• Ambient nitrogen dioxide is associated with emergency hospital visits for atrial fibrillation: a population-based case-crossover study in Reykjavik, Iceland.

      Halldorsdottir, Solveig; Finnbjornsdottir, Ragnhildur Gudrun; Elvarsson, Bjarki Thor; Gudmundsson, Gunnar; Rafnsson, Vilhjalmur; 1University of Iceland, Centre of Public Health Science, Reykjavik, Iceland. 2Environment Agency of Iceland, Reykjavik, Iceland. 3Marine and Freshwater Research Institute, Reykjavik, Iceland. 4Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 5Department of Respiratory Medicine & Sleep, Landspitali University Hospital, Reykjavik, Iceland. 6University of Iceland, Department of Preventive Medicine, Reykjavik, Iceland. vilraf@hi.is. (BioMed Central, 2022-01-03)
      Background: In Iceland air quality is generally good; however, previous studies indicate that there is an association between air pollution in Reykjavik and adverse health effects as measured by dispensing of medications, mortality, and increase in health care utilisation. The aim was to study the association between traffic-related ambient air pollution in the Reykjavik capital area and emergency hospital visits for heart diseases and particularly atrial fibrillation and flutter (AF). Methods: A multivariate time-stratified case-crossover design was used to study the association. Cases were those patients aged 18 years or older living in the Reykjavik capital area during the study period, 2006-2017, who made emergency visits to Landspitali University Hospital for heart diseases. In this population-based study, the primary discharge diagnoses were registered according to International Classification of Diseases, 10th edition (ICD-10). The pollutants studied were NO2, PM10, PM2.5, and SO2, with adjustment for H2S, temperature, and relative humidity. The 24-h mean of pollutants was used with lag 0 to lag 4. Results: During the study period 9536 cases of AF were identified. The 24-h mean NO2 was 20.7 μg/m3. Each 10 μg/m3 increase in NO2 was associated with increased risk of heart diseases (ICD-10: I20-I25, I44-I50), odds ratio (OR) 1.023 (95% CI 1.012-1.034) at lag 0. Each 10 μg/m3 increase in NO2 was associated with an increased risk of AF (ICD-10: I48) on the same day, OR 1.030 (95% CI: 1.011-1.049). Females were at higher risk for AF, OR 1.051 (95% CI 1.019-1.083) at lag 0, and OR 1.050 (95% CI 1.019-1.083) at lag 1. Females aged younger than 71 years had even higher risk for AF, OR 1.077 (95% CI: 1.025-1.131) at lag 0. Significant associations were found for other pollutants and emergency hospital visits, but they were weaker and did not show a discernable pattern. Conclusions: Short-term increase in NO2 concentrations was associated with heart diseases, more precisely with AF. The associations were stronger among females, and among females at younger age. This is the first study in Iceland that finds an association between air pollution and cardiac arrhythmias, so the results should be interpreted with caution. Keywords: Atrial fibrillation; Cardiac arrhythmia; Case-crossover; Hospital registry; Ischemic heart diseases; Nitrogen dioxide; Population-based.
    • BRCA2 Haploinsufficiency in Telomere Maintenance

      Gunnarsdottir, Soffía R.; Bjarnason, Hördur; Thorvaldsdottir, Birna; Paland, Felice; Steinarsdottir, Margrét; Eyfjörd, Jórunn E.; Bödvarsdottir, Sigrídur K.; a BioMedical Center, School of Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, 101, Iceland b Faculty of Medicine, Eberhard Karls University, Tübingen, 72074, Germany c Department of Genetics and Molecular Medicine, Landspitali the National University Hospital of Iceland, Reykjavík, 101, Iceland (MDPI, 2022-01-01)
      Our previous studies showed an association between monoallelic BRCA2 germline mutations and dysfunctional telomeres in epithelial mammary cell lines and increased risk of breast cancer diagnosis for women with BRCA2 999del5 germline mutation and short telomeres in blood cells. In the current study, we analyzed telomere dysfunction in lymphoid cell lines from five BRCA2 999del5 mutation carriers and three Fanconi Anemia D1 patients by fluorescence in situ hybridization (FISH). Metaphase chromosomes were harvested from ten lymphoid cell lines of different BRCA2 genotype origin and analyzed for telomere loss (TL), multitelomeric signals (MTS), interstitial telomere signals (ITS) and extra chromosomal telomere signals (ECTS). TL, ITS and ECTS were separately found to be significantly increased gradually between the BRCA2+/+, BRCA2+/- and BRCA2-/- lymphoid cell lines. MTS were found to be significantly increased between the BRCA2+/+ and the BRCA2+/-heterozygous (p < 0.0001) and the BRCA2-/- lymphoid cell lines (p < 0.0001) but not between the BRCA2 mutated genotypes. Dysfunctional telomeres were found to be significantly increased in a stepwise manner between the BRCA2 genotypes indicating an effect of BRCA2 haploinsufficiency on telomere maintenance. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Author keywords BRCA2; Chromosomal instability; Fanconi anemia; Haploinsufficiency; Telomere
    • Taking phenomenology beyond the first-person perspective: conceptual grounding in the collection and analysis of observational evidence

      Klinke, Marianne Elisabeth; Fernandez, Anthony Vincent; a Faculty of Nursing, School of Health Sciences, University of Iceland Eirberg, Eiriksgata 34, Reykjavik, 107, Iceland b The National University Hospital of Iceland, Reykjavik, Iceland c Faculty of Philosophy, University of Oxford, Oxford, United Kingdom d Danish Institute for Advanced Study and Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark (Springer, 2022-01-01)
      Phenomenology has been adapted for use in qualitative health research, where it’s often used as a method for conducting interviews and analyzing interview data. But how can phenomenologists study subjects who cannot accurately reflect upon or report their own experiences, for instance, because of a psychiatric or neurological disorder? For conditions like these, qualitative researchers may gain more insight by conducting observational studies in lieu of, or in conjunction with, interviews. In this article, we introduce a phenomenological approach to conducting this kind of observational research. The approach relies on conceptual grounding to focus a study on specific aspects of the participants’ experiences. Moreover, the approach maintains the openness to novel discoveries that qualitative research requires while also providing a structured framework for data collection and analysis. To illustrate its practical application, we use examples of hemispatial neglect—a neurologic disorder in which patients characteristically lack awareness of their own illness and bodily capacities. However, the approach that we describe can be applied more broadly to the study of complex illness experiences and other experiential alterations. © 2021, The Author(s). Author keywords Embodiment; Hemispatial neglect; Observational research; Phenomenology; Qualitative methods
    • Angiotensin converting enzyme inhibitors/cyclodextrin inclusion complexes: solution and solid-state characterizations and their thermal stability

      Hnin, Hay Marn; Stefánsson, Einar; Loftsson, Thorsteinn; Rungrotmongkol, Thanyada; Jansook, Phatsawee; a Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254 Phyathai Rd., Pathumwan, Bangkok, 10330, Thailand b Department of Ophthalmology, Faculty of Medicine, National University Hospital, University of Iceland, Landspitalinn, Reykjavik, 101, Iceland c Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, Reykjavik, 107, Iceland d Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand (Springer, 2022-01-01)
      Angiotensin converting enzyme (ACE) inhibitors have recently gained attention as a new class of drug in the therapeutic management of glaucoma. However, the application of eye drops is limited because of their chemical instability in aqueous solutions. To overcome such a problem, cyclodextrins (CDs) were introduced to form inclusion complexes. Three ACE inhibitors, namely, captopril, quinapril and fosinopril (FOS), were chosen and the effect of CDs on their thermal stability in aqueous solutions was investigated. All three drugs formed inclusion complexes of 1:1 stoichiometry with all three natural CDs and the FOS/γCD inclusion complex possessed the highest stability constant, resulting in thermal stability enhancement. Furthermore, the addition of antioxidants could greatly enhance the thermal stability of FOS in the presence of γCD in aqueous solutions. The inclusion complex formation of FOS/γCD was further examined by computational and experimental characterizations. All these characterization results confirmed that FOS and γCD formed a true inclusion complex that provided drug stabilization in the aqueous eye drop medium. © 2021, The Author(s), under exclusive licence to Springer Nature B.V. Author keywords ACE inhibitors; Complexation; Cyclodextrins; Glaucoma; Stability
    • Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

      Barnes, Daniel R; Silvestri, Valentina; Leslie, Goska; McGuffog, Lesley; Dennis, Joe; Yang, Xin; Adlard, Julian; Agnarsson, Bjarni A; Ahmed, Munaza; Aittomäki, Kristiina; et al. (Oxford University Press, 2022-01)
      Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
    • Once after a full moon: acute type A aortic dissection and lunar phases.

      Bjursten, Henrik; Oudin Åström, Daniel; Nozohoor, Shahab; Ahmad, Khalil; Tang, Mariann; Bjurbom, Markus; Hansson, Emma C; Jeppsson, Anders; Joost Holdflod Møller, Christian; Jormalainen, Miko; et al. (Oxford University Press, 2022-01)
      Objectives: Acute type A aortic dissection (ATAAD) is a rare but severe condition, routinely treated with emergent cardiac surgery. Many surgeons have the notion that patients with ATAAD tend to come in clusters, but no studies have examined these observations. This investigation was undertaken to study the potential association between the lunar cycle and the incidence of ATAAD. Methods: We collected information on 2995 patients who underwent ATAAD surgery at centres from the Nordic Consortium for Acute Type A Aortic Dissection collaboration. We cross-referenced the time of surgery with lunar phase using a case-crossover design with 2 different definitions of full moon (>99% illumination and the 7-day full moon period). Results: The period when the moon was illuminated the most (99% definition) did not show any significant increase in incidence for ATAAD surgery. However, when the full moon period was compared with all other moon phases, it yielded a relative risk of 1.08 [95% confidence interval (CI) 1.00-1.17, P = 0.057] and, compared to waxing moon, only the relative risk was 1.11 (95% CI 1.01-1.23, P = 0.027). The peak incidence came 4-6 days after the moon was fully illuminated. Conclusions: This study found an overrepresentation of surgery for ATAAD during the full moon phase. The explanation for this is not known, but we speculate that sleep deprivation during full moon leads to a temporary increase in blood pressure, which in turn could trigger rupture of the aortic wall. While this finding is interesting, it needs to be corroborated and the clinical implications are debateable. Keywords: Dissection of the aorta; Moon.
    • Postoperative Acute Kidney Injury Is Associated With Progression of Chronic Kidney Disease Independent of Severity.

      Privratsky, Jamie R; Krishnamoorthy, Vijay; Raghunathan, Karthik; Ohnuma, Tetsu; Rasouli, Mohammad R; Long, Thorir E; Sigurdsson, Martin I; 1From the Critical Care and Perioperative Population Health Research (CAPER) Unit. 2Center for Perioperative Organ Protection (CPOP), Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina. 3Anesthesiology Service Division, Durham Veterans Affairs Medical Center, Durham, North Carolina. 4Department of Anesthesiology, Stanford University, Palo Alto, California. 5Division of Nephrology, Department of Medicine. 6Division of Anesthesia and Intensive Care Medicine, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 7Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Lippincott Williams & Wilkins, 2022-01)
      Background: Both postoperative acute kidney injury (AKI) and preoperative chronic kidney disease (CKD) are associated with significantly worse outcomes following surgery. The relationship of both of these conditions with each other and with CKD progression after surgery remains poorly studied. Our objective was to assess if there was an interaction between preoperative kidney function estimated by preoperative estimated glomerular filtration rate (eGFR)/CKD stage, postoperative AKI, and eGFR/CKD progression within 1 year of surgery. Our hypothesis was that AKI severity would be associated with a faster time to eGFR/CKD stage progression within 1 year of surgery in a graded-fashion, which would be exacerbated by preoperative kidney dysfunction. Methods: This was a retrospective cohort study at Landspitali University Hospital in Iceland, which serves about 75% of the population. Participants included adults receiving their first major anesthetic between 2005 and 2018. Patients with CKD stage 5, undergoing major urologic procedures, or having missing creatinine values for follow-up of eGFR stage were excluded from analysis. The primary exposure was postoperative AKI stage within 7 days after surgery classified by the kidney disease improving global outcome (KDIGO) criteria. The primary outcome was time to progression of CKD by at least 1 eGFR/CKD stage within 1-year following surgery. Multivariable Cox proportional hazards models were used to estimate hazard of eGFR/CKD stage progression, including an interaction between AKI and preoperative CKD on eGFR/CKD stage progression. Results: A total of 5548 patients were studied. In the multivariable model adjusting for baseline eGFR/CKD stage, when compared to patients without AKI, postoperative AKI stage 1 (hazard ratio [HR], 5.91; 95% confidence interval [CI], 4.34-8.05), stage 2 (HR, 3.86; 95% CI, 1.82-8.16), and stage 3 (HR, 3.61; 95% CI, 1.49-8.74) were all independently associated with faster time to eGFR/CKD stage progression within 1 year following surgery, though increasing AKI severity did not confer additional risk. The only significant interaction between the degree of AKI and the preexisting renal function was for stage 1 AKI, where the odds of 1-year eGFR/CKD stage progression actually decreased in patients with preoperative CKD categories 3a, 3b, and 4. Conclusions: KDIGO-AKI was independently associated with eGFR/CKD stage progression within the year following surgery after adjustment for baseline eGFR/CKD stage and without an interaction between worse preoperative kidney function and higher stage AKI. Our observations suggest that further studies are warranted to test whether CKD progression could be prevented by the adoption of perioperative kidney protective practices.
    • Functional Connectivity and Speech Entrainment Speech Entrainment Improves Connectivity Between Anterior and Posterior Cortical Speech Areas in Non-fluent Aphasia.

      Johnson, Lisa; Yourganov, Grigori; Basilakos, Alexandra; Newman-Norlund, Roger David; Thors, Helga; Keator, Lynsey; Rorden, Chris; Bonilha, Leonardo; Fridriksson, Julius; 1Department of Communication Sciences and Disorders, 2629University of South Carolina, Columbia, SC, USA. 2Cyberinfrastructure and Technology Integration, 2545Clemson University, Clemson, SC, USA. 3Department of Psychology, 2629University of South Carolina, Columbia, SC, USA. 437557Landspitali University Hospital, Iceland. 5Department of Neurology, 2345Medical University of South Carolina, Charleston, SC, USA. (SAGE Publications, 2021-12-30)
      Background: Speech entrainment (SE), the online mimicking of an audio-visual speech model, has been shown to increase speech fluency in individuals with non-fluent aphasia. One theory that may explain why SE improves speech output is that it synchronizes functional connectivity between anterior and posterior language regions to be more similar to that of neurotypical speakers. Objectives: The present study tested this by measuring functional connectivity between 2 regions shown to be necessary for speech production, and their right hemisphere homologues, in 24 persons with aphasia compared to 20 controls during both free (spontaneous) speech and SE. Methods: Regional functional connectivity in participants with aphasia were normalized to the control data. Two analyses were then carried out: (1) normalized functional connectivity was compared between persons with aphasia and controls during free speech and SE and (2) stepwise linear models with leave-one-out cross-validation including normed functional connectivity during both tasks and proportion damage to the left hemisphere as independent variables were created for each language score. Results: Left anterior-posterior functional connectivity and left posterior to right anterior functional connectivity were significantly more similar to connectivity of the control group during SE compared to free speech. Additionally, connectivity during free speech was more associated with language measures than connectivity during SE. Conclusions: Overall, these results suggest that SE promotes normalization of functional connectivity (i.e., return to patterns observed in neurotypical controls), which may explain why individuals with non-fluent aphasia produce more fluent speech during SE compared to spontaneous speech. Keywords: aphasia; aphasia recovery; chronic stroke; functional connectivity; speech entrainment.
    • Peroxidasin Enhances Basal Phenotype and Inhibits Branching Morphogenesis in Breast Epithelial Progenitor Cell Line D492.

      Sigurdardottir, Anna Karen; Jonasdottir, Arna Steinunn; Asbjarnarson, Arni; Helgudottir, Hildur Run; Gudjonsson, Thorarinn; Traustadottir, Gunnhildur Asta; 1Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 2Department of Laboratory Haematology, Landspitali - University Hospital, Reykjavik, Iceland. 3Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. gutra@hi.is. (Springer, 2021-12-28)
      The human breast is composed of terminal duct lobular units (TDLUs) that are surrounded by stroma. In the TDLUs, basement membrane separates the stroma from the epithelial compartment, which is divided into an inner layer of luminal epithelial cells and an outer layer of myoepithelial cells. Stem cells and progenitor cells also reside within the epithelium and drive a continuous cycle of gland remodelling that occurs throughout the reproductive period. D492 is an epithelial cell line originally isolated from the stem cell population of the breast and generates both luminal and myoepithelial cells in culture. When D492 cells are embedded into 3D reconstituted basement membrane matrix (3D-rBM) they form branching colonies mimicking the TDLUs of the breast, thereby providing a well-suited in vitro model for studies on branching morphogenesis and breast development. Peroxidasin (PXDN) is a heme-containing peroxidase that crosslinks collagen IV with the formation of sulfilimine bonds. Previous studies indicate that PXDN plays an integral role in basement membrane stabilisation by crosslinking collagen IV and as such contributes to epithelial integrity. Although PXDN has been linked to fibrosis and cancer in some organs there is limited information on its role in development, including in the breast. In this study, we demonstrate expression of PXDN in breast epithelium and stroma and apply the D492 cell line to investigate the role of PXDN in cell differentiation and branching morphogenesis in the human breast. Overexpression of PXDN induced basal phenotype in D492 cells, loss of plasticity and inhibition of epithelial-to-mesenchymal transition as is displayed by complete inhibition of branching morphogenesis in 3D culture. This is supported by results from RNA-sequencing which show significant enrichment in genes involved in epithelial differentiation along with significant negative enrichment of EMT factors. Taken together, we provide evidence for a novel role of PXDN in breast epithelial differentiation and mammary gland development. Keywords: Branching morphogenesis; D492; Mammary gland; Mammary stem cells; Peroxidasin; p63.
    • European bio-naïve spondyloarthritis patients initiating TNFi: Time trends in baseline characteristics, treatment retention and response.

      Christiansen, Sara Nysom; Ørnbjerg, Lykke Midtbøll; Horskjær Rasmussen, Simon; Loft, Anne Gitte; Askling, Johan; Iannone, Florenzo; Zavada, Jakub; Michelsen, Brigitte; Nissen, Michael; Onen, Fatos; et al. (Oxford University Press, 2021-12-23)
      Objectives: To investigate time trends in baseline characteristics and retention, remission and response rates in bio-naïve axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) patients initiating tumour necrosis factor inhibitor (TNFi) treatment. Methods: Prospectively collected data on bio-naïve axSpA and PsA patients from routine care in 15 European countries were pooled. Three cohorts were defined according to year of TNFi-initiation: A (1999-2008), B (2009-2014) and C (2015-2018). Retention, remission and response rates were assessed at 6, 12 and 24 months. Results: In total, 27 149 axSpA and 17 446 PsA patients were included.Cohort A patients had longer disease duration compared with B and C. In axSpA, cohort A had the largest proportion of male and HLA-B27 positive patients. In PsA, baseline disease activity was highest in cohort A.Retention rates in axSpA/PsA were highest in cohort A and differed only slightly between B and C.For all cohorts, disease activity decreased markedly from 0 to 6 months. In axSpA, disease activity at 24 months was highest in cohort A, where also remission and response rates were lowest. In PsA, remission rates at 6 and 12 months tended to be lowest in cohort A. Response rates were at all time points comparable across cohorts, and less between-cohort disease activity differences were seen at 24 months. Conclusion: Our findings indicate that over the past decades, clinicians have implemented more aggressive treatment strategies in spondyloarthritis. This was illustrated by shorter disease duration at treatment initiation, decreased retention rates and higher remission rates during recent years. Keywords: TNFi retention; axial spondyloarthritis; psoriatic arthritis; remission; response; time trends.
    • The occurrence of multiple treatment switches in axial spondyloarthritis. Results from five Nordic rheumatology registries.

      Di Giuseppe, Daniela; Lindström, Ulf; Aaltonen, Kalle; Relas, Heikki; Provan, Sella; Gudbjornsson, Bjorn; Hetland, Merete Lund; Askling, Johan; Kauppi, Markku; Geirsson, Arni Jon; et al. (Oxford University Press, 2021-12-23)
      Objectives: In axial spondyloarthritis (axSpA), switching between multiple biologic or targeted synthetic (b/ts-) DMARDs might indicate difficult-to-treat disease. We aimed to explore the occurrence of multiple switching in routine care axSpA patients using various definitions, and to identify associated clinical characteristics upon start of first b/tsDMARD (baseline). Methods: Observational cohort study including patients with axSpA starting a first-ever b/tsDMARD 2009-2018 based on data from five biologic registries (Denmark/Sweden/Finland/Norway/Iceland). Comorbidities and extra-articular manifestations were identified through linkage to national registries. Multi-switching was defined in overlapping categories according to b/tsDMARD treatment history: treatment with ≥3 b/tsDMARDs, ≥4 or ≥ 5 b/tsDMARDs during follow-up. We explored the cumulative incidence of patients becoming multi-switchers with ≥3 b/tsDMARDs stratified by calendar-period (2009-11/2012-13/2014-15/2016-2018). In the subgroup of patients starting a first b/tsDMARD 2009-2015, baseline characteristics associated with multi-switching (within 3 years' follow-up) were explored using multiple logistic regression analyses. Results: Among 8,398 patients included, 6,056 patients (63% male, median age 42 years) started a first b/tsDMARD 2009-2015, whereof proportions treated with ≥3, ≥4 or ≥ 5 b/tsDMARDs within 3 years' follow-up were 8%, 3%, 1%, respectively.Calendar-period did not affect the cumulative incidence of multi-switching.Baseline characteristics associated with multi-switching (≥3 b/tsDMARDs) were female gender, shorter disease duration, higher patient global score, comorbidities, and having psoriasis but not uveitis. Conclusion: In this large Nordic observational cohort of axSpA patients, multiple switching was frequent with no apparent time-trend. Clinical associated factors included gender, but also previous comorbidities and extraarticular manifestations illustrating the ongoing challenge of treating this patient group. Keywords: Biological treatment; axial spondyloarthritis; registry; routine care; switching.
    • Effect of Soluplus® on γ-cyclodextrin solubilization of irbesartan and candesartan and their nanoaggregates formation

      Soe, Hay Man Saung Hnin; Sripetch, Suppakan; Loftsson, Thorsteinn; Stefánsson, Einar; Jansook, Phatsawee; 1 Chulalongkorn Univ, Fac Pharmaceut Sci, Bangkok, Thailand 2 Univ Iceland, Fac Pharmaceut Sci, Reykjavik, Iceland 3 Univ Iceland, Natl Univ Hosp, Fac Med, Dept Ophthalmol, Reykjavik, Iceland (Taylor & Francis, 2021-12-20)
      The poor aqueous solubility of irbesartan (IRB) and candesartan cilexetil (CAC) may hamper their bioavailability when orally or topically administered. Among several attempts, the promising nanoaggregate formation by gamma-cyclodextrin (gamma CD) complexation of drugs in aqueous solution with or without water-soluble polymers was investigated. According to phase solubility studies, Soluplus (R) showed the highest complexation efficiency (CE) of drug/gamma CD complexes among the polymers tested. The aqueous solubility of IRB and CAC was markedly increased as a function of Soluplus(R) concentrations. The binary drug/gamma CD and ternary drug/gamma CD/Soluplus(R) complex formations were supported and confirmed by solid-state characterizations, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FT-IR) spectroscopy. The true inclusion mode was also proved by proton nuclear magnetic resonance (H-1-NMR) spectroscopy. The nanoaggregate size and morphology of binary and ternary systems were observed using dynamic light scattering (DLS), and transmission electron microscopy (TEM) techniques. The size of these nanocarriers depends on the concentration of Soluplus(R). The use of Soluplus(R) could significantly enhance drug solubility and stabilize complex nanoaggregates, which could be a prospective platform for drug delivery systems.
    • Author Correction: GWAS of thyroid stimulating hormone highlights the pleiotropic effects and inverse association with thyroid cancer

      Zhou, Wei; Brumpton, Ben; Kabil, Omer; Gudmundsson, Julius; Thorleifsson, Gudmar; Weinstock, Josh; Zawistowski, Matthew; Nielsen, Jonas B.; Chaker, Layal; Medici, Marco; et al. (NATURE RESEARCH, 2021-12-16)
    • Flares after hydroxychloroquine reduction or discontinuation: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.

      Almeida-Brasil, Celline C; Hanly, John G; Urowitz, Murray; Clarke, Ann Elaine; Ruiz-Irastorza, Guillermo; Gordon, Caroline; Ramsey-Goldman, Rosalind; Petri, Michelle; Ginzler, Ellen M; Wallace, D J; et al. (BMJ Publishing Group, 2021-12-15)
      Objectives: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. Methods: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. Results: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. Conclusions: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful. Keywords: autoimmune diseases; epidemiology; hydroxychloroquine; systemic lupus erythematosus.
    • Management of acute atrial fibrillation in the intensive care unit: An international survey.

      Wetterslev, Mik; Møller, Morten Hylander; Granholm, Anders; Hassager, Christian; Haase, Nicolai; Aslam, Tayyba Naz; Shen, Jiawei; Young, Paul J; Aneman, Anders; Hästbacka, Johanna; et al. (Wiley, 2021-12-14)
      Background: Atrial fibrillation (AF) is common in intensive care unit (ICU) patients and is associated with poor outcomes. Different management strategies exist, but the evidence is limited and derived from non-ICU patients. This international survey of ICU doctors evaluated the preferred management of acute AF in ICU patients. Method: We conducted an international online survey of ICU doctors with 27 questions about the preferred management of acute AF in the ICU, including antiarrhythmic therapy in hemodynamically stable and unstable patients and use of anticoagulant therapy. Results: A total of 910 respondents from 70 ICUs in 14 countries participated in the survey with 24%-100% of doctors from sites responding. Most ICUs (80%) did not have a local guideline for the management of acute AF. The preferred first-line strategy for the management of hemodynamically stable patients with acute AF was observation (95% of respondents), rhythm control (3%), or rate control (2%). For hemodynamically unstable patients, the preferred strategy was observation (48%), rhythm control (48%), or rate control (4%). Overall, preferred antiarrhythmic interventions included amiodarone, direct current cardioversion, beta-blockers other than sotalol, and magnesium in that order. A total of 67% preferred using anticoagulant therapy in ICU patients with AF, among whom 61% preferred therapeutic dose anticoagulants and 39% prophylactic dose anticoagulants. Conclusion: This international survey indicated considerable practice variation among ICU doctors in the clinical management of acute AF, including the overall management strategies and the use of antiarrhythmic interventions and anticoagulants. Keywords: anticoagulant therapy; atrial fibrillation; intensive care unit; management strategies.
    • Validity of chronic disease diagnoses in Icelandic healthcare registries.

      Rögnvaldsson, Sæmundur; Long, Thorir Einarsson; Thorsteinsdottir, Sigrun; Love, Thorvardur Jon; Kristinsson, Sigurður Yngvi; 1Faculty of Medicine, University of Iceland, Iceland. 2Department of Nephrology, Lund University Hospital, Sweden. 3Department of Haematology, Rigshospitalet, Denmark. 4Department of Science and Research, Landspitali University Hospital, Iceland. 5Department of Haematology, Landspítali University Hospital, Iceland. (Sage Publications, 2021-12-13)
      Aims: To evaluate the validity of recorded chronic disease diagnoses in Icelandic healthcare registries. Methods: Eight different chronic diseases from multiple sub-specialties of medicine were validated with respect to accuracy, but not to timeliness. For each disease, 30 patients with a recorded diagnosis and 30 patients without the same diagnosis were randomly selected from >80,000 participants in the iStopMM trial, which includes 54% of the Icelandic population born before 1976. Each case was validated by chart review by physicians using predefined criteria. Results: The overall accuracy of the chronic disease diagnoses was 96% (95% CI 94-97%), ranging from 92 to 98% for individual diseases. After weighting for disease prevalence, the accuracy was estimated to be 98.5%. The overall positive predictive value (PPV) of chronic disease diagnosis was 93% (95% CI 89-96%) and the overall negative predictive value (NPV) was 99% (95% CI 96-100%). There were disease-specific differences in validity, most notably multiple sclerosis, where the PPV was 83%. Other disorders had PPVs between 93 and 97%. The NPV of most disorders was 100%, except for hypertension and heart failure, where it was 97 and 93%, respectively. Those who had the registered chronic disease had objective findings of disease in 96% of cases. Conclusions: When determining the presence of chronic disease, diagnosis data from the Icelandic healthcare registries has a high PPV, NPV and accuracy. Furthermore, most diagnoses can be confirmed by objective findings such as imaging or blood testing. These findings can inform the interpretation of studies using diagnostic data from the Icelandic healthcare registries. Keywords: Chronic diseases; Iceland; comorbidity; data accuracy; registries; validation study.
    • Metabolic and Transcriptional Changes across Osteogenic Differentiation of Mesenchymal Stromal Cells.

      Sigmarsdottir, Thora Bjorg; McGarrity, Sarah; de Lomana, Adrián López García; Kotronoulas, Aristotelis; Sigurdsson, Snaevar; Yurkovich, James T; Rolfsson, Ottar; Sigurjonsson, Olafur Eysteinn; 1School of Science and Engineering, Reykjavík University, 101 Reykjavik, Iceland. 2Center for Systems Biology, University of Iceland, 101 Reykjavik, Iceland. 3Biomedical Center, University of Iceland, 101 Reykjavik, Iceland. 4Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA. 5The Blood Blank, Department of RnD, Landspitali-The National University Hospital of Iceland, 101 Reykjavik, Iceland. (MDPI, 2021-12-10)
      Mesenchymal stromal cells (MSCs) are multipotent post-natal stem cells with applications in tissue engineering and regenerative medicine. MSCs can differentiate into osteoblasts, chondrocytes, or adipocytes, with functional differences in cells during osteogenesis accompanied by metabolic changes. The temporal dynamics of these metabolic shifts have not yet been fully characterized and are suspected to be important for therapeutic applications such as osteogenesis optimization. Here, our goal was to characterize the metabolic shifts that occur during osteogenesis. We profiled five key extracellular metabolites longitudinally (glucose, lactate, glutamine, glutamate, and ammonia) from MSCs from four donors to classify osteogenic differentiation into three metabolic stages, defined by changes in the uptake and secretion rates of the metabolites in cell culture media. We used a combination of untargeted metabolomic analysis, targeted analysis of 13C-glucose labelled intracellular data, and RNA-sequencing data to reconstruct a gene regulatory network and further characterize cellular metabolism. The metabolic stages identified in this proof-of-concept study provide a framework for more detailed investigations aimed at identifying biomarkers of osteogenic differentiation and small molecule interventions to optimize MSC differentiation for clinical applications.
    • The Wittig bioconjugation of maleimide derived, water soluble phosphonium ylides to aldehyde-tagged proteins.

      Hartmann, Rafael W; Pijnappel, Matthijs; Nilvebrant, Johan; Helgudottir, Hildur Run; Asbjarnarson, Arni; Traustadottir, Gunnhildur Asta; Gudjonsson, Thorarinn; Nygren, Per-Åke; Lehmann, Fredrik; Odell, Luke R; et al. (Royal Society of Chemistry, 2021-12-08)
      Herein we disclose the transformation of maleimides into water-soluble tris(2-carboxyethyl)phosphonium ylides and their subsequent application in the bioconjugation of protein- and peptide-linked aldehydes. The new entry into Wittig bioconjugate chemistry proceeds under mild conditions and relies on highly water soluble reagents, which are likely already part of most biochemists' inventory.
    • Antibiotic oral provocation challenge in children.

      Guðnadóttir, Gyða Katrín; Jónasson, Gunnar; Clausen, Michael; Sørensen, Tonie Gertin; Kristjánsson, Sigurður; 1University of Iceland, Reykjavik, Iceland. 2Children's Hospital Iceland, Landspítalinn University Hospital, Reykjavik, Iceland. (Wiley, 2021-12-08)
      Aim: The main objective of this study was to see how many of the children, with a suspected antibiotic allergy, developed an allergic or adverse reaction to a drug provocation test. Methods: Data on children that had undergone a drug provocation test for a suspected antibiotic allergy were compiled retrospectively for the period from 2007-2018. The median age at the first provocation was 2.25 years (1.5-5.7). Standardised questionnaires, the children's parents had answered before the provocation, were used to evaluate the originally suspected allergic reaction, previous health, atopic diseases and family history. Results: Ninety-two (6.4%) of the 1440 children showed a possible mild allergic reaction. Sixty-four of the 92 children underwent a second drug provocation test 1-2 years later. At that time, only eleven developed a positive- or a possible-delayed reaction. Conclusion: An immediate moderate or severe allergic reaction was excluded in all cases of suspected antibiotic allergy in this study. Our study indicates that an oral drug provocation test is safe. It may be appropriate to wait for 6 months or more after the initial event of ADR before these tests are performed. A second oral provocation 1-2 years after the first one shows that ADRs are outgrown in most children. Keywords: acute otitis media (AOM); adverse drug reactions (ADRs); oral provocation test.
    • Different components of excessive daytime sleepiness and the change with positive airway pressure treatment in patients with obstructive sleep apnea: Results from the Icelandic Sleep Apnea Cohort (ISAC).

      Thorarinsdottir, Elin H; Janson, Christer; Aspelund, Thor; Benediktsdottir, Bryndis; Júlíusson, Sigurður; Gislason, Thorarinn; Kuna, Samuel T; Pack, Allan I; Keenan, Brendan T; 1Primary Health Care of the Capital Area, Reykjavik, Iceland. 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden. 4Icelandic Heart Association, Kopavogur, Iceland. 5Ear, Nose and Throat (ENT) Department, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 6Sleep Department, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 7Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 8Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA. (Wiley, 2021-12-03)
      Excessive daytime sleepiness includes both an inability to stay awake during the day and a general feeling of sleepiness. We describe different dimensions of daytime sleepiness in adults with moderate-severe obstructive sleep apnea (OSA) before and after 2 years of positive airway pressure (PAP) treatment. Using the Epworth Sleepiness Scale (score >10 defined as "risk of dozing") and Basic Nordic Sleep Questionnaire (feeling sleepy ≥3 times/week defined as "feeling sleepy"), participants were categorised into sleepiness phenotypes labelled non-sleepy, risk of dozing only, feeling sleepy only, or both symptoms. Participants repeated baseline assessments and PAP adherence was evaluated after 2 years. PAP-adherent subjects with sleepiness symptoms at both baseline and follow-up were considered persistently sleepy. Of the 810 participants, 722 (89%) returned for follow-up. At baseline, 17.7% were non-sleepy, 7.7% were at risk of dozing only, 24.7% were feeling sleepy only, and 49.9% had both symptoms. PAP adherence did not differ by baseline sleepiness phenotype. Patients with risk of dozing demonstrated greater PAP benefits for sleepiness symptoms than non-sleepy and feeling sleepy only phenotypes. Using these phenotypes, 42.3% of PAP users had persistent sleepiness; they had less severe OSA (p < 0.001), more persistent OSA symptoms and more often had symptoms of insomnia than patients in whom sleepiness resolved. Our present results, therefore, suggest that measuring the risk of dozing and the feeling of sleepiness reflect different sleepiness components and may respond differently to PAP. Patients feeling sleepy without risk of dozing may need more thorough evaluation for factors contributing to sleepiness before initiating treatment. Keywords: Basic Nordic Sleep Questionnaire; Epworth Sleepiness Scale; subjective sleepiness.