Recent Submissions

  • Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.

    Hetland, Merete Lund; Haavardsholm, Espen A; Rudin, Anna; Nordström, Dan; Nurmohamed, Michael; Gudbjornsson, Bjorn; Lampa, Jon; Hørslev-Petersen, Kim; Uhlig, Till; Grondal, Gerdur; et al. (British Medical Association, 2020-12-02)
    Objective: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Design: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Setting: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Participants: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Interventions: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Main outcome measures: The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. Results: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. Conclusions: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.
  • Clinical spectrum of coronavirus disease 2019 in Iceland: population based cohort study.

    Eythorsson, Elias; Helgason, Dadi; Ingvarsson, Ragnar Freyr; Bjornsson, Helgi K; Olafsdottir, Lovisa Bjork; Bjarnadottir, Valgerdur; Runolfsdottir, Hrafnhildur Linnet; Bjarnadottir, Solveig; Agustsson, Arnar Snaer; Oskarsdottir, Kristin; et al. (British Medical Association, 2020-12-02)
    Objective: To characterise the symptoms of coronavirus disease 2019 (covid-19). Design: Population based cohort study. Setting: Iceland. Participants: All individuals who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcription polymerase chain reaction (RT-PCR) between 17 March and 30 April 2020. Cases were identified by three testing strategies: targeted testing guided by clinical suspicion, open invitation population screening based on self referral, and random population screening. All identified cases were enrolled in a telehealth monitoring service, and symptoms were systematically monitored from diagnosis to recovery. Main outcome measures: Occurrence of one or more of 19 predefined symptoms during follow-up. Results: Among 1564 people positive for SARS-CoV-2, the most common presenting symptoms were myalgia (55%), headache (51%), and non-productive cough (49%). At the time of diagnosis, 83 (5.3%) individuals reported no symptoms, of whom 49 (59%) remained asymptomatic during follow-up. At diagnosis, 216 (14%) and 349 (22%) people did not meet the case definition of the Centers for Disease Control and Prevention and the World Health Organization, respectively. Most (67%) of the SARS-CoV-2-positive patients had mild symptoms throughout the course of their disease. Conclusion: In the setting of broad access to RT-PCR testing, most SARS-CoV-2-positive people were found to have mild symptoms. Fever and dyspnoea were less common than previously reported. A substantial proportion of SARS-CoV-2-positive people did not meet recommended case definitions at the time of diagnosis.
  • Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia.

    Jarvis, Kirsten Brunsvig; Nielsen, Rikke Linnemann; Gupta, Ramneek; Hede, Freja Dahl; Huttunen, Pasi; Jónsson, Ólafur Gisli; Rank, Cecilie Utke; Ranta, Susanna; Saks, Kadri; Trakymiene, Sonata Saulyte; et al. (PERGAMON-ELSEVIER SCIENCE, 2020-08-12)
    Introduction: Thromboembolism (TE) is a common and serious toxicity of acute lymphoblastic leukemia (ALL) treatment, but studies of genetic predisposition have been underpowered with conflicting results. We tested whether TE in ALL and TE in the general adult population have a shared genetic etiology. Materials and methods: We prospectively registered TE events and collected germline DNA in patients 1.0-45.9 years in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 study (7/2008-7/2016). Based on summary statistics from two large genome-wide association studies (GWAS) on venous TE in adults (the International Network of VENous Thromboembolism Clinical Research Networks (INVENT) consortium and the UK Biobank), we performed polygenic risk score (PRS) analysis on TE development in the NOPHO cohort, progressively expanding the PRS by increasing the p-value threshold of single nucleotide polymorphism (SNP) inclusion. Results and conclusion: Eighty-nine of 1252 patients with ALL developed TE, 2.5 year cumulative incidence 7.2%. PRS of genome-wide significant SNPs from the INVENT and UK Biobank data were not significantly associated with TE, HR 1.16 (p 0.14) and 1.02 (p 0.86), respectively. Expanding PRS by increasing p-value threshold did not reveal polygenic overlap. However, subgroup analysis of adolescents 10.0-17.9 years (n = 231), revealed significant polygenic overlap with the INVENT GWAS. The best fit PRS, including 16,144 SNPs, was associated with TE with HR 1.76 (95% CI 1.23-2.52, empirical p-value 0.02). Our results support an underlying genetic predisposition for TE in adolescents with ALL and should be explored further in future TE risk prediction models. Keywords: Acute lymphoblastic leukemia; Polygenic risk score; Thromboembolism.
  • Sepsis after elective surgery - Incidence, aetiology and outcome.

    Vesteinsdottir, Edda; Gottfredsson, Magnus; Blondal, Asbjorn; Sigurdsson, Martin I; 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, Reykjavik, Iceland. (Wiley, 2020-11-18)
    Background: Sepsis requiring admission to intensive care (ICU) is a rare complication of elective surgery, but is associated with high morbidity and mortality. The aim of this study was to describe the incidence and outcome of sepsis following elective surgery. Methods: This was a retrospective, observational study where all admissions to Icelandic ICUs during calendar years 2006, 2008, 2010, 2012, 2014 and 2016 were screened, identifing patients with sepsis following elective surgery (ACCP/SCCM criteria). The number of elective operations performed at the largest center (Landspitali) during the study years were collected. Descriptive statistics were used to assess the incidence and outcome of patients with sepsis after elective surgery. Results: During the study years, 88 patients were admitted to Icelandic ICUs with sepsis following elective surgery. Of those, 80 were operated at Landspitali, where the incidence of sepsis was 0.19% per elective procedure, highest following pancreaticoduodenectomies (14%, CI 6-25) and esophagectomies (13%, CI 4-27), but the greatest number of patients (30% (26/88)) developed sepsis after a colorectal procedure. The most common infection sources were the abdomen (65% (57/88)) and lungs/mediastinum (22% (19/88)), frequently polymicrobial (58% (36/62) of patients with cultures). The incidence of insufficient empirical antibiotics was high (50% (30/60)). The median ICU and hospital length-of-stay were 5.5 and 26 days and the 28-day and 1-year mortality rates were 16% (14/88) and 41% (36/87), respectively. Conclusions: Incidence of sepsis following elective surgery is low in Iceland but mortality is high. Initial antimicrobial therapy needs careful consideration in these hospital-acquired, often polymicrobial infections. Keywords: Sepsis; nosocomial infections; post-operative complications; surgery.
  • Increased risk of inflammatory bowel disease among patients treated with rituximab in Iceland from 2001 to 2018.

    Kristjánsson, Valdimar B; Lund, Sigrún H; Gröndal, Gerður; Sveinsdóttir, Signý V; Agnarsson, Hjálmar R; Jónasson, Jón G; Björnsson, Einar S; 1Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 2Department of Internal Medicine, National University Hospital, Reykjavík, Iceland. 3Department of Pathology, National University Hospital, Reykjavík, Iceland. 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, National University Hospital, Reykjavík, Iceland. (Taylor & Francis, 2020-12-05)
    Objective: Immune-mediated diseases are on the rise after the introduction of powerful immunomodulating drugs. The objective of this study was to determine the population-based incidence rate of inflammatory bowel disease (IBD) among patients treated with the monoclonal antibody rituximab in Iceland and compare it to the baseline incidence rate of IBD in the general population. Methods: We identified all patients treated with rituximab in Iceland from 2001 to 2018 through a central medicine database. IBD cases were indexed from medical records and ICD-10 codes and further confirmed by colonoscopy- and pathology reports. An experienced pathologist compared the pathology of IBD cases with matched controls of IBD patients. Results: Lymphomas and related neoplasms were the most frequent indication for treatment with rituximab (n = 367) among the 651 patients included in the analysis. Following treatment, seven patients developed IBD: two cases of Crohn's disease, three with ulcerative colitis, and two with indeterminate IBD. The incidence rate of IBD among rituximab treated patients was 202 cases per 100,000 person-years. Comparing our data to IBD incidence in Iceland, rituximab treated patients have an age-adjusted hazard ratio of 6.6 for developing IBD. The risk did not correlate with dose or treatment duration. Prior diagnosis of an autoimmune illness did not increase the risk of IBD in rituximab treated patients. Conclusions: Patients on rituximab have a sixfold increased risk of developing IBD compared to the general population. This risk was not affected by the indication for treatment and was not associated with concurrent immune-mediated diseases. Summary This population-based retrospective cohort study included all patients receiving treatment with rituximab between 2001 and 2018 in Iceland and identified a sixfold increased risk of developing IBD when compared to the general population. Keywords: IBD-basic; IBD-clinical; Immunology; colonic-disorders; endoscopy-general.
  • Hepatotoxicity associated with ribociclib among breast cancer patients.

    Finnsdottir, Stefania; Sverrisdottir, Asgerdur; Björnsson, Einar S; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Oncology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 3Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2020-12-04)
  • B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

    Desmirean, Minodora; Rauch, Sebastian; Jurj, Ancuta; Pasca, Sergiu; Iluta, Sabina; Teodorescu, Patric; Berce, Cristian; Zimta, Alina-Andreea; Turcas, Cristina; Tigu, Adrian-Bogdan; et al. (MDPI, 2020-10-24)
    Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman. Keywords: B lymphocytes; T lymphocytes; lymphocyte inter-talk; malignant lymphomas; tumor microenvironment.
  • P300 Analysis Using High-Density EEG to Decipher Neural Response to rTMS in Patients With Schizophrenia and Auditory Verbal Hallucinations.

    Aubonnet, Romain; Banea, Ovidiu C; Sirica, Roberta; Wassermann, Eric M; Yassine, Sahar; Jacob, Deborah; Magnúsdóttir, Brynja Björk; Haraldsson, Magnús; Stefansson, Sigurjon B; Jónasson, Viktor D; et al. (Frontiers Research Foundation, 2020-11-20)
    Schizophrenia is a complex disorder about which much is still unknown. Potential treatments, such as transcranial magnetic stimulation (TMS), have not been exploited, in part because of the variability in behavioral response. This can be overcome with the use of response biomarkers. It has been however shown that repetitive transcranial magnetic stimulation (rTMS) can the relieve positive and negative symptoms of schizophrenia, particularly auditory verbal hallucinations (AVH). This exploratory work aims to establish a quantitative methodological tool, based on high-density electroencephalogram (HD-EEG) data analysis, to assess the effect of rTMS on patients with schizophrenia and AVH. Ten schizophrenia patients with drug-resistant AVH were divided into two groups: the treatment group (TG) received 1 Hz rTMS treatment during 10 daily sessions (900 pulses/session) over the left T3-P3 International 10-20 location. The control group (CG) received rTMS treatment over the Cz (vertex) EEG location. We used the P300 oddball auditory paradigm, known for its reduced amplitude in schizophrenia with AVH, and recorded high-density electroencephalography (HD-EEG, 256 channels), twice for each patient: pre-rTMS and 1 week post-rTMS treatment. The use of HD-EEG enabled the analysis of the data in the time domain, but also in the frequency and source-space connectivity domains. The HD-EEG data were linked with the clinical outcome derived from the auditory hallucinations subscale (AHS) of the Psychotic Symptom Rating Scale (PSYRATS), the Quality of Life Scale (QoLS), and the Depression, Anxiety and Stress Scale (DASS). The general results show a variability between subjects, independent of the group they belong to. The time domain showed a higher N1-P3 amplitude post-rTMS, the frequency domain a higher power spectral density (PSD) in the alpha and beta bands, and the connectivity analysis revealed a higher brain network integration (quantified using the participation coefficient) in the beta band. Despite the small number of subjects and the high variability of the results, this work shows a robust data analysis and an interplay between morphology, spectral, and connectivity data. The identification of a trend post-rTMS for each domain in our results is a first step toward the definition of quantitative neurophysiological parameters to assess rTMS treatment. Keywords: P300; TMS (repetitive transcranial magnetic stimulation); brain connectivity; high-density EEG; schizophrenia; spectral analysis; temporal analysis.
  • Bromotryptamine and Imidazole Alkaloids with Anti-inflammatory Activity from the Bryozoan .

    Di, Xiaxia; Wang, Shuqi; Oskarsson, Jon T; Rouger, Caroline; Tasdemir, Deniz; Hardardottir, Ingibjorg; Freysdottir, Jona; Wang, Xiao; Molinski, Tadeusz F; Omarsdottir, Sesselja; et al. (American Society of Pharmacognosy, 2020-10-05)
    Chemical investigation of the marine bryozoan Flustra foliacea collected in Iceland resulted in isolation of 13 new bromotryptamine alkaloids, flustramines Q-W (1-7) and flustraminols C-H (8-13), and two new imidazole alkaloids, flustrimidazoles A and B (14 and 15), together with 12 previously described compounds (16-27). Their structures were established by detailed spectroscopic analysis using 1D and 2D NMR and HRESIMS. Structure 2 was verified by calculations of the 13C and 1H NMR chemical shifts using density functional theory. The relative and absolute configurations of the new compounds were elucidated on the basis of coupling constant analysis, NOESY, [α]D, and ECD spectroscopic data, in addition to chemical derivatization. The compounds were tested for in vitro anti-inflammatory activity using a dendritic cell model. Eight compounds (1, 3, 5, 13, 16, 18, 26, and 27) decreased dendritic cell secretion of the pro-inflammatory cytokine IL-12p40, and two compounds (4 and 14) increased secretion of the anti-inflammatory cytokine IL-10. Deformylflustrabromine B (27) showed the most potent anti-inflammatory effect (IC50 2.9 μM). These results demonstrate that F. foliacea from Iceland expresses a broad range of brominated alkaloids, many without structural precedents. The potent anti-inflammatory activity in vitro of metabolite 27 warrants further investigations into its potential as a lead for inflammation-related diseases.
  • Frustrated Caring: Family Members' Experience of Motivating COPD Patients Towards Self-Management.

    Sigurgeirsdottir, Jonina; Halldorsdottir, Sigridur; Arnardottir, Ragnheidur Harpa; Gudmundsson, Gunnar; Bjornsson, Eythor Hreinn; 1University of Iceland, Medical Faculty, Reykjavik, Iceland. 2Reykjalundur Rehabilitation Center, Lung Department, Mosfellsbaer, Iceland. 3University of Akureyri, School of Health Sciences, Faculty of Graduate Studies, Akureyri, Iceland. 4Akureyri Hospital, Department of Rehabilitation, Akureyri, Iceland. 5Uppsala University, Department of Medical Sciences, Respiratory-, Allergy- and Sleep Research, Uppsala, Sweden. 6Landspitali University Hospital, Department of Respiratory Medicine, Reykjavik, Iceland. (DOVE Medical Press, 2020-11-17)
    Aim: The aim of this phenomenological study was to explore principal family members' experience of motivating patients with chronic obstructive pulmonary disease (COPD) towards self-management. Methods: Interviews were conducted with 10 family members (spouses and adult children) of COPD patients. The interviews were audio recorded, transcribed and analyzed thematically. Results: Being a principal family member of a COPD patient is characterized by frustrated caring; wanting the best for him/her and yet carrying a heavier burden than the person feels equipped for, lacking both knowledge about the disease progress and information about available healthcare resources. The situation demands much energy, due to COPD patients' lack of stamina; family members' fear of the patient's possible breathlessness; willingness to help, though sometimes meeting with negative reactions from the patient; and feeling ignored by health professionals (HPs). Family members expressed a need for a formal connection between patient-family-HPs. The increasing burden experienced by patients' family members is characterized by a sequential process in three phases of the patient's declining self-management. In the early phase, family and patient are ignorant of COPD yet recognize the patient's smoking as a risky lifestyle. In the intermediary phase, signs of COPD become evident to the family. The first turning point is when the family first observes the patient's acute exacerbation. A second turning point is in the advanced phase, when family and patient recognize COPD as a progressive disease, possibly fatal. We also identified family members' views on COPD patients' needs, and their own roles, main frustrations and concerns. Conclusion: Family members' experience of motivating COPD patients towards self-management is a sequential process where the family experiences advancing caring burden and declining self-management by the patient. We propose the establishment of COPD patients' teams consisting of patient-family-HP, aimed at the patients' best possible self-management. Keywords: PR; chronic; family’s needs; obstructive; pulmonary rehabilitation; qualitative research; self-management.
  • Economic Evaluation of Damage Accrual in an International Systemic Lupus Erythematosus Inception Cohort Using a Multistate Model Approach.

    Barber, Megan R W; Hanly, John G; Su, Li; Urowitz, Murray B; St Pierre, Yvan; Romero-Diaz, Juanita; Gordon, Caroline; Bae, Sang-Cheol; Bernatsky, Sasha; Wallace, Daniel J; et al. (Wiley, 2020-12)
    Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling. Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model. Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0. Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.
  • Preferences for the measurement and supplementation of magnesium, phosphate and zinc in ICUs: The international WhyTrace survey.

    Vesterlund, Gitte K; Ostermann, Marlies; Myatra, Sheila N; Arabi, Yaseen M; Sadat, Musharaf; Zampieri, Fernando G; Cronhjort, Maria; Schefold, Joerg C; Stöhr, Frederik; Buanes, Eirik A; et al. (Wiley, 2020-11-09)
    Background: Patients admitted to the Intensive Care Unit (ICU) often have low magnesium, phosphate and zinc levels. Monitoring of serum concentrations and supplementation may be important, but there is no consensus on optimal practice. The objective of the WhyTrace survey was to describe current practice regarding the measurement and supplementation of magnesium, phosphate and zinc in ICUs. Methods: A 54-item electronic questionnaire was developed in accordance with SURGE, SUrvey Reporting GuidelinE, to address international clinical practice in the ICU. National investigators recruited ICUs in ten countries with one physician responding per ICU using a unique e-mail distributed survey-link. Results: The questionnaire was sent to clinicians in 336 ICUs of whom 283 (84%) responded. In 62% of the ICUs, a standard procedure was in place regarding the measurement of serum magnesium levels, in 58% for phosphate and in 9% for zinc. Zinc was never or rarely measured in 64% of ICUs. The frequency of requesting serum levels varied from twice daily to once weekly. Regarding supplementation, 66% of ICUs had a standard procedure for magnesium, 63% for phosphate and 15% for zinc. Most procedures recommended supplementation when serum levels were below the lower reference level, but some used the upper reference levels as the threshold for supplementation and others decided on a case-by-case basis. Conclusion: The practice of measuring and supplementing magnesium, phosphate and zinc differed substantially between ICUs. Our findings indicate that there is a need for high-quality prospective data on frequencies of measurements, treatment goals and effects of supplementation on patient-important outcomes. Keywords: ICU; critically ill; magnesium; phosphate; trace elements; zinc.
  • Opportunistic genomic screening. Recommendations of the European Society of Human Genetics.

    de Wert, Guido; Dondorp, Wybo; Clarke, Angus; Dequeker, Elisabeth M C; Cordier, Christophe; Deans, Zandra; van El, Carla G; Fellmann, Florence; Hastings, Ros; Hentze, Sabine; et al. (Nature Publishing Group, 2020-11-22)
    If genome sequencing is performed in health care, in theory the opportunity arises to take a further look at the data: opportunistic genomic screening (OGS). The European Society of Human Genetics (ESHG) in 2013 recommended that genome analysis should be restricted to the original health problem at least for the time being. Other organizations have argued that 'actionable' genetic variants should or could be reported (including American College of Medical Genetics and Genomics, French Society of Predictive and Personalized Medicine, Genomics England). They argue that the opportunity should be used to routinely and systematically look for secondary findings-so-called opportunistic screening. From a normative perspective, the distinguishing characteristic of screening is not so much its context (whether public health or health care), but the lack of an indication for having this specific test or investigation in those to whom screening is offered. Screening entails a more precarious benefits-to-risks balance. The ESHG continues to recommend a cautious approach to opportunistic screening. Proportionality and autonomy must be guaranteed, and in collectively funded health-care systems the potential benefits must be balanced against health care expenditures. With regard to genome sequencing in pediatrics, ESHG argues that it is premature to look for later-onset conditions in children. Counseling should be offered and informed consent is and should be a central ethical norm. Depending on developing evidence on penetrance, actionability, and available resources, OGS pilots may be justified to generate data for a future, informed, comparative analysis of OGS and its main alternatives, such as cascade testing.
  • A European Research Agenda for Geriatric Emergency Medicine: a modified Delphi study.

    Mooijaart, Simon P; Nickel, Christian H; Conroy, Simon P; Lucke, Jacinta A; van Tol, Lisa S; Olthof, Mareline; Blomaard, Laura C; Buurman, Bianca M; Dundar, Zerrin D; de Groot, Bas; et al. (Springer, 2020-11-21)
    Purpose: Geriatric Emergency Medicine (GEM) focuses on delivering optimal care to (sub)acutely ill older people. This involves a multidisciplinary approach throughout the whole healthcare chain. However, the underpinning evidence base is weak and it is unclear which research questions have the highest priority. The aim of this study was to provide an inventory and prioritisation of research questions among GEM professionals throughout Europe. Methods: A two-stage modified Delphi approach was used. In stage 1, an online survey was administered to various professionals working in GEM both in the Emergency Department (ED) and other healthcare settings throughout Europe to make an inventory of potential research questions. In the processing phase, research questions were screened, categorised, and validated by an expert panel. Subsequently, in stage 2, remaining research questions were ranked based on relevance using a second online survey administered to the same target population, to identify the top 10 prioritised research questions. Results: In response to the first survey, 145 respondents submitted 233 potential research questions. A total of 61 research questions were included in the second stage, which was completed by 176 respondents. The question with the highest priority was: Is implementation of elements of CGA (comprehensive geriatric assessment), such as screening for frailty and geriatric interventions, effective in improving outcomes for older patients in the ED? Conclusion: This study presents a top 10 of high-priority research questions for a European Research Agenda for Geriatric Emergency Medicine. The list of research questions may serve as guidance for researchers, policymakers and funding bodies in prioritising future research projects. Keywords: Geriatric Emergency Medicine; Research prioritisation.
  • Angiotensin Receptor Blockers in cyclodextrin nanoparticle eye drops: Ocular pharmacokinetics and pharmacologic effect on intraocular pressure.

    Lorenzo-Soler, Laura; Olafsdottir, Olof Birna; Garhöfer, Gerhard; Jansook, Phatsawee; Kristinsdottir, Iris Myrdal; Tan, Aimin; Loftsson, Thorsteinn; Stefansson, Einar; 1Faculty of Medicine, University of Iceland, Reykjavík, Iceland. 2Department of Ophthalmology, Landspitali University Hospital, Reykjavík, Iceland. 3Oculis ehf., Reykjavík, Iceland. 4Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 5Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. 6Nucro-Technics, Toronto, ON, Canada. 7Faculty of Pharmacy, University of Iceland, Reykjavík, Iceland. (Wiley, 2020-11-16)
    Purpose: Orally administered angiotensin II receptor blockers (ARBs) decrease intraocular pressure (IOP). Topical administration may reduce systemic side effects and result in a useful glaucoma drug. The aim of this study is to test the ocular delivery and pharmacologic effect of nanoparticle eye drops containing ARBs (e.g. irbesartan and candesartan). Methods: 1.5% irbesartan and 0.15% candesartan eye drops were applied to rabbits. The pharmacokinetics in cornea and aqueous humour after single eye drop application were studied in 49 rabbits. The effect of the eye drops on IOP was studied in 10 rabbits using an iCare (® TonoVet Plus, iCare, Finland) tonometer and compared with 0.5% timolol eye drops. Results: Candesartan lowered IOP from 24.6 ± 5.1 mmHg at baseline to 19.0 ± 2.9 mmHg (mean ± SD, p = 0.030, n = 10) 4 hr after application. Irbesartan lowered IOP from 24.2 ± 1.7 mmHg to 20.2 ± 0.9 mmHg (p = 0.14, n = 10). Timolol decreased the IOP from 24.9 ± 4.2 mmHg to 20.4 ± 4.8 mmHg (mean ± SD, p = 0.036, n = 10). The pharmacokinetics data show that both formulations deliver effective amounts of drug into the intraocular tissues, with irbesartan and candesartan reaching concentrations of 121 ± 69 and 30.43 ± 13.93 ng/g (mean ± SD), respectively, in the aqueous humour 3 hr after a single-dose administration. Conclusions: Topical application of irbesartan and candesartan eye drops delivers effective drug concentrations to the anterior segment of the eye in rabbits, achieving drug concentrations 100 times above the IC50 for angiotensin II receptor and showing an IOP-lowering effect. Angiotensin receptor blocker (ARB) eye drops have potential as a new class of glaucoma drugs. Keywords: angiotensin receptor blockers; glaucoma; intraocular pressure; pharmacokinetics.
  • Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid.

    Brouwers, Hilde; Jónasdóttir, Hulda S; Kuipers, Marije E; Kwekkeboom, Joanneke C; Auger, Jennifer L; Gonzalez-Torres, Mayra; López-Vicario, Cristina; Clària, Joan; Freysdottir, Jona; Hardardottir, Ingibjorg; et al. (American Association of Immunologists, 2020-10-02)
    Polyunsaturated fatty acids (PUFAs) and their metabolites are potent regulators of inflammation. Generally, omega (n)-3 PUFAs are considered proresolving whereas n-6 PUFAs are classified as proinflammatory. In this study, we characterized the inflammatory response in murine peritonitis and unexpectedly found the accumulation of adrenic acid (AdA), a poorly studied n-6 PUFA. Functional studies revealed that AdA potently inhibited the formation of the chemoattractant leukotriene B4 (LTB4), specifically in human neutrophils, and this correlated with a reduction of its precursor arachidonic acid (AA) in free form. AdA exposure in human monocyte-derived macrophages enhanced efferocytosis of apoptotic human neutrophils. In vivo, AdA treatment significantly alleviated arthritis in an LTB4-dependent murine arthritis model. Our findings are, to our knowledge, the first to indicate that the n-6 fatty acid AdA effectively blocks production of LTB4 by neutrophils and could play a role in resolution of inflammation in vivo.
  • A comparison of platelet quality between platelets from healthy donors and hereditary hemochromatosis donors over seven-day storage.

    Mikaelsdottir, Marta; Vidarsson, Brynjar; Runarsson, Gudmundur; Bjarnadottir, Una; Onundarson, Pall T; Sigurjonsson, Olafur E; Halldorsdottir, Anna M; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Hematology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 3Department of Immunology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 4The Blood Bank, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland. 5School of Science and Engineering, Reykjavik University, Reykjavik, Iceland. (Wiley, 2020-11-09)
    Background: Therapeutic phlebotomy is the standard treatment of hereditary hemochromatosis (HH), the most common genetic disease in people of Northern European descent. Red cell concentrates from HH donors have been reported safe for transfusion, but little data is available on the storage properties of platelet concentrates from HH donors. Study design and methods: Whole blood was collected from 10 healthy individuals and 10 newly diagnosed HH patients with elevated serum ferritin. Platelet-rich plasma (PRP) was prepared and split into four 20-mL units. Platelet quality tests were performed on days 0, 1, 3, 5, and 7 of storage, including platelet aggregation (ADP, arachidonic acid, collagen, and epinephrine agonists), blood gas analysis, flow cytometry (CD41, CD42b, and CD62P expression), and ELISA (sCD40L and sCD62p in supernatant). Results: Mean serum ferritin levels were higher in HH patients than in controls (847.5 vs 45.8 ng/mL, P < .001). Overall, no difference in quality test results was observed between the two study groups over 7-day storage (P > .05), including blood gas analysis, platelet aggregation, and expression of surface (CD62p and CD42b) and secreted (sCD62P and sCD40L) activation markers. Expected alterations in metabolic (CO2 and glucose decrease, O2 and lactate increase, P < .001) and platelet activation markers (CD42b decrease, CD62P increase, P < .05) over time were observed in both groups. Conclusion: Although these findings indicate that platelets of individuals with HH are comparable to platelets from healthy donors, more extensive studies are needed before definite conclusions can be drawn.
  • A poor appetite or ability to eat and its association with physical function amongst community-dwelling older adults: age, gene/environment susceptibility-Reykjavik study

    Chang, Milan; Geirsdottir, Olof G.; Launer, Lenore J.; Gudnasson, Vilmundur; Visser, Marjolein; Gunnarsdottir, Ingibjorg; aThe Icelandic Gerontological Research Center, Landspitali University Hospital and University of Iceland, Reykjavík, Iceland bSport Science, School of Science and Engineering, Reykjavik University, Reykjavík, Iceland cFaculty of Food Science and Nutrition, School of Health Science, University of Iceland, Reykjavík, Iceland dUnit for Nutrition Research, University of Iceland and Landspitali University Hospital, Reykjavík, Iceland eEpidemiology and Pop Science Lab, National Institute on Aging, National Institute of Health, Bethesda, MD, United States fIcelandic Heart Association, Kopavogur, Reykjavík, Iceland gFaculty of Medicine, School of Health Science, University of Iceland, Reykjavík, Iceland hDepartment of Health Sciences, Faculty of Science, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands (Springer, 2020-01-01)
    A poor appetite or ability to eat and its association with physical function have not been explored considerably amongst community-dwelling older adults. The current study examined whether having an illness or physical condition affecting one's appetite or ability to eat is associated with body composition, muscle strength, or physical function amongst community-dwelling older adults. This is a secondary analysis of cross-sectional data from the age, gene/environment susceptibility-Reykjavik study (n = 5764). Illnesses or physical conditions affecting one's appetite or ability to eat, activities of daily living, current level of physical activity, and smoking habits were assessed with a questionnaire. Fat mass, fat-free mass, body mass index, knee extension strength, and grip strength were measured, and the 6-m walk test and timed up-and-go test were administered. Individuals who reported illnesses or physical conditions affecting their appetite or ability to eat were considered to have a poor appetite. The associations of appetite or the ability to eat with body composition and physical function were analysed with stepwise linear regression models. A total of 804 (14%) individuals reported having conditions affecting their appetite or ability to eat and had a significantly lower fat-free mass and body mass index, less grip strength, and poorer physical function than did those without any conditions affecting their appetite or ability to eat. Although the factors reported to affect one's appetite or ability to eat are seldom considered severe, their strong associations with physical function suggest that any condition affecting one's appetite or ability to eat requires attention.
  • Predicting body mass index and isometric leg strength using soft tissue distributions from computed tomography scans

    Recenti, Marco; Ricciardi, Carlo; Monet, Anaïs; Jacob, Deborah; Ramos, Jorgelina; Gìslason, Magnus; Edmunds, Kyle; Carraro, Ugo; Gargiulo, Paolo; aInstitute of Biomedical and Neural Engineering, Reykjavik University, Menntavegi 1, Reykjavik, 102, Iceland bDepartment of Advanced Biomedical Sciences, University Hospital of Naples ‘Federico II’, Via Sergio Pansini 5, Naples, 80131, Italy cCIR-Myo, Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, Padova, 35121, Italy dDepartment of Science, Landspitali, Hingbraut, Reykjavik, 101, Iceland (SPRINGER HEIDELBERG, 2020-01-01)
    This paper describes the interconnections and predictive value between Body Mass Index (BMI), Isometric Leg Strength (ISO) and soft tissue distribution from mid-thigh Computed Tomography (CT) scans using Machine Learning (ML) regression and classification algorithms. A novel methodology for soft tissue patient specific CT profile called Nonlinear Trimodal Regression Analysis (NTRA) was developed using radiodensitomentric distribution from a CT scan. This method defines 11 parameters used as input features for Tree-Based ML algorithms in order to apply regression and classification on BMI and ISO. K_fold Cross-Validation with k = 10 is applied to obtain several models to choose the best one using the higher coefficient of determination (R-2) as an evaluator of the quality of regression prediction. Following this, BMI and ISO are divided into 3 and 5 classes and the same methodology is used to classify them. For this analysis, an accuracy parameter is calculated to evaluate the quality of the results. The max R-2 is 88.9 for the BMI and it is obtained using the Gradient-Boosting Algorithm. The best accuracy was 76.1 for 3 classes and 73.1 for 5 classes. The best results obtained for ISO are R-2 = 66.5 and an accuracy of 65.5 for the 3 classes classification. Furthermore, the connective tissue assumes high importance in the prediction process. In this methodological study the feasibility of a ML approach was tested with good results, in order to show a novel approach to study the correlation between physiology parameters and imaging.

    Brouwer, Niels J; Marinkovic, Marina; Bleeker, Jaco C; El Filali, Mariam; Stefansson, Einar; Luyten, Gregorius P M; Jager, Martine J; 1Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. 2Department of Ophthalmology, Reinier de Graaf Gasthuis, Delft, The Netherlands. 3Department of Ophthalmology, Landspitali University Hospital, University of Iceland, Reykjavik, Iceland. (Lippincott Williams & Wilkins, 2020-11)
    Purpose: To compare retinal vessel oxygenation in eyes with an untreated choroidal nevus or choroidal melanoma. Methods: The affected and fellow eye of patients with an untreated choroidal nevus (n = 42) or choroidal melanoma (n = 45) were investigated using noninvasive retinal oximetry (Oxymap T1). Oxygen saturation of arterioles (ArtSat) and venules (VenSat) was determined, together with the arteriovenous difference (AV-difference). Results: In choroidal nevus patients, retinal oximetry did not differ between the affected and fellow eye: the mean ArtSat was 94.5% and 94.2% (P = 0.56), the VenSat was 60.5% and 61.3% (P = 0.35), and the AV-difference was 34.0% and 32.9% (P = 0.18), respectively. In choroidal melanoma patients, alterations were detected: the mean ArtSat was 94.8% and 93.2% (P = 0.006), the VenSat was 58.0% and 60.0% (P = 0.014), and the AV-difference was 36.8% and 33.2% (P < 0.001), respectively. The largest increase in AV-difference was observed between the retinal halves without the lesion in melanoma eyes compared with the corresponding half in the fellow eye (37.5% vs. 32.1%, P < 0.001). Conclusion: Although retinal oximetry was not significantly altered in eyes with a choroidal nevus, eyes with choroidal melanoma showed an increased ArtSat and decreased VenSat, leading to an increased AV-difference. These changes may be caused by inflammation and a higher metabolism, with larger oxygen consumption, leading to altered blood flow and intraocular oxygen relocation.

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