: The prevalence of food allergy (FA) among European school children is poorly defined. Estimates have commonly been based on parent-reported symptoms. We aimed to estimate the frequency of FA and sensitization against food allergens in primary school children in eight European countries. Methods: A follow-up assessment at age 6-10 years of a multicentre European birth cohort based was undertaken using an online parental questionnaire, clinical visits including structured interviews and skin prick tests (SPT). Children with suspected FA were scheduled for double-blind, placebo-controlled oral food challenges (DBPCFC). Results: A total of 6105 children participated in this school-age follow-up (57.8% of 10 563 recruited at birth). For 982 of 6069 children (16.2%), parents reported adverse reactions after food consumption in the online questionnaire. Of 2288 children with parental face-to-face interviews and/or skin prick testing, 238 (10.4%) were eligible for a DBPCFC. Sixty-three foods were challenge-tested in 46 children. Twenty food challenges were positive in 17 children, including seven to hazelnut and three to peanut. Another seventy-one children were estimated to suffer FA among those who were eligible but refused DBPCFC. This yielded prevalence estimates for FA in school age between 1.4% (88 related to all 6105 participants of this follow-up) and 3.8% (88 related to 2289 with completed eligibility assessment). Interpretation: In primary school children in eight European countries, the prevalence of FA was lower than expected even though parents of this cohort have become especially aware of allergic reactions to food. There was moderate variation between centres hampering valid regional comparisons. Keywords: IgE; birth cohort study; epidemiology; food allergy; prevalence.
  • Are conventional stone analysis techniques reliable for the identification of 2,8-dihydroxyadenine kidney stones? A case series.

    Runolfsdottir, Hrafnhildur L; Lin, Tzu-Ling; Goldfarb, David S; Sayer, John A; Michael, Mini; Ketteridge, David; Rich, Peter R; Edvardsson, Vidar O; Palsson, Runolfur; 1Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 2Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 3Department of Renal Medicine, University College London, London, UK. 4Nephrology Section, VA New York Harbor Healthcare System, and Division of Nephrology, New York University Langone Medical Center, New York, NY, USA. 5Renal Services, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 6Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. 7NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK. 8Renal Section, Department of Pediatrics, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX, USA. 9Department of Genetics and Molecular Pathology, Women's and Children's Hospital, Adelaide, Australia. 10Department of Structural and Molecular Biology, University College London, London, UK. 11Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 12Children's Medical Center, Landspitali-The National University Hospital of Iceland, Hringbraut, 101, Reykjavik, Iceland. 13Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 14Division of Nephrology, Landspitali-The National University Hospital of Iceland, Hringbraut, 101, Reykjavik, Iceland. (Springer, 2020-05-12)
    We have recently encountered patients incorrectly diagnosed with adenine phosphoribosyltransferase (APRT) deficiency due to misidentification of kidney stones as 2,8-dihydroxyadenine (DHA) stones. The objective of this study was to examine the accuracy of stone analysis for identification of DHA. Medical records of patients referred to the APRT Deficiency Research Program of the Rare Kidney Stone Consortium in 2010-2018 with a diagnosis of APRT deficiency based on kidney stone analysis were reviewed. The diagnosis was verified by measurement of APRT enzyme activity or genetic testing. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra of pure crystalline DHA and a kidney stone obtained from one of the confirmed APRT deficiency cases were generated. The ATR-FTIR spectrum of the kidney stone matched the crystalline DHA spectrum and was used for comparison with available infrared spectra of stone samples from the patients. Of 17 patients referred, 14 had sufficient data available to be included in the study. In all 14 cases, the stone analysis had been performed by FTIR spectroscopy. The diagnosis of APRT deficiency was confirmed in seven cases and rejected in the remaining seven cases. Comparison of the ATR-FTIR spectrum of the DHA stone with the FTIR spectra from three patients who did not have APRT deficiency showed no indication of DHA as a stone component. Misidentification of DHA as a kidney stone component by clinical laboratories appears common among patients referred to our program. Since current clinical protocols used to interpret infrared spectra for stone analysis cannot be considered reliable for the identification of DHA stones, the diagnosis of APRT deficiency must be confirmed by other methods. Keywords: APRT deficiency; Infrared spectroscopy; Kidney stone composition; Misdiagnosis; Nephrolithiasis.
  • Feasibility and accuracy of a robotic guidance system for navigated spine surgery in a hybrid operating room: a cadaver study.

    Burström, Gustav; Balicki, Marcin; Patriciu, Alexandru; Kyne, Sean; Popovic, Aleksandra; Holthuizen, Ronald; Homan, Robert; Skulason, Halldor; Persson, Oscar; Edström, Erik; et al. (Nature Publishing Group, 2020-05-05)
    The combination of navigation and robotics in spine surgery has the potential to accurately identify and maintain bone entry position and planned trajectory. The goal of this study was to examine the feasibility, accuracy and efficacy of a new robot-guided system for semi-automated, minimally invasive, pedicle screw placement. A custom robotic arm was integrated into a hybrid operating room (OR) equipped with an augmented reality surgical navigation system (ARSN). The robot was mounted on the OR-table and used to assist in placing Jamshidi needles in 113 pedicles in four cadavers. The ARSN system was used for planning screw paths and directing the robot. The robot arm autonomously aligned with the planned screw trajectory, and the surgeon inserted the Jamshidi needle into the pedicle. Accuracy measurements were performed on verification cone beam computed tomographies with the planned paths superimposed. To provide a clinical grading according to the Gertzbein scale, pedicle screw diameters were simulated on the placed Jamshidi needles. A technical accuracy at bone entry point of 0.48 ± 0.44 mm and 0.68 ± 0.58 mm was achieved in the axial and sagittal views, respectively. The corresponding angular errors were 0.94 ± 0.83° and 0.87 ± 0.82°. The accuracy was statistically superior (p < 0.001) to ARSN without robotic assistance. Simulated pedicle screw grading resulted in a clinical accuracy of 100%. This study demonstrates that the use of a semi-automated surgical robot for pedicle screw placement provides an accuracy well above what is clinically acceptable.
  • Sleep time and sleep-related symptoms across two generations - results of the community-based RHINE and RHINESSA studies.

    Lindberg, Eva; Janson, Christer; Johannessen, Ane; Svanes, Cecilie; Real, Francisco Gomez; Malinovschi, Andrei; Franklin, Karl A; Holm, Mathias; Schlünssen, Vivi; Jogi, Nils Oskar; et al. (Elsevier Science, 2020-01-10)
    Study objectives: To analyze the association between sleep-related symptoms and sleep length in parents and their children in relation to other risk factors in both generations. Method: The participants were parents (n = 5,855, age 54.3 ± 6.5 years, 45.2% men) who participated in the community-based Respiratory Health in Northern Europe (RHINE) study and one random member of their adult offspring (n = 5,855, age 30.2 ± 7.7 years, 41.5% men) who participated in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) study. Both generations responded to identical questionnaires on sleep symptoms, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), snoring, nocturnal sweating, nocturnal gastroesophageal reflux (nGER), sleep time and excessive daytime sleepiness (EDS). Insomnia was defined as either, or both, DIS and DMS in combination with EDS. Results: All sleep variables except nocturnal sweating were more common in offspring whose parents had reported the same symptom. After adjusting for age, gender, BMI, smoking, physical activity, education, center and parents' total number of children, there were independent associations between sleep symptoms in parents and offspring for DIS (adj. OR, 95% CI: 1.52, 1.20-1.93), DMS (1.34, 1.15-1.56), snoring (1.45, 1.15,1.83), nGER (1.65, 1.15-2.37), insomnia (1.39, 1.13-1.73), short sleep time (<6 h/night) (2.51, 1.72-3.68) and EDS (1.48, 1.26,1.72). There were no independent relationships between symptoms in parents and offspring for EMA, nocturnal sweating or long sleep time (>9 h/night). Conclusion: The familiar aggregation of many sleep disturbances was not explained by investigated lifestyle and environmental factors. This supports a heritable factor in sleep problems.
  • Reoperation for bleeding following coronary artery bypass surgery with special focus on long-term outcomes.

    Marteinsson, Steinthor A; Heimisdóttir, Alexandra A; Axelsson, Tomas A; Johannesdottir, Hera; Arnadottir, Linda O; Gardarsdottir, Helga R; Johnsen, Arni; Sigurdsson, Martin I; Helgadottir, Solveig; Gudbjartsson, Tomas; et al. (Taylor & Francis, 2020-04-30)
    Objectives: We studied the incidence and risk factors of reoperation for bleeding following CABG in a nationwide cohort with focus on long-term complications and survival. Design: A retrospective study on 2060 consecutive, isolated CABG patients operated 2001-2016. Outcome of reoperated patients (n = 130) were compared to non-reoperated ones (n = 1930), including major adverse cardiac and cerebrovascular events (MACCE) and overall survival. Risk factors for reoperation were determined using multivariate logistic regression and a Cox proportional hazards model to assess prognostic factors of long-term survival. Median follow-up was 7.6 years. Results: One hundred thirty patients (6.3%) were reoperated with an annual decrease of 4.1% per year over the study period (p=.04). Major complications (18.5 vs. 9.6%) and 30-day mortality (8.5 vs. 1.9%,) were higher in the reoperation group (p<.001). The use of clopidogrel preoperatively (OR 3.62, 95% CI: 1.90-6.57) and reduced left ventricular ejection fraction (OR 2.23, 95% CI: 1.25-3.77) were the strongest predictors of reoperation, whereas off-pump surgery was associated with a lower reoperation risk (OR 0.44, 95% CI: 0.22-0.85). After exluding patients that died within 30 days postoperatively, no difference in long-term survival or freedom from MACCE was found between groups, and reoperation was not an independent risk factor for long-term mortality in multivariate analysis. Conclusions: The reoperation rate in this study was relatively high but decreased significantly over time. Reoperation was associated with twofold increased risk for major complications and fourfold 30-day mortality, but comparable long-term MACCE and survival rates. This implies that if patients survive the first 30 days following reoperation, their long-term outcome is comparable to non-reoperated patients.
  • Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000-1.

    Poikonen-Saksela, Paula; Lindman, Henrik; Sverrisdottir, Asgerdur; Edlund, Per; Villman, Kenneth; Tennvall Nittby, Lena; Cold, Søren; Bechmann, Troels; Stenbygaard, Lars; Ejlertsen, Bent; et al. (Taylor & Francis, 2020-04-29)
    Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000-1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18-60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m2). Patients (n = 1052) with nadir leukopenia grade 0-2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3-4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74-0.96, p = .008) and overall survival (HR 0.87 (0.76-0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.
  • Do negative intrusive thoughts at diagnosis predict impaired quality of life, depressed mood and waking up with anxiety 3, 12 and 24 months after radical prostatectomy? - a longitudinal study.

    Bock, David; Angenete, Eva; Asplund, Dan; Bjartell, Anders; Carlsson, Stefan; Hugosson, Jonas; Stinesen Kollberg, Karin; Lantz, Anna; Nilsson, Hanna; Prytz, Mattias; et al. (Taylor & Francis, 2020-04-28)
    Objective: To evaluate the effect of intrusive thoughts at diagnosis on quality of life, depressed mood and waking up with anxiety up to two years after radical prostatectomy.Method: The Laparoscopic Prostatectomy Robot Open (LAPPRO) trial was a prospective, longitudinal multicenter study of 4003 patients undergoing radical prostatectomy. Questionnaire data were collected preoperatively, at 3, 12 and 24 months after surgery.Results: The group of patients with intrusive thoughts at diagnosis had a statistically significant higher postoperative prevalence of impaired quality of life, depressed mood and waking up with anxiety as compared with the group of patients with no or minor intrusive thoughts. The highest risk increase for impaired QoL, depressed mood and waking up with anxiety ≥1/week was at 12, 3 and 3 months, respectively, where the three outcomes increased by 38% (RR: 1.38; 95%CI: 1.27-1.49)), 136% (RR: 2.36; 95%CI: 1.74-3.19)) and 165% (RR: 2.65; 95%CI: 2.22-3.17)), respectively.Conclusions: The demonstrated link between intrusive thoughts and quality of life, depressed mood and waking up with anxiety deliver is further evidence to the idea that intrusive thoughts has potential as an endpoint for assessing and predicting psychological distress among men with prostate cancer diagnosis.Trial registration number: ISRCTN06393679 ( Date of registration: 07/02/2008. Retrospectively registered.
  • Effects of amotosalen treatment on human platelet lysate bioactivity: A proof-of-concept study.

    Christensen, Christian; Jonsdottir-Buch, Sandra Mjoll; Sigurjonsson, Olafur Eysteinn; 1The Blood Bank, The National University Hospital of Iceland, Reykjavik, Iceland. 2Faculty of Medicine, Biomedical Center, University of Iceland, Reykjavik, Iceland. 3Platome Biotechnology, Hafnarfjörður, Iceland. 4School of Science and Engineering, University of Reykjavik, Reykjavik, Iceland. (Public Library of Science, 2020-04-15)
    Background: Clinical application of mesenchymal stromal cells (MSCs) usually requires an in vitro expansion step to reach clinically relevant numbers. In vitro cell expansion necessitates supplementation of basal mammalian cell culture medium with growth factors. To avoid using supplements containing animal substances, human platelet lysates (hPL) produced from expired and pathogen inactivated platelet concentrates can be used in place of fetal bovine serum. However, globally, most transfusion units are currently not pathogen inactivated. As blood banks are the sole source of platelet concentrates for hPL production, it is important to ensure product safety and standardized production methods. In this proof-of-concept study we assessed the feasibility of producing hPL from expired platelet concentrates with pathogen inactivation applied after platelet lysis by evaluating the retention of growth factors, cytokines, and the ability to support MSC proliferation and tri-lineage differentiation. Methodology/principal findings: Bone marrow-derived MSCs (BM-MSCs) were expanded and differentiated using hPL derived from pathogen inactivated platelet lysates (hPL-PIPL), with pathogen inactivation by amotosalen/ultraviolet A treatment applied after lysis of expired platelets. Results were compared to those using hPL produced from conventional expired pathogen inactivated platelet concentrates (hPL-PIPC), with pathogen inactivation applied after blood donation. hPL-PIPL treatment had lower concentrations of soluble growth factors and cytokines than hPL-PIPC treatment. When used as supplementation in cell culture, BM-MSCs proliferated at a reduced rate, but more consistently, in hPL-PIPL than in hPL-PIPC. The ability to support tri-lineage differentiation was comparable between lysates. Conclusion/significance: These results suggest that functional hPL can be produced from expired and untreated platelet lysates by applying pathogen inactivation after platelet lysis. When carried out post-expiration, pathogen inactivation may provide a valuable solution for further standardizing global hPL production methods, increasing the pool of starting material, and meeting future demand for animal-free supplements in human cell culturing.
  • Radiographic scoring systems for psoriatic arthritis are insufficient for psoriatic arthritis mutilans: results from the Nordic PAM Study.

    Laasonen, Leena; Lindqvist, Ulla; Iversen, Lars; Ejstrup, Leif; Jonmundsson, Thorarinn; Ståhle, Mona; Gudbjornsson, Bjorn; 1Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland. 2Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden. 3Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark. 4Department of Rheumatology, Odense University Hospital, Odense, Denmark. 5Centre for Rheumatology Research, University Hospital and Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 6Dermatology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. (SAGE Publications, 2020-04-27)
    Background: Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis (PsA). Purpose: To describe the radiological features in PAM and explore whether existing scoring systems for radiological damage in psoriatic arthritis are applicable for PAM. Material and methods: Radiographs were scored according to the modified Sharp-van der Heijde (mSvdH) and the Psoriatic Arthritis Ratingen Score (PARS) systems for PsA. Results: At inclusion, 55 PAM patients (49% women, mean age 58 ± 12 years) had conventional radiographs of both hands and feet. A total of 869 PAM joints were detected and 193 joints with ankylosis. The mean total mSvdH score was 213.7 ± 137.8 (41% of maximum) with a higher score for hands than for feet: 136.6 ± 90.1 vs. 79.1 ± 60.9. However, the total score was relatively higher in the feet than in the hands when compared to the highest possible scoring (47% vs. 38% of max). The mean total PARS score was 126.3 ± 79.6 (35% of max). Scoring for joint destruction was higher than for proliferation (22% vs. 11% of max). Strong correlation was found between mSvdH and PARS (r2 = 0.913). A significant correlation was found between scoring and duration of arthritis and the Health Assessment Questionnaire. History of smoking, BMI, and gender did not influence the scoring values. Conclusions: The two scoring systems studied may not be ideal to indicate progression of PAM in advanced disease since they reach ceiling effects rather early. Therefore, reporting early signs suggestive of PAM, e.g. signs of pencil-in-cup deformities or osteolysis, is crucial. This would reveal the presence of PAM and might lead to improved treatment in order to minimize joint damage. Keywords: Psoriatic arthritis; mutilans; psoriasis; radiology; scoring systems.
  • Reduction of antimicrobial resistant pneumococci seven years after introduction of pneumococcal vaccine in Iceland.

    Hjálmarsdóttir, Martha Á; Haraldsson, Gunnsteinn; Quirk, Sigríður Júlía; Haraldsson, Ásgeir; Erlendsdóttir, Helga; Kristinsson, Karl G; 1Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 2Department of Clinical Microbiology, Landspitali University Hospital, Reykjavík, Iceland. 3BioMedical Centre of the University of Iceland, Reykjavik, Iceland. 4Children´s Hospital Iceland, Landspitali University Hospital, Reykjavík, Iceland. (Public Library of Science, 2020-03-17)
    Background: Penicillin non-susceptible (PNSP) and multi-resistant pneumococci have been prevalent in Iceland since early nineties, mainly causing problems in treatment of acute otitis media. The 10-valent protein conjugated pneumococcal vaccine (PHiD-CV) was introduced into the childhood vaccination program in 2011. The aim of the study was to investigate the changes in antimicrobial susceptibility and serotype distribution of penicillin non-susceptible pneumococci (PNSP) in Iceland 2011-2017. Methods and findings: All pneumococcal isolates identified at the Landspítali University Hospital in 2011-2017, excluding isolates from the nasopharynx and throat were studied. Susceptibility testing was done according to the EUCAST guidelines using disk diffusion with chloramphenicol, erythromycin, clindamycin, tetracycline, trimethoprim/sulfamethoxazole and oxacillin for PNSP screening. Penicillin and ceftriaxone minimum inhibitory concentrations (MIC) were measured for oxacillin resistant isolates using the E-test. Serotyping was done using latex agglutination and/or multiplex PCR. The total number of pneumococcal isolates that met the study criteria was 1,706, of which 516 (30.2%) were PNSP, and declining with time. PNSP isolates of PHiD-CV vaccine serotypes (VT) were 362/516 (70.2%) declining with time, 132/143 (92.3%) in 2011 and 17/54 (31.5%) in 2017. PNSP were most commonly of serotype 19F, 317/516 isolates declining with time, 124/143 in 2011 and 15/54 in 2017. Their number decreased in all age groups, but mainly in the youngest children. PNSP isolates of non PHiD-CV vaccine serotypes (NVT) were 154/516, increasing with time, 11/14, in 2011 and 37/54 in 2017. The most common emerging NVTs in 2011 and 2017 were 6C, 1/143 and 10/54 respectively. Conclusions: PNSP of VTs have virtually disappeared from children with pneumococcal diseases after the initiation of pneumococcal vaccination in Iceland and a clear herd effect was observed. This was mainly driven by a decrease of PNSP isolates belonging to a serotype 19F multi-resistant lineage. However, emerging multi-resistant NVT isolates are of concern.
  • The role of C-reactive protein levels on the association of physical activity with lung function in adults.

    Fuertes, Elaine; Carsin, Anne-Elie; Garcia-Larsen, Vanessa; Guerra, Stefano; Pin, Isabelle; Leynaert, Bénédicte; Accordini, Simone; Martinez-Moratalla, Jesús; Antó, Josep M; Urrutia, Isabel; et al. (Public Library of Science, 2019-09-23)
    Objective: Regular physical activity may be associated with improved lung function via reduced systemic inflammation, although studies exploring this mechanism are rare. We evaluated the role of C-reactive protein in blood, which is a common marker of systemic inflammation, on the association of physical activity with forced expiratory volume in one second and forced vital capacity. Methods: Cross-sectional data on spirometry, C-reactive protein levels and self-reported physical activity (yes/no; ≥2 times and ≥1hr per week of vigorous physical activity) were available in the European Community Respiratory Health Survey (N = 2347 adults, 49.3% male, 28-56 years-old). A subsample was also assessed 10 years later using the International Physical Activity Questionnaire, and tertiles of Metabolic Equivalent of Task-minutes per week spent in vigorous, moderate and walking activities were calculated (N = 671, 49.6% male, 40-67 years-old). Adjusted cross-sectional mixed linear regression models and the "mediate" package in "R" were used to assess the presence of mediation. Results: Despite positive significant associations between nearly all physical activity metrics with forced expiratory volume in one second and forced vital capacity, there was no evidence that C-reactive protein levels played a role. An influence of C-reactive protein levels was only apparent in the smaller subsample when comparing the medium to low tertiles of moderate activity (mean difference [95% CIs]: 21.1ml [5.2, 41.9] for forced expiratory volume in one second and 17.3ml [2.6, 38.0] for forced vital capacity). Conclusions: In a population of adults, we found no consistent evidence that the association of physical activity with forced expiratory volume in one second or forced vital capacity is influenced by the level of C-reactive protein in blood.
  • 'You should always look at the washing machine without actually being in it!' Thematic framework analysis of patients' understanding of transdiagnostic cognitive behaviour therapy and its mechanisms.

    Sighvatsson, Magnus Blondahl; Salkovskis, Paul M; Sigurdsson, Engilbert; Valdimarsdottir, Heiddis B; Thorsdottir, Fanney; Sigurdsson, Jon Fridrik; 1University of Iceland, Reykjavík, Iceland. 2Reykjavik University, Iceland. 3University of Oxford, UK. 4Landspitali-The National University Hospital of Iceland, Reykjavík, Iceland. 5Mount Sinai School of Medicine, New York City, New York, USA. (Wiley, 2019-02-07)
    Objective: Transdiagnostic cognitive behaviour therapy (TCBT) is an efficacious treatment for anxiety and depression, but its mechanisms of change remain poorly understood. The current study used thematic framework analysis to analyse how patients, recruited in a recent trial on transdiagnostic group CBT (TGCBT), understood the treatment and its mechanisms. Design: Cross-sectional thematic framework analysis. Method: The sample included 24 participants suffering from anxiety and/or depression, divided into two groups by treatment efficacy (i.e., group doing well and group doing not so well) in order to evaluate whether different understandings of the treatment affected its efficacy. The participants were interviewed and completed self-report measures. They were encouraged to discuss what they believed to be helpful and unhelpful in the TGCBT and what they believed to be the mechanisms of change in the treatment. Each interview was recorded, transcribed verbatim and themes were identified. Results: The analysis revealed four overarching themes and 18 subthemes. The overarching themes were as follows: Cognitive and behavioural flexibility, Awareness/understanding of symptoms and triggers, Therapeutic alliance and engagement, and finally Attitudes towards treatment. Four of the 18 subthemes corresponded to a differentiation between the groups: Cognitive flexibility and Comparison with others in the group on the one hand and Cognitive inflexibility and Negative attitudes towards treatment on the other. Conclusion: The most important difference between the groups appeared to be CBT-specific, that is, cognitive flexibility that characterized the group doing well where thematic analysis did not indicate that other themes were important. Practitioner points: Findings The analysis revealed four overarching themes and 18 subthemes, four of which corresponded to the difference between the two groups of participants based on treatment efficacy. The four differentiating subthemes were cognitive flexibility and comparison with others, which characterized the group doing well, and cognitive inflexibility and negative attitude towards treatment, which characterized the group doing less well. The theme evaluated as the most important for the efficacy of the transdiagnostic cognitive behaviour therapy and patients' understanding of the treatment was cognitive flexibility, which characterized the group doing well. Limitations Use of qualitative methodology restricts the generalizability of our results. Data are built on answers from only 24 participants.
  • Changes in the left temporal microstate are a sign of cognitive decline in patients with Alzheimer's disease.

    Musaeus, Christian S; Engedal, Knut; Høgh, Peter; Jelic, Vesna; Khanna, Arjun R; Kjaer, Troels Wesenberg; Mørup, Morten; Naik, Mala; Oeksengaard, Anne-Rita; Santarnecchi, Emiliano; et al. (Wiley, 2020-04-27)
    Introduction: Large-scale brain networks are disrupted in the early stages of Alzheimer's disease (AD). Electroencephalography microstate analysis, a promising method for studying brain networks, parses EEG signals into topographies representing discrete, sequential network activations. Prior studies indicate that patients with AD show a pattern of global microstate disorganization. We investigated whether any specific microstate changes could be found in patients with AD and mild cognitive impairment (MCI) compared to healthy controls (HC). Materials and methods: Standard EEGs were obtained from 135 HC, 117 patients with MCI, and 117 patients with AD from six Nordic memory clinics. We parsed the data into four archetypal microstates. Results: There was significantly increased duration, occurrence, and coverage of microstate A in patients with AD and MCI compared to HC. When looking at microstates in specific frequency bands, we found that microstate A was affected in delta (1-4 Hz), theta (4-8 Hz), and beta (13-30 Hz), while microstate D was affected only in the delta and theta bands. Microstate features were able to separate HC from AD with an accuracy of 69.8% and HC from MCI with an accuracy of 58.7%. Conclusions: Further studies are needed to evaluate whether microstates represent a valuable disease classifier. Overall, patients with AD and MCI, as compared to HC, show specific microstate alterations, which are limited to specific frequency bands. These alterations suggest disruption of large-scale cortical networks in AD and MCI, which may be limited to specific frequency bands.
  • Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

    Oskarsson, Gudjon R; Oddsson, Asmundur; Magnusson, Magnus K; Kristjansson, Ragnar P; Halldorsson, Gisli H; Ferkingstad, Egil; Zink, Florian; Helgadottir, Anna; Ivarsdottir, Erna V; Arnadottir, Gudny A; et al. (Nature Publishing Group, 2020-04-23)
    Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
  • Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.

    Klinkhammer, Barbara Mara; Djudjaj, Sonja; Kunter, Uta; Palsson, Runolfur; Edvardsson, Vidar Orn; Wiech, Thorsten; Thorsteinsdottir, Margret; Hardarson, Sverrir; Foresto-Neto, Orestes; Mulay, Shrikant R; et al. (American Society of Nephrology, 2020-02-21)
    Background: Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown. Methods: Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies. Results: Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy. Conclusions: Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.
  • Severe desaturations increase psychomotor vigilance task-based median reaction time and number of lapses in obstructive sleep apnoea patients.

    Kainulainen, Samu; Duce, Brett; Korkalainen, Henri; Oksenberg, Arie; Leino, Akseli; Arnardottir, Erna S; Kulkas, Antti; Myllymaa, Sami; Töyräs, Juha; Leppänen, Timo; et al. (European Respiratory Society, 2020-04-09)
    Current diagnostic parameters estimating obstructive sleep apnoea (OSA) severity have a poor connection to the psychomotor vigilance of OSA patients. Thus, we aimed to investigate how the severity of apnoeas, hypopnoeas and intermittent hypoxaemia is associated with impaired vigilance.We retrospectively examined type I polysomnography data and corresponding psychomotor vigilance tasks (PVTs) of 743 consecutive OSA patients (apnoea-hypopnoea index (AHI) ≥5 events·h-1). Conventional diagnostic parameters (e.g. AHI and oxygen desaturation index (ODI)) and novel parameters (e.g. desaturation severity and obstruction severity) incorporating duration of apnoeas and hypopnoeas as well as depth and duration of desaturations were assessed. Patients were grouped into quartiles based on PVT outcome variables. The odds of belonging to the worst-performing quartile were assessed. Analyses were performed for all PVT outcome variables using binomial logistic regression.A relative 10% increase in median depth of desaturations elevated the odds (ORrange 1.20-1.37, p<0.05) of prolonged mean and median reaction times as well as increased lapse count. Similarly, an increase in desaturation severity (ORrange 1.26-1.52, p<0.05) associated with prolonged median reaction time. Female sex (ORrange 2.21-6.02, p<0.01), Epworth Sleepiness Scale score (ORrange 1.05-1.07, p<0.01) and older age (ORrange 1.01-1.05, p<0.05) were significant risk factors in all analyses. In contrast, increases in conventional AHI, ODI and arousal index were not associated with deteriorated PVT performance.These results show that our novel parameters describing the severity of intermittent hypoxaemia are significantly associated with increased risk of impaired PVT performance, whereas conventional OSA severity and sleep fragmentation metrics are not. These results underline the importance of developing the assessment of OSA severity beyond the AHI.
  • Effect of two different nutritional supplements on postprandial glucose response and energy- and protein intake in hospitalised patients with COPD: A randomised cross-over study.

    Ingadottir, Arora Ros; Bjorgvinsdottir, Eva Bjorg; Beck, Anne Marie; Baldwin, Christine; Weekes, C Elizabeth; Geirsdottir, Olof Gudny; Ramel, Alfons; Birgisdottir, Bryndis Eva; Gislason, Thorarinn; Gunnarsdottir, Ingibjorg; et al. (Elsevier, 2019-04-25)
    Introduction: Oral nutrition support is frequently used in treatment of malnutrition in patients with chronic obstructive pulmonary disease (COPD). Considering the use of corticoidsteroids in patients with COPD, little is known about the effect on postprandial glucose response and if they might interfere with glucose control. Our aims were to compare the effect of a liquid oral nutritional supplement (ONS) and semi solid inbetween meal snack (snack) on postprandial glucose and energy- and protein intake, and to compare the effect of timing of each intervention on postprandial glucose and energy- and protein intake. Methods: Patients with COPD (n = 17) admitted to the Department of Pulmonary Medicine, Iceland and defined as at low or medium nutritional risk (score 0-3) were recruited. In a randomised cross-over design, subjects consumed ONS or snack either in a fasting state (study 1) or following breakfast (study 2) and postprandial glucose responses were assessed at regular intervals for two hours (t = 15, t = 30, t = 45, t = 60, t = 90, t = 120 min). Energy- and protein intake was estimated using a validated plate diagram sheet. Wilcoxon Signed-Rank test was used to compare the two interventions. Results: In study 2, following breakfast, postprandial glucose was significantly higher after consuming ONS than the snack after 60 min (9.7 ± 2.4 mmol/L vs. 8.2 ± 3.2 mmol/L, p = 0.013 and 120 min 9.2 ± 3.2 mmol/L vs. 7.9 ± 2.4 mmol/L, p = 0.021, respectively). No difference was found in postprandial glucose concentrations between ONS and the snack when consumed after overnight fasting (study 1). No difference in energy or protein intake from hospital food was seen between supplement types neither in study 1 or 2. Conclusion: Lower postprandial glucose concentrations were associated with the snack compared to ONS when taken after a meal compared to either type directly after overnight fasting. The clinical relevance of higher postprandial blood glucose after consuming a liquid ONS after breakfast compared with a semi solid snack needs to be studied further.
  • Profiling inflammatory response in lesions of cutaneous leishmaniasis patients using a non-invasive sampling method combined with a high-throughput protein detection assay

    Taslimi, Yasaman; Agbajogu, Christopher; Brynjolfsson, Siggeir Fannar; Masoudzadeh, Nasrin; Mashayekhi, Vahid; Gharibzadeh, Safoora; Östensson, Malin; Nakka, Sravya Sowdamini; Mizbani, Amir; Rafati, Sima; et al. (Elsevier Science, 2020-06-01)
    Background: Cutaneous leishmaniasis (CL) is an infection caused by Leishmania (L.) protozoa transmitted through the bite of infected sand fly. Previously, invasive sampling of blood and skin along with low throughput methods were used for determination of inflammatory response in CL patients. Aims/methodology: We established a novel approach based on a non-invasive adhesive tape-disc sampling combined with a powerful multiplexing technique called proximity extension assay for profiling 92 inflammatory cytokines, chemokines and surface molecules in the lesions of CL patients infected with L. tropica. Sample collection was done non-invasively by using adhesive tape-discs from lesion and normal skin of 33 L. tropica positive patients. Results: Out of 92 inflammatory proteins, the level of 34 proteins was significantly increased in the lesions of CL patients compared to their normal skin. This includes the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL5, CXCL9, CXCL10 and CXCL11, together with the interleukins IL-6, IL-8, IL-18, LIF and OSM. The remaining significantly changed inflammatory proteins include 7 surface molecules and receptors: CD5, CD40, CDCP1, 4E-BP1, TNFRSF9, IL-18R1 and OPG as well as 16 other cytokines and proteins: MMP-1, CSF-1, VEGFA, uPA, EN-RAGE, LAP TGF-β1, HGF, MMP-10, CASP-8, TNFSF14, STAMPB, ADA, TRAIL and ST1A1. Further, 13 proteins showed an increasing trend, albeit not statistically significant, in the CL lesions, including TGF-α, CCL23, MCP-2, IL-12B, CXCL6, IL-24, FGF-19, TNFβ, CD6, TRANCE, IL10, SIR2 and CCL20. Conclusion: We herein report a novel approach based on a non-invasive sampling method combined with the high-throughput protein assay for profiling inflammatory proteins in CL lesions. Using this approach, we could profile inflammatory proteins in the lesions from CL patients. This new non-invasive approach may have implications for studying skin inflammatory mediators in CL and other skin disorders.

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