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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Martin R. Larsen; Anna Saran; Dirk Janik; Zarko Barjaktarovic; +5 Authors

    Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer´s pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Europe PubMed Centra...arrow_drop_down
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Oncotarget
    Article
    License: CC BY
    Data sources: UnpayWall
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    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    ENEA Open Archive
    Article . 2016
    Data sources: ENEA Open Archive
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    Oncotarget; ENEA Open Archive
    Other ORP type . Article . 2016 . Peer-reviewed
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    ENEA Open Archive
    Article . 2016
    Data sources: ENEA Open Archive
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      Oncotarget
      Article
      License: CC BY
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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      ENEA Open Archive
      Article . 2016
      Data sources: ENEA Open Archive
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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      Oncotarget; ENEA Open Archive
      Other ORP type . Article . 2016 . Peer-reviewed
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      ENEA Open Archive
      Article . 2016
      Data sources: ENEA Open Archive
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    Authors: Meyerowitz-Katz, Gideon; Kashnitsky, Ilya;

    We are writing this openly-published letter to express deep concerns regarding the paper recently published in JAMA Network Open: Estimation of US Children’s Educational Attainment and Years of Life Lost Associated With Primary School Closures During the Coronavirus Disease 2019 Pandemic DOI: 10.1001/jamanetworkopen.2020.28786The paper by Christakis, Van Cleve, and Zimmerman(2020,abbrev. CVZ) is built upon multiple critically flawed assumptions, obvious misuse of the standard analytical tools, and clear mistakes in study design. Additionally, the analysis presented contains crucial mathematical and statistical errors that completely revert the main results, sufficient that if the estimates had been calculated according to the declared methodology, the results would completely contradict the stated conclusions and policy recommendations. These are not idle criticisms. This study has received enormous public attention, and its results immediately appeared in discussions of public health policies around schools worldwide. The central question is resolving an evidence base for the inevitable tradeoff between (a) the very real harms of missed education provoked by policies that decrease viral spread vs. (b) the resumption of education as a social good which increases viral spread. This is an incredibly important public health question, and it demands careful cost-benefit analysis. To that end, this paper adds no usable evidence whatsoever.

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    Authors: Bergenholtz, Heidi; Weibull, Anna; Raunkiær, Mette;
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    Authors: Keating, Vincent Charles; Thrandardottir, Erla;
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    Authors: Lichtenstein, Mia Beck;
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    Authors: Burke, Danita Catherine;

    (Dansk) Mange miljø-ngo’er (engo’er) er interesseret i Arktis. I Grønland kæmper de dog med at blive taget seriøst. En årsag er manglen på lokal tilstedeværelse./ (English) Many environmental non-governmental organizations (ENGOs) are interested in the North. In Greenland, ENGOs struggle to be taken seriously. One reason that contributes to the ENGO struggle is their lack of local representation.This article is published in Danish, but was originally written in English. The English version is available here as a PDF and links are provided to the published article in Danish.

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    Authors: Ekdahl, David;

    Organiseret computerspil på konkurrenceplan, eller ’esport’, har de sidste ti år gennemgået en enorm vækst og er siden 2020 blevet en milliardindustri. Som følge af denne udvikling, er esportsudøvelse i stigende grad blevet et bredt forskningsområde. Der findes dog i dag kun en meget begrænset mængde af forskning der har undersøgt de former for kropsbevidsthed og kropslighed som esporten kan fordre for udøverne selv. Denne afhandling er et fænomenologisk interviewstudie af esportsudøvelse som et muligt kropsbevidst fænomen. Afhandlingen undersøger og analyserer forskellige former for kropsbevidsthed der karakteriserer præsterende esportsudøveres erfaring – hovedsageligt indenfor spillene League of Legends og Counter Strike: Global Offensive. Resultaterne i denne afhandling baserer sig på fire artikler der enten fremhæver nødvendigheden af fænomenologisk analyse af esportsudøvelse eller gennemfører sådanne analyser. Afhandlingen består af fem overordnede dele. Efter en generel introduktion i første del, begynder afhandlingens anden del med at danne et overblik over esporten samt af den esportsforskning der i dag findes. Dernæst præsenteres diskussionen om esportens forhold til sporten. Med udgangspunkt i de uklarheder og misforståelser der har karakteriseret denne diskussion, argumenterer jeg for nødvendigheden af en klarere forståelse af esporten som et kropsbevidst fænomen. Baseret på dette, præsenterer afhandlingen sine epistemologiske rødder i form af et sæt af fænomenologiske grundantagelser, inklusive begrænsningerne ved dette fænomenologiske greb. Disse fænomenologiske grundantagelser fremlægges som noget der kan facilitere en mere direkte tilgang til esportsudøveres erfaringer og kropsbevidsthed. Dernæst, i tredje del, diskuterer jeg kritisk de metodologiske muligheder for fænomenologisk at undersøge andres erfaringer samt hvordan de interviewede informanters beskrivelser kan bruges til at udvide og udfordre vores nuværende forståelse af både esport samt virtuel kropsbevidsthed. Metodologisk er disse fænomenologiske analyser udført baseret på data generet igennem semistrukturerede, kvalitative interviews med tolv erfarne, danske esportsudøvere. I denne forbindelse følger en punktvis gennemgang af afhandlingens fulgte metode. Efterfølgende, i fjerde del, fremstilles de to esportsspil hvorefter de fænomenologiske analyser af esportsudøvernes beskrivelser præsenteres og diskuteres. Resultaterne af disse analyser fremhæver tre centrale dimensioner af kropsbevidsthed der karakteriserer esportsudøvernes erfaring når de præsterer. Disse er, et, basal kropsbevidsthed: Udøverne erfarer deres virtuelle verdener på grundlæggende kropslige og praksisorienterede måder. To, inkorporering: Med øvelse integrerer de præsterende esportsudøvere både tilgængelige fysiske samt virtuelle redskaber og evner som en del af deres kropslighed. Tre, interkropslighed: Med øvelse erfarer udøverne deres egen samt andres avatarer i kraft af en gensidig kropslig intentionalitet mens de præsterer. I femte og sidste del af afhandlingen vurderes de endelige resultater kritisk før de slutteligt drages ind i en større perspektivering. Organized competitive video gaming or ‘esports’ has undergone immense growth over the past ten years, into a billion-dollar industry as of 2020. Following this trend, a broad scope of research has increasingly been directed at the phenomenon as a set of novel and unique competitive, spectator platforms. Yet, little research on what kind of embodied involvement esports practice can afford has so far been conducted with actual esports practitioners. This thesis is a phenomenological interview study of esports practice, exploring and analyzing the different forms of embodied involvement esports practitioners experience during performance – primarily in the games League of Legends and Counter Strike: Global Offensive. The findings of the thesis are based on four articles that either emphasize the need for phenomenological analysis of esports practice or provide such analyses. The thesis proceeds in five parts. Outside of the overall introduction which makes up Part I, the thesis begins in Part II by providing an overview of esports practice and state-of-the-art research on esports, before engaging directly with the contemporary debate on esports’ relationship to the world of sports. Based on confusions and ambiguities in this debate, I emphasize the need for a clearer understanding of esports practice as embodied. The thesis then introduces a set of phenomenological assumptions as its epistemological roots. These phenomenological assumptions are introduced as elements that can facilitate a more direct engagement with the embodied experiences of esports practitioners. Following this, in Part III, the thesis engages in a critical methodological discussion on how to phenomenologically study the experiences of other subjects and how the interviewed informants’ descriptions can be used to expand and challenge our understanding of esports and virtual embodiment. Methodologically, these phenomenological analyses are conducted based on data generated through semi-structured, qualitative interviews with twelve talented, Danish esports practitioners. In this context, I provide a point-by-point introduction to the method. Then, in Part IV, the two esports games are introduced, before the phenomenological analyses of esports practice are presented and discussed. The results of these analyses show the central importance of three distinct dimensions of embodiment for the esports practitioners. These are, first, basic embodiment: The practitioners experience their virtual worlds in fundamentally embodied and practical ways. Second, incorporation: The practitioners come to integrate both the physical and the virtual tools and abilities available to them during performance into their body. Third, intercorporeality: The practitioners come to experience their own avatars and other players’ avatars reciprocally in terms of bodily intentionality. These final results are then, in Part V, critically assessed before being brought into broader perspectival considerations.

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    Authors: Kristensen, Kasper Bruun;

    Lægemidler kan, som andre udefrakommende eksponeringer, påvirke risikoen for kræft. Farmakoepidemiologi, studiet af lægemidler i populationer, er et nyttigt redskab til at undersøge sådanne effekter, men det er en udfordring, at det kan tageadskillige år fra lægemiddeleksponeringen indtil en eventuel kræftsygdom opstår. Denne afhandling inkluderer fem studier, hvoraf tre undersøger specifikke lægemidler og kræfttyper, et studie er et hypotesegenerende screeningsstudie for hidtil ukendte sammenhænge mellem lægemidler og kræft og det sidste studie præsenterer et komorbiditetsindeks til brug i farmakoepidemiologiske studier. I det første studie sammenfattede vi de eksisterende studier omhandlende vitamin K antagonister og prostatakræft og udførte selv et case-kontrolstudie med danske registerdata. Konklusionen var, at de eksisterende studier var heterogene, men at en klinisk relevant effekt af vitamin K antagonister i forhold til forebyggelse af prostatakræft var usandsynlig. I det andet studie undersøgte vi, om brug af antiepileptika var forbundet med en øget risiko for hudkræft og modermærkekræft i en række case-kontrol studier. Resultaterne var overordnet betryggende, idet vi ikke observerede en sammenhængmellem de undersøgte kræftformer og de fleste antiepileptiske lægemidler. Vi fandt dog en sammenhæng mellem spinocellulært karcinom, en sjælden form for hudkræft, og brug af carbamazepin og lamotrigin. På grund af studiets hypotesegenerende natur, har disse fund ingen direkte kliniske konsekvenser og flere studier er nødvendige for at karakterisere disse signaler yderligere.I det tredje studie undersøgte vi, om brug af calcium kanal blokkere var forbundet med øget risiko for nyrekræft. Vi demonstrerede samtidig metoder til at identificere og imødegå `confounding by indication´ inklusive evaluering af kumulative dosis- respons sammenhænge, justering for sværhedsgrad af sygdom, brug af andre eksponeringer som negative kontroller, og brug af aktive komparatorer. Vi konkluderede, at sammenhængen mellem calcium kanal blokkere og nyrekræft til dels var påvirket af `confounding by indication´. Det fjerde studie, et hypotese-generende screeningsstudie, havde til formål at identificere lægemidler med mulige karcinogene egenskaber. Vi undersøgte sammenhænge mellem lægemidler og kræft i 33 forskellige organer delt på 85 forskellige histologiske typer i en række case-kontrol studier. Vi undersøgte cirka14,000 associationer, og alle resultater blev gjort tilgængelige til forskningsmæssige formål. Vi identificerede kendte sammenhænge mellem lægemidler og kræft, eksempelvis brug af azathioprin og non-Hodgkin lymfom og beskrev en rækkesammenhænge, der ikke tidligere er beskrevet og fortjener at blive undersøgt nærmere. Studiet demonstrerede, at det er muligt at udføre sådanne hypotesegenerende screenings studier, men også at den efterfølgende sortering af signaler skal udvikles og at det er vigtigt at understrege den hypotese-generende natur afstudiet når resultater herfra præsenteres. I det femte studie udviklede vi et numerisk komorbiditetsindeks, med det formål at justere for og beskrive den samlede sygdomsbyrde i farmakoepidemiologiske studier. Indekset blev udviklet i en kohorte udtrukket tilfældigt fra den samledepopulation af indbyggere i Danmark. Indekset inkluderede 50 tilstande defineret ved diagnose eller lægemiddelbrug og blev udviklet til at forudsige 5-års dødelighed. Vi konkluderede at vores indeks var bedre til at forudsige dødelighed end de hyppigtbrugte Charlson og Elixhauser komorbiditesindekser og at indekset kan bruges som en indikator for sygelighed i studier baseret på Nordiske registre. Vi konkluderede dog også at indekset skulle valideres i specifikke patientpopulationer og øvrige Nordiske lande. Exogenous exposures such as prescription drugs may affect the risk of cancer. Pharmacoepidemiology, the study of drugs in groups of people, can be used to study these effects, however, drug-cancer studies pose a particular challenge since it may take years or even decades from the initial exposure until a cancer is diagnosed. This thesis includes five studies, of which three examined specific drug-cancer associations, one was a hypothesis-free screening study for carcinogenic effects of drugs, and the last study focused on developing a comorbidity summary score for use in pharmacoepidemiologic studies. In the first study, we summarized existing evidence on vitamin K antagonists and their association with prostate cancer risk and conducted a case-control study using Danish registries to add to the existing evidence. Taken together, the identified studies reported heterogenous results, however, we concluded that a clinically relevant preventive effect of vitamin K antagonists against prostate cancer was unlikely. In the second study, we examined whether antiepileptic drugs were associated with non-melanoma skin cancer and malignant melanoma in a series of case-control studies. Reassuringly, associations were close to unity for most antiepileptic drugsand outcomes except for a positive association between squamous cell carcinoma and lamotrigine and carbamazepine. Due to the hypothesis-generating nature of the study, we concluded that the results had no direct clinical implications and that further research was needed to qualify these signals further.In the third study, we examined whether use of calcium channel blockers was associated with increased risk of kidney cancer. We illustrated methods to identify and account for confounding by indication including the assessment of cumulative dose-response relationships, adjusting for severity of disease, using negative control exposures, and using active comparators. We concluded that the observed association between calcium channel blockers and kidney cancer was at least partly explained by confounding by indication. The fourth study, a hypothesis-free screening study, aimed to identify carcinogenic effects of drugs by examining all drugs and cancers in a series of case-control studies. We identified individuals with incident cancer of 33 sites and 85 histologicalsubtypes. Approximately 14,000 drug-cancer pairs were evaluated, and the estimates were made available online for research purposes. We identified known drug-cancer associations e.g., azathioprine and non-Hodgkin lymphoma, and highlighted anumber of drug-cancer associations that deserved further scrutiny. We concluded that hypothesis-free screening of drug-cancer associations were feasible, however, signal identification remained an issue and the hypothesis-generating nature of theresults should be stressed when communicating the findings of the study. In the fifth study, we developed a numerical score to adjust for comorbidity in pharmacoepidemiologic studies, the Nordic Comorbidity Index. We developed the index in a population-based cohort of randomly sampled Danish residents and theindex included a total of 50 diagnoses or drugs that predicted 5-year mortality. We concluded that the index was superior to the Charlson and Elixhauser comorbidity scores in predicting mortality and that it could be preferred as a summary score instudies utilizing Nordic registry data, however, it remains to be validated in specific patient populations and other Nordic countries.

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    Authors: Kavan, Stephanie;

    Brystkræft er den mest udbredte invasive cancerlidelse og den største årsag til cancer relateret død blandt kvinder. En af de største udfordringer i behandlingen af brystkræftpatienter er den ekstensive inter- og intratumorale heterogenitet som er et resultat af naturlig og terapeutisk selektion. Data indhentet fra en bred række af genomiske studier på primære tumorer og metastaser, viser forskellige modeller af evolutionære mønstre, der adskiller sig ved timing af metastaseudløste genetiske forandringer og graden af genetisk konkordans. Karakterisering af det evolutionære landskab i brystkræfttumorer kan bidrage med biologisk forståelse af tumorprogression fra primærcancer til dissemination og kan blive et vigtigt redskab til vejledning af effektiv behandling. Aktuelt er vævsbiopsier betragtet som guldstandard til diagnostik og behandling af cancer, om end der er risiko for, at disse ikke repræsenterer hele det genetiske landskab af tumoren. Disse begrænsninger har ledt til forslag om ”liquid biopsies” som et attraktivt supplement til vævsbiopsier. ”Liquid biopsy” i form af cirkulerende tumor DNA (ctDNA) kan have potentiale til at fange den inter- og intratumorale heterogenitet i metastaserende brystkræft gennem serielle blodprøver, som sporer klonal evolution i cancergenomet.Studie I er en gennemgang af publicerede studier med fokus på intratumoral og temporal genetisk heterogenitet i brystkræft, med vægt på studier, der sporer klonal evolution ved global analyse i multiple progressionstrin fra samme patient. Derudover diskuterer vi potentialet for plasma ctDNA i forhold til vævsbiopsier fra primærtumorer og metastaser, for at opnå et mere komplet overblik over det molekylære landskab i tumorer. Taget i betragtning af de få studier der er udgivet inden for området af globale analyser har vi også inkluderet studier der bruger panelsekvensering. Endelig har vi sammenlignet studier med fokus på relevansen af genetisk heterogenitet og klonal evolution i klinikken. Her argumenterer vi for plasma ctDNA som en kraftfuld tilgang til monitorering af det klonale landskab af cancer under behandling og tilbagefald.Brystkræft er en spatial og temporal dynamisk sygdom, hvor forskelligt udviklede kloner er ansvarlige for progression og klinisk outcome, men betydningen af systemisk behandling for klonal evolution og tumor heterogenitet er fortsat uklar. I Studie II definerer vi de genetiske forandringer i systemisk ubehandlet brystkræft patienter med metastaserende sygdom. Vi analyserede data fra helexomsekvensering af parrede primærtumorer og metastaser fra tre brystkræft patienter, der endnu ikke havde modtaget systemisk behandling. Punktmutationer, copy number forandringer, potentielle driver gener og mutational cancer cell fraktioner blev identificeret ved brug af state-of-the-art metoder i bioinformatik. Genetiske forskelle blev bemærket mellem primærtumor og metastaser, der alle viste høj grad af genetisk divergens. Alle tre patienter fulgte en parallel progressionsmodel med tidlig monoclonal dissemination fra primærtumor efterfulgt af separat klonal evolution. Metastasespecifikke mutationer involverede generne EP300, APOBEC3B, KDM5C, ASXL1 og EPCAM. Alle associeret til cancer migration og progression. Disse resultater blev støttet af pathway analyser, der viste cancer driving pathways hovedsageligt er signifikant i stem mutationer med tilstedeværelse i både primærtumor og metastaser. Det er bemærkelsesværdigt , at påvirkede pathways reflekterede patientens molekylære subtype og metastaselokation. Metastasespecifikke forandringer påvirkede driver gener involveret i kollagen udvikling, muskelkontration, kernemembran depolymerisation. Disseforandringer medvirker til metastiske mekanismer såsom migration, invasion og genomisk instabilitet. De beskrevne mønstre af evolution og den polyklonale natur af brystkræft har potentielt kliniske konsekvenser og bør tages i betragtning i forhold til diagnostik og valg af behandling. Nye studier fokuserer på relevansen af clonal evolution i de kliniske rammer og belyser ”liquid biopsies” som en non-invasiv biomarkør til monitorering af klonal progression og respons til behandling. I klinisk sammenhæng, kan ctDNA sandsynligvis bidrage med en ideel støtte sammen med vævsbiopsier til karakterisering af det genetiske landskab i metastaserende sygdom. Desuden kan ctDNA potentielt forbedre longitudinel monitorering af sygdomsdynamikker og behandlingseffektivitet for derfor bedre, at kunne opspore residual tumorvæv efter resektion, tilbagefald af sygdom eller metastaser.I studie III foretog vi copy-number profiling og detektion af somatiske mutationer på baggrund af helexomsekvensering i primærtumorer, fjernmetastaser og plasma ctDNA fra otte patienter med metastaserende brystkræft. Vores data viste forskellige mønstre af tumor evolution. Selvom lineær udvikling med sen spredning af metastatiske celler blev påvist i nogle tilfælde, observerede vi for det meste parallel udvikling med tidlig spredning fra primære tumorer til fjernmetastaser. Ved sammenligning af vævsprøver med plasmaprøver fandt vi varianter der repræsenterer primærtumor og/eller metastaser. Dette er afhængig af tiden mellem progressionstrin. De gamle mutationer fra den tidlige tumorklon dominerer i plasma, efterfulgt af metastasespecifikke mutationer. Dog blev forskellige mønstre observeret. De genomiske forskelle mellem de forskellige stadier af tumor evolution understreger vigtigheden af molekylær profilering af metastatiske vævsprøver og mulighederne for ”liquid biopsies” og real-time sporing af tumor dynamikker.  Breast cancer is the most common invasive malignancy and the leading cause of cancer-related deaths among women. One of the biggest challenges in handling breast cancer is the extensive inter-and intra-tumoral heterogeneity resulting from a natural or therapeutic selection. Data obtained from various genomic profiling studies on primary tumors and matched metastases suggested different models of evolutionary patterns that differ in timing of metastasis-enabling genomic alterations and the degree of genomic concordance between progression states. Characterizing the evolutionary landscape of breast tumors can provide a biological understanding of tumor progression from primary cancers to dissemination and may be necessary for directing effective treatments. Currently, tissue biopsy is considered the gold standard for diagnosis and treatment guidance in breast cancer, although it may insufficiently represent the entire genomic landscape of a tumor. Multiple limitations of this technique have led to the proposal of liquid biopsies as an attractive complementary tool to tissue biopsies. In the form of circulating tumor DNA (ctDNA), liquid biopsy could potentially capture the inter-and intra-tumoral heterogeneity present in metastatic breast cancer and, through serial blood draws, track the clonal evolution of the cancer genome.Study I is a literature review focused on intratumor and temporal genetic heterogeneity in breast cancer, emphasizing studies tracking clonal evolution by global analysis in multiple progression steps from the same patient. Additionally, we discussed the potential of plasma ctDNA compared to tissue biopsies from primary tumors and metastases for a complete overview of the molecular tumor landscape. Considering the low number of papers published in this part using global analysis, we also included studies using targeted sequencing approaches. Finally, we compared studies focusing on the relevance of genetic heterogeneity and clonal evolution in the clinical setting and discussed plasma circulating tumor DNA as a powerful real-time approach for monitoring the clonal landscape of cancer during treatment and recurrence. Breast Cancer is a spatial and temporal dynamic disease where differently evolving genetic clones are responsible for progression and clinical outcome. Still, the impact of systemic treatment on clonal evolution and tumor heterogeneity is poorly understood. In Study II, we ought to map the repertoire of genetic alterations in systemically untreated breast cancer patients with de novo metastatic disease. We analyzed wholeexome sequencing data from the paired primary tumor and metastatic samples from three breast cancer patients who had not received systemic therapy yet. Point mutations, copy number alterations, potential driver genes, and mutational cancer cell fractions were identified using state-of-the-art bioinformatics methods. Genomic differences were observed between primary tumor and metastatic lesion, showing a high level of genetic divergence. All three patients followed the parallel progression model, with early monoclonal dissemination from the primary tumor followed by separate clonal evolution. Interestingly, metastasis-specific mutations involved genes EP300, APOBEC3B, KDM5C, ASXL1, and EPCAM, all associated with cancer migration and progression. These results were supported by pathway analysis, showing cancer-driving pathways are mainly significant in stem mutations present in both primary tumor and metastasis. Notably, affected pathways reflected the patient’s molecular subtype and metastasis location. Lastly, alterations specific to the metastasis affected driver genes involved in collagen formation, muscle contraction, and nuclear envelope depolymerizations supporting metastatic tumor cell migration, invasion, and genomic instability. The described patterns of evolution and the polyclonal nature of breast cancer have clinical consequences and should be considered during patient diagnosis and treatment selection. Current studies focusing on the relevance of clonal evolution in the clinical setting elucidate the role of liquid biopsy as a noninvasive biomarker for monitoring clonal progression and response to treatment. In the clinical setting, circulating tumor DNA may constitute ideal support for tumor biopsies to characterize the genetic landscape of metastatic disease. This might improve longitudinal monitoring of disease dynamics and treatment effectiveness to detect any residual tumor after resection, relapse, or metastasis within a particular patient.In Study III, we performed copy number profiling and somatic mutation detection based on whole-exome sequencing of primary tumors, distant metastasis, and plasma circulating tumor DNA from eight metastatic breast cancer patients. Our data showed diverse patterns of tumor evolution. Although linear evolution with late dissemination of metastatic cells was detected in some cases, we mainly observed parallel evolution with early dissemination from primary tumors to distant sites. Comparing tissue biopsies with plasma samples, we detected variants mirroring primary tumor and/or metastasis, depending on the period between the progression steps. The old mutations from the early tumor clone dominate in plasma, followed by metastasis-specific mutations. However, different patterns were observed. The genomic discordance between the various stages of tumor evolution emphasizes the importance of molecular profiling of metastatic tissue and the possibilities of liquid biopsies for real-time tracking of tumor dynamics.

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    Authors: Budtz-Jørgensen, Esben; Grandjean, Philippe;
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    Authors: Martin R. Larsen; Anna Saran; Dirk Janik; Zarko Barjaktarovic; +5 Authors

    Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer´s pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.

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    Authors: Meyerowitz-Katz, Gideon; Kashnitsky, Ilya;

    We are writing this openly-published letter to express deep concerns regarding the paper recently published in JAMA Network Open: Estimation of US Children’s Educational Attainment and Years of Life Lost Associated With Primary School Closures During the Coronavirus Disease 2019 Pandemic DOI: 10.1001/jamanetworkopen.2020.28786The paper by Christakis, Van Cleve, and Zimmerman(2020,abbrev. CVZ) is built upon multiple critically flawed assumptions, obvious misuse of the standard analytical tools, and clear mistakes in study design. Additionally, the analysis presented contains crucial mathematical and statistical errors that completely revert the main results, sufficient that if the estimates had been calculated according to the declared methodology, the results would completely contradict the stated conclusions and policy recommendations. These are not idle criticisms. This study has received enormous public attention, and its results immediately appeared in discussions of public health policies around schools worldwide. The central question is resolving an evidence base for the inevitable tradeoff between (a) the very real harms of missed education provoked by policies that decrease viral spread vs. (b) the resumption of education as a social good which increases viral spread. This is an incredibly important public health question, and it demands careful cost-benefit analysis. To that end, this paper adds no usable evidence whatsoever.

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    Authors: Bergenholtz, Heidi; Weibull, Anna; Raunkiær, Mette;
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    Authors: Keating, Vincent Charles; Thrandardottir, Erla;
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    Authors: Lichtenstein, Mia Beck;
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    Authors: Burke, Danita Catherine;

    (Dansk) Mange miljø-ngo’er (engo’er) er interesseret i Arktis. I Grønland kæmper de dog med at blive taget seriøst. En årsag er manglen på lokal tilstedeværelse./ (English) Many environmental non-governmental organizations (ENGOs) are interested in the North. In Greenland, ENGOs struggle to be taken seriously. One reason that contributes to the ENGO struggle is their lack of local representation.This article is published in Danish, but was originally written in English. The English version is available here as a PDF and links are provided to the published article in Danish.

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    Authors: Ekdahl, David;

    Organiseret computerspil på konkurrenceplan, eller ’esport’, har de sidste ti år gennemgået en enorm vækst og er siden 2020 blevet en milliardindustri. Som følge af denne udvikling, er esportsudøvelse i stigende grad blevet et bredt forskningsområde. Der findes dog i dag kun en meget begrænset mængde af forskning der har undersøgt de former for kropsbevidsthed og kropslighed som esporten kan fordre for udøverne selv. Denne afhandling er et fænomenologisk interviewstudie af esportsudøvelse som et muligt kropsbevidst fænomen. Afhandlingen undersøger og analyserer forskellige former for kropsbevidsthed der karakteriserer præsterende esportsudøveres erfaring – hovedsageligt indenfor spillene League of Legends og Counter Strike: Global Offensive. Resultaterne i denne afhandling baserer sig på fire artikler der enten fremhæver nødvendigheden af fænomenologisk analyse af esportsudøvelse eller gennemfører sådanne analyser. Afhandlingen består af fem overordnede dele. Efter en generel introduktion i første del, begynder afhandlingens anden del med at danne et overblik over esporten samt af den esportsforskning der i dag findes. Dernæst præsenteres diskussionen om esportens forhold til sporten. Med udgangspunkt i de uklarheder og misforståelser der har karakteriseret denne diskussion, argumenterer jeg for nødvendigheden af en klarere forståelse af esporten som et kropsbevidst fænomen. Baseret på dette, præsenterer afhandlingen sine epistemologiske rødder i form af et sæt af fænomenologiske grundantagelser, inklusive begrænsningerne ved dette fænomenologiske greb. Disse fænomenologiske grundantagelser fremlægges som noget der kan facilitere en mere direkte tilgang til esportsudøveres erfaringer og kropsbevidsthed. Dernæst, i tredje del, diskuterer jeg kritisk de metodologiske muligheder for fænomenologisk at undersøge andres erfaringer samt hvordan de interviewede informanters beskrivelser kan bruges til at udvide og udfordre vores nuværende forståelse af både esport samt virtuel kropsbevidsthed. Metodologisk er disse fænomenologiske analyser udført baseret på data generet igennem semistrukturerede, kvalitative interviews med tolv erfarne, danske esportsudøvere. I denne forbindelse følger en punktvis gennemgang af afhandlingens fulgte metode. Efterfølgende, i fjerde del, fremstilles de to esportsspil hvorefter de fænomenologiske analyser af esportsudøvernes beskrivelser præsenteres og diskuteres. Resultaterne af disse analyser fremhæver tre centrale dimensioner af kropsbevidsthed der karakteriserer esportsudøvernes erfaring når de præsterer. Disse er, et, basal kropsbevidsthed: Udøverne erfarer deres virtuelle verdener på grundlæggende kropslige og praksisorienterede måder. To, inkorporering: Med øvelse integrerer de præsterende esportsudøvere både tilgængelige fysiske samt virtuelle redskaber og evner som en del af deres kropslighed. Tre, interkropslighed: Med øvelse erfarer udøverne deres egen samt andres avatarer i kraft af en gensidig kropslig intentionalitet mens de præsterer. I femte og sidste del af afhandlingen vurderes de endelige resultater kritisk før de slutteligt drages ind i en større perspektivering. Organized competitive video gaming or ‘esports’ has undergone immense growth over the past ten years, into a billion-dollar industry as of 2020. Following this trend, a broad scope of research has increasingly been directed at the phenomenon as a set of novel and unique competitive, spectator platforms. Yet, little research on what kind of embodied involvement esports practice can afford has so far been conducted with actual esports practitioners. This thesis is a phenomenological interview study of esports practice, exploring and analyzing the different forms of embodied involvement esports practitioners experience during performance – primarily in the games League of Legends and Counter Strike: Global Offensive. The findings of the thesis are based on four articles that either emphasize the need for phenomenological analysis of esports practice or provide such analyses. The thesis proceeds in five parts. Outside of the overall introduction which makes up Part I, the thesis begins in Part II by providing an overview of esports practice and state-of-the-art research on esports, before engaging directly with the contemporary debate on esports’ relationship to the world of sports. Based on confusions and ambiguities in this debate, I emphasize the need for a clearer understanding of esports practice as embodied. The thesis then introduces a set of phenomenological assumptions as its epistemological roots. These phenomenological assumptions are introduced as elements that can facilitate a more direct engagement with the embodied experiences of esports practitioners. Following this, in Part III, the thesis engages in a critical methodological discussion on how to phenomenologically study the experiences of other subjects and how the interviewed informants’ descriptions can be used to expand and challenge our understanding of esports and virtual embodiment. Methodologically, these phenomenological analyses are conducted based on data generated through semi-structured, qualitative interviews with twelve talented, Danish esports practitioners. In this context, I provide a point-by-point introduction to the method. Then, in Part IV, the two esports games are introduced, before the phenomenological analyses of esports practice are presented and discussed. The results of these analyses show the central importance of three distinct dimensions of embodiment for the esports practitioners. These are, first, basic embodiment: The practitioners experience their virtual worlds in fundamentally embodied and practical ways. Second, incorporation: The practitioners come to integrate both the physical and the virtual tools and abilities available to them during performance into their body. Third, intercorporeality: The practitioners come to experience their own avatars and other players’ avatars reciprocally in terms of bodily intentionality. These final results are then, in Part V, critically assessed before being brought into broader perspectival considerations.

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    Authors: Kristensen, Kasper Bruun;

    Lægemidler kan, som andre udefrakommende eksponeringer, påvirke risikoen for kræft. Farmakoepidemiologi, studiet af lægemidler i populationer, er et nyttigt redskab til at undersøge sådanne effekter, men det er en udfordring, at det kan tageadskillige år fra lægemiddeleksponeringen indtil en eventuel kræftsygdom opstår. Denne afhandling inkluderer fem studier, hvoraf tre undersøger specifikke lægemidler og kræfttyper, et studie er et hypotesegenerende screeningsstudie for hidtil ukendte sammenhænge mellem lægemidler og kræft og det sidste studie præsenterer et komorbiditetsindeks til brug i farmakoepidemiologiske studier. I det første studie sammenfattede vi de eksisterende studier omhandlende vitamin K antagonister og prostatakræft og udførte selv et case-kontrolstudie med danske registerdata. Konklusionen var, at de eksisterende studier var heterogene, men at en klinisk relevant effekt af vitamin K antagonister i forhold til forebyggelse af prostatakræft var usandsynlig. I det andet studie undersøgte vi, om brug af antiepileptika var forbundet med en øget risiko for hudkræft og modermærkekræft i en række case-kontrol studier. Resultaterne var overordnet betryggende, idet vi ikke observerede en sammenhængmellem de undersøgte kræftformer og de fleste antiepileptiske lægemidler. Vi fandt dog en sammenhæng mellem spinocellulært karcinom, en sjælden form for hudkræft, og brug af carbamazepin og lamotrigin. På grund af studiets hypotesegenerende natur, har disse fund ingen direkte kliniske konsekvenser og flere studier er nødvendige for at karakterisere disse signaler yderligere.I det tredje studie undersøgte vi, om brug af calcium kanal blokkere var forbundet med øget risiko for nyrekræft. Vi demonstrerede samtidig metoder til at identificere og imødegå `confounding by indication´ inklusive evaluering af kumulative dosis- respons sammenhænge, justering for sværhedsgrad af sygdom, brug af andre eksponeringer som negative kontroller, og brug af aktive komparatorer. Vi konkluderede, at sammenhængen mellem calcium kanal blokkere og nyrekræft til dels var påvirket af `confounding by indication´. Det fjerde studie, et hypotese-generende screeningsstudie, havde til formål at identificere lægemidler med mulige karcinogene egenskaber. Vi undersøgte sammenhænge mellem lægemidler og kræft i 33 forskellige organer delt på 85 forskellige histologiske typer i en række case-kontrol studier. Vi undersøgte cirka14,000 associationer, og alle resultater blev gjort tilgængelige til forskningsmæssige formål. Vi identificerede kendte sammenhænge mellem lægemidler og kræft, eksempelvis brug af azathioprin og non-Hodgkin lymfom og beskrev en rækkesammenhænge, der ikke tidligere er beskrevet og fortjener at blive undersøgt nærmere. Studiet demonstrerede, at det er muligt at udføre sådanne hypotesegenerende screenings studier, men også at den efterfølgende sortering af signaler skal udvikles og at det er vigtigt at understrege den hypotese-generende natur afstudiet når resultater herfra præsenteres. I det femte studie udviklede vi et numerisk komorbiditetsindeks, med det formål at justere for og beskrive den samlede sygdomsbyrde i farmakoepidemiologiske studier. Indekset blev udviklet i en kohorte udtrukket tilfældigt fra den samledepopulation af indbyggere i Danmark. Indekset inkluderede 50 tilstande defineret ved diagnose eller lægemiddelbrug og blev udviklet til at forudsige 5-års dødelighed. Vi konkluderede at vores indeks var bedre til at forudsige dødelighed end de hyppigtbrugte Charlson og Elixhauser komorbiditesindekser og at indekset kan bruges som en indikator for sygelighed i studier baseret på Nordiske registre. Vi konkluderede dog også at indekset skulle valideres i specifikke patientpopulationer og øvrige Nordiske lande. Exogenous exposures such as prescription drugs may affect the risk of cancer. Pharmacoepidemiology, the study of drugs in groups of people, can be used to study these effects, however, drug-cancer studies pose a particular challenge since it may take years or even decades from the initial exposure until a cancer is diagnosed. This thesis includes five studies, of which three examined specific drug-cancer associations, one was a hypothesis-free screening study for carcinogenic effects of drugs, and the last study focused on developing a comorbidity summary score for use in pharmacoepidemiologic studies. In the first study, we summarized existing evidence on vitamin K antagonists and their association with prostate cancer risk and conducted a case-control study using Danish registries to add to the existing evidence. Taken together, the identified studies reported heterogenous results, however, we concluded that a clinically relevant preventive effect of vitamin K antagonists against prostate cancer was unlikely. In the second study, we examined whether antiepileptic drugs were associated with non-melanoma skin cancer and malignant melanoma in a series of case-control studies. Reassuringly, associations were close to unity for most antiepileptic drugsand outcomes except for a positive association between squamous cell carcinoma and lamotrigine and carbamazepine. Due to the hypothesis-generating nature of the study, we concluded that the results had no direct clinical implications and that further research was needed to qualify these signals further.In the third study, we examined whether use of calcium channel blockers was associated with increased risk of kidney cancer. We illustrated methods to identify and account for confounding by indication including the assessment of cumulative dose-response relationships, adjusting for severity of disease, using negative control exposures, and using active comparators. We concluded that the observed association between calcium channel blockers and kidney cancer was at least partly explained by confounding by indication. The fourth study, a hypothesis-free screening study, aimed to identify carcinogenic effects of drugs by examining all drugs and cancers in a series of case-control studies. We identified individuals with incident cancer of 33 sites and 85 histologicalsubtypes. Approximately 14,000 drug-cancer pairs were evaluated, and the estimates were made available online for research purposes. We identified known drug-cancer associations e.g., azathioprine and non-Hodgkin lymphoma, and highlighted anumber of drug-cancer associations that deserved further scrutiny. We concluded that hypothesis-free screening of drug-cancer associations were feasible, however, signal identification remained an issue and the hypothesis-generating nature of theresults should be stressed when communicating the findings of the study. In the fifth study, we developed a numerical score to adjust for comorbidity in pharmacoepidemiologic studies, the Nordic Comorbidity Index. We developed the index in a population-based cohort of randomly sampled Danish residents and theindex included a total of 50 diagnoses or drugs that predicted 5-year mortality. We concluded that the index was superior to the Charlson and Elixhauser comorbidity scores in predicting mortality and that it could be preferred as a summary score instudies utilizing Nordic registry data, however, it remains to be validated in specific patient populations and other Nordic countries.

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