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  • Fósturgreining og meðgöngusjúkdómar, undirsérgrein fæðingaog kvensjúkdómalækninga - Yfirlitsgrein

    Hildur Harðardóttir; Kvennadeild Landspítala og læknadeild Háskóla Íslands. (Læknafélag Íslands, Læknafélag Reykjavíkur, 2020-01)
    Læknisfræði fósturs er undirsérgrein fæðinga- og kvensjúkdómalækninga og lýtur að rannsóknum á þróun, vexti og sjúkdómum fóstra. Það má telja eðlilegt að hafa eina sérgrein fyrir þá órjúfanlegu heild sem móðir og fóstur mynda og er íslenska undirsérgreinin í samræmi við það og ber heitið fósturgreining og meðgöngusjúkdómar (FM). Stórstígar framfarir hafa átt sér stað í FM hvað varðar myndgreiningu fóstra með ómskoðun og segulómun. Einnig á sviði erfða- og sameindalæknisfræði við sjúkdómsgreiningar með kjarnsýrutækni auk þess sem aðgerðir á fóstrum eru nú mögulegar í vissum tilfellum. Í vinnu við fósturgreiningar er samstarf við fjölmarga aðra sérfræðinga mikilvægt, til dæmis nýburalækna, barnalækna í ýmsum undirsérgreinum, barnaskurðlækna, erfðalækna og lækna sem vinna á sviði myndgreiningar. Í stærri samfélögum starfa FM-læknar gjarnan sem ráðgefandi fyrir fæðingalækna og aðra sérgreinalækna auk þess að vinna við fósturskimanir, greiningar og meðferð. Hér á landi er sérhæfing styttra á veg komin. Hér eru tekin dæmi um verkefni FM-lækna og lýst hvernig tækniframfarir hafa breytt fósturskimun fyrir litningafrávikum, eftirliti og meðferð við rhesus-varnir auk aðgerða á fósturskeiði. Þá er sagt frá samstarfi norrænna FM-lækna.
  • Heilsuhagfræðilegt mat á þverfaglegri verkjameðferð á Reykjalundi - Ein króna í endurhæfingu – átta til baka

    Magnús Ólason; Héðinn Jónsson; Rúnar H. Andrason; Inga H. Jónsdóttir; Hlín Kristbergsdóttir; 1) Reykjalundi, endurhæfingarmiðstöð SÍBS, 2) Embætti landlæknis, 3) sálfræðideild Háskólans í Reykjavík. (Læknafélag Íslands, Læknafélag Reykjavíkur, 2020-01)
    TILGANGUR Fáar rannsóknir hafa metið langtímaárangur þverfaglegrar verkjameðferðar þó árangur til skemmri tíma sé vel þekktur. Hér er lýst árangri slíkrar meðferðar á Reykjalundi, endurhæfingarmiðstöð SÍBS, með þriggja ára eftirfylgd. Sérstaklega er fjallað um heilsuhagfræðilegan ávinning af meðferðinni. EFNIVIÐUR OG AÐFERÐIR Um kerfisbundið slembiúrtak var að ræða þar sem fimmta hver beiðni um meðferð á verkjasviði Reykjalundar var valin til þátttöku. Gagnasöfnun stóð yfir í fjögur og hálft ár og eftirfylgd lauk þremur árum síðar. Heilsuhagfræðileg úttekt var gerð að rannsókn lokinni. NIÐURSTÖÐUR Helstu niðurstöður eru þær að sjúklingar upplifa minni verki, minni ótta og hliðrun tengda vinnufærni, færri þunglyndis- og kvíðaeinkenni og upplifa meiri félagslega færni eftir meðferð. Vinnugeta hópsins í heild jókst og fór vinnufærni úr 36% í 47% eftir meðferðina og við þriggja ára eftirfylgd voru 57% vinnufærir. Heilsuhagfræðileg úttekt sýndi að meðferðin hafði borgað sig upp á þremur árum og ávinningurinn jókst út lífið. ÁLYKTANIR Niðurstöður rannsóknarinnar sýna að þverfagleg endurhæfingarmeðferð gegn þrálátum verkjum skilar árangri varðandi færni, verki og sálfélagslegar afleiðingar þeirra. Heilsuhagfræðilegur ávinningur af meðferðinni er verulegur og miðað við vísitölu neysluverðs í október 2018 skilar kostnaður af meðferðinni sér áttfalt til baka til samfélagsins.
  • Blæðingar frá meltingarvegi í íslensku og erlendu samhengi – yfirlitsgrein

    Jóhann P. Hreinsson; Einar S. Björnsson; 1) Meltingarlækningum, lyflækningasviði Sahlgrenska sjúkrahússins í Gautaborg, Svíþjóð, 2) Læknadeild Háskóla Íslands og meltingarlækningum, lyflækningasviði Landspítala (Læknafélag Íslands, Læknafélag Reykjavíkur, 2019-12)
    Bráð blæðing frá meltingarvegi er algeng ástæða komu á bráðamóttöku og innlagnar á spítala. Þessum blæðingum er vanalega skipt í efri og neðri meltingarvegarblæðingar. Í þessari yfirlitsgrein verður farið yfir nýgengi þessara blæðinga, áhættuþætti, orsakir, þátt blóðþynningarlyfja, mat á alvarleika blæðinga, meðferðarúrræði og horfur. Reynt verður að varpa ljósi á þetta viðfangsefni í íslensku heilbrigðiskerfi en einnig í víðara samhengi.
  • Meðferð með hreyfiseðli í kjölfar meðgöngusykursýki

    Þórunn Jóhanna Júlíusdóttir; Hannes Hrafnkelsson; Ragnheiður I. Bjarnadóttir; Sesselja Guðmundsdóttir; Ragnheiður Bachmann; Karitas Ívarsdóttir; Jón Steinar Jónsson; 1 Heilsugæslu höfuðborgarsvæðisins, 2 Háskóla Íslands, 3 Þróunarmiðstöð íslenskrar heilsugæslu (Læknafélag Íslands, Læknafélag Reykjavíkur, 2019-12)
    TILGANGUR Algengi meðgöngusykursýki fer hratt vaxandi og tæplega 19% kvenna sem fæddu á Landspítala á árinu 2018 höfðu þessa greiningu. Þær konur sem fá meðgöngusykursýki eru í aukinni hættu að fá hana aftur á síðari meðgöngum og einnig í aukinni áhættu á að þróa sykursýki tegund 2 síðar á ævinni. Ofþyngd og hreyfingarleysi eru sterkir áhættuþættir. Hreyfiseðill er meðferðarúrræði sem stendur til boða á öllum heilbrigðisstofnunum. Markmið rannsóknarinnar var að kanna áhrif meðferðar með hreyfiseðli eftir fæðingu hjá konum sem höfðu meðgöngusykursýki, á virkni þeirra, líðan og þætti sem tengjast efnaskiptavillu. EFNIVIÐUR OG AÐFERÐIR Konur sem fæddu börn frá 1. janúar 2016 til 30. júní 2017, voru í mæðravernd hjá Heilsugæslu höfuðborgarsvæðisins og greindust með meðgöngusykursýki var boðin þátttaka. Þátttakendum var skipt tilviljanakennt í tvo hópa þar sem annar hópurinn fékk meðferð með hreyfiseðli í 5 mánuði en viðmiðunarhópurinn hefðbundna meðferð. Mælingar á blóðgildum, hæð, þyngd, virkni og líðan voru gerðar þremur mánuðum og 8 mánuðum eftir fæðingu. NIÐURSTÖÐUR Áttatíu og fjórar konur tóku þátt, 45 í íhlutunarhópi og 39 í viðmiðunarhópi. Virkni jókst marktækt í íhlutunarhópi en ekki urðu marktækar breytingar á blóðmælingum. Viss áhrif en ekki marktæk mældust á þyngd, líkamsþyngdarstuðli og lífsgæðum. Þær konur sem voru með barn sitt á brjósti voru með marktækt lægra insúlín en þær konur sem ekki voru með barn sitt á brjósti. Sterkari fylgni var á milli þyngdar og insúlíns en á milli fastandi blóðsykurs og insúlíns. ÁLYKTUN Meðferð með hreyfiseðli eftir fæðingu jók marktækt virkni kvenna sem höfðu meðgöngusykursýki. Brjóstagjöf hefur mögulega áhrif til lækkunar insúlíns.
  • Greining meðfæddra missmíða í miðtaugakerfi hjá fóstrum og nýburum á Íslandi 1992-2016

    Ásdís Björk Gunnarsdóttir; Sara Lillý Þorsteinsdóttir; Hulda Hjartardóttir; Hildur Harðardóttir; ¹Læknadeild Háskóla Íslands, ²fósturgreiningardeild kvennadeildar Landspítala. (Læknafélag Íslands, Læknafélag Reykjavíkur, 2019-12)
    INNGANGUR Nýgengi meðfæddra missmíða í miðtaugakerfi fóstra og nýbura á Íslandi 1992-2016 var skoðað, ásamt tímasetningu greiningar, búsetu mæðra, tíðni þekktra áhættuþátta og afdrifum fóstra/barna. EFNIVIÐUR OG AÐFERÐIR Rannsóknin var afturskyggn. Rannsóknarþýðið samanstóð af öllum fóstrum og nýburum sem greindust með meðfædda missmíð í miðtaugakerfi á rannsóknartímabilinu og mæðrum þeirra. Upplýsingar fengust úr Fæðingaskrá Embættis landlæknis og sjúkraskrám mæðra og barna. Við gagnaúrvinnslu var notuð lýsandi tölfræði og ályktunartölfræði. NIÐURSTÖÐUR Á rannsóknartímabilinu greindust árlega 3-12 tilfelli af meðfæddri missmíð í miðtaugakerfi. Árlegt nýgengi var skoðað og 5 ára tímabil borin saman. Nýgengi var á bilinu 1,4-2,4/1000 nýburar, hæst árin 2012-2016. Tæplega 90% tilfellanna greindust á fósturskeiði og af þeim enduðu 80% með meðgöngurofi. Greiningarhlutfall á fósturskeiði var marktækt hærra hjá mæðrum á höfuðborgarsvæðinu en annars staðar á landinu (94 á móti 80%; p=0,006). Meðalmeðgöngulengd við greiningu heilaleysis var 19,3 vikur 1992-1996 en 11,6 vikur 2012-2016 (p=0,006). Tíðni þekktra áhættuþátta meðal mæðra var lág, fyrir utan offitu mæðra á tímabilinu 2012-2016 (23%). Af 57 lifandi fæddum börnum voru 37 (65%) enn á lífi þegar rannsóknin fór fram. ÁLYKTUN Nýgengi meðfæddra missmíða í miðtaugakerfi var stöðugt og áhættuþættir sjaldnast þekktir. Um 90% tilfella greindust á fósturskeiði og heilaleysi greindist marktækt fyrr við lok rannsóknartímabilsins samanborið við upphaf þess. Það má skýra með tilkomu almennrar fósturskimunar við 11-14 vikur frá árinu 2003 auk bættrar þjálfunar heilbrigðisstarfsfólks og betri tækjabúnaðar. Munur á greiningarhlutfalli á fósturskeiði milli landshluta getur skýrst af færri ómskoðunum í minni heilbrigðisumdæmum sem hefur áhrif á sérhæfingu við greiningu fósturfrávika.
  • Epidemiology, Predisposing Factors, and Outcomes of Drug-Induced Liver Injury.

    Björnsson, Einar S; 1Department of Internal Medicine, Faculty of Medicine, Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, University of Iceland, Hringbraut, Reykjavík 101, Iceland. Electronic address: einarsb@landspitali.is. (W B SAUNDERS CO-ELSEVIER INC, 2019-10-28)
    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. A recent population-based study found a crude incidence of approximately 19 cases per 100,000 a year. Amoxicillin-clavulanate continues to be the most commonly implicated agent in most Western countries, reported to occur in approximately 1 of 2300 users. In patients with drug-induced autoimmune hepatitis, liver tests often do not normalize with cessation of the drugs and require corticosteroids. DILI associated with jaundice can lead to death from liver failure or require liver transplantation in at least 10% of cases.
  • Rhesus D alloimmunization in pregnancy from 1996 to 2015 in Iceland: a nation-wide population study prior to routine antenatal anti-D prophylaxis.

    Gudlaugsson, Brynjar; Hjartardottir, Hulda; Svansdottir, Gudrun; Gudmundsdottir, Gudny; Kjartansson, Sveinn; Jonsson, Thorbjorn; Gudmundsson, Sveinn; Halldorsdottir, Anna M; 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 2Department of Obstetrics and Gynecology, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 3Blood Bank, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 4Department of Pediatrics, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. (Wiley, 2019-12)
    Background: Rhesus D (RhD) incompatibility is still the most important cause of hemolytic disease of the fetus and newborn (HDFN) worldwide. The aim of this study was to investigate the incidence, causes, and consequences of anti-D alloimmunizations in pregnancy in Iceland, prior to implementation of targeted routine antenatal anti-D prophylaxis (RAADP) in 2018. Study design and methods: This was a nation-wide cohort study of 130 pregnancies affected by RhD alloimmunization in Iceland in the period from 1996 through 2015. Data were collected from transfusion medicine databases, medical records, and the Icelandic Medical Birth Register. Results: Of 130 RhD alloimmunizations, 80 cases (61.5%) represented new RhD immunization in the current pregnancy. Sensitization was discovered in the third trimester in 41 (51.3%) and occurred in the first pregnancy in 14 cases (17.5%). The most likely causative immunization event was the index pregnancy for 45 (56.25%), a previous pregnancy/birth for 26 (32.5%), abortion for 3 (3.75%), and unknown for 6 women (7.5%). Higher anti-D titers were associated with shorter gestational length, cesarean sections, positive direct antiglobulin test (DAT), and severe HDFN. Intrauterine transfusion (IUT) was performed in five pregnancies (3.8%), and 35 of 132 (26.5%) live-born neonates received treatment for HDFN; 32 received phototherapy (24.2%), 13 exchange transfusion (9.8%), and seven simple blood transfusion (5.3%). Conclusion: In about half of cases, RhD alloimmunization was caused by the index pregnancy and discovered in the third trimester. Thus, the newly implemented RAADP protocol should be effective in reducing the incidence of RhD immunization in Iceland in the future.
  • Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes.

    Gudbjartsson, Daniel F; Thorgeirsson, Gudmundur; Sulem, Patrick; Helgadottir, Anna; Gylfason, Arnaldur; Saemundsdottir, Jona; Bjornsson, Eythor; Norddahl, Gudmundur L; Jonasdottir, Aslaug; Jonasdottir, Adalbjorg; et al. (Elsevier Science, 2019-12-17)
    Background: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). Objectives: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. Methods: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. Results: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. Conclusions: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk. Keywords: Lp(a); Mendelian randomization; coronary artery disease; genetics; type 2 diabetes.
  • Prevalence of allergic sensitization to storage mites in Northern Europe.

    Jõgi, Nils Oskar; Kleppe Olsen, Robin; Svanes, Cecilie; Gislason, David; Gislason, Thorarinn; Schlünssen, Vivi; Sigsgaard, Torben; Sundbom, Fredrik; Storaas, Torgeir; Bertelsen, Randi Jacobsen; et al. (Wiley, 2019-11-19)
    BACKGROUND: Allergic sensitization to storage mites has mostly been related to occupational exposures like farming, grain/cattle handling, whereas for non-occupational settings, storage mite sensitization has been attributed to cross-reactivity with house dust mite (HDM) allergens. OBJECTIVE: We aimed to describe the prevalence of allergic sensitization to storage mites, co-sensitization to HDM allergens and respiratory symptoms in Denmark, Iceland, Norway and Sweden. METHODS: The population comprised of 1180 participants born 1945-1972 of the third follow-up of the population-based cohort European Community Respiratory Health Survey (ECRHS) in Aarhus, Bergen, Reykjavik and Uppsala. A clinical examination included skin prick tests (SPT) to Lepidoglyphus destructor, Tyrophagus putrescentiae, Acarus siro and common inhalant allergens, as well as standardized interviews. RESULTS: 8% were sensitized to HDM and 10% to storage mite, with some variation by study centre: Reykjavik 13%, Bergen 8% and Aarhus 7%. In Uppsala, only L destructor (3%) was measured. Storage mite sensitization was higher among men (11%) than women (8%). Among storage mite sensitized, 44% were also sensitized to HDM. Storage mite sensitization was associated with asthma and nasal allergies, but not with age, education, pet keeping or place of upbringing. CONCLUSIONS AND CLINICAL RELEVANCE: In this Northern European population-based study, allergic sensitization to storage mite was as common as HDM sensitization. Storage mite sensitization was, independently of HDM sensitization, associated with respiratory symptoms and asthma. Our findings suggest that storage mite sensitization should be evaluated with regard to inclusion into the common inhalant allergen panel in Northern Europe.
  • Immediate and long-term need for permanent cardiac pacing following aortic valve replacement.

    Viktorsson, Sindri A; Orrason, Andri W; Vidisson, Kristjan O; Gunnarsdottir, Anna G; Johnsen, Arni; Helgason, Dadi; Arnar, David O; Geirsson, Arnar; Gudbjartsson, Tomas; 1 Division of Cardiothoracic Surgery, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 2 Internal Medicine Services, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 3 Division of Cardiology, Landspitali -The National University Hospital of Iceland, Reykjavik, Iceland. 4 Division of Cardiac Surgery, Yale School of Medicine, New Haven, CT, USA. 5 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. (Taylor & Francis, 2019-12-06)
    Introduction: Atrioventricular (AV) node conduction disturbances are common following surgical aortic valve replacement (SAVR), and in some cases the patient needs a permanent pacemaker (PPM) implantation before discharge from hospital. Little is known about the long-term need for PPM and the PPM dependency of these individuals. We determined the incidence of PPM implantation before and after discharge in SAVR patients. Methods: We studied 557 consecutive patients who underwent SAVR for aortic stenosis in Iceland between 2002 and 2016. Timing and indication for PPM were registered, with a new concept, ventricular pacing proportion (VPP), defined as ventricular pacing ≥90% of the time, being used to approximate pacemaker dependency. The median follow-up time was 73 months. We plotted the cumulative incidence of pacemaker implantation, treating death as a competing risk. Results: Of the 557 patients, 22 (3.9%) received PPM in the first 30 days after surgery, most commonly for complete AV block (n = 14) or symptomatic bradycardia (n = 8); Thirty-eight other patients (6.8%) had a PPM implanted >30 days postoperatively, at a median of 43 months after surgery (range 0‒181), most often for AV block (n = 13) or sick-sinus syndrome (n = 10). The cumulative incidence of PPM implantation at 1, 5, and 10 years postoperatively was 5.0%, 9.2%, and 12.3%, respectively. During follow-up, 45.0% of the 60 patients had VPP ≥90%. Conclusion: The cumulative incidence of permanent pacemaker implantation following SAVR was about 12% at 10 years, with every other patient having VPP ≥90% during follow-up. This suggests that AV node conduction disturbances extend significantly beyond the perioperative period.
  • The challenges of primary biliary cholangitis: What is new and what needs to be done.

    Terziroli Beretta-Piccoli, Benedetta; Mieli-Vergani, Giorgina; Vergani, Diego; Vierling, John M; Adams, David; Alpini, Gianfranco; Banales, Jesus M; Beuers, Ulrich; Björnsson, Einar; Bowlus, Christopher; et al. (Academic Press, 2019-09-20)
    Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
  • Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects.

    Fahrner, Jill A; Bjornsson, Hans T; 1 McKusick-Nathans Institute of Genetic Medicine, 21205. 2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 3 Landspitali University Hospital, Reykjavik 101, Iceland. 4 Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland. (Oxford University Press, 2019-11-21)
    he epigenetic machinery in conjunction with the transcriptional machinery is responsible for maintaining genome-wide chromatin states and dynamically regulating gene expression. Mendelian disorders of the epigenetic machinery (MDEMs) are genetic disorders resulting from mutations in components of the epigenetic apparatus. Though individually rare, MDEMs have emerged as a collectively common etiology for intellectual disability (ID) and growth disruption. Studies in model organisms and humans have demonstrated dosage sensitivity of this gene group with haploinsufficiency as a predominant disease mechanism. The epigenetic machinery consists of three enzymatic components (writers, erasers and chromatin remodelers) as well as one non-enzymatic group (readers). A tally of the entire census of such factors revealed that although multiple enzymatic activities never coexist within a single component, individual enzymatic activities often coexist with a reader domain. This group of disorders disrupts both the chromatin and transcription states of target genes downstream of the given component but also DNA methylation on a global scale. Elucidation of these global epigenetic changes may inform our understanding of disease pathogenesis and have diagnostic utility. Moreover, many therapies targeting epigenetic marks already exist, and some have proven successful in treating cancer. This, along with the recent observation that neurological dysfunction in these disorders may in fact be treatable in postnatal life, suggests that the scientific community should prioritize this group as a potentially treatable cause of ID. Here we summarize the recent expansion and major characteristics of MDEMs, as well as the unique therapeutic prospects for this group of disorders.
  • Urinary 2,8-dihydroxyadenine excretion in patients with adenine phosphoribosyltransferase deficiency, carriers and healthy control subjects.

    Runolfsdottir, Hrafnhildur L; Palsson, Runolfur; Thorsteinsdottir, Unnur A; Indridason, Olafur S; Agustsdottir, Inger M Sch; Oddsdottir, G Steinunn; Thorsteinsdottir, Margret; Edvardsson, Vidar O; 1 Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 2 Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Division of Nephrology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. Electronic address: runolfur@landspitali.is. 3 Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 4 Internal Medicine Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland; Division of Nephrology, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 5 Children's Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 6 Department of Clinical Biochemistry, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 7 Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, Reykjavik, Iceland; ArcticMass, Reykjavik, Iceland. 8 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Children's Medical Center, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. Electronic address: vidare@landspitali.is. (Academic Press, 2019-05-28)
    BACKGROUND: Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of adenine metabolism that results in excessive urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to kidney stones and chronic kidney disease. The purpose of this study was to assess urinary DHA excretion in patients with APRT deficiency, heterozygotes and healthy controls, using a recently developed ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) assay. METHODS: Patients enrolled in the APRT Deficiency Registry and Biobank of the Rare Kidney Stone Consortium (http://www.rarekidneystones.org/) who had provided 24-h and first-morning void urine samples for DHA measurement were eligible for the study. Heterozygotes and healthy individuals served as controls. Wilcoxon-Mann-Whitney test was used to compare 24-h urinary DHA excretion between groups. Associations were examined using Spearman's correlation coefficient (rs). RESULTS: The median (range) 24-h urinary DHA excretion was 138 (64-292) mg/24 h and the DHA-to-creatinine (DHA/Cr) ratio in the first-morning void samples was 13 (4-37) mg/mmol in APRT deficiency patients who were not receiving xanthine oxidoreductase inhibitor therapy. The 24-h DHA excretion was highly correlated with the DHA/Cr ratio in first-morning void urine samples (rs = 0.84, p < .001). DHA was detected in all urine samples from untreated patients but not in any specimens from heterozygotes and healthy controls. CONCLUSIONS: High urinary DHA excretion was observed in patients with APRT deficiency, while urine DHA was undetectable in heterozygotes and healthy controls. Our results suggest that the UPLC-MS/MS assay can be used for diagnosis of APRT deficiency.
  • Metabolomics study of platelet concentrates photochemically treated with amotosalen and UVA light for pathogen inactivation.

    Jóhannsson, Freyr; Árnason, Níels Á; Landrö, Ragna; Guðmundsson, Sveinn; Sigurjonsson, Ólafur E; Rolfsson, Óttar; 1 Center for Systems Biology, University of Iceland, Sturlugata 8, Reykjavik, Iceland. 2 Medical Department, University of Iceland, Sturlugata 8, Reykjavik, Iceland. 3 The Blood Bank, Landspitali-University Hospital, Snorrabraut 60, Reykjavik, Iceland. 4 School of Science and Engineering, Reykjavik University, Menntavegur 1, Reykjavik, Iceland. (Wiley, 2019-12-05)
    BACKGROUND: The risk of bacterial contamination and the deterioration of platelet (PLT) quality limit the shelf-life of platelet concentrates (PCs). The INTERCEPT pathogen inactivation system reduces the risk of pathogen transmission by inhibiting nucleic acid replication using a combination of a photo-reactive compound and UVA illumination. The goal of this study was to investigate the effects the INTERCEPT system has on the PLT metabolome and metabolic activity. STUDY DESIGN AND METHODS: Paired units of buffy coat-derived PCs were generated using a pool and split strategy (n = 8). The paired PCs were either treated with the INTERCEPT system or left untreated. Samples were collected on Days 1, 2, 4, and 7 of storage. Ultra-performance chromatography coupled with time-of-flight mass spectrometry was used to analyze the extra- and intracellular metabolomes. Constraint-based metabolic modeling was then used to predict the metabolic activity of the stored PLTs. RESULTS: A relatively large number of metabolites in the extracellular environment were depleted during the processing steps of the INTERCEPT system, in particular, metabolites with hydrophobic functional groups, including acylcarnitines and lysophosphatidylcholines. In the intracellular environment, alterations in glucose and glycerophospholipid metabolism and decreased levels of 2-hydroxyglutarate were observed following the INTERCEPT treatment. Untargeted metabolomics analysis revealed residual amotosalen dimers present in the treated PCs. Systems-level analysis of PLT metabolism indicated that the INTERCEPT system does not have a significant impact on the PLT energy metabolism and nutrient utilization. CONCLUSIONS: The INTERCEPT system significantly alters the metabolome of the stored PCs without significantly influencing PLT energy metabolism.
  • New-onset postoperative atrial fibrillation after heart surgery.

    Gudbjartsson, Tomas; Helgadottir, Solveig; Sigurdsson, Martin Ingi; Taha, Amar; Jeppsson, Anders; Christensen, Thomas Decker; Riber, Lars Peter Schoedt; 1 Department of Cardiothoracic Surgery, Landspitali University Hospital, Reykjavik, Iceland. 2 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3 Department of Cardiothoracic Surgery and Anaesthesia, Uppsala University Hospital, Uppsala, Sweden. 4 Department of Anaesthesia and Critical Care, Landspitali University Hospital, Reykjavik, Iceland. 5 Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. 6 Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 7 Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden. 8 Department of Cardiothoracic and Vascular Surgery, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. 9 Department of Cardiothoracic and Vascular Surgery, Department of Clinical Medicine, Odense University Hospital, University of Southern Denmark, Odense, Denmark. (Wiley, 2019-11-14)
    BACKGROUND: New-onset postoperative atrial fibrillation (poAF) complicates approximately 20-60% of all cardiac surgical procedures and is associated with an increased periprocedural mortality and morbitity, prolonged hospital stay, increased costs, and worse long-term survival. Unfortunately multiple advances in surgery and perioperative care over the last two decades have not led to a reduction in the incidence of poAF or associated complications in the daily clinical practice. METHODS: A narrative review of the available literature was performed. RESULTS: An extensive review of the pathophysiology of poAF following cardiac surgery, clinical, and procedural risk-factors is provided, as well as prophylactic measures and treatment. CONCLUSION: Multiple strategies to prevent and manage poAF following heart surgery already exist. Our hope is that this review will facilitate more rigorous testing of prevention strategies, implementation of prophylaxis regimens as well as optimal treatment of this common and serious complication.
  • Post cholecystectomy bile duct injury: early, intermediate or late repair with hepaticojejunostomy - an E-AHPBA multi-center study.

    Rystedt, Jenny M. L.; Kleeff, Joerg; Salvia, Roberto; Besselink, Mark G.; Prasad, Raj; Lesurtel, Mickael; Sturesson, Christian; Abu Hilal, M.; Aljaiuossi, A.; Antonucci, A.; et al. (Elsevier Science, 2019-12)
    BACKGROUND: Treatment of bile duct injuries (BDI) during cholecystectomy depends on the severity of injury and the timing of diagnosis. Standard of care for severe BDIs is hepaticojejunostomy. The aim of this retrospective multi-center study was to assess the optimal timing for repair of BDI with hepaticojejunostomy. METHODS: Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients with hepaticojejunostomy after BDI from January 2000 to June 2016. Patients were stratified according to the timing of biliary reconstruction with hepaticojejunostomy: early (day 0-7), intermediate (1-6 weeks) and late (6 weeks-6 months). Primary endpoint was re-intervention >90 days after the hepaticojejunostomy and secondary endpoints were severe 90-day complications and liver-related mortality. RESULTS: In total 913 patients from 48 centers were included in the analysis. In 401 patients (44%) the bile duct injury was diagnosed intraoperatively, and 126 patients (14%) suffered from concomitant vascular injury. In multivariable analysis the timing of hepaticojejunostomy had no impact on postoperative complications, the need for re-intervention after 90 days nor liver-related mortality. The rate of re-intervention more than 90 days after the hepaticojejunostomy was significantly increased in male patients but decreased in older patients. Severe co-morbidity increased the risk for liver-related mortality (HR 3.439; CI 1.37-8.65; p = 0.009). CONCLUSION: After BDI occurring during cholecystectomy, the timing of biliary reconstruction with hepaticojejunostomy did not have any impact on severe postoperative complications, the need for re-intervention or liver-related mortality. Individualised treatment after iatrogenic bile duct injury is still advisable.
  • Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

    Hobbs, Brian D; Putman, Rachel K; Araki, Tetsuro; Nishino, Mizuki; Gudmundsson, Gunnar; Gudnason, Vilmundur; Eiriksdottir, Gudny; Zilhao Nogueira, Nuno Rodrigues; Dupuis, Josée; Xu, Hanfei; et al. (American Thoracic Society, 2019-12)
    Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.
  • YKL-40/CHI3L1 facilitates migration and invasion in HER2 overexpressing breast epithelial progenitor cells and generates a niche for capillary-like network formation.

    Morera, Erika; Steinhäuser, Sarah Sophie; Budkova, Zuzana; Ingthorsson, Saevar; Kricker, Jennifer; Krueger, Aileen; Traustadottir, Gunnhildur Asta; Gudjonsson, Thorarinn; 1 Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Vatnsmyrarvegi 16, 101, Reykjavik, Iceland. 2 Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany. 3 Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Vatnsmyrarvegi 16, 101, Reykjavik, Iceland. tgudjons@hi.is. 4 Department of Laboratory Hematology, Landspitali - University Hospital, Reykjavik, Iceland. tgudjons@hi.is. (Springer, 2019-12)
    Epithelial to mesenchymal transition (EMT) is a developmental event that is hijacked in some diseases such as fibrosis and cancer. In cancer, EMT has been linked to increased invasion and metastasis and is generally associated with a poor prognosis. In this study, we have compared phenotypic and functional differences between two isogenic cell lines with an EMT profile: D492M and D492HER2 that are both derived from D492, a breast epithelial cell line with stem cell properties. D492M is non-tumorigenic while D492HER2 is tumorigenic. Thus, the aim of this study was to analyze the expression profile of these cell lines, identify potential oncogenes, and evaluate their effects on cellular phenotype. We performed transcriptome and secretome analyses of D492M and D492HER2 and verified expression of selected genes at the RNA and protein level. One candidate, YKL-40 (also known as CHI3L1), was selected for further studies due to its differential expression between D492M and D492HER2, being considerably higher in D492HER2. YKL-40 has been linked to chronic inflammation diseases and cancer, yet its function is not fully understood. Knock-down experiments of YKL-40 in D492HER2 resulted in reduced migration and invasion as well as reduced ability to induce angiogenesis in an in vitro assay, plus changes in the EMT-phenotype. In summary, our data suggest that YKL-40 may provide D492HER2 with increased aggressiveness, supporting cancer progression and facilitating angiogenesis.
  • Staying hepatitis C negative: A systematic review and meta-analysis of cure and reinfection in people who inject drugs.

    Latham, Ned H; Doyle, Joseph S; Palmer, Anna Y; Vanhommerig, Joost W; Agius, Paul; Goutzamanis, Stelliana; Li, Zinia; Pedrana, Alisa; Gottfredsson, Magnus; Bouscaillou, Julie; et al. (Wiley, 2019-06-10)
    BACKGROUND AND AIMS: Direct-acting antivirals (DAAs) are highly effective in treating hepatitis C. However, there is concern that cure rates may be lower, and reinfection rates higher, among people who inject drugs. We conducted a systematic review of treatment outcomes achieved with DAAs in people who inject drugs (PWID). METHODS: A search strategy was used to identify studies that reported sustained viral response (SVR), treatment discontinuation, adherence or reinfection in recent PWID and/or opioid substitution therapy (OST) recipients. Study quality was assessed using the Newcastle-Ottawa Scale. Meta-analysis of proportions was used to estimate pooled SVR and treatment discontinuation rates. The pooled relative risk of achieving SVR and pooled reinfection rate were calculated using generalized mixed effects linear models. RESULTS: The search identified 8075 references; 26 were eligible for inclusion. The pooled SVR for recent PWID was 88% (95% CI, 83%-92%) and 91% (95% CI 88%-95%) for OST recipients. The relative risk of achieving SVR for recent PWID compared to non-recent PWID was 0.99 (95% CI, 0.94-1.06). The pooled treatment discontinuation was 2% (95% CI, 1%-4%) for both recent PWID and OST recipients. Amongst recent PWID, the pooled incidence of reinfection was 1.94 per 100 person years (95% CI, 0.87-4.32). In OST recipients, the incidence of reinfection was 0.55 per 100 person years (95% CI, 0.17-1.76). CONCLUSIONS: Treatment outcomes were similar in recent PWID compared to non-PWID treated with DAAs. People who report recent injecting or OST recipients should not be excluded from hepatitis C treatment.
  • Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study.

    Jarvis, Kirsten Brunsvig; LeBlanc, Marissa; Tulstrup, Morten; Nielsen, Rikke Linnemann; Albertsen, Birgitte Klug; Gupta, Ramneek; Huttunen, Pasi; Jónsson, Ólafur Gisli; Rank, Cecilie Utke; Ranta, Susanna; et al. (Pergamon Press, 2019-12)
    1 Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Postbok 4950, Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072, Blindern, 0316 Oslo, Norway. Electronic address: kirjar@ous-hf.no. 2 Oslo Center for Biostatistics and Epidemiology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway. 3 Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark. 4 Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark; Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, 380 Huaibeizhuang, Huairou district, Beijing, China. 5 Children and Adolescent Health, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark. 6 Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark. 7 Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, New Children's Hospital, Helsinki University Hospital, Stenbäckinkatu 9, 00290 Helsinki, Finland. 8 Children's Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Hringbraut 101, 101 Reykjavik, Iceland. 9 Department of hematology, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Pediatric Oncology Research Laboratory, Rigshospitalet, University of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark. 10 Department of Women's and Children's Health, Karolinska University Hospital, Eugeniavägen 3, 171 76 Solna, Sweden; Childhood Cancer Research Unit, Women's and Children's Health, Karolinska Insitutet, Solnavägen 1, 171 77 Solna, Sweden. 11 Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950, Nydalen, 0424 Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Postbok 4950, Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072, Blindern, 0316 Oslo, Norway. 12 Department of Hematology and Oncology, Tallinn Children's Hospital, 13419 Tallinn, Estonia. 13 Center for Pediatric Oncology and Hematology, Children's Hospital, Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius 08410, Lithuania. 14 Department of Pediatrics, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark. 15 Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Nørregade 10, 1165 Copenhagen, Denmark.

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