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  • Recent advances in the treatment of primary sclerosing cholangitis.

    Björnsson, Einar S; Kalaitzakis, Evangelos; 1Department of Internal Medicine, Faculty of Medicine, University of Iceland, Division of Gastroenterology and Hepatology, Landspitali University Hospital of Iceland. 2Department of Internal Medicine, University Hospital Heraklion, Faculty of Medicine, University of Crete , Rethymno, Greece. (Taylor & Francis, 2020-12-14)
    Introduction: PSC is a rare liver disease that leads frequently to cirrhosis and need for liver transplantation. No medical treatment is of proven value. Liver transplantation is the only curative therapy available. There is a big medical need to find medical therapy that can alter the natural history of the disease. Areas covered: The authors highlight advances in PSC, based on recent literature retrieved from PubMed until September 2020 regarding both medical and endoscopic biliary therapy. Future possibilities for treatment of PSC are discussed. Expert opinion: Biliary endoscopy is the cornerstone in the treatment of dominant strictures. Single-user peroral cholangioscopy is an emerging modality. Balloon dilatation therapy is the treatment of choice of dominant strictures. The most promising medical therapies showing efficacy in phase II trials are nor-Ursodeoxycholic acid, obethicolic acid, the non-steroidal FXR agonist Cilofexor and Aldafermin, a synthetic analogue of FGF-19. Antibiotics, particularly vancomycin have shown potential benefits, particularly in children but phase III studies are lacking. In observational studies of effects of biological therapy in patients with IBD/PSC adalimumab was associated with reduction in ALP. Results of liver transplantation are favorable but recurrence can be of clinical relevance particularly in patients transplanted before the age of 40.
  • Decrement Evoked Potential Mapping to Guide Ventricular Tachycardia Ablation: Elucidating the Functional Substrate.

    Bhaskaran, Abhishek; Fitzgerald, John; Jackson, Nicholas; Gizurarson, Sigfus; Nanthakumar, Kumaraswamy; Porta-Sánchez, Andreu; 1University Health Network, University of Toronto, Ontario, Canada. 2University of Adelaide, Australia. 3John Hunter Hospital, Newcastle, Australia. 4Landspitali, Reykjavik, Iceland. 5Hospital Universitario Quirónsalud Madrid, Molecular Cardiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Spain. (Radcliffe Cardiology, 2020-12)
    Empirical approaches to targeting the ventricular tachycardia (VT) substrate include mapping of late potentials, local abnormal electrogram, pace-mapping and homogenisation of the abnormal signals. These approaches do not try to differentiate between the passive or active role of local signals as the critical components of the VT circuit. By not considering the functional components, these approaches often view the substrate as a fixed anatomical barrier. Strategies to improve the success of VT ablation need to include the identification of critical functional substrate. Decrement-evoked potential (DeEP) mapping has been developed to elucidate this using an extra-stimulus added to a pacing drive train. With knowledge translation in mind, the authors detail the evolution of the DeEP concept by way of a study of simultaneous panoramic endocardial mapping in VT ablation; an in silico modelling study to demonstrate the factors influencing DeEPs; a multicentre VT ablation validation study; a practical approach to DeEP mapping; the potential utility of DeEPs to identify arrhythmogenic atrial substrate; and, finally, other functional mapping strategies.
  • A nationwide study on hepatocellular carcinoma.

    Sigurdsson, Bjarki; Sigurdardottir, Ragna; Arnardottir, Margret B; Lund, Sigrun H; Jonasson, Jon G; Björnsson, Einar S; 1Department of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbraut, 101, Reykjavik, Iceland; Department of Pathology, Landspitali University Hospital, Hringbraut, 101, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland. Electronic address: bjs270292@gmail.com. 2Department of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbraut, 101, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland. Electronic address: ragnasi@landspitali.is. 3Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland. Electronic address: margretbjort9@gmail.com. 4Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland; Decode Genetics, Sturlugata 8, 101, Reykjavik, Iceland. Electronic address: sigrunhelga@gmail.com. 5Department of Pathology, Landspitali University Hospital, Hringbraut, 101, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland. Electronic address: jongj@landspitali.is. 6Department of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbraut, 101, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland. Electronic address: einarsb@landspitali.is. (Elsevier, 2020-10-14)
    Background & aims: Population based studies on the epidemiology of HCC are scarce. We aimed to compare CG (cirrhotic HCC group) with NCG (non-cirrhotic HCC group), analyze incidence, etiology and survival among patients diagnosed in Iceland in a population-based cohort. A previous study from Iceland (1984-1998) showed an incidence of HCC of 1.1/100.000, mostly with NCG. Methods: A nationwide, population based retrospective study. Information on patients with HCC during 1998-2017 was obtained and medical records viewed. Results: Overall 152 patients with HCC were identified. The mean incidence was 1.7/100.000 and increased by 8% annually. Alcohol and hepatitis C combined was more common as a risk factor in CG than in the NCG (13 % vs. 2%, p = 0.03). Tumor size was larger in NCG (11 cm vs 5 cm, p < 0.01) and portal vein thrombosis less common (11 % vs. 30 %, p = 0.03). Overall, 44 % in NCG underwent surgical treatment vs. 23 % in CG (p = 0.02). The proportion of patients diagnosed by surveillance in 1998-2007 was 3% and 19 % in 2008-2017 (p = 0.03). The disease specific median survival for cirrhotic patients diagnosed by surveillance was 519 days and 86 days in other cirrhotic patients, hazard ratio 0.45 (p = 0.007, CI 0.25-0.81). Conclusions: A major increase in the incidence of patients with HCC has occurred. The non-cirrhotic HCC presented with larger size tumors, lower proportion of portal vein thrombosis and were more likely to be surgical candidates, although not affecting prognosis. Diagnosis by surveillance in patients with cirrhosis has increased and the survival of those patients is better compared to others. Keywords: Cirrhosis; Epidemiology; Hepatocellular carcinoma; Non-cirrhotic etiology.
  • Development and Validation of a Prediction Model for 6-Month Societal Costs in Older Community Care-Recipients in Multiple Countries; the IBenC Study

    van Lier, Lisanne I.; Bosmans, Judith E.; van der Roest, Henriëtte G.; Heymans, Martijn W.; Garms-Homolová, Vjenka; Declercq, Anja; V Jónsson, Pálmi; van Hout, Hein P.J.; aDepartment of General Practice and Medicine of Older People, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Department on Aging, Amsterdam, Netherlands bDepartment of Health Sciences, Faculty of Science, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands cDepartment of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam, Netherlands dDepartment III, Economy and Law, Hochschule für Technik und Wirtschaft Berlin, Berlin, Germany eLUCAS, Centre for Care Research and Consultancy, and CESO, Center for Sociological Research, KU Leuven (University of Leuven), Leuven, Belgium fDepartment of Geriatrics, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland gInstitute of Mental Health and Addiction (Trimbos Institute), Utrecht, Utrecht, Netherlands hUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands (SAGE Publications, 2020-01-01)
    This study aims to develop and validate a prediction model of societal costs during a period of 6-months in older community care-recipients across multiple European countries. Participants were older community care-recipients from 5 European countries. The outcome measure was mean 6-months total societal costs of resource utilisation (healthcare and informal care). Potential predictors included sociodemographic characteristics, functional limitations, clinical conditions, and diseases/disorders. The model was developed by performing Linear Mixed Models with a random intercept for the effect of country and validated by an internal-external validation procedure. Living alone, caregiver distress, (I)ADL impairment, required level of care support, health instability, presence of pain, behavioural problems, urinary incontinence and multimorbidity significantly predicted societal costs during 6 months. The model explained 32% of the variation within societal costs and showed good calibration in Iceland, Finland and Germany. Minor model adaptations improved model performance in The Netherland and Italy. The results can provide a valuable orientation for policymakers to better understand cost development among older community care-recipients. Despite substantial differences of countries' care systems, a validated cross-national set of key predictors could be identified.
  • Editor's Choice - International Variations and Sex Disparities in the Treatment of Peripheral Arterial Occlusive Disease: A Report from VASCUNET and the International Consortium of Vascular Registries.

    Behrendt, Christian-Alexander; Sigvant, Birgitta; Kuchenbecker, Jenny; Grima, Matthew J; Schermerhorn, Marc; Thomson, Ian A; Altreuther, Martin; Setacci, Carlo; Svetlikov, Alexei; Laxdal, Elin H; et al. (Elsevier, 2020-09-29)
    Objective: The aim of this study was to determine sex specific differences in the invasive treatment of symptomatic peripheral arterial occlusive disease (PAOD) between member states participating in the VASCUNET and International Consortium of Vascular Registries. Methods: Data on open surgical revascularisation and peripheral vascular intervention (PVI) of symptomatic PAOD from 2010 to 2017 were collected from population based administrative and registry data from 11 countries. Differences in age, sex, indication, and invasive treatment modality were analysed. Results: Data from 11 countries covering 671 million inhabitants and 1 164 497 hospitalisations (40% women, mean age 72 years, 49% with intermittent claudication, 54% treated with PVI) in Europe (including Russia), North America, Australia, and New Zealand were included. Patient selection and treatment modality varied widely for the proportion of female patients (23% in Portugal and 46% in Sweden), the proportion of patients with claudication (6% in Italy and 69% in Russia), patients' mean age (70 years in the USA and 76 years in Italy), the proportion of octogenarians (8% in Russia and 33% in Sweden), and the proportion of PVI (24% in Russia and 88% in Italy). Numerous differences between females and males were observed in regard to patient age (72 vs. 70 years), the proportion of octogenarians (28% vs. 15%), proportion of patients with claudication (45% vs. 51%), proportion of PVI (57% vs. 51%), and length of hospital stay (7 days vs. 6 days). Conclusion: Remarkable differences regarding the proportion of peripheral vascular interventions, patients with claudication, and octogenarians were seen across countries and sexes. Future studies should address the underlying reasons for this, including the impact of national societal guidelines, reimbursement, and differences in health maintenance. Keywords: Administrative data; Diabetic foot syndrome (DFS); Epidemiology; Lower extremity artery disease; Peripheral arterial occlusive disease (PAOD); Registries.
  • Untargeted metabolomics as an unbiased approach to the diagnosis of inborn errors of metabolism of the non-oxidative branch of the pentose phosphate pathway.

    Shayota, Brian J; Donti, Taraka R; Xiao, Jing; Gijavanekar, Charul; Kennedy, Adam D; Hubert, Leroy; Rodan, Lance; Vanderpluym, Christina; Nowak, Catherine; Bjornsson, Hans T; et al. (Academic Press, 2020-08-05)
    Inborn errors of metabolism (IEM) involving the non-oxidative pentose phosphate pathway (PPP) include the two relatively rare conditions, transketolase deficiency and transaldolase deficiency, both of which can be difficult to diagnosis given their non-specific clinical presentations. Current biochemical testing approaches require an index of suspicion to consider targeted urine polyol testing. To determine whether a broad-spectrum biochemical test could accurately identify a specific metabolic pattern defining IEMs of the non-oxidative PPP, we employed the use of clinical metabolomic profiling as an unbiased novel approach to diagnosis. Subjects with molecularly confirmed IEMs of the PPP were included in this study. Targeted quantitative analysis of polyols in urine and plasma samples was accomplished with chromatography and mass spectrometry. Semi-quantitative unbiased metabolomic analysis of urine and plasma samples was achieved by assessing small molecules via liquid chromatography and high-resolution mass spectrometry. Results from untargeted and targeted analyses were then compared and analyzed for diagnostic acuity. Two siblings with transketolase (TKT) deficiency and three unrelated individuals with transaldolase (TALDO) deficiency were identified for inclusion in the study. For both IEMs, targeted polyol testing and untargeted metabolomic testing on urine and/or plasma samples identified typical perturbations of the respective disorder. Additionally, untargeted metabolomic testing revealed elevations in other PPP metabolites not typically measured with targeted polyol testing, including ribonate, ribose, and erythronate for TKT deficiency and ribonate, erythronate, and sedoheptulose 7-phosphate in TALDO deficiency. Non-PPP alternations were also noted involving tryptophan, purine, and pyrimidine metabolism for both TKT and TALDO deficient patients. Targeted polyol testing and untargeted metabolomic testing methods were both able to identify specific biochemical patterns indicative of TKT and TALDO deficiency in both plasma and urine samples. In addition, untargeted metabolomics was able to identify novel biomarkers, thereby expanding the current knowledge of both conditions and providing further insight into potential underlying pathophysiological mechanisms. Furthermore, untargeted metabolomic testing offers the advantage of having a single effective biochemical screening test for identification of rare IEMs, like TKT and TALDO deficiencies, that may otherwise go undiagnosed due to their generally non-specific clinical presentations. Keywords: Developmental delay; Inborn error of metabolism; Metabolome; Pentose phosphate
  • Tíðatengt loftbrjóst vegna endómetríósu í lunga - sjúkratilfelli

    Ásdís Kristjánsdóttir; Gunnar Mýrdal; Margrét Sigurðardóttir; Reynir Tómas Geirsson; 1 Læknadeild Háskóla Íslands, 2skurðlækningar, aðgerðasviði Landspítala, 3 rannsóknastofu í meinafræði, rannsóknasviði Landspítala, 4 kvennadeild, aðgerðasviði Landspítala. (Læknafélag Íslands, 2021-01)
    Endómetríósa getur verið langvinn orsök verkja, blæðingaóreglu og ófrjósemi meðal kvenna. Sjúkdómurinn er vanalega í grindarholi, en getur birst á óvenjulegum stöðum. Hér er lýst tilfelli 39 ára konu með gamla endómetríósugreiningu sem leitaði á heilsugæslu og sjúkrahús í þrígang á öðrum degi blæðinga vegna andþyngsla, takverks og mæði. Myndgreining sýndi loftbrjóst hægra megin í öll skiptin. Við brjóstholsspeglun voru endómetríósu-líkir blettir á yfirborði hægra lunga. Vefjagreining sýndi merki um endómetríósu. Konan hefur verið einkennalaus eftir kemíska fleiðruertingu og hormónameðferð. Greining tíðatengds loftbrjósts þarf að byggjast á samhliða brjósthols- og kviðarholsspeglun með vefjasýnatöku til að fá staðfestingu á sjúkdómnum og tryggja grundvöll meðferðar.
  • Viðhorf hjúkrunarfræðinga og almenn viðhorf til ákæru vegna alvarlegra sjúklingaatvika í heilbrigðisþjónustu: Eru blikur á lofti?

    Sigurbjörg Sigurgeirsdóttir; Elísabet Benedikz; Anna María Þórðardóttir; 1) Stjórnmálafræðideild Háskóla Íslands, 2) gæða- og sýkingarvarnadeild Landspítala (Læknafélag Íslands, 2021-01)
    INNGANGUR Markmið rannsóknarinnar er að stuðla að upplýstri umræðu um öryggi sjúklinga og viðbrögð við óvæntum atvikum í heilbrigðisþjónustu. Í þessum tilgangi leitast rannsóknin við að varpa ljósi á þá spurningu hvað einkenni viðhorf til þess hvort kæra eigi fyrir slík atvik eða ekki. Tildrögin eru ákæra fyrir manndráp af gáleysi á hendur hjúkrunarfræðingi í maí 2014 og áhrif þeirrar ákæru á heilbrigðisstarfsfólk. EFNIVIÐUR OG AÐFERÐIR I þessari lýsandi samanburðarrannsókn var kannað hvort munur væri á viðhorfum til ákæru vegna atvika í heilbrigðisþjónustu milli slembiúrtaks úr Þjóðskrá (Þjóðgátt) og allra félagsmanna í Félagi íslenskra hjúkrunarfræðinga. Báðir hópar voru spurðir hvort ákæra ætti heilbrigðisstarfsmann sem veldur alvarlegum skaða eða andláti vegna mannlegra mistaka, slysni, vanrækslu eða af ásetningi. Svör voru gefin á Likert- kvarða. NIÐURSTÖÐUR Marktækur munur reyndist á svörum hópanna um það hvort ákæra ætti fyrir skaða eða andlát af völdum mannlegra mistaka eða slysni, þar sem hjúkrunarfræðingar voru líklegri til að vera mjög eða frekar ósammála ákæru en Þjóðgáttarhópurinn var líklegri til að vera mjög eða frekar sammála. Munurinn milli hópanna minnkaði með hærra menntunarstigi Þjóðgáttarhópsins. Þegar spurt var um hvort ákæra ætti heilbrigðisstarfsmann fyrir skaða eða andlát vegna vanrækslu eða ásetnings var munurinn ekki marktækur. ÁLYKTANIR Niðurstöður rannsóknarinnar benda til þess að viðhorf hjúkrunarfræðinga endurspegli ekki tilhneigingu til að víkjast undan ábyrgð á óvæntum atvikum í heilbrigðisþjónustu, heldur mikilvægi þess að gera greinarmun á eðli slíkra atvika. Þessar niðurstöður sýna að þörf er á upplýstri opinni umræðu um óvænt atvik í heilbrigðisþjónustu og viðeigandi ráðstafanir og viðbrögð sem best tryggja öryggi bæði sjúklinga og starfsfólk
  • Algengi og þróun geðraskana og geðlyfjanotkunar meðal íbúa íslenskra hjúkrunarheimila frá 2003 til 2018

    Páll Biering; Ingibjörg Hjaltadóttir; 1)Hjúkrunarfræðideild Háskóla Íslands, 2)meðferðarsviði Landspítala. (Læknafélag Íslands, 2021-01)
    INNGANGUR Faraldsfræðilegar rannsóknir sýna mikla útbreiðslu geðræns vanda og geðlyfjanotkunar meðal aldraðra í þróuðum löndum, ekki síst meðal þeirra sem búa á hjúkrunarheimilum. Þekkingu á geðrænum vanda og geðlyfjanotkun íbúa íslenskra hjúkrunarheimila er ábótavant, en mikilvæg fyrir stefnumótun í geðheilbrigðisþjónustu á heimilunum. Því var tilgangur rannsóknarinnar að kanna algengi geðsjúkdómsgreininga og geðlyfjanotkunar meðal íbúa íslenskra hjúkrunarheimila, samspil þessara þátta og hvernig þeir hafa þróast frá 2003 til 2018. EFNIVIÐUR OG AÐFERÐIR Rannsóknargögnin voru fengin úr niðurstöðum matsgerða með annarri útgáfu interRAI mælitækisins á tímabilinu frá 2003 til 2018. Í rannsókninni var stuðst við síðasta mat hvers árs (N=47,526). NIÐURSTÖÐUR Á tímabilinu hafði um það bil helmingur íbúanna kvíða- og/eða þunglyndisgreiningu; 49,4% árið 2003, en 54,5% 2018. Þessi tíðni jókst til ársins 2010 er hún var 60,9%. Hún hefur síðan farið hægt minnkandi. Neysla geðlyfja jókst úr 66,3% í 72,5%. þunglyndislyf eru algengust og jókst neysla þeirra úr 47,5% í 56,2. Neysla geðrofslyfja hefur haldist nær óbreytt, eða í kringum 26%. Nokkurt ósamræmi var á milli geðsjúkdómagreininga og geðlyfjanotkunar. Þannig fengu að meðaltali 18,2% geðlyf að staðaldri án þess að hafa greiningu og 22,3% tóku geðrofslyf í öðrum tilfellum en mælt er með. ÁLYKTANIR Aldursbreytingar hafa áhrif á verkun geðlyfja og rannsóknir hafa ekki staðfest jákvæða langtímaverkun þeirra fyrir aldraða. Þeir eru einnig viðkvæmir fyrir skaðlegum aukaverkunum lyfjanna sem aukast enn með fjöllyfjanotkun. Því er mikilvægt að geðlyfjanotkun aldraðra sé byggð á nákvæmri geðskoðun. Eins er mikilvægt að þróa önnur úrræði til að efla geðheilsu íbúa íslenskra hjúkrunarheimila.
  • Development of an international Core Outcome Set (COS) for best care for the dying person: study protocol.

    Zambrano, Sofia C; Haugen, Dagny Faksvåg; van der Heide, Agnes; Tripodoro, Vilma A; Ellershaw, John; Fürst, Carl Johan; Voltz, Raymond; Mason, Stephen; Daud, María L; De Simone, Gustavo; et al. (BioMed Central, 2020-11-30)
    Background: In contrast to typical measures employed to assess outcomes in healthcare such as mortality or recovery rates, it is difficult to define which specific outcomes of care are the most important in caring for dying individuals. Despite a variety of tools employed to assess different dimensions of palliative care, there is no consensus on a set of core outcomes to be measured in the last days of life. In order to optimise decision making in clinical practice and comparability of interventional studies, we aim to identify and propose a set of core outcomes for the care of the dying person. Methods: Following the COMET initiative approach, the proposed study will proceed through four stages to develop a set of core outcomes: In stage 1, a systematic review of the literature will identify outcomes measured in existing peer reviewed literature, as well as outcomes derived through qualitative studies. Grey literature, will also be included. Stage 2 will allow for the identification and determination of patient and proxy defined outcomes of care at the end of life via quantitative and qualitative methods at an international level. In stage 3, from a list of salient outcomes identified through stages 1 and 2, international experts, family members, patients, and patient advocates will be asked to score the importance of the preselected outcomes through a Delphi process. Stage 4 consists of a face-to-face consensus meeting of international experts and patient/family representatives in order to define, endorse, and propose the final Core Outcomes Set. Discussion: Core Outcome Sets aim at promoting uniform assessment of care outcomes in clinical practice as well as research. If consistently employed, a robust set of core outcomes for the end of life, and specifically for the dying phase, defined by relevant stakeholders, can ultimately be translated into best care for the dying person. Patient care will be improved by allowing clinicians to choose effective and meaningful treatments, and research impact will be improved by employing internationally agreed clinically relevant endpoints and enabling accurate comparison between studies in systematic reviews and/or in meta-analyses. Keywords: Core outcomes set; Delphi study; End of life; Last days of life; Outcomes; Outcomes research; Palliative care.
  • Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

    Steinthorsdottir, Valgerdur; McGinnis, Ralph; Williams, Nicholas O; Stefansdottir, Lilja; Thorleifsson, Gudmar; Shooter, Scott; Fadista, João; Sigurdsson, Jon K; Auro, Kirsi M; Berezina, Galina; et al. (Nature Publishing Group, 2020-11-25)
    Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
  • Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting.

    Modvig, S; Hallböök, H; Madsen, H O; Siitonen, S; Rosthøj, S; Tierens, A; Juvonen, V; Osnes, L T N; Vålerhaugen, H; Hultdin, M; et al. (Nature Publishing Group, Specialist Journals, 2020-12-14)
    PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p < 0.0001), 29 (HzR 2.7, p < 0.0001), and 79 (HzR 3.5, p < 0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4 × 10-2 versus 5.2 × 10-3, p < 0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y = 3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD > 10-4 associated with a CIR5y = 22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.
  • Pharmacokinetics of single and repeated oral doses of esomeprazole and gastrin elevation in healthy males and females.

    Helgadóttir, Hólmfríður; Lund, Sigrún H; Gizurarson, Sveinbjörn; Waldum, Helge; Björnsson, Einar S; 1Department of Internal Medicine, Division of Gastroenterology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 2deCODE genetics/Amgen Inc., Reykjavik, Iceland. 3Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland. 4Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. (Taylor & Francis, 2020-12-17)
    Objective: Gastrin elevation secondary to proton pump inhibitor (PPI) therapy is well documented. Recent studies have demonstrated a sex-related difference where females on PPIs have significantly higher baseline gastrin levels than males. The aim of the study was to analyse the pharmacokinetics of esomeprazole and short-term effect on serum gastrin levels and evaluate potential sex-related difference. Materials and methods: Healthy volunteers received 40 mg of esomeprazole daily for five days. After the 1st and 5th dose blood samples for fasting gastrin and pharmacokinetic analysis were collected at scheduled time-points for eight hours. Esomeprazole was analysed by liquid chromatography and gastrin concentrations were measured using radioimmunoassay. Results: A total of 30 volunteers were enrolled. Females had higher median baseline gastrin (pM) than males 12 (IQR 10-15) vs. 7 (IQR 4-11) (p = .03). In the study cohort, median gastrin levels rose from 10 (IQR 6-14) to 15 (IQR 13-20) (p = .0002). The serum levels for esomeprazole increased by an average of 299.8 ng/mL (p < .001) from day 1 to day 5. Comparison of the esomeprazole pharmacokinetic parameters between males and females revealed no significant sex-related differences. No significant correlation was found between the AUC and the gastrin level on day 5 (p = .15). Conclusions: In healthy volunteers, serum gastrin increased significantly after a four-day PPI-therapy. There was also a significant increase in serum esomeprazole from day 1 to day 5. The increase in gastrin and esomeprazole concentration was not related to sex and no significant sex-related difference was found in terms of pharmacokinetic parameters. European Clinical Trial Database (2015-002230-41). Keywords: Proton pump inhibitors; area under the serum concentration curve; gastrin; pharmacokinetics; pharmacology; sex-related difference.
  • Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens.

    Nicoletti, Paola; Devarbhavi, Harshad; Goel, Ashish; Venkatesan, Radha; Eapen, Chundamannil E; Grove, Jane I; Zafer, Samreen; Bjornsson, Einar; Lucena, M Isabel; Andrade, Raul J; et al. (Wiley, 2020-11-01)
    Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P = 9.4 × 10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.
  • A nationwide study on inpatient opportunistic infections in patients with chronic lymphocytic leukemia in the pre-ibrutinib era.

    Steingrímsson, Vilhjálmur; Gíslason, Gauti Kjartan; Þorsteinsdóttir, Sigrún; Rögnvaldsson, Saemundur; Gottfreðsson, Magnús; Aspelund, Thor; Turesson, Ingemar; Björkholm, Magnus; Landgren, Ola; Kristinsson, Sigurdur Y; et al. (Wiley, 2020-11-19)
    Objective: Opportunistic infections in chronic lymphocytic leukemia (CLL) have been described in clinical trials, single-center studies, and case reports. We performed a nationwide study to estimate the incidence and impact of inpatient opportunistic infections. Methods: The incidence rate (IR) and incidence rate ratio (IRR) for Swedish CLL patients diagnosed 1994-2013, and matched controls were calculated, as well as the case-fatality ratio (CFR). Results: Among 8989 CLL patients, a total of 829 opportunistic infections were registered (IR 16.6 per 1000 person-years) compared with 252 opportunistic infections in 34 283 matched controls (IR 0.99). The highest incidence in the CLL cohort was for Pneumocystis pneumonia (200 infections, IR 4.03); Herpes zoster (146 infections, IR 2.94), and Pseudomonas (83 infections, IR 1.66) infections. The highest risk relative to matched controls was observed for Pneumocystis pneumonia (IRR 114, 95% confidence interval 58.7-252). The 60-day CFR for CLL patients with opportunistic infections was 23% (188/821), highest for progressive multifocal encephalopathy (5/7, 71%) and aspergillosis (25/60, 42%). Conclusion: We have uniquely depicted the incidence of rare and serious infections in CLL patients and found a relatively high incidence of Pneumocystis pneumonia. Of the most common opportunistic infections, CLL patients with aspergillosis had the poorest prognosis. Keywords: chronic lymphocytic leukemia; immunology and infectious diseases; lymphoproliferative diseases.
  • 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.

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