Advanced search in
Research products
arrow_drop_down
Searching FieldsTerms
Any field
arrow_drop_down
includes
arrow_drop_down
Include:
2,800 Research products, page 1 of 280

  • Other research products
  • DK
  • English
  • University of Southern Denmark Research Output

10
arrow_drop_down
Date (most recent)
arrow_drop_down
  • Open Access English
    Authors: 
    Kavan, Stephanie;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    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.

  • Open Access English
    Authors: 
    Frederiksen, Trine;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Cytokrom P450 (CYP) 2D6 enzymet er den primære rute for elimination eller aktivering af en lang række lægemidler. Grundet polymorfi af CYP2D6 genet, udviser individer varierende grad af CYP2D6 enzymaktivitet. Dette forårsager variabilitet i mængden af lægemiddel i kroppen, hvilket kan resultere i forskelle i lægemiddeleffekt og -tolerabilitet. For at guide individualiseret lægemiddelbehandling med CYP2D6 substrater, er det vigtigt at have en god forståelse af forholdet mellem CYP2D6 polymorfi og enzymaktivitet. Hovedformålet med dette ph.d.-projekt var at kvantificere CYP2D6 enzymaktiviteten for forskellige CYP2D6 genotyper og alleler ved at undersøge farmakokinetikken af tre forskellige CYP2D6 substrater og deres metabolitter. Denne oversigt præsenterer tre populationsfarmakokinetik (popPK) analyser, som karakteriserer farmakokinetikken af hhv. vortioxetin, tedatioxetin, brexpiprazol og deres respektive metabolitter. Baseret på estimater fra de modellerne, blev den CYP2D6-medierede metabolisme kvantificeret for mere end 2,000 individer med et bredt spektrum af CYP2D6 genotyper.Analyserne viste, at alleler med nedsat funktion (f.eks. CYP2D6*9, *10, *17 and *41) generelt forårsagede mere end 50% reduktion af enzymaktivitet sammenlignet med vildtypen (CYP2D6*1). Særligt allelerne CYP2D6*17 og *41 udviste en lavere enzymaktivitet end forventet på tværs af de tre substrater, mens CYP2D6*10 havde ca. 30% enzymaktivitet sammenlignet med CYP2D6*1 for alle tre substrater. Bemærkelsesværdigt udviste CYP2D6*2 (som normalt forbindes med normal enzymaktivitet) en væsentlig nedsættelse af enzymaktivitet i omdannelsen af brexpiprazol til DM-3412, hvilket kunne tyde på en substratspecifik aktivitet af denne allel. Samlet set indikerer resultaterne, at nuværende systemer til oversættelse af CYP2D6 genotype til fænotype kan forbedres, især for alleler med nedsat enzymaktivitet og for substratspecifik enzymaktivitet.Data fra rutinemæssig lægemiddelmonitorering blev brugt til at evaluere popPK modellen for vortioxetin. Valideringsstudiet viste, at popPK modellen var god til at forudsige vortioxetin serumkoncentrationer målt som en del af klinisk praksis. Modellen havde en svag tendens til at overprediktere vortioxetin koncentrationer, hvilket til dels kan tilskrives typen af de indsamlede monitoreringsdata. Derudover viste en gennemgang af individuelle patientdata, at langsomme omsættere af CYP2D6 substrater oftere skiftede fra vortioxetin et andet antidepressivt lægemiddel sammenlignet med patienter med normal CYP2D6 aktivitet. Parallelt med dette fund så man en højere vortioxetin koncentration hos langsomme omsættere. Således kunne den højere frekvens af lægemiddelskift blandt langsomme omsættere muligvis forklares ved en øget risiko for bivirkninger forårsaget af høje lægemiddelkoncentrationer. Selvom denne afhandling bidrager til evidensen bag CYP2D6 genotype-fænotype bestemmelse, er der mange aspekter som mangler at blive belyst. Fremtidige studier kunne med fordel fokusere på CYP2D6 alleler, som endnu er dårligt karakteriseret og flere undersøgelser af faktorer såsom patologi, etnicitet, transkriptionsfaktorer og mikroRNA kunne øge vores forståelse af CYP2D6 yderligere. Slutteligt, for at facilitere implementering af farmakogenetik i klinisk praksis, er der fortsat behov for stærk evidens vedrørende cost-benefit samt etablering af nødvendig teknisk infrastruktur. The cytochrome P450 (CYP) 2D6 enzyme is the predominant pathway for the elimination or bioactivation of numerous drugs. Due to genetic polymorphism of the CYP2D6 gene, individuals display varying degrees of CYP2D6 enzyme activity. This causes variability in drug exposure which in turn may result in differences in drug efficacy and tolerability. To guide personalized dosing of CYP2D6 substrates, it is essential to have a good understanding of the impact of CYP2D6 polymorphism on enzyme activity. The main objective of this PhD project was to quantify the CYP2D6 activity associated with various CYP2D6 genotypes and alleles by studying the pharmacokinetics (PK) of three different CYP2D6 substrates and their metabolites.This thesis presents three population pharmacokinetic (popPK) studies characterizing the joint parent-metabolite PK of vortioxetine, tedatioxetine and brexpiprazole, respectively. Based on estimates from the final popPK models, the CYP2D6-mediated metabolism was quantified for more than 2,000 individuals carrying a wide range of CYP2D6 genotypes.The analyses showed that decreased function alleles (e.g. CYP2D6*9, *10, *17 and *41) were generally associated with a more than 50% reduction of CYP2D6 enzyme activity relative to the wild-type (CYP2D6*1). Particularly, the CYP2D6*17 and *41 alleles showed lower than expected enzyme activity across the substrates, while CYP2D6*10 exhibited ~30% enzyme activity relative to CYP2D6*1 for all three substrates. It is worth highlighting that the normal function allele, CYP2D6*2, exhibited a substantially decreased enzyme activity in the biotransformation of brexpiprazole to DM-3412 suggesting substrate-specific activity of this allele. Collectively, the results indicate that CYP2D6 genotype-phenotype translation schemes could benefit from further refinement particularly with regards to decreased function alleles and substrate-specific behaviour.Data from a therapeutic drug monitoring (TDM) unit was used to assess the performance of the popPK model developed for vortioxetine in a real-life clinical setting. Overall, the validation study showed a good ability of the popPK model to predict vortioxetine serum concentrations measured as part of routine clinical practice. The model had a slight tendency to overpredict concentrations, which may be partly due to the naturalistic nature of the TDM data. Longitudinal reviews of TDM profiles showed that CYP2D6 poor metabolisers (PMs) had an increased frequency of switching to an alternative antidepressant compared to normal metabolisers. This was paralleled by significantly higher exposures among the PMs, and therefore the higher rate of treatment switch might be explained by an increased risk of adverse events caused by supratherapeutic drug concentrations. While this thesis contributes to the evidence of CYP2D6 genotype-phenotype relationships, several aspects remain to be addressed. Future studies should aim to evaluate poorly characterized CYP2D6 alleles and further investigations of the impact of factors such as pathology, ethnicity, transcription factors and microRNA could contribute to our understanding of CYP2D6. Lastly, to facilitate successful implementation of pharmacogenetics in the clinic, solid evidence of cost-effectiveness and adequate technical infrastructure remains to be established.

  • Open Access English
    Authors: 
    Piri, Reza;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Introduktion: Iskæmisk hjertesygdom og slagtilfælde er nummer et og to på listen over de mest almindelige dødsårsager på verdensplan. Årsagen er typisk åreforkalkning, som kan forblive asymptomatisk i årevis og som regel diagnosticeres sent i forløbet på grund af en komplikation eller under et helbredstjek vha. traditionel billeddiagnostik, herunder ultralyd med Doppler, computertomografi (CT) eller magnetisk resonans, metoder, som også kan afsløre, om der er en stenose. Nylige rapporter tyder på, at meget tidlige ændringer i arterievæggen kan påvises og måles med positronemissionstomografi (PET) med sporstofferne 18F-fluordeoxyglucose (FDG) eller 18F-natriumfluorid (NaF). I dette ph.d.-projekt ønskede vi i første omgang at studere åreforkalkning i karotiderne vha. PET, men snart ændrede vi fokus til også at omfatte hjertet og aorta samt brugen af kunstig intelligens (artificial intelligence (AI)) til at segmentere de pågældende strukturer for at belyse, om dette kunne gøre segmentering og kvantificering hurtigere og mere pålidelig. På denne måde endte projektet med at omfatte fire undersøgelser publiceret i fire artikler. Artikel I var en systematisk gennemgang af PET studier af karotissklerose, herunder deren klinisk anvendelighed og relation til konventionel billeddiagnostik. Artikel II var en undersøgelse af 2-års ændringer i NaF-optagelsen i hjertet og aorta hos raske individer og anginapatienter ved brug af konventionel manuel segmentering. Artikel III var et forsøg på at etablere og teste en automatiseret AI-baseret metode til hurtig segmentering af NaF-PET/CT optagelser af hjertet, mens artikel IV var et forsøg på at gøre det samme i aorta.Metoder: I det systematiske review ledte vi efter forskningsartikler om PET-scanninger af karotiderne med forskellige sporstoffer i forskellige databaser. Duplikater, lederartikler, samt artikler om teknisk funktionsduelighed og reproducerbarhedsartikler blev fjernet. Det samme gjald artikler om patienter i terminalfasen eller i immunosuppressiv behandling. De mulige artikler blev vurderet af én bedømmer. I kohortestudiet blev 29 raske individer og 20 patienter med angina pectoris undersøgt med NaF-PET/CT to gange med to års mellemrum. Aortabuen, aorta thoracalis og abdominalis samt karotiderne blev manuelt segmenteret. Optagelsen af NaF blev angivet som den gennemsnitlige, maximale og total standardiserede aktiviteter med og uden partial volume korrektion (SUVmax, SUVmean, SUVtotal og cSUVmean, cSUVtotal). Efterfølgende blev et konvolutionelt neuralt netværk (CNN) udviklet til at identificere og segmentere hjertet i sin helhed og aorta i tre dele. CNN-modellen blev trænet vha. NaF-PET/CT-scanninger fra andre patienter og testet i de samme 49 personer som nævnt ovenfor ved sammenligning med data opnået ved manuel segmentering. Bland-Altman grænser for overensstemmelse blev brugt til at vurdere sammenligningerne. Reproducerbarheden af den manuelle metode undersøgt ved fornyet segmentering af 25 tilfældigt udvalgte scanninger.Resultater: I det systematiske review blev det vist, at patienter med symptomatisk karotissklerose har højere FDG optagelse end patienter med asymptomatisk karotissklerose. Histologisk vurderet var der en stærk sammenhæng mellem mikroforkalkning og NaF-optagelsen hos symptomatiske patienter, men forkalkning var inverst korreleret til optagelsen af FDG. I det manuelle kohortestudie var NaF-optagelsen ubetydeligt højere i angina-gruppen på begge tidspunkter, med mindre optagelse i den raske gruppe og lidt højere optagelse i angina-gruppen efter to år. NaF-optagelsen ved baseline kunne ikke forudsige en ændring i CT-forkalkning efter 2 år. NaF-optagelsen var positivt korreleret til alder i alle dele af aorta. Der var ingen ændring i arteriel CT-densitet efter 2 års opfølgning. I den sidste del af projektet var CNN-baserede målinger i hjertet 0-4 % højere end med den manuelle metode og 0-17 % lavere i aorta. Men SUV-middelværdierne opnået med de to metoder var både i hjertet og i aorta næsten identiske. Den CNN-baserede segmenteringsmetode var meget hurtigere end den manuelle metode. Der var ved gentagen manuel segmentering i henholdsvis hjertet og aorta en maksimal variation på hhv. 0,5 % og 6 % mod 100 % overensstemmelse med CNN-metoden.Konklusion: PET-billeddannelse er en nyligt introduceret modalitet til vurdering af åreforkalkning, som er en langsom og variabel proces hos både raske personer og patienter med angina pectoris, dog med en tendens til lidt højere NaF-optagelse hos anginapatienter. Den AI-baserede fremgangsmåde leverer gennemsnitlige værdier for NaF-optagelsen som svare nøje til de manuelt opnåede. Desuden er AI-baserede teknik observatøruafhængig, meget reproducerbare og meget hurtige end manuel segmentering, der er omstændelig og langsom. Med yderligere træning er det sandsynligt at den AI-baserede metode bliver standarden ved vurdering af patienter med formodet eller kendt åreforkalkning. Introduction: Ischemic heart disease and stroke are the world’s number one and two killers. The underlying cause is usually atherosclerosis, which may stay asymptomatic for years and is usually diagnosed late in the course due to a complication or during a health check using common types of imaging such as ultrasound with Doppler, computed tomography (CT) or magnetic resonance imaging, all of which can also determine if a stenosis is present. Recent reports suggest that very early changes in the artery wall can be detected and measured by positron emission tomography (PET) imaging with tracers 18F-fluorodeoxyglucose (FDG) or 18F-sodium fluoride (NaF). In this PhD project, we initially wanted to study atherosclerosis in the carotids by PET imaging, but we soon changed our focus to also include the heart and aorta and the use of AI to segment the targeted structures in order to elucidate if this could make segmentation and quantification faster and more reliable. Thus, the project ended comprising four studies published in four articles. Article I was a systematic review on PET imaging of carotid atherosclerosis, emphasizing clinical usefulness and relations to conventional imaging modalities. Article II was a study of 2-year changes in carotid and aortic NaF uptake in healthy individuals and angina patients using conventional manual segmentation. Article III was an attempt to establish and test an automated AI-based method for fast segmentation of the heart in NaF-PET/CT scans, while Article IV was an attempt to do the same in the aorta.Methods: In the systematic review, articles on carotid artery PET imaging with different radiotracers were searched in several databases. Duplicates, editorials, case stories, studies regarding feasibility or reproducibility of PET imaging, and studies on patients with end-stage diseases or receiving immunosuppressive medication were omitted. All eligible articles were reviewed by one observer. In the cohort study using manual segmentation only, 29 healthy subjects and 20 angina pectoris patients underwent NaF-PET/CT twice two years apart. The arch, thoracic, and abdominal aorta and the carotids were manually segmented. NaF uptake was expressed as the maximum, mean and total standardized uptake values without and with partial volume correction (SUVmax, SUVmean, SUVtotal and cSUVmean, cSUVtotal). Subsequently, a convolutional neural network (CNN) based method was developed to identify and segment the heart and the aorta in three mentioned parts. The CNN model was trained in NaF- PET/CT scans of other patients and tested in the same 49 subjects as above by comparison with data obtained by manual segmentation. Bland-Altman limits of agreement were used to compare derived parameters. Furthermore, the reproducibility of the manual method was examined by repeated segmentation in 25 randomly selected scans.Results: In the systematic review, it was shown that patients with symptomatic carotid atherosclerosis have higher FDG uptake than patients with asymptomatic carotid atherosclerosis. There was a strong correlation between microcalcification and NaF uptake in symptomatic patients in histopathological assessment, but calcification had a negative correlation with uptake of FDG. In the manual cohort study, NaF uptake was insignificantly higher in the angina group at both time points, with less uptake in the healthy group and slightly higher uptake in the angina group after two years. NaF uptake at baseline could not predict a change in CT calcification after 2 years. NaF uptake correlated positively with age in all parts of the aorta. CT scan did not indicate any change in density of major arteries after 2 years of follow-up. In the final part of the project, CNN derived heart segmentation measures were 0% to 4% higher than by the manual method and 0% to 17% lower than with manual aortic segmentation. However, with CNN-based and manual method the SUVmean values in both heart and aorta were almost identical. Cardiac and aortic CNN-based segmentation method was much faster than the manual approach, which had a maximal 0.5% and 6% variation at repeated segmentation of the heart and the aorta, respectively, compared to a 100 % inborn CNN reproducibility.Conclusion: PET imaging is a newly introduced modality for imaging of atherosclerosis, which is a slow and variable process in healthy individuals and patients with angina pectoris, albeit with a tendency of slightly higher NaF uptake in angina patients. Although current technical difficulties such as time-taking image analysis exist, the AI-based models could present values for Volume, SUVmean, SUVmax, and SUVtotal similar to the manually obtained ones. These AI-based models are observer-independent, highly reproducible and very fast alternative alternatives for slow manual segmentation. With further training, the AI-based approach may become the standard for assessing patients with suspected or known atherosclerosis.

  • Open Access English
    Authors: 
    Isaksson, Gustaf Lissel;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Proteinuri er en tilstand som forekommer ved en række nyresygdomme og er karakteriseret ved at nyrerne ”lækker” protein så det kan måles i urinen. Det er en selvstændig prædiktor for forværring af nyrefunktion, øget sygelighed og død. Meget tyder på at det er proteinerne selv, der er skadelige for nyren, men mekanismen er ikke kendt. Proteiner fra koagulationssystemet, herunder plasminogen, og komplementsystemet (del af det medfødte immunforsvar) findes i urin ved defekt filtrationsbarriere, men ikke i urin fra raske. Fra in vitro studier vides, at plasmin kan aktivere og kløve de kritiske komponenter C3 og C5 i komplementsystemet. Derved dannes de proinflammatoriske molekyler C3a og C5a samt under visse omstændigheder ”membran attak” komplekser (MAC, C5b-9). Plasmin aktiveres fra inaktivt plasminogen i proteinurisk urin via urokinase-type plasminogen aktivator (uPA), som findes i urin fra raske. I studierne undersøges en række hypoteser: plasminogen og komplement filtreres sammen ved proteinuri; at aktiveret plasmin driver komplementaktivering og inflammation fra nyrernes tubulussystem; samt at dette kan forhindres helt eller delvist ved at hæmme uPA med amilorid.Studie I undersøger udskillelsen af komplementaktiveringsprodukter i urinen hos nyretransplanterede med albuminuri som er en særlig høj-risikogruppe for tab af nyrefunktion og død og i en mindre gruppe ikke transplanterede nyresyge patienter, ligeledes med albuminuri. Endvidere undersøges ekstracellulære vesikler i urin for at lokalisere hvor henne i nyre komplement slår ned. Vi fandt at udskillelsen af splitprodukterne C3c, C3dg, og sC5b-9 associeret C9 neoantigen, normaliseret for kreatinin i spoturinprøver, var stærkt og signifikant øget ved albuminuri hos nyretransplanterede og ikke i urin fra transplanterede uden proteinuri. Samtidig sås der ikke forskelle i plasmakoncentrationer mellem de 2 grupper. Produkterne var også øget i urin fra patienter med proteinuri der ikke var transplanteret sammenlignet med raske kontroller. I ekstracellulære vesikler fra urin påvistes C9 neoantigenet kun ved albuminuri og yderligere undersøgelse via lektinaffinitetsisolering viste at både C3dg og C5b-9 var bundet til vesikler som stammede fra cellemembraner i proximale tubulus.Studie II tager konceptet videre og undersøger en eventuel aktiveringsmekanisme via uPA-plasminogen ved eksperimenter in vitro med kommercielt tilgængelige rene komplement- og koagulations proteiner samt hvorvidt dette kunne hæmmes med amilorid. Vi undersøgte også to kohorter med patienter med albuminuri som behandles med amilorid, samt et studie med mus med inducerbar progressiv proteinuri. I proteinurisk fase blev mus behandlet med enten amilorid eller saltvandsinjektion. Vi fandt en signifikant aktivering af både C3 og C5 direkte via uPA-plasmin i buffere in vitro og i urin ex vivo. C3 og C5 aktivering kunne hæmmes på en gradueret måde ved at hæmme uPA med amilorid in vitro. C3 kunne aktiveres ved at inkubere normal rask urin ved samtidig tilsættelse af eksogent plasminogen på en amiloridfølsom måde. Patientundersøgelserne viste at en dags amiloridbehandling kun tenderede til at nedbringe C3a i urinen hos nyretransplanterede. To dages amilorid behandling i patienter med diabetisk nyresygedom og proteinuri nedsatte C3dg og C9 neoantigen udskillelse. I dyreforsøget viste vi at amilorid i 4 dage signifikant sænkede døgnudskillelsen af C3a og C5a i urinen. Specifik hæmning af uPA i 11 dage i podocin (-/-) mus med et monoklonalt hæmmende antistof der modvirkede aktivering af plasminogen medførte også en signifikant reduktion i C3a og C5a udskillelseshastighed.I Studie III undersøges C3dg og sC5b-9 associeret C9 neoantigen i urin og plasma i konsekutive prøver opsamlet under graviditeten i en gruppe gravide med type 1 diabetes, n = 88 deltagere, hvoraf n = 14 udviklede preeklamspsi. Vi viste en signifikant stigning i både C3dg og C9 neoantigen i urinen mod slutningen af graviditeten som fulgte albuminudskillelsen hos de patienter der udviklede præeklampsi. Både C3dg og C9 neoantigen relaterede signifikant til albumin i urin men korrelationen til C9 total plasmin(ogen) var stærkere. Ekstracellulære vesikler blev også undersøgt og C3dg og C9 neoantigen blev kun påvist hos preeklampsipatienter ved gestationsuge 36, men ikke i kontroller eller ved 12 uger.De tre studier viser at udskillelsen af aktiveringsprodukter fra komplementsystemet i urinen følger graden af proteinuri men ikke plasmakoncentrationer og at aktiveringen derfor mest sandsynligt sker i tubulussytemet efter filtrering. Endvidere kan komplement membran-attak kompleks bindes specifikt men ikke eksklusivt til proximale tubulus apikale membraner vist via ekstracellulære vesikler i urin. Korrelationen mellem komplementfaktorer til plasmin(ogen) i urin var stærkere end til albumin, foreneligt med at plasminogen kan være medvirkende til aktivering. Amilorid har in vitro en hæmmende effekt på uPA i lav mikromolærområdet, som kan eftervises in vivo i patienter med proteinuri. Den signifikante afsvækkelse men ikke fulde blokering skyldes formentlig at det findes yderligere pleiotrope aktiveringsveje som også kan drive komplementaktivering intratubulært. Resultaterne tyder på en mekanistisk kobling mellem uPAplasminogenkaskaden og komplementaktivering som alene eller sammen med andre mekanismer kan drive inflammation og vævsskade i nyrerne ved proteinuri. Dette kan også være en forklaring på hvorfor proteinuri over lang tid er associeret med fald i nyrefunktionen og kunne give ophav til nye farmakologiske mål. Amilorid og/eller stoffer med plasmin- eller komplementhæmmende effekt og som når tubulussystemet kan have en nyrebeskyttende virkning ved nyresygedom med proteinuri. Dette bør testes i fremtidige studier. Proteinuria is a common feature in chronic kidney disease (CKD) and an independent risk factor for accelerated disease progression. CKD affects approximately 10% of the global population and leads to hypertension, cardiovascular disease, and increased mortality. Aberrantly filtered plasma proteins, including zymogens and active proteases have potential activity in the tubular lumen. Our group previously demonstrated that plasminogen, a component of the fibrinolytic system, is abundantly present in urine and activated by urokinase-type plasminogen activator (uPA) in proteinuria. uPA is physiologically secreted to the tubular fluid and is significantly increased in urine in proteinuria. Complement factors are found in urine from patients with proteinuria. Plasmin cleaves the key components C3 and C5 in vitro and C5 in vivo during thrombus formation, generating biologically active C3a and C5a, which are potent proinflammatory anaphylatoxins. In the present project, it was hypothesized that i) complement factors are aberrantly filtered from plasma and activated in the tubular lumen via the uPA-plasminogen cascade in proteinuria, ii) complement activation split products are detectable in urine in relation to grade of proteinuria, and deposited in the apical membrane of tubular cells, and iii) uPA-plasmin driven complement activation can be attenuated pharmacologically by amiloride (an off target uPA inhibitor).Study I Complement proteins were measured in kidney transplant recipients (KTR) with albuminuria using in-house enzyme linked immunosorbent assays (ELISA) with neoepitope-specific monoclonal antibodies. Two cohorts were examined, one cross-sectional and one longitudinal. Urine excretion of mannose-binding lectin (MBL, 10-fold, p<0.001), C3c (2-fold, p<0.05), C3dg (3-fold, p<0.01), and sC5b-9 associated C9 neoantigen (20-fold, p<0.001) were significantly elevated in proteinuria, and C3dg and C9 neoantigen excretion followed changes in albuminuria over time, without changes in plasma concentrations. The fractional excretion of C9 neoantigen was significantly increased compared to albumin in cases, suggesting a net addition of sC5b-9 after filtration or preferential reabsorption of albumin. Nephron segment specific uEV-isolation documented an association of iC3b/C3dg and C5b-9 to proximal tubular apical membranes in albuminuria. The results strongly indicate intra tubular complement activation and deposition in the proximal tubular epithelium. In extension, suggesting that inhibiting complement in the intra tubular space could reduce the negative intra renal effects of proteinuria.Study II In vitro studies showed that C3 and C5 were activated by uPA-plasminogen but not by uPA or plasminogen alone in physiological and buffered solutions in an amiloride sensitive way. Pooled urine from healthy humans generated C3a from purified human C3 by addition of exogenous plasminogen (activated by endogenous uPA). Pre-incubation of urine with 2 mM amiloride or 500 KIU/ml aprotinin, but not 20 mM ethylenediaminetetraacetic acid (EDTA) inhibited C3a generation. C3a urine excretion was increased significantly KTRs with proteinuria (n = 7) compared to KTR controls (n = 7) but was not reduced by high dose amiloride for one day (p = 0.08). In patients with diabetes type-1 with (n = 16) or without (n = 14) diabetic nephropathy, high dose amiloride treatment for two days reduced C3dg (p < 0.05, n = 5) and C9 neoantigen (p < 0.05, n = 7) excretion rates in cases with detectable urine complement. In proteinuric podocin (-/-) mice, amiloride treatment for four days reduced 24 h urine C3a and C5a excretions (p < 0.05 for both) with no effect on albuminuria compared to vehicle. Inhibition of uPA for 11 days by a monoclonal α-uPA antibody reduced 24 h C5a and C3a excretions by ~50% (p = 0.012 and p = 0.019, respectively). uPAplasminogen play a significant role in intra tubular complement activation and uPA inhibition or direct complement inhibition might slow the progression to end stage kidney disease in proteinuria.Study III Preeclampsia (PE) is a severe complication of pregnancy with sudden onset of proteinuria and increased blood pressure. Since plasmin activated complement in urine and both complement and plasminogen excretion is elevated in PE, we sought to address the temporal association in an existing prospective cohort of 88 pregnant women with pregestational type-1 diabetes. Participants were included at gestational age (GA) 12 weeks and followed to parturition with urine and plasma sampling at GA 20, 28, 32, 36 and 38 weeks. 14 women developed preeclampsia in the study period and 8 controls with complete sample set were selected. Urine excretion of C3dg (p < 0.001) and C9 neoantigen (p = 0.002) increased gradually and in parallel to albumin in PE. C3dg and C9 neoantigen correlated to plasminogen (r = 0.51, p < 0.001 and r = 0.68, p < 0.001, respectively) and albumin (r = 0.44, p < 0.001 and C9 neoantigen, r = 0.59, p < 0.001, respectively) in urine. Receiver operating characteristic (ROC) analysis showed that C3dg and C9 neoantigen/creatinine ratios (AUC= 0.53 and 0.57 respectively) were inferior to albumin/creatinine ratio (ACR; AUC = 0.86) as biomarkers. uEVs were positive for C3dg in one of three and C9 neoantigen in three of three PE patients at GA 36 weeks but were absent in controls, suggesting tubular cell association. The temporal association is compatible with a direct relation between plasmin and complement activation, but complement was not a superior biomarker for PE.Conclusion Studies I-III demonstrate that 1) complement split products are aberrantly filtered in relation to albumin and plasminogen, 2) complement precursors are activated in the tubular lumen and deposited on proximal tubular apical cell membranes, 3) uPA-plasminogen activates complement in vitro and 4) uPAplasmin mediated complement activation is attenuated by uPA inhibition and in vitro and in vivo. The findings links proteinuria to intratubular proinflammatory signaling and complement deposition in tubular epithelial cells. This might lead to epithelial cell injury and progression of CKD and suggest a reno-protective effect of amiloride that goes beyond blood pressure reduction.

  • Open Access English
    Authors: 
    Jibril Abdi, Ahmed;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Introduktion: Røntgen billeddannelse anvender ioniserende stråling, som kan påvirke biologiske celler og dermed potentielt medføre en risiko for celle skader. Derfor er der en potentiel risiko for genetiske skader og for stråleinduceret cancer, som er eksponentielt stigende med stigende røntgenstråledosis. Selvom risikoen ved diagnostiske røntgenundersøgelser ikke er stor, vil der altid være en teoretisk risiko og derfor skal stråledosis til patienter holdes laveste muligt, for at opfylde ”Aslow As Reasonible Achievebe (ALARA)” princippet. Røntgenudstyrs producenterne forsøger hele tiden at forbedre deres produkter med henblik på at minimere stråledosis til patienterne samtidig med at bevare eller forbedre billedkvaliteten. På trods af at røntgenteknologien teoretisk medfører en risiko for strålingsinducerede skader, er der stadigvæk en fordel ved brug af røntgen til diagnostiske formål, som overvejer denne risiko. Røntgenteknologierne er uundværlige, idet ikke-ioniserende teknologier som ultralyd- og MR undersøgelser ikke har vist sig at kunne erstattealle røntgenundersøgelser. Desuden har det vist sig at klinisk brug af røntgenteknologier steget igennem de seneste årtier, idet røntgenteknologier giver diagnostiske resultater, som ofte redder liv ved at diagnosticere livstruende sygdomme f.eks. af akut eller malign karakter. Der er nødvendigt at foretage optimering af røntgensystemer for at reducere stråledosis til patienterne og dermed minimere strålingsdosis. 2D/3D lavdosis slot scanner (LDSS) er et relativt nyt røntgen system, som udsætter patienterne for lavere stråledosis med samtidig bevaret uændret tilstrækkelig diagnostisk information sammenlignet med konventionel digital radiografi (DR). LDSS har ikke været optimeret og anvendt til udbredte kliniske undersøgelser for diagnostiske formål, men overvejende kun brugt til oversigtsbilleder af patienter med skoliose og måling af længden af underekstremiteter. I denne afhandling er foretaget en omfattende evaluering af billedkvalitet og strålingsbesparelse ved LDSS sammenlignet med konventionelle DR systemer. Der er desuden foretaget en optimering og evaluering af billedkvalitet samt strålingsbesparelse på LDSS ved thorax- og knæundersøgelser. Stråledosis og billedkvalitet ved LDSS er desuden sammenlignet med to forskellige konventionelle DR røntgensystemer. Denne Ph.d. afhandling består af tre studier med tre forskellige billedkvalitets evaluerings metoder.Formål var: 1) at evaluere billedkvaliteten samt undersøger om LDSS kan bruges til mere udbredte diagnostisk formål sammenlignet konventionelle DR røntgensystemer ved brug af tre forskellige billedkvalitets vurderingsteknikker. 2) At undersøge stråledosis besparelse ved LDSS i forhold til de konventionelle DR systemer, samt 3) At optimere kliniske protokoller på LDSS således at billedkvalitet ved LDSS var sammenligneligt med de konventionelle DR systemer. Hypotesen var, at LDSS kan give samme diagnostisk billedkvalitet som konventionelle DR-systemer ved anvendelse af lavere stråledosis til patienten.Materialer og metoder: For at kunne sammenligne billedkvaliteten og stråledosis ved LDSS med konventionelle røntgen systemer, blev der brugt to DR røntgensystemer fra to forskellige leverandører. I studie I af afhandlingen blevet antropomorft (alderson) fantombrugt til organdosis måling af thorax alle systemer. I knæ undersøgeler blev brugt et polymethylmethacrylat (PMMA) fantom på 20 cm i tykkelsen svarende til en gennemsnitlig voksen patientstørrelse også brugt til at evaluere kontrast-detalje opløsningen af systemerne i thorax. Et kontrast-detalje test objekt (CDRAD) 2.0 phantom og CDRAD v2.1.9 softwareanalyse blev brugt til at evaluere kontrast-detalje opløsningen af alle systemer i både thorax og knæ. I studie II af afhandlingen blev et thorax fantom med hybrid PMMA og aluminiumsfolier brugt til at evaluere den kvantitative billedkvalitet af thorax i alle systemer. I knæ undersøgelserne blev 15 cm PMMA brugt til at evaluere den kvantitative billedkvalitet i alle systemer. I studie III af afhandlingen, blev et antropomorft thorax (LungMan, Kyoto Kagaku Co., Ltd., Kyoto, Japan) med et ekstra fedtlag brugt til at producere et thorax billede til evaluering af visuel billedkvalitet af thorax for alle røntgen systemer. Et knæfantom medindsat naturlig knogle blev brugt til at evaluere den visuelle billedkvalitet af knæ protokoller i alle tre systemer. Monte Carlo-simuleringssoftwaren PCXMC blev brugt til at beregne den effektive dosis og organdosis for både knæ og thorax alle systemer. IQworks software blev brugt til at beregner de kvantitative parametre, herunder effektiv modulation transfer funktion og effektiv normalised noise power spektrum. Statistical Package for the Social Sciences, Release 26.0.0.0 software blev brugt til al statistisk analyse af afhandlingen. Det statistiske signifikansniveau brugt i alle statistiske analyser var 5 %. Thermoluminescerende dosimetre (TLD) var brugt til at måleorgandoserne direkte i lungerne og skjoldbruskkirtlen i thorax.Den effektive dosis til patienter for både Thorax og knæblev estimeret ved hjælp af verificerede dosis arealprodukt værdier (DAP) fra alle systemer. En halvlede dosimeter blev brugt til måling af air kerma (AK) for at verificere systemernes DAP-målere. Den beregnede (simulerede) og den direkte målte organdosis for lungerne, skjoldbruskkirtlen og ekstremitetsknogler for både thorax og knæ blev sammenlignet på tværs af systemerne. Default dosis opsætningen af LDSS, som blev brugt til skoliose oversigtsbilleder og benlængde målinger, var signifikant lavere end ved DR-systemerne. Derfor blev stråledosis ved LDSS for både thorax og knæ optimeret. I forbindelse med denne undersøgelse. Dosisniveauet af LDSS blev øget for at give omtrent den samme diagnostiske information som i de konventionelle DR-systemer. I modsætning hertil blev den optimale rutinemæssigt anvendte dosisindstilling af konventionelle DR røntgensystemer anvendt uændret. Tre forskellige og væsentlige billedkvalitetsevalueringsteknikker blev brugt til at vurdere billedkvaliteten af LDSS sammenlignet med konventionelle DR røntgensystemer. Billedkvalitets-evalueringsmetoderne var baseret på både subjektive og objektive teknikker. Der blev optaget og indsamlet 470 røntgenbilleder til både billedkvalitets-evaluering og stråledosisberegning/måling i alle systemer og protokoller.Resultater: De optimerede scanningshastigheder for LDSS var speed 6 og 8 for henholdsvis thorax- og knæundersøgelser, med billedkvalitet sammenlignelig med DRsystemer. Default indstillet scan hastighed for LDSS var speed 4 og 6 for henholdsvis thorax- og knæundersøgelser. Effektiv dosis sammenlignings resultater har vist, at optimeret protokoller på LDSS udsætter patienterne for (41,7-42,6 % og 29,5-35,0 %) lavere effektive doser end konventionelle DR-røntgensystemer til henholdsvis thorax- og knæundersøgelser. LDSS gav også en signifikant (20-40%) lavere organdosis til patienterne end DRsystemerne. Billedkvalitetsresultater fra alle tre forskellige billedkvalitetsteknikker har vist, at de optimerede thorax- og knæ undersøgelser for LDSS har enten højere eller samme billedkvalitet end de konventionelle DR-systemer. Visual grading analysis (VGA)-analyseresultaterne har også vist god inter- og intra-observer enigheden for alle VGA-billedkvalitetskriterier for både thorax- og knæ undersøgelser.Konklusion: De overordnede resultater af disse tre forskellige billedkvalitetsevalueringsstudier viser, at LDSS har samme billedkvalitet som DR røntgensystemerne til både knæ- og thorax undersøgelser. LDSS har den fordel at den udsætter patienterne for en signifikant lavere stråledosis end DR røntgensystemerne. Derfor har LDSS demonstreret potentiale til at opnå billedkvalitet til diagnostisk brug i både thorax- og knæ undersøgelser under anvendelse af øget stråledosis. X-ray imaging technology uses ionising radiation and thus exposes the patients to radiation. X-ray vendors are constantly trying to improve their products with the intention of minimising radiation exposure to patients while at the same time, maintaining or improving image quality. Radiation exposure from the X-ray imaging modalities has the potential to damage the biological cells and is followed by the risk of radiation-induced cancers, and this should not be ignored. However, the diagnostic use of X-rays has great benefits that outweigh the potential risks. X-ray technology is highly clinically relevant and can save many patients’ lives by enabling the diagnosis of life-threatening diseases and is therefore indispensable for patient examinations. The use of X-ray technology in clinical settings has increased in recent decades, and optimising X-ray systems by reducing the radiation dose is still an essential task. The 2D/3D low-dose slot scanner (LDSS) imaging system is a relatively new X-ray imaging technology that exposes patients to lower radiation doses and at the same time provides sufficient diagnostic information compared to conventional X-ray imaging systems. The LDSS system has not been generally approved as a diagnostic tool for radiological diagnosis in several clinical settings, as the system is not optimised for these diagnostic purposes. So far, the LDSS systems has mainly been used to obtain overview images of patients with scoliosis and to measure the length of lower extremities, especially in children. In this thesis, a comprehensive investigation of image quality and radiation dose saving in the LDSS imaging system was conducted and the system was compared with conventional digital radiography (DR) X-ray systems. This thesis is a collection of three different studies using three different methods to evaluate image quality and to estimate the imaging system's radiation dose to patients. For each of these three studies, a scientific article was published in the field of medical imaging and in radiology journals. Aims: The aim of the thesis was to investigate the image quality and suitability of the LDSS imaging system for diagnostic purposes using three different image quality assessment techniques. The image quality achieved in the LDSS imaging system was compared with the image quality of two conventional DR X-ray systems through different image quality evaluation techniques. In addition, the radiation exposure to patients from the LDSS imaging system was optimised and compared to the conventional DR systems.The objective of this thesis was to investigate whether the LDSS imaging system could provide diagnostic images of the same quality as conventional DR systems without compromising image quality. Two DR X-ray systems from two different vendors were used to evaluate the image quality and radiation dose and to compare these with the LDSS imaging system. In Study I, an anthropomorphic phantom was used for organ dose measurement for the chest protocol in all systems. In Study I, a Polymethyl Methacrylate (PMMA) plate phantom of 20 cm equivalent to a typical average patient size was also used to evaluate contrast detail resolution of the systems in the chest protocol. A contrast-detail for radiography (CDRAD) 2.0 phantom and CDRAD v2.1.9 software analysis were used to evaluate the contrast detail resolution of the imaging system. In Study II, an in-house chest phantom with hybrid Polymethyl Methacrylate (PMMA) and aluminium foils was used to evaluate the quantitative image quality of the imaging systems and 15 cm PMMA was used to assess the contrast detail resolution of the systems in knee protocol. In Study III, an anthropomorphic chest phantom and a native-bone knee phantom were used to evaluate the visual image quality of the system. Monte Carlo simulation software PCXMC was used to calculate the effective dose and organ dose for both knee and chest protocols in all imaging systems. Statistical Package for the Social Sciences (SPSS), Release 26.0.0.0 software was used for all statistical analysis of thesis. The statistical significance level used in all analyses was 5%. Thermo-luminescent dosimeters (TLD) were used to measure the organ doses of the lungs and thyroid directly in the chest protocol. The effective dose of systems in both chest and knee protocols was estimated using verified dose area product (DAP) values from all of the imaging systems. However, a solid-state dosimeter was used to verify the DAP meters of the systems.A calculated (simulated) and a directly measured organ dose for the lungs, thyroids, and lower leg bones in both chest and knee protocols were compared across systems. The default dose setup of the LDSS imaging system, which was used for scoliosis overview images and leg length measurements, was significantly lower than in the DR systems. Therefore, the radiation exposure of the LDSS imaging systems for both chest and knee protocols were optimized. The dose level of the LDSS imaging system has been increased to provide approximately the same diagnostic information as in the conventional DR systems. In contrast, the optimal routinely used dose setting of conventional DR X-ray systems was used. Three different and essential image quality evaluations were used to assess the image quality of the LDSS imaging system compared with conventional DR imaging systems. These three image quality evaluation methods were performed in three separate studies: the technical (contrast detail resolution), quantitative, and visual grading analysis (VGA) image quality evaluation. The image quality evaluations methods were based on both subjective and objective techniques. In all three studies in this thesis, 468 images were acquired for both image quality assessment and radiation dose calculation/measurement in all imaging systems and protocols. For the visual image quality assessment, three experienced radiologists practising thoracic radiology who are specialised in the reporting of thoracic images visually scored 60 chest PA and LAT projection images for all imaging systems. However, two experienced diagnostic radiographers with postgraduate degrees in appendicular skeletal reporting and one research radiographer scored the 60 images of knee PA and LAT for all three imaging systems. The optimised scan speeds of the LDSS imaging system were speeds 6 and 8 for chest and knee protocols, respectively, with image quality comparable to that of DR systems. The default setting scan speeds of the LDSS imaging system were speed 4 and speed 6 for the chest and knee protocols, respectively. The dose comparison results obtained showed that LDSS imaging system exposed patients to significantly (41.–42.6% and 29.5–35.0%) lower effective dose than conventional DR X-ray systems for the chest and knee protocols, respectively. The LDSS imaging system also obtained a significantly (20- 40%) lower organ dose to the patients than with DR systems. The evaluated image quality results of all three different image quality studies have shown that the optimised chest and knee protocols for the LDSS imaging system have equal image quality to that of the conventional DR systems. The VGA analysis results have shown good inter-observer and intra-observer agreement for all VGA image quality criteria for both chest and knee protocols. The overall results of these three different image quality assessment studies show that the LDSS imaging system has equal image quality to the DR imaging system for both extremity and chest radiography. The LDSS imaging has the advantage of exposing patients to a lower radiation dose than do the DR systems. Thus, the LDSS imaging system has demonstrated the potential to obtain image quality for diagnosis in chest and knee protocols.

  • Closed Access English
    Authors: 
    Heinsen, Laurits;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Denne PhD-afhandling er baseret på tre originale manuskrifter. Studierne er gennemført på den Kardiologiske Forskningsenhed, OUH Svendborg Hospital.Baggrund Type 2 diabetes mellitus er en betydelig risikofaktor for iskæmisk hjertesygdom. Patienter med type 2diabetes har en høj byrde af traditionelle risikofaktorer, og behandlingen af disse medfører en betydeligreduktion i dødelighed og risikoen for blodprop i hjertet. Til trods for god risikofaktor-kontrol og normalisering af LDL med kolesterolsænkende medicin er disse patienter fortsat i øget risiko for blodprop i hjertet. Dette fænomen betegnes residualrisiko og har været i fokus i de seneste år. Hovedformålet med denne afhandling var at undersøge og beskrive åreforkalkning i asymptomatiske patienter med type 2diabetes som ikke er kendt med iskæmisk hjertesygdom. Delformål 1) At beskrive forekomsten af høj risiko plaque (HRP) og sammenhængen med risikofaktorer samt den koronare kalk score (CACS). 2) At undersøge sammenhængen mellem ændringer i kolesterol, triglycerider, og langtidsblodsukker i forhold til sammensætning og progression af koronar åreforkalkning 3) At evaluere sammenhængen mellem GLP-1 antagonisten liraglutide og ændringer i det totale plaque volumen samt plaque komposition ved opfølgning efter et år. Metode Dette studie var det prospektivt observationsstudie og patienterne blev rekrutteret og undersøgt i perioden fra marts 2016 til september 2017. Patienter med type 2 diabetes uden symptomer og historik mediskæmisk hjertesygdom blev inviteret til at deltage i studiet. Hjerte-CT blev udført ved studiets start og efter et års opfølgning. Det totale plaque-volumen samt plaque sammensætning og højrisiko plaque-morfologi(HRP) blev estimeret ved studiets start og ved opfølgning efter et år. Kliniske data som blodtryk, hjertekardiogram, medicinsk behandling, diabetiske komplikationer, samt blodprøver blev indsamlet ved studietsstart og ved opfølgning efter et år. Opsummering af afhandlingens hovedfund:1) HRP blev observeret hos 37% af patienterne og var associeret med højere langtidsblodsukker, større tobaks-eksponering og mandligt køn. HRP blev identificeret i alle CACS grupper inklusiv CACS på nul.2) Stigende triglycerider var associeret med progression af både høj-risiko plaque og det total plaque volumen. Stigningen i triglycerider var tæt associeret med stigning i vægt, stagnerende HbA1c, samtfaldende lever attenuation. Ydermere var der en klar sammenhængen mellem stigende triglycerider og rest-partikel kolesterol.3) Ændringer i det totale plaque volumen var ikke associeret med liraglutid behandling. Analysen af plaque kompositionen viste, at liraglutide behandling var associeret med øget progression af fibrøst plaque.KonklusionKonklusionen på dette studie er at hjerte-CT er noninvasiv metode som muliggør at karakterisere typen af åreforkalkning samt ændringer over tid. Høj-risiko plaque morfologi blev identificeret hos 37% af patienterne og var associeret med risikofaktorerne langtidsblodsukker, tobaks-eksponering, og mandligt køn, men kunne ikke udelukkes ved fraværet af koronar kalk. En stigning i triglycerider var associeret med plaque progression af høj risiko plaque og en en forværring af den glukometaboliske kontrol samt stigende rest-partikel kolesterol. Liraglutide behandling var associeret med øget progression af fibrøst plaque og er en mulig mekanisme som kan forklare den kardiovaskulære risikoreduktion associeret med liraglutid behandling. This PhD thesis is based on three original manuscripts, and the studies were carried out at the Cardiovascular Research Unit at OUH Svendborg.BackgroundIschemic heart disease remains the leading cause of mortality in type 2 diabetes mellitus (T2D). Despite a significant risk reduction in the last decades, T2D remains associated with twice the risk of all-cause mortality, mainly due to coronary artery disease (CAD). Coronary computed tomography angiography(CCTA) allows the characterization of coronary artery plaque and disease progression, and several studies have demonstrated that high-risk plaque (HRP) is associated with acute coronary syndrome (ACS). Risk stratification of asymptomatic diabetes is challenging and a better understanding of the extent and progression of coronary atherosclerosis in relation to patient characteristics and risk factors is of interest. The overall aim of this PhD study was to assess plaque characteristics and predictions of plaque progression in a cohort of asymptomatic patients with diabetes without CAD. Study objective:1) To assess the prevalence of HRP in asymptomatic T2D and the relationship between HRP and cardiovascular disease (CVD) risk factors, diabetes profile, and the coronary artery calcium score(CACS).2) To assess the association of changes in lipoproteins and glycated hemoglobin (HbA1c) in relation to changes in HRP volumes.3) To assess changes in the total atheroma (TAV) and composition from baseline to follow-up stratified by liraglutide treatmentMethods This PhD thesis is based on data from a prospective observational study performed between March 2016and September 2017 at Odense University Hospital Svendborg. Patients were asymptomatic and without a history of CAD. Serial CCTA was performed to assess total atheroma volume (TAV) and plaque composition at baseline and one-year follow-up. In addition, CACS was assessed from non-enhanced images. A clinical assessment including blood pressure, electrocardiogram, current medication, diabetic complications, and blood test was performed at baseline and at follow-up. The main findings of this PhD thesis were:1) HRP was identified in 37% of patients and was associated with higher HbA1c, greater tobacco exposure, and male gender. HRP was detected in all groups of CACS, and the absence of coronary artery calcium (CACS = 0) could not rule out HRP.2) An increase in triglycerides was associated with the progression of HRP as well as an overall plaque progression. Changes in triglycerides were closely associated with weight gain, stagnant HbA1c, and evidence of increased hepatic fat accumulation. Furthermore, there was a strong association between the increase in triglyceride and the increase in remnant cholesterol.3) We found no association between changes in TAV and liraglutide treatment. The secondary endpoint, changes in plaque composition stratified by liraglutide treatment was positive, and a significant increase in the fibrous plaque volume was detected in the liraglutide treated patients.ConclusionsIn conclusion, CCTA is a non-invasive examination that allows the characterization of plaque composition and changes over time. HRP was detected in 37% of the patients and was associated with higher HbA1c,tobacco exposure, and male gender. Our results warrant caution for use of calcium scoring in this patient group as the absence of coronary artery calcium could not rule out CAD. We found a significant association between an increase in triglyceride levels and HRP progression. The data suggested that this finding was mediated by an increase in remnant cholesterol driven by a worsening in glucometabolic control. Finally, liraglutide was associated with an increase in fibrous plaque which could indicate plaque stabilization. To the best of our knowledge, this study is the first study to assess the association between liraglutide treatment and coronary atherosclerosis in humans.

  • Other research product . Other ORP type . 2022
    Closed Access English
    Authors: 
    Zhang, Rui;
    Publisher: Syddansk Universitet. Det Naturvidenskabelige Fakultet
    Country: Denmark

    Tekst og netværk er to almindelige former for data. De kan altid bruges samme til at beskrive forskellige applikationer, såsom kommentarsystemer, sociale netværk, og akademiske netværk. Dataanalyse bliver vigtig nu. Det er et afgørende spørgsmålat præsentere tekst- og netværksdata på en effektiv måde. Mange repræsentation læringsmodeller er blevet foreslået til dette problem. Men de fleste metoder har brug for dataetiketter, komplekse systemer og/eller højdimensionelle vektorer forat opnå de gode repræsentationer, og dette er ofte udfordrende for beregning og lagring af både upstream og downstream applikationer. Derfor adresserer denne afhandling ovenstående udfordringer og yder bidrag til repræsentationslæring på tekst- og tekstbaserede netværksdata.Til tekstrepræsentation læring foreslås en multi-label-læringsmodel baseret på semantisk etiketlæring for at kategorisere tekstbaserede publikationer med hierarkiskkategoristruktur. Denne model lærer først repræsentationer af publikationer og kategorier. Derefter genkender og videregiver modellen den matchende information hierarkisk. Endelig opnår denne model bedre forudsigelser i hierarkisk kategori af publikationer.Til tekstbaserede netværksdata foreslås først en metapath-baseret repræsentationsmodel. Denne model kan lære lavdimensionelle repræsentationer for målknuder fra deres tekstattributter og topologiske strukturer ved hjælp af en kaskadestyret selvovervåget læring mekanisme. For at overvinde begrænsningen af metapath og reducere de ekstra omkostninger, foreslår vi også en selvovervåget metapath-fri algoritme med relationsbaseret nabo-graf kontrastlæring. Denne model kan producere globale repræsentationer ved at lære alle knudepunkter og links. Repræsentationerne kan bruges til mange downstream-opgaver. Modellen udkonkurrerer de nyeste metoder.Samlet set giver afhandlingen en omfattende gennemgang af eksisterende repræsentation læringsmetoder og foreslår nye metoder baseret på dyb læring for at producere meget mere effektive og effektive repræsentationer til tekst og netværk. Bidragene er empirisk valideret på adskillige datasæt og opgaver i den virkelige verden. Text and networks, as two common forms of data, always appear cooperatively in describing diverse applications in the real world, such as review systems, social networks, and citation networks. As the demand of data analytics continues to grow, how to effectively and efficiently represent text and network data has become a critical research issue. To resolve this problem, various machine learning models have been proposed for text and network representation learning, but most of them mainly rely on tons of manually labeled training samples, complex systems, and/or high-dimensional vectors to improve the accuracy and precision of representations, which often bring new challenges to computation and storage costs in both upstream and downstream applications. Thus, this thesis addresses the above challengesand makes contributions to representation learning on the text and text-attributed network data.For text representation learning, a label-semantic augmented multi-label-learning model is proposed to categorize text-based publications with hierarchical category structure, which creatively learns representations of publications and categories, recognizes and passes their matching information hierarchically, and as a result, achieves better hierarchical-category predictions.For text-attributed network representation learning, a meta-path-based embedding method is first developed, which is able to learn low-dimensional representations for target-typed nodes from their text attributes and topological structures by a cascaded self-supervised mechanism. Moreover, in order to overcome the limitation of preset meta-paths and reduce the extra learning cost, we also propose a selfsupervised meta-path-free algorithm with relation-based neighbor-graph contrast learning, which could produce global node representations by encoding all-typednodes and relations. These representations can be used for a variety of downstream tasks and outperform state-of-the-art baselines.Overall, this thesis provides a comprehensive review of existing representation learning methods and proposes several novel approaches based on deep learning to produce much more effective and efficient representations for text and networks.The contributions are empirically validated on several real-world datasets and tasks.

  • Other research product . Other ORP type . 2022
    Open Access English
    Authors: 
    Raadal Skov, Inge;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Steroidtabletter er en effektiv behandling til ukontrolleret astma, men behandlingen er desværre også associeret med en lang række bivirkninger. Gennem de sidste årtier er der tilkommet mange nye behandlingsmuligheder til astma, men internationale studier viser, at steroidtabletter fortsat bliver brugt i stort omfang. Der er dog endnu ingen studier, der har belyst omfanget i Danmark. Denne afhandling er baseret på tre landsdækkende register-baserede observationsstudier af unge voksne i alderen 18-45 år i aktiv behandling for astma i perioden 1999-2018.I studie I undersøgte vi medicinforbrugsmønstre ved hjælp af årlige tværsnitsundersøgelser og fandt, at næsten én ud af tyve personer med aktivt behandlet astma indløste en recept påsteroidtabletter i løbet af ét år, og at dette stort set ikke havde ændret sig over den 20-årige periode. Når vi opdelte forbrugerne efter mængden af steroid, de havde indløst i løbet af et år, fandt vi, at storforbrug (svarende til ≥5 mg prednisolon per dag over et år) var sjældent forekommende og at den samlede mængde steroid per person generelt var faldende over perioden. Desuden blev der indløst færre lavdosis-steroidtabletter med ≤10 mg per tablet som et tegn på et faldende forbrug af lavdosisvedligeholdelsesbehandling. I studie II sammenlignede vi steroidtabletforbrugere med ikkeforbrugere og fandt, at steroidtabletforbrugerne udviklede flere sygdomme, såsom osteoporose, type 2 diabetes, hjertesvigt, med flere, og at denne risiko steg, desto højere forbrug de havde. Interessant nok så vi, at risikoen allerede steg efter lave doser svarede til ≤500 mg, hvilket svarer til kun en eller to steroidtablet-kure for akut astmaforværring. I studie III fandt vi, at 70% af personer med gentagne behandlinger med steroidtabletter ikke har kontakt med en speciallæge. Dog steg antallet af årlige nyhenviste fra 6,3% i 1999 til 18% i 2018. Patienter med ekstremt højt forbrug af anfaldsmedicin samt nylige akutte skadestuebesøg og indlæggelser blev i højere grad henvist til speciallæge. Samlet set har forekomsten af astmapatienter, der bruger steroidtabletter, været uændret gennem 20 år, men den mængde steroid, de udsættes for per år, er faldende. Forbrug af steroidtabletter er associeret med øget risiko for at udvikle en lang række sygdomme - selv ved lave doser. Kun et mindretal af forbrugerne opnår speciallægevurdering. I betragtning af de seneste årtiers store fremskridt inden for diagnostik og behandling af astma er det essentielt at sikre en optimeret ogindividualiseret håndtering af patienter med behov for steroidtabletbehandling, herunder øget fokus på steroidbesparende tiltag, tidlig håndtering af associerede følgesygdomme, og rettidig henvisning til speciallæge når indikeret. Oral corticosteroids (OCS) are effective in treating uncontrolled inflammatory diseases such as asthma, but they are unfortunately associated with serious adverse effects. Many efforts have beenmade to reduce the use of OCS in asthma over the decades, but international studies suggest OCS continue to be frequently used, and overused, in asthma management. However, limited information has been available on the OCS use among individuals with asthma in Denmark. In this thesis we have conducted three nationwide, registry-based observational studies among cohorts of young adult users of asthma medication aged 18-45 years during 1999 to 2018.In study I, we performed annual cross-sectional drug analyses and found that almost one in twenty among the annual asthma population would fill a prescription for OCS within a given year,and that this had essentially not changed over the 20-year period. However, we found that the annual cumulative exposure per user decreased. High use ≥5 mg/day (prednisolone equivalents) was rare and decreased by almost 40%. Furthermore, the usage of low-dose tablets ≤10 mg/tablet decreased markedly, indicating a reduction in low-dose maintenance use. In study II, we performed a propensity score matched study of incident OCS users compared to nonusers. We found OCS users to have an increased risk of all prespecified comorbidities with evidence of positive dose-response relationships. Interestingly, the increased risks were evident at even low cumulative exposures of ≤500 mg (equivalent to only one or two OCS exacerbation courses). Mortality rates and rates of unscheduled hospital visits similarly increased with increasing OCS exposure. In study III, we investigated thefrequency and predictors of receiving specialist care among individuals with repeated OCS use (i.e., two prescriptions within 12 months). We found that 70% of repeated OCS users did not have contact to specialised care. However, the annual frequency of referrals for specialist care almost tripled from 6.3% in 1999 to 18% in 2018. Patients with excessive use of reliever medication and recent acute asthma-related hospital visits were more likely to receive specialist care. In conclusion, the frequency of OCS use in asthma management of young adults has remained stable over a 20-year-period, but the cumulative exposure per person has decreased. OCS use isassociated with increased risk of incident comorbidities, mortality, and health care utilisation even at low cumulative doses. Only a minority of repeated OCS users are assessed by a specialist.Considering recent advances in both diagnostic tools and available treatments, it is pivotal to ensure optimised management of patients exposed to OCS with focus on OCS sparing initiatives, managing of comorbidities, and early referral for specialist care when appropriate.

  • Open Access English
    Authors: 
    Duch Kiilerich Andresen, Andreas;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    På grund af uoverensstemmelser i litteraturen og ingen klare retningslinjer for lumbal fusion hos ældre, havde dette ph.d.-studie til formål at undersøge resultatet og omkostningseffektiviteten af at tilføje instrumentering i lumbal fusions kirurgi hos ændre, ved behandling af degenerativt led skred med samtidig forsnævring i rygmarvskanalen. Yderligere ville vi undersøge vigtigheden af balance i sagittal planet, når der foretages stivøgrende operation på et niveau, uanset valgt fusionsmetode.MetodeEt kontrolleret lodtrækningsforsøg blev udført, her blev 108 patienter inkluderet og ved lodtrækning opdelt i to grupper. Gruppe 1 gennemgik standard midtlinjebesparende frilægning af nerverne og en uinstrumenteret stivgørende opeation med egen knogle fra frilægningen samt donorknogle udtaget i forbindelsemed hoftekirurgi Gruppe 2 gennemgik den samme standard-midtlinjebesparende frilægning af nerverne, og udover knogletransplantatet blev der udført instrumenteret operation med pedikel skruer Ved operationen besvarede patienterne et standardbatteri af spørgeskemaer, inklusive Oswestry Disability Index, EuroQoL-5D-3L, VAS-ryg og -ben, Zurich ClaudicationQuestionnaire og ShortForm36. Et lateralt 36" røntgenbillede blev taget før operationen for at måle den sagittale balance.Patienterne blev fulgt i to år efter operationen, med patientrapporterede resultater og 36" røntgenbilleder ved et- og toårs opfølgning. Ved et års opfølgning blev der udførten CT-scanning for at undersøge succesen af den stivgørende operation.Resultater Vi fandt ingen forskel mellem grupperne i funktion, livskvalitet eller smerter ved etog toårs opfølgning. Der var en markant forskel i fusionssucces til fordel for den instrumenterede fusion (94% vs. 31%) Syv patienter gennemgik reoperation i den uinstrumenterede gruppe versus én patient i den instrumenterede gruppe efter to års opfølgning. Sideløbende med lodtrækningsforsøget forsøg blev der udført en økonomisk evaluering. De samlede omkostninger for behandlingen var baseret på en journalrevision, og generering af omkostninger blev konstrueret fra bunden og op. Med en moderat stigning i kvalitetsjusterede leveår i den instrumenterede gruppe på 0.095 og en øget omkostning på €146 fandt vi et trinvis omkostningseffektivitetsforhold (ICER) på €1536, hvilket tydede på, at den instrumenteret fusion var omkostningseffektiv. Ved udførelse af sensitivitetsanalyse baseret på alle reoperationer eller når beregningen baseres på hospitalets standardtilskud for operationerne, dominerede den instrumenterede fusion med både et bedre resultat og lavere omkostninger, hvilket tyder på en moderat omkostningsbesparelse ved instrumentering. Ved undersøgelse af effekten af en præoperativ sagittale ubalance fandt vi en sammenhæng mellem balancen før operationen, og de patientbesvarede spørgeskemaer udfyldt før operationen, men der var ingen sammenhæng mellem balancen og det patient rapporterede udfald af operationen ved hverken et- eller toårs opfølgning.Konklusion Som konklusion fandt vi, at selvom der ikke var statistisk signifikante forskelle mellem grupper baseret på patientrapporterede resultater, havde patienter i den instrumenterede gruppe færre reoperationer og en højere fusionssucces sammenlignet med den uinstrumenterede gruppe. Omkostningsanalysen tyder på, at instrumenteret fusion er omkostningseffektiv med en ICER på 1536. Det konkluderes derfor at ved behandling af degenerativt led skred med spinalstenose hos ældre vil instrumenteret stivgørende operation være tilrådeligt hos patienter, hvor den stivgørende operation vurderes nødvendig. Due to inconsistencies in the literature, and no clear guidelines for lumbar fusion in the elderly, this PhD study aimed to investigated the outcome and cost effectiveness of added instrumentation in lumbar spinal fusion in the elderly, when treating degenerative spondylolisthesis. Further, we aimed to investigate the importance of a preoperative sagittal imbalance in one-level in-situ fusion, regardless of fusion method.MethodsA randomized controlled trial was performed, 108 were included and by randomization divided into two groups. Group 1 underwent standard midline sparing decompression and uninstrumented fusion, with allograft mixed with local autograftfrom the decompression, due to degenerative spondylolisthesis and spinal stenosis. Group 2 underwent the same standard midline sparing decompression, and in addition to the bone graft, pedicle screw instrumentation was performed at the index level.At surgery, patients answered a standard battery of questionnaire, including Oswestry Disability Index, EuroQoL-5D-3L, VAS-back and -leg, Zurich Claudication Questionnaire and ShortForm-36. A lateral 36” X-ray was taken before surgery, to measures preoperative sagittal balance. Patients were followed for two years after surgery, with patient reported outcomes and 36” X-rays at one- and two-year follow-up. At one-year follow up, a CT-scan was performed to investigate fusion status.Results We found no difference in disability, quality of life or pain at one- and two- year follow up. There was a marked difference in fusion rates in favor of the instrumented fusion (94% vs 31%) Seven patients underwent reoperation in the uninstrumented group versus one patient in the instrumented group, at two-year follow up. Alongside the randomized trial, a micro-adjusted economical evaluation was performed. The accumulated costs were based on a journal audit, and generation of costs were done from a bottom-up perspective. With a moderate increase in quality adjusted life years in the instrumented group of 0.095, and an increased cost of €146, we found an incremental cost effectiveness ratio of €1536, suggesting that instrumented fusion was cost-effective. When performing sensitivity analysis based on all reoperations or based on standard hospital reimbursement rates, instrumented fusion dominated uninstrumented fusion with better outcome and lower costs, suggesting a moderate cost saving with instrumentation. When investigating the effect of a preoperative sagittal imbalance, we found a correlation between preoperative sagittal vertical axis and preoperative patient reported outcomes, but there were no correlations to sagittal vertical axis and outcome at either one- or two-year follow up. Conclusion In conclusion, we found that, although there were no statistically significant differences between groups based on patient reported outcomes, patients in the instrumented group had fewer reoperations and a higher fusion rate compared to the uninstrumented group. The cost analysis suggest that instrumented fusion is cost effective with an ICER of 1536. Concluding that, in treating degenerative spondylolisthesis in the elderly, instrumented fusion would be advisable in patients where fusion is needed. 

  • Restricted English
    Authors: 
    Møller, Merete; Roos, Ewa Maria; Andersen, Lotte Nygaard; Juhl, Carsten; Kongsted, Alice; Villumsen, Martin Dalgaard;
    Publisher: Syddansk Universitet
    Country: Denmark
Advanced search in
Research products
arrow_drop_down
Searching FieldsTerms
Any field
arrow_drop_down
includes
arrow_drop_down
Include:
2,800 Research products, page 1 of 280
  • Open Access English
    Authors: 
    Kavan, Stephanie;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    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.

  • Open Access English
    Authors: 
    Frederiksen, Trine;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Cytokrom P450 (CYP) 2D6 enzymet er den primære rute for elimination eller aktivering af en lang række lægemidler. Grundet polymorfi af CYP2D6 genet, udviser individer varierende grad af CYP2D6 enzymaktivitet. Dette forårsager variabilitet i mængden af lægemiddel i kroppen, hvilket kan resultere i forskelle i lægemiddeleffekt og -tolerabilitet. For at guide individualiseret lægemiddelbehandling med CYP2D6 substrater, er det vigtigt at have en god forståelse af forholdet mellem CYP2D6 polymorfi og enzymaktivitet. Hovedformålet med dette ph.d.-projekt var at kvantificere CYP2D6 enzymaktiviteten for forskellige CYP2D6 genotyper og alleler ved at undersøge farmakokinetikken af tre forskellige CYP2D6 substrater og deres metabolitter. Denne oversigt præsenterer tre populationsfarmakokinetik (popPK) analyser, som karakteriserer farmakokinetikken af hhv. vortioxetin, tedatioxetin, brexpiprazol og deres respektive metabolitter. Baseret på estimater fra de modellerne, blev den CYP2D6-medierede metabolisme kvantificeret for mere end 2,000 individer med et bredt spektrum af CYP2D6 genotyper.Analyserne viste, at alleler med nedsat funktion (f.eks. CYP2D6*9, *10, *17 and *41) generelt forårsagede mere end 50% reduktion af enzymaktivitet sammenlignet med vildtypen (CYP2D6*1). Særligt allelerne CYP2D6*17 og *41 udviste en lavere enzymaktivitet end forventet på tværs af de tre substrater, mens CYP2D6*10 havde ca. 30% enzymaktivitet sammenlignet med CYP2D6*1 for alle tre substrater. Bemærkelsesværdigt udviste CYP2D6*2 (som normalt forbindes med normal enzymaktivitet) en væsentlig nedsættelse af enzymaktivitet i omdannelsen af brexpiprazol til DM-3412, hvilket kunne tyde på en substratspecifik aktivitet af denne allel. Samlet set indikerer resultaterne, at nuværende systemer til oversættelse af CYP2D6 genotype til fænotype kan forbedres, især for alleler med nedsat enzymaktivitet og for substratspecifik enzymaktivitet.Data fra rutinemæssig lægemiddelmonitorering blev brugt til at evaluere popPK modellen for vortioxetin. Valideringsstudiet viste, at popPK modellen var god til at forudsige vortioxetin serumkoncentrationer målt som en del af klinisk praksis. Modellen havde en svag tendens til at overprediktere vortioxetin koncentrationer, hvilket til dels kan tilskrives typen af de indsamlede monitoreringsdata. Derudover viste en gennemgang af individuelle patientdata, at langsomme omsættere af CYP2D6 substrater oftere skiftede fra vortioxetin et andet antidepressivt lægemiddel sammenlignet med patienter med normal CYP2D6 aktivitet. Parallelt med dette fund så man en højere vortioxetin koncentration hos langsomme omsættere. Således kunne den højere frekvens af lægemiddelskift blandt langsomme omsættere muligvis forklares ved en øget risiko for bivirkninger forårsaget af høje lægemiddelkoncentrationer. Selvom denne afhandling bidrager til evidensen bag CYP2D6 genotype-fænotype bestemmelse, er der mange aspekter som mangler at blive belyst. Fremtidige studier kunne med fordel fokusere på CYP2D6 alleler, som endnu er dårligt karakteriseret og flere undersøgelser af faktorer såsom patologi, etnicitet, transkriptionsfaktorer og mikroRNA kunne øge vores forståelse af CYP2D6 yderligere. Slutteligt, for at facilitere implementering af farmakogenetik i klinisk praksis, er der fortsat behov for stærk evidens vedrørende cost-benefit samt etablering af nødvendig teknisk infrastruktur. The cytochrome P450 (CYP) 2D6 enzyme is the predominant pathway for the elimination or bioactivation of numerous drugs. Due to genetic polymorphism of the CYP2D6 gene, individuals display varying degrees of CYP2D6 enzyme activity. This causes variability in drug exposure which in turn may result in differences in drug efficacy and tolerability. To guide personalized dosing of CYP2D6 substrates, it is essential to have a good understanding of the impact of CYP2D6 polymorphism on enzyme activity. The main objective of this PhD project was to quantify the CYP2D6 activity associated with various CYP2D6 genotypes and alleles by studying the pharmacokinetics (PK) of three different CYP2D6 substrates and their metabolites.This thesis presents three population pharmacokinetic (popPK) studies characterizing the joint parent-metabolite PK of vortioxetine, tedatioxetine and brexpiprazole, respectively. Based on estimates from the final popPK models, the CYP2D6-mediated metabolism was quantified for more than 2,000 individuals carrying a wide range of CYP2D6 genotypes.The analyses showed that decreased function alleles (e.g. CYP2D6*9, *10, *17 and *41) were generally associated with a more than 50% reduction of CYP2D6 enzyme activity relative to the wild-type (CYP2D6*1). Particularly, the CYP2D6*17 and *41 alleles showed lower than expected enzyme activity across the substrates, while CYP2D6*10 exhibited ~30% enzyme activity relative to CYP2D6*1 for all three substrates. It is worth highlighting that the normal function allele, CYP2D6*2, exhibited a substantially decreased enzyme activity in the biotransformation of brexpiprazole to DM-3412 suggesting substrate-specific activity of this allele. Collectively, the results indicate that CYP2D6 genotype-phenotype translation schemes could benefit from further refinement particularly with regards to decreased function alleles and substrate-specific behaviour.Data from a therapeutic drug monitoring (TDM) unit was used to assess the performance of the popPK model developed for vortioxetine in a real-life clinical setting. Overall, the validation study showed a good ability of the popPK model to predict vortioxetine serum concentrations measured as part of routine clinical practice. The model had a slight tendency to overpredict concentrations, which may be partly due to the naturalistic nature of the TDM data. Longitudinal reviews of TDM profiles showed that CYP2D6 poor metabolisers (PMs) had an increased frequency of switching to an alternative antidepressant compared to normal metabolisers. This was paralleled by significantly higher exposures among the PMs, and therefore the higher rate of treatment switch might be explained by an increased risk of adverse events caused by supratherapeutic drug concentrations. While this thesis contributes to the evidence of CYP2D6 genotype-phenotype relationships, several aspects remain to be addressed. Future studies should aim to evaluate poorly characterized CYP2D6 alleles and further investigations of the impact of factors such as pathology, ethnicity, transcription factors and microRNA could contribute to our understanding of CYP2D6. Lastly, to facilitate successful implementation of pharmacogenetics in the clinic, solid evidence of cost-effectiveness and adequate technical infrastructure remains to be established.

  • Open Access English
    Authors: 
    Piri, Reza;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Introduktion: Iskæmisk hjertesygdom og slagtilfælde er nummer et og to på listen over de mest almindelige dødsårsager på verdensplan. Årsagen er typisk åreforkalkning, som kan forblive asymptomatisk i årevis og som regel diagnosticeres sent i forløbet på grund af en komplikation eller under et helbredstjek vha. traditionel billeddiagnostik, herunder ultralyd med Doppler, computertomografi (CT) eller magnetisk resonans, metoder, som også kan afsløre, om der er en stenose. Nylige rapporter tyder på, at meget tidlige ændringer i arterievæggen kan påvises og måles med positronemissionstomografi (PET) med sporstofferne 18F-fluordeoxyglucose (FDG) eller 18F-natriumfluorid (NaF). I dette ph.d.-projekt ønskede vi i første omgang at studere åreforkalkning i karotiderne vha. PET, men snart ændrede vi fokus til også at omfatte hjertet og aorta samt brugen af kunstig intelligens (artificial intelligence (AI)) til at segmentere de pågældende strukturer for at belyse, om dette kunne gøre segmentering og kvantificering hurtigere og mere pålidelig. På denne måde endte projektet med at omfatte fire undersøgelser publiceret i fire artikler. Artikel I var en systematisk gennemgang af PET studier af karotissklerose, herunder deren klinisk anvendelighed og relation til konventionel billeddiagnostik. Artikel II var en undersøgelse af 2-års ændringer i NaF-optagelsen i hjertet og aorta hos raske individer og anginapatienter ved brug af konventionel manuel segmentering. Artikel III var et forsøg på at etablere og teste en automatiseret AI-baseret metode til hurtig segmentering af NaF-PET/CT optagelser af hjertet, mens artikel IV var et forsøg på at gøre det samme i aorta.Metoder: I det systematiske review ledte vi efter forskningsartikler om PET-scanninger af karotiderne med forskellige sporstoffer i forskellige databaser. Duplikater, lederartikler, samt artikler om teknisk funktionsduelighed og reproducerbarhedsartikler blev fjernet. Det samme gjald artikler om patienter i terminalfasen eller i immunosuppressiv behandling. De mulige artikler blev vurderet af én bedømmer. I kohortestudiet blev 29 raske individer og 20 patienter med angina pectoris undersøgt med NaF-PET/CT to gange med to års mellemrum. Aortabuen, aorta thoracalis og abdominalis samt karotiderne blev manuelt segmenteret. Optagelsen af NaF blev angivet som den gennemsnitlige, maximale og total standardiserede aktiviteter med og uden partial volume korrektion (SUVmax, SUVmean, SUVtotal og cSUVmean, cSUVtotal). Efterfølgende blev et konvolutionelt neuralt netværk (CNN) udviklet til at identificere og segmentere hjertet i sin helhed og aorta i tre dele. CNN-modellen blev trænet vha. NaF-PET/CT-scanninger fra andre patienter og testet i de samme 49 personer som nævnt ovenfor ved sammenligning med data opnået ved manuel segmentering. Bland-Altman grænser for overensstemmelse blev brugt til at vurdere sammenligningerne. Reproducerbarheden af den manuelle metode undersøgt ved fornyet segmentering af 25 tilfældigt udvalgte scanninger.Resultater: I det systematiske review blev det vist, at patienter med symptomatisk karotissklerose har højere FDG optagelse end patienter med asymptomatisk karotissklerose. Histologisk vurderet var der en stærk sammenhæng mellem mikroforkalkning og NaF-optagelsen hos symptomatiske patienter, men forkalkning var inverst korreleret til optagelsen af FDG. I det manuelle kohortestudie var NaF-optagelsen ubetydeligt højere i angina-gruppen på begge tidspunkter, med mindre optagelse i den raske gruppe og lidt højere optagelse i angina-gruppen efter to år. NaF-optagelsen ved baseline kunne ikke forudsige en ændring i CT-forkalkning efter 2 år. NaF-optagelsen var positivt korreleret til alder i alle dele af aorta. Der var ingen ændring i arteriel CT-densitet efter 2 års opfølgning. I den sidste del af projektet var CNN-baserede målinger i hjertet 0-4 % højere end med den manuelle metode og 0-17 % lavere i aorta. Men SUV-middelværdierne opnået med de to metoder var både i hjertet og i aorta næsten identiske. Den CNN-baserede segmenteringsmetode var meget hurtigere end den manuelle metode. Der var ved gentagen manuel segmentering i henholdsvis hjertet og aorta en maksimal variation på hhv. 0,5 % og 6 % mod 100 % overensstemmelse med CNN-metoden.Konklusion: PET-billeddannelse er en nyligt introduceret modalitet til vurdering af åreforkalkning, som er en langsom og variabel proces hos både raske personer og patienter med angina pectoris, dog med en tendens til lidt højere NaF-optagelse hos anginapatienter. Den AI-baserede fremgangsmåde leverer gennemsnitlige værdier for NaF-optagelsen som svare nøje til de manuelt opnåede. Desuden er AI-baserede teknik observatøruafhængig, meget reproducerbare og meget hurtige end manuel segmentering, der er omstændelig og langsom. Med yderligere træning er det sandsynligt at den AI-baserede metode bliver standarden ved vurdering af patienter med formodet eller kendt åreforkalkning. Introduction: Ischemic heart disease and stroke are the world’s number one and two killers. The underlying cause is usually atherosclerosis, which may stay asymptomatic for years and is usually diagnosed late in the course due to a complication or during a health check using common types of imaging such as ultrasound with Doppler, computed tomography (CT) or magnetic resonance imaging, all of which can also determine if a stenosis is present. Recent reports suggest that very early changes in the artery wall can be detected and measured by positron emission tomography (PET) imaging with tracers 18F-fluorodeoxyglucose (FDG) or 18F-sodium fluoride (NaF). In this PhD project, we initially wanted to study atherosclerosis in the carotids by PET imaging, but we soon changed our focus to also include the heart and aorta and the use of AI to segment the targeted structures in order to elucidate if this could make segmentation and quantification faster and more reliable. Thus, the project ended comprising four studies published in four articles. Article I was a systematic review on PET imaging of carotid atherosclerosis, emphasizing clinical usefulness and relations to conventional imaging modalities. Article II was a study of 2-year changes in carotid and aortic NaF uptake in healthy individuals and angina patients using conventional manual segmentation. Article III was an attempt to establish and test an automated AI-based method for fast segmentation of the heart in NaF-PET/CT scans, while Article IV was an attempt to do the same in the aorta.Methods: In the systematic review, articles on carotid artery PET imaging with different radiotracers were searched in several databases. Duplicates, editorials, case stories, studies regarding feasibility or reproducibility of PET imaging, and studies on patients with end-stage diseases or receiving immunosuppressive medication were omitted. All eligible articles were reviewed by one observer. In the cohort study using manual segmentation only, 29 healthy subjects and 20 angina pectoris patients underwent NaF-PET/CT twice two years apart. The arch, thoracic, and abdominal aorta and the carotids were manually segmented. NaF uptake was expressed as the maximum, mean and total standardized uptake values without and with partial volume correction (SUVmax, SUVmean, SUVtotal and cSUVmean, cSUVtotal). Subsequently, a convolutional neural network (CNN) based method was developed to identify and segment the heart and the aorta in three mentioned parts. The CNN model was trained in NaF- PET/CT scans of other patients and tested in the same 49 subjects as above by comparison with data obtained by manual segmentation. Bland-Altman limits of agreement were used to compare derived parameters. Furthermore, the reproducibility of the manual method was examined by repeated segmentation in 25 randomly selected scans.Results: In the systematic review, it was shown that patients with symptomatic carotid atherosclerosis have higher FDG uptake than patients with asymptomatic carotid atherosclerosis. There was a strong correlation between microcalcification and NaF uptake in symptomatic patients in histopathological assessment, but calcification had a negative correlation with uptake of FDG. In the manual cohort study, NaF uptake was insignificantly higher in the angina group at both time points, with less uptake in the healthy group and slightly higher uptake in the angina group after two years. NaF uptake at baseline could not predict a change in CT calcification after 2 years. NaF uptake correlated positively with age in all parts of the aorta. CT scan did not indicate any change in density of major arteries after 2 years of follow-up. In the final part of the project, CNN derived heart segmentation measures were 0% to 4% higher than by the manual method and 0% to 17% lower than with manual aortic segmentation. However, with CNN-based and manual method the SUVmean values in both heart and aorta were almost identical. Cardiac and aortic CNN-based segmentation method was much faster than the manual approach, which had a maximal 0.5% and 6% variation at repeated segmentation of the heart and the aorta, respectively, compared to a 100 % inborn CNN reproducibility.Conclusion: PET imaging is a newly introduced modality for imaging of atherosclerosis, which is a slow and variable process in healthy individuals and patients with angina pectoris, albeit with a tendency of slightly higher NaF uptake in angina patients. Although current technical difficulties such as time-taking image analysis exist, the AI-based models could present values for Volume, SUVmean, SUVmax, and SUVtotal similar to the manually obtained ones. These AI-based models are observer-independent, highly reproducible and very fast alternative alternatives for slow manual segmentation. With further training, the AI-based approach may become the standard for assessing patients with suspected or known atherosclerosis.

  • Open Access English
    Authors: 
    Isaksson, Gustaf Lissel;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Proteinuri er en tilstand som forekommer ved en række nyresygdomme og er karakteriseret ved at nyrerne ”lækker” protein så det kan måles i urinen. Det er en selvstændig prædiktor for forværring af nyrefunktion, øget sygelighed og død. Meget tyder på at det er proteinerne selv, der er skadelige for nyren, men mekanismen er ikke kendt. Proteiner fra koagulationssystemet, herunder plasminogen, og komplementsystemet (del af det medfødte immunforsvar) findes i urin ved defekt filtrationsbarriere, men ikke i urin fra raske. Fra in vitro studier vides, at plasmin kan aktivere og kløve de kritiske komponenter C3 og C5 i komplementsystemet. Derved dannes de proinflammatoriske molekyler C3a og C5a samt under visse omstændigheder ”membran attak” komplekser (MAC, C5b-9). Plasmin aktiveres fra inaktivt plasminogen i proteinurisk urin via urokinase-type plasminogen aktivator (uPA), som findes i urin fra raske. I studierne undersøges en række hypoteser: plasminogen og komplement filtreres sammen ved proteinuri; at aktiveret plasmin driver komplementaktivering og inflammation fra nyrernes tubulussystem; samt at dette kan forhindres helt eller delvist ved at hæmme uPA med amilorid.Studie I undersøger udskillelsen af komplementaktiveringsprodukter i urinen hos nyretransplanterede med albuminuri som er en særlig høj-risikogruppe for tab af nyrefunktion og død og i en mindre gruppe ikke transplanterede nyresyge patienter, ligeledes med albuminuri. Endvidere undersøges ekstracellulære vesikler i urin for at lokalisere hvor henne i nyre komplement slår ned. Vi fandt at udskillelsen af splitprodukterne C3c, C3dg, og sC5b-9 associeret C9 neoantigen, normaliseret for kreatinin i spoturinprøver, var stærkt og signifikant øget ved albuminuri hos nyretransplanterede og ikke i urin fra transplanterede uden proteinuri. Samtidig sås der ikke forskelle i plasmakoncentrationer mellem de 2 grupper. Produkterne var også øget i urin fra patienter med proteinuri der ikke var transplanteret sammenlignet med raske kontroller. I ekstracellulære vesikler fra urin påvistes C9 neoantigenet kun ved albuminuri og yderligere undersøgelse via lektinaffinitetsisolering viste at både C3dg og C5b-9 var bundet til vesikler som stammede fra cellemembraner i proximale tubulus.Studie II tager konceptet videre og undersøger en eventuel aktiveringsmekanisme via uPA-plasminogen ved eksperimenter in vitro med kommercielt tilgængelige rene komplement- og koagulations proteiner samt hvorvidt dette kunne hæmmes med amilorid. Vi undersøgte også to kohorter med patienter med albuminuri som behandles med amilorid, samt et studie med mus med inducerbar progressiv proteinuri. I proteinurisk fase blev mus behandlet med enten amilorid eller saltvandsinjektion. Vi fandt en signifikant aktivering af både C3 og C5 direkte via uPA-plasmin i buffere in vitro og i urin ex vivo. C3 og C5 aktivering kunne hæmmes på en gradueret måde ved at hæmme uPA med amilorid in vitro. C3 kunne aktiveres ved at inkubere normal rask urin ved samtidig tilsættelse af eksogent plasminogen på en amiloridfølsom måde. Patientundersøgelserne viste at en dags amiloridbehandling kun tenderede til at nedbringe C3a i urinen hos nyretransplanterede. To dages amilorid behandling i patienter med diabetisk nyresygedom og proteinuri nedsatte C3dg og C9 neoantigen udskillelse. I dyreforsøget viste vi at amilorid i 4 dage signifikant sænkede døgnudskillelsen af C3a og C5a i urinen. Specifik hæmning af uPA i 11 dage i podocin (-/-) mus med et monoklonalt hæmmende antistof der modvirkede aktivering af plasminogen medførte også en signifikant reduktion i C3a og C5a udskillelseshastighed.I Studie III undersøges C3dg og sC5b-9 associeret C9 neoantigen i urin og plasma i konsekutive prøver opsamlet under graviditeten i en gruppe gravide med type 1 diabetes, n = 88 deltagere, hvoraf n = 14 udviklede preeklamspsi. Vi viste en signifikant stigning i både C3dg og C9 neoantigen i urinen mod slutningen af graviditeten som fulgte albuminudskillelsen hos de patienter der udviklede præeklampsi. Både C3dg og C9 neoantigen relaterede signifikant til albumin i urin men korrelationen til C9 total plasmin(ogen) var stærkere. Ekstracellulære vesikler blev også undersøgt og C3dg og C9 neoantigen blev kun påvist hos preeklampsipatienter ved gestationsuge 36, men ikke i kontroller eller ved 12 uger.De tre studier viser at udskillelsen af aktiveringsprodukter fra komplementsystemet i urinen følger graden af proteinuri men ikke plasmakoncentrationer og at aktiveringen derfor mest sandsynligt sker i tubulussytemet efter filtrering. Endvidere kan komplement membran-attak kompleks bindes specifikt men ikke eksklusivt til proximale tubulus apikale membraner vist via ekstracellulære vesikler i urin. Korrelationen mellem komplementfaktorer til plasmin(ogen) i urin var stærkere end til albumin, foreneligt med at plasminogen kan være medvirkende til aktivering. Amilorid har in vitro en hæmmende effekt på uPA i lav mikromolærområdet, som kan eftervises in vivo i patienter med proteinuri. Den signifikante afsvækkelse men ikke fulde blokering skyldes formentlig at det findes yderligere pleiotrope aktiveringsveje som også kan drive komplementaktivering intratubulært. Resultaterne tyder på en mekanistisk kobling mellem uPAplasminogenkaskaden og komplementaktivering som alene eller sammen med andre mekanismer kan drive inflammation og vævsskade i nyrerne ved proteinuri. Dette kan også være en forklaring på hvorfor proteinuri over lang tid er associeret med fald i nyrefunktionen og kunne give ophav til nye farmakologiske mål. Amilorid og/eller stoffer med plasmin- eller komplementhæmmende effekt og som når tubulussystemet kan have en nyrebeskyttende virkning ved nyresygedom med proteinuri. Dette bør testes i fremtidige studier. Proteinuria is a common feature in chronic kidney disease (CKD) and an independent risk factor for accelerated disease progression. CKD affects approximately 10% of the global population and leads to hypertension, cardiovascular disease, and increased mortality. Aberrantly filtered plasma proteins, including zymogens and active proteases have potential activity in the tubular lumen. Our group previously demonstrated that plasminogen, a component of the fibrinolytic system, is abundantly present in urine and activated by urokinase-type plasminogen activator (uPA) in proteinuria. uPA is physiologically secreted to the tubular fluid and is significantly increased in urine in proteinuria. Complement factors are found in urine from patients with proteinuria. Plasmin cleaves the key components C3 and C5 in vitro and C5 in vivo during thrombus formation, generating biologically active C3a and C5a, which are potent proinflammatory anaphylatoxins. In the present project, it was hypothesized that i) complement factors are aberrantly filtered from plasma and activated in the tubular lumen via the uPA-plasminogen cascade in proteinuria, ii) complement activation split products are detectable in urine in relation to grade of proteinuria, and deposited in the apical membrane of tubular cells, and iii) uPA-plasmin driven complement activation can be attenuated pharmacologically by amiloride (an off target uPA inhibitor).Study I Complement proteins were measured in kidney transplant recipients (KTR) with albuminuria using in-house enzyme linked immunosorbent assays (ELISA) with neoepitope-specific monoclonal antibodies. Two cohorts were examined, one cross-sectional and one longitudinal. Urine excretion of mannose-binding lectin (MBL, 10-fold, p<0.001), C3c (2-fold, p<0.05), C3dg (3-fold, p<0.01), and sC5b-9 associated C9 neoantigen (20-fold, p<0.001) were significantly elevated in proteinuria, and C3dg and C9 neoantigen excretion followed changes in albuminuria over time, without changes in plasma concentrations. The fractional excretion of C9 neoantigen was significantly increased compared to albumin in cases, suggesting a net addition of sC5b-9 after filtration or preferential reabsorption of albumin. Nephron segment specific uEV-isolation documented an association of iC3b/C3dg and C5b-9 to proximal tubular apical membranes in albuminuria. The results strongly indicate intra tubular complement activation and deposition in the proximal tubular epithelium. In extension, suggesting that inhibiting complement in the intra tubular space could reduce the negative intra renal effects of proteinuria.Study II In vitro studies showed that C3 and C5 were activated by uPA-plasminogen but not by uPA or plasminogen alone in physiological and buffered solutions in an amiloride sensitive way. Pooled urine from healthy humans generated C3a from purified human C3 by addition of exogenous plasminogen (activated by endogenous uPA). Pre-incubation of urine with 2 mM amiloride or 500 KIU/ml aprotinin, but not 20 mM ethylenediaminetetraacetic acid (EDTA) inhibited C3a generation. C3a urine excretion was increased significantly KTRs with proteinuria (n = 7) compared to KTR controls (n = 7) but was not reduced by high dose amiloride for one day (p = 0.08). In patients with diabetes type-1 with (n = 16) or without (n = 14) diabetic nephropathy, high dose amiloride treatment for two days reduced C3dg (p < 0.05, n = 5) and C9 neoantigen (p < 0.05, n = 7) excretion rates in cases with detectable urine complement. In proteinuric podocin (-/-) mice, amiloride treatment for four days reduced 24 h urine C3a and C5a excretions (p < 0.05 for both) with no effect on albuminuria compared to vehicle. Inhibition of uPA for 11 days by a monoclonal α-uPA antibody reduced 24 h C5a and C3a excretions by ~50% (p = 0.012 and p = 0.019, respectively). uPAplasminogen play a significant role in intra tubular complement activation and uPA inhibition or direct complement inhibition might slow the progression to end stage kidney disease in proteinuria.Study III Preeclampsia (PE) is a severe complication of pregnancy with sudden onset of proteinuria and increased blood pressure. Since plasmin activated complement in urine and both complement and plasminogen excretion is elevated in PE, we sought to address the temporal association in an existing prospective cohort of 88 pregnant women with pregestational type-1 diabetes. Participants were included at gestational age (GA) 12 weeks and followed to parturition with urine and plasma sampling at GA 20, 28, 32, 36 and 38 weeks. 14 women developed preeclampsia in the study period and 8 controls with complete sample set were selected. Urine excretion of C3dg (p < 0.001) and C9 neoantigen (p = 0.002) increased gradually and in parallel to albumin in PE. C3dg and C9 neoantigen correlated to plasminogen (r = 0.51, p < 0.001 and r = 0.68, p < 0.001, respectively) and albumin (r = 0.44, p < 0.001 and C9 neoantigen, r = 0.59, p < 0.001, respectively) in urine. Receiver operating characteristic (ROC) analysis showed that C3dg and C9 neoantigen/creatinine ratios (AUC= 0.53 and 0.57 respectively) were inferior to albumin/creatinine ratio (ACR; AUC = 0.86) as biomarkers. uEVs were positive for C3dg in one of three and C9 neoantigen in three of three PE patients at GA 36 weeks but were absent in controls, suggesting tubular cell association. The temporal association is compatible with a direct relation between plasmin and complement activation, but complement was not a superior biomarker for PE.Conclusion Studies I-III demonstrate that 1) complement split products are aberrantly filtered in relation to albumin and plasminogen, 2) complement precursors are activated in the tubular lumen and deposited on proximal tubular apical cell membranes, 3) uPA-plasminogen activates complement in vitro and 4) uPAplasmin mediated complement activation is attenuated by uPA inhibition and in vitro and in vivo. The findings links proteinuria to intratubular proinflammatory signaling and complement deposition in tubular epithelial cells. This might lead to epithelial cell injury and progression of CKD and suggest a reno-protective effect of amiloride that goes beyond blood pressure reduction.

  • Open Access English
    Authors: 
    Jibril Abdi, Ahmed;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Introduktion: Røntgen billeddannelse anvender ioniserende stråling, som kan påvirke biologiske celler og dermed potentielt medføre en risiko for celle skader. Derfor er der en potentiel risiko for genetiske skader og for stråleinduceret cancer, som er eksponentielt stigende med stigende røntgenstråledosis. Selvom risikoen ved diagnostiske røntgenundersøgelser ikke er stor, vil der altid være en teoretisk risiko og derfor skal stråledosis til patienter holdes laveste muligt, for at opfylde ”Aslow As Reasonible Achievebe (ALARA)” princippet. Røntgenudstyrs producenterne forsøger hele tiden at forbedre deres produkter med henblik på at minimere stråledosis til patienterne samtidig med at bevare eller forbedre billedkvaliteten. På trods af at røntgenteknologien teoretisk medfører en risiko for strålingsinducerede skader, er der stadigvæk en fordel ved brug af røntgen til diagnostiske formål, som overvejer denne risiko. Røntgenteknologierne er uundværlige, idet ikke-ioniserende teknologier som ultralyd- og MR undersøgelser ikke har vist sig at kunne erstattealle røntgenundersøgelser. Desuden har det vist sig at klinisk brug af røntgenteknologier steget igennem de seneste årtier, idet røntgenteknologier giver diagnostiske resultater, som ofte redder liv ved at diagnosticere livstruende sygdomme f.eks. af akut eller malign karakter. Der er nødvendigt at foretage optimering af røntgensystemer for at reducere stråledosis til patienterne og dermed minimere strålingsdosis. 2D/3D lavdosis slot scanner (LDSS) er et relativt nyt røntgen system, som udsætter patienterne for lavere stråledosis med samtidig bevaret uændret tilstrækkelig diagnostisk information sammenlignet med konventionel digital radiografi (DR). LDSS har ikke været optimeret og anvendt til udbredte kliniske undersøgelser for diagnostiske formål, men overvejende kun brugt til oversigtsbilleder af patienter med skoliose og måling af længden af underekstremiteter. I denne afhandling er foretaget en omfattende evaluering af billedkvalitet og strålingsbesparelse ved LDSS sammenlignet med konventionelle DR systemer. Der er desuden foretaget en optimering og evaluering af billedkvalitet samt strålingsbesparelse på LDSS ved thorax- og knæundersøgelser. Stråledosis og billedkvalitet ved LDSS er desuden sammenlignet med to forskellige konventionelle DR røntgensystemer. Denne Ph.d. afhandling består af tre studier med tre forskellige billedkvalitets evaluerings metoder.Formål var: 1) at evaluere billedkvaliteten samt undersøger om LDSS kan bruges til mere udbredte diagnostisk formål sammenlignet konventionelle DR røntgensystemer ved brug af tre forskellige billedkvalitets vurderingsteknikker. 2) At undersøge stråledosis besparelse ved LDSS i forhold til de konventionelle DR systemer, samt 3) At optimere kliniske protokoller på LDSS således at billedkvalitet ved LDSS var sammenligneligt med de konventionelle DR systemer. Hypotesen var, at LDSS kan give samme diagnostisk billedkvalitet som konventionelle DR-systemer ved anvendelse af lavere stråledosis til patienten.Materialer og metoder: For at kunne sammenligne billedkvaliteten og stråledosis ved LDSS med konventionelle røntgen systemer, blev der brugt to DR røntgensystemer fra to forskellige leverandører. I studie I af afhandlingen blevet antropomorft (alderson) fantombrugt til organdosis måling af thorax alle systemer. I knæ undersøgeler blev brugt et polymethylmethacrylat (PMMA) fantom på 20 cm i tykkelsen svarende til en gennemsnitlig voksen patientstørrelse også brugt til at evaluere kontrast-detalje opløsningen af systemerne i thorax. Et kontrast-detalje test objekt (CDRAD) 2.0 phantom og CDRAD v2.1.9 softwareanalyse blev brugt til at evaluere kontrast-detalje opløsningen af alle systemer i både thorax og knæ. I studie II af afhandlingen blev et thorax fantom med hybrid PMMA og aluminiumsfolier brugt til at evaluere den kvantitative billedkvalitet af thorax i alle systemer. I knæ undersøgelserne blev 15 cm PMMA brugt til at evaluere den kvantitative billedkvalitet i alle systemer. I studie III af afhandlingen, blev et antropomorft thorax (LungMan, Kyoto Kagaku Co., Ltd., Kyoto, Japan) med et ekstra fedtlag brugt til at producere et thorax billede til evaluering af visuel billedkvalitet af thorax for alle røntgen systemer. Et knæfantom medindsat naturlig knogle blev brugt til at evaluere den visuelle billedkvalitet af knæ protokoller i alle tre systemer. Monte Carlo-simuleringssoftwaren PCXMC blev brugt til at beregne den effektive dosis og organdosis for både knæ og thorax alle systemer. IQworks software blev brugt til at beregner de kvantitative parametre, herunder effektiv modulation transfer funktion og effektiv normalised noise power spektrum. Statistical Package for the Social Sciences, Release 26.0.0.0 software blev brugt til al statistisk analyse af afhandlingen. Det statistiske signifikansniveau brugt i alle statistiske analyser var 5 %. Thermoluminescerende dosimetre (TLD) var brugt til at måleorgandoserne direkte i lungerne og skjoldbruskkirtlen i thorax.Den effektive dosis til patienter for både Thorax og knæblev estimeret ved hjælp af verificerede dosis arealprodukt værdier (DAP) fra alle systemer. En halvlede dosimeter blev brugt til måling af air kerma (AK) for at verificere systemernes DAP-målere. Den beregnede (simulerede) og den direkte målte organdosis for lungerne, skjoldbruskkirtlen og ekstremitetsknogler for både thorax og knæ blev sammenlignet på tværs af systemerne. Default dosis opsætningen af LDSS, som blev brugt til skoliose oversigtsbilleder og benlængde målinger, var signifikant lavere end ved DR-systemerne. Derfor blev stråledosis ved LDSS for både thorax og knæ optimeret. I forbindelse med denne undersøgelse. Dosisniveauet af LDSS blev øget for at give omtrent den samme diagnostiske information som i de konventionelle DR-systemer. I modsætning hertil blev den optimale rutinemæssigt anvendte dosisindstilling af konventionelle DR røntgensystemer anvendt uændret. Tre forskellige og væsentlige billedkvalitetsevalueringsteknikker blev brugt til at vurdere billedkvaliteten af LDSS sammenlignet med konventionelle DR røntgensystemer. Billedkvalitets-evalueringsmetoderne var baseret på både subjektive og objektive teknikker. Der blev optaget og indsamlet 470 røntgenbilleder til både billedkvalitets-evaluering og stråledosisberegning/måling i alle systemer og protokoller.Resultater: De optimerede scanningshastigheder for LDSS var speed 6 og 8 for henholdsvis thorax- og knæundersøgelser, med billedkvalitet sammenlignelig med DRsystemer. Default indstillet scan hastighed for LDSS var speed 4 og 6 for henholdsvis thorax- og knæundersøgelser. Effektiv dosis sammenlignings resultater har vist, at optimeret protokoller på LDSS udsætter patienterne for (41,7-42,6 % og 29,5-35,0 %) lavere effektive doser end konventionelle DR-røntgensystemer til henholdsvis thorax- og knæundersøgelser. LDSS gav også en signifikant (20-40%) lavere organdosis til patienterne end DRsystemerne. Billedkvalitetsresultater fra alle tre forskellige billedkvalitetsteknikker har vist, at de optimerede thorax- og knæ undersøgelser for LDSS har enten højere eller samme billedkvalitet end de konventionelle DR-systemer. Visual grading analysis (VGA)-analyseresultaterne har også vist god inter- og intra-observer enigheden for alle VGA-billedkvalitetskriterier for både thorax- og knæ undersøgelser.Konklusion: De overordnede resultater af disse tre forskellige billedkvalitetsevalueringsstudier viser, at LDSS har samme billedkvalitet som DR røntgensystemerne til både knæ- og thorax undersøgelser. LDSS har den fordel at den udsætter patienterne for en signifikant lavere stråledosis end DR røntgensystemerne. Derfor har LDSS demonstreret potentiale til at opnå billedkvalitet til diagnostisk brug i både thorax- og knæ undersøgelser under anvendelse af øget stråledosis. X-ray imaging technology uses ionising radiation and thus exposes the patients to radiation. X-ray vendors are constantly trying to improve their products with the intention of minimising radiation exposure to patients while at the same time, maintaining or improving image quality. Radiation exposure from the X-ray imaging modalities has the potential to damage the biological cells and is followed by the risk of radiation-induced cancers, and this should not be ignored. However, the diagnostic use of X-rays has great benefits that outweigh the potential risks. X-ray technology is highly clinically relevant and can save many patients’ lives by enabling the diagnosis of life-threatening diseases and is therefore indispensable for patient examinations. The use of X-ray technology in clinical settings has increased in recent decades, and optimising X-ray systems by reducing the radiation dose is still an essential task. The 2D/3D low-dose slot scanner (LDSS) imaging system is a relatively new X-ray imaging technology that exposes patients to lower radiation doses and at the same time provides sufficient diagnostic information compared to conventional X-ray imaging systems. The LDSS system has not been generally approved as a diagnostic tool for radiological diagnosis in several clinical settings, as the system is not optimised for these diagnostic purposes. So far, the LDSS systems has mainly been used to obtain overview images of patients with scoliosis and to measure the length of lower extremities, especially in children. In this thesis, a comprehensive investigation of image quality and radiation dose saving in the LDSS imaging system was conducted and the system was compared with conventional digital radiography (DR) X-ray systems. This thesis is a collection of three different studies using three different methods to evaluate image quality and to estimate the imaging system's radiation dose to patients. For each of these three studies, a scientific article was published in the field of medical imaging and in radiology journals. Aims: The aim of the thesis was to investigate the image quality and suitability of the LDSS imaging system for diagnostic purposes using three different image quality assessment techniques. The image quality achieved in the LDSS imaging system was compared with the image quality of two conventional DR X-ray systems through different image quality evaluation techniques. In addition, the radiation exposure to patients from the LDSS imaging system was optimised and compared to the conventional DR systems.The objective of this thesis was to investigate whether the LDSS imaging system could provide diagnostic images of the same quality as conventional DR systems without compromising image quality. Two DR X-ray systems from two different vendors were used to evaluate the image quality and radiation dose and to compare these with the LDSS imaging system. In Study I, an anthropomorphic phantom was used for organ dose measurement for the chest protocol in all systems. In Study I, a Polymethyl Methacrylate (PMMA) plate phantom of 20 cm equivalent to a typical average patient size was also used to evaluate contrast detail resolution of the systems in the chest protocol. A contrast-detail for radiography (CDRAD) 2.0 phantom and CDRAD v2.1.9 software analysis were used to evaluate the contrast detail resolution of the imaging system. In Study II, an in-house chest phantom with hybrid Polymethyl Methacrylate (PMMA) and aluminium foils was used to evaluate the quantitative image quality of the imaging systems and 15 cm PMMA was used to assess the contrast detail resolution of the systems in knee protocol. In Study III, an anthropomorphic chest phantom and a native-bone knee phantom were used to evaluate the visual image quality of the system. Monte Carlo simulation software PCXMC was used to calculate the effective dose and organ dose for both knee and chest protocols in all imaging systems. Statistical Package for the Social Sciences (SPSS), Release 26.0.0.0 software was used for all statistical analysis of thesis. The statistical significance level used in all analyses was 5%. Thermo-luminescent dosimeters (TLD) were used to measure the organ doses of the lungs and thyroid directly in the chest protocol. The effective dose of systems in both chest and knee protocols was estimated using verified dose area product (DAP) values from all of the imaging systems. However, a solid-state dosimeter was used to verify the DAP meters of the systems.A calculated (simulated) and a directly measured organ dose for the lungs, thyroids, and lower leg bones in both chest and knee protocols were compared across systems. The default dose setup of the LDSS imaging system, which was used for scoliosis overview images and leg length measurements, was significantly lower than in the DR systems. Therefore, the radiation exposure of the LDSS imaging systems for both chest and knee protocols were optimized. The dose level of the LDSS imaging system has been increased to provide approximately the same diagnostic information as in the conventional DR systems. In contrast, the optimal routinely used dose setting of conventional DR X-ray systems was used. Three different and essential image quality evaluations were used to assess the image quality of the LDSS imaging system compared with conventional DR imaging systems. These three image quality evaluation methods were performed in three separate studies: the technical (contrast detail resolution), quantitative, and visual grading analysis (VGA) image quality evaluation. The image quality evaluations methods were based on both subjective and objective techniques. In all three studies in this thesis, 468 images were acquired for both image quality assessment and radiation dose calculation/measurement in all imaging systems and protocols. For the visual image quality assessment, three experienced radiologists practising thoracic radiology who are specialised in the reporting of thoracic images visually scored 60 chest PA and LAT projection images for all imaging systems. However, two experienced diagnostic radiographers with postgraduate degrees in appendicular skeletal reporting and one research radiographer scored the 60 images of knee PA and LAT for all three imaging systems. The optimised scan speeds of the LDSS imaging system were speeds 6 and 8 for chest and knee protocols, respectively, with image quality comparable to that of DR systems. The default setting scan speeds of the LDSS imaging system were speed 4 and speed 6 for the chest and knee protocols, respectively. The dose comparison results obtained showed that LDSS imaging system exposed patients to significantly (41.–42.6% and 29.5–35.0%) lower effective dose than conventional DR X-ray systems for the chest and knee protocols, respectively. The LDSS imaging system also obtained a significantly (20- 40%) lower organ dose to the patients than with DR systems. The evaluated image quality results of all three different image quality studies have shown that the optimised chest and knee protocols for the LDSS imaging system have equal image quality to that of the conventional DR systems. The VGA analysis results have shown good inter-observer and intra-observer agreement for all VGA image quality criteria for both chest and knee protocols. The overall results of these three different image quality assessment studies show that the LDSS imaging system has equal image quality to the DR imaging system for both extremity and chest radiography. The LDSS imaging has the advantage of exposing patients to a lower radiation dose than do the DR systems. Thus, the LDSS imaging system has demonstrated the potential to obtain image quality for diagnosis in chest and knee protocols.

  • Closed Access English
    Authors: 
    Heinsen, Laurits;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Denne PhD-afhandling er baseret på tre originale manuskrifter. Studierne er gennemført på den Kardiologiske Forskningsenhed, OUH Svendborg Hospital.Baggrund Type 2 diabetes mellitus er en betydelig risikofaktor for iskæmisk hjertesygdom. Patienter med type 2diabetes har en høj byrde af traditionelle risikofaktorer, og behandlingen af disse medfører en betydeligreduktion i dødelighed og risikoen for blodprop i hjertet. Til trods for god risikofaktor-kontrol og normalisering af LDL med kolesterolsænkende medicin er disse patienter fortsat i øget risiko for blodprop i hjertet. Dette fænomen betegnes residualrisiko og har været i fokus i de seneste år. Hovedformålet med denne afhandling var at undersøge og beskrive åreforkalkning i asymptomatiske patienter med type 2diabetes som ikke er kendt med iskæmisk hjertesygdom. Delformål 1) At beskrive forekomsten af høj risiko plaque (HRP) og sammenhængen med risikofaktorer samt den koronare kalk score (CACS). 2) At undersøge sammenhængen mellem ændringer i kolesterol, triglycerider, og langtidsblodsukker i forhold til sammensætning og progression af koronar åreforkalkning 3) At evaluere sammenhængen mellem GLP-1 antagonisten liraglutide og ændringer i det totale plaque volumen samt plaque komposition ved opfølgning efter et år. Metode Dette studie var det prospektivt observationsstudie og patienterne blev rekrutteret og undersøgt i perioden fra marts 2016 til september 2017. Patienter med type 2 diabetes uden symptomer og historik mediskæmisk hjertesygdom blev inviteret til at deltage i studiet. Hjerte-CT blev udført ved studiets start og efter et års opfølgning. Det totale plaque-volumen samt plaque sammensætning og højrisiko plaque-morfologi(HRP) blev estimeret ved studiets start og ved opfølgning efter et år. Kliniske data som blodtryk, hjertekardiogram, medicinsk behandling, diabetiske komplikationer, samt blodprøver blev indsamlet ved studietsstart og ved opfølgning efter et år. Opsummering af afhandlingens hovedfund:1) HRP blev observeret hos 37% af patienterne og var associeret med højere langtidsblodsukker, større tobaks-eksponering og mandligt køn. HRP blev identificeret i alle CACS grupper inklusiv CACS på nul.2) Stigende triglycerider var associeret med progression af både høj-risiko plaque og det total plaque volumen. Stigningen i triglycerider var tæt associeret med stigning i vægt, stagnerende HbA1c, samtfaldende lever attenuation. Ydermere var der en klar sammenhængen mellem stigende triglycerider og rest-partikel kolesterol.3) Ændringer i det totale plaque volumen var ikke associeret med liraglutid behandling. Analysen af plaque kompositionen viste, at liraglutide behandling var associeret med øget progression af fibrøst plaque.KonklusionKonklusionen på dette studie er at hjerte-CT er noninvasiv metode som muliggør at karakterisere typen af åreforkalkning samt ændringer over tid. Høj-risiko plaque morfologi blev identificeret hos 37% af patienterne og var associeret med risikofaktorerne langtidsblodsukker, tobaks-eksponering, og mandligt køn, men kunne ikke udelukkes ved fraværet af koronar kalk. En stigning i triglycerider var associeret med plaque progression af høj risiko plaque og en en forværring af den glukometaboliske kontrol samt stigende rest-partikel kolesterol. Liraglutide behandling var associeret med øget progression af fibrøst plaque og er en mulig mekanisme som kan forklare den kardiovaskulære risikoreduktion associeret med liraglutid behandling. This PhD thesis is based on three original manuscripts, and the studies were carried out at the Cardiovascular Research Unit at OUH Svendborg.BackgroundIschemic heart disease remains the leading cause of mortality in type 2 diabetes mellitus (T2D). Despite a significant risk reduction in the last decades, T2D remains associated with twice the risk of all-cause mortality, mainly due to coronary artery disease (CAD). Coronary computed tomography angiography(CCTA) allows the characterization of coronary artery plaque and disease progression, and several studies have demonstrated that high-risk plaque (HRP) is associated with acute coronary syndrome (ACS). Risk stratification of asymptomatic diabetes is challenging and a better understanding of the extent and progression of coronary atherosclerosis in relation to patient characteristics and risk factors is of interest. The overall aim of this PhD study was to assess plaque characteristics and predictions of plaque progression in a cohort of asymptomatic patients with diabetes without CAD. Study objective:1) To assess the prevalence of HRP in asymptomatic T2D and the relationship between HRP and cardiovascular disease (CVD) risk factors, diabetes profile, and the coronary artery calcium score(CACS).2) To assess the association of changes in lipoproteins and glycated hemoglobin (HbA1c) in relation to changes in HRP volumes.3) To assess changes in the total atheroma (TAV) and composition from baseline to follow-up stratified by liraglutide treatmentMethods This PhD thesis is based on data from a prospective observational study performed between March 2016and September 2017 at Odense University Hospital Svendborg. Patients were asymptomatic and without a history of CAD. Serial CCTA was performed to assess total atheroma volume (TAV) and plaque composition at baseline and one-year follow-up. In addition, CACS was assessed from non-enhanced images. A clinical assessment including blood pressure, electrocardiogram, current medication, diabetic complications, and blood test was performed at baseline and at follow-up. The main findings of this PhD thesis were:1) HRP was identified in 37% of patients and was associated with higher HbA1c, greater tobacco exposure, and male gender. HRP was detected in all groups of CACS, and the absence of coronary artery calcium (CACS = 0) could not rule out HRP.2) An increase in triglycerides was associated with the progression of HRP as well as an overall plaque progression. Changes in triglycerides were closely associated with weight gain, stagnant HbA1c, and evidence of increased hepatic fat accumulation. Furthermore, there was a strong association between the increase in triglyceride and the increase in remnant cholesterol.3) We found no association between changes in TAV and liraglutide treatment. The secondary endpoint, changes in plaque composition stratified by liraglutide treatment was positive, and a significant increase in the fibrous plaque volume was detected in the liraglutide treated patients.ConclusionsIn conclusion, CCTA is a non-invasive examination that allows the characterization of plaque composition and changes over time. HRP was detected in 37% of the patients and was associated with higher HbA1c,tobacco exposure, and male gender. Our results warrant caution for use of calcium scoring in this patient group as the absence of coronary artery calcium could not rule out CAD. We found a significant association between an increase in triglyceride levels and HRP progression. The data suggested that this finding was mediated by an increase in remnant cholesterol driven by a worsening in glucometabolic control. Finally, liraglutide was associated with an increase in fibrous plaque which could indicate plaque stabilization. To the best of our knowledge, this study is the first study to assess the association between liraglutide treatment and coronary atherosclerosis in humans.

  • Other research product . Other ORP type . 2022
    Closed Access English
    Authors: 
    Zhang, Rui;
    Publisher: Syddansk Universitet. Det Naturvidenskabelige Fakultet
    Country: Denmark

    Tekst og netværk er to almindelige former for data. De kan altid bruges samme til at beskrive forskellige applikationer, såsom kommentarsystemer, sociale netværk, og akademiske netværk. Dataanalyse bliver vigtig nu. Det er et afgørende spørgsmålat præsentere tekst- og netværksdata på en effektiv måde. Mange repræsentation læringsmodeller er blevet foreslået til dette problem. Men de fleste metoder har brug for dataetiketter, komplekse systemer og/eller højdimensionelle vektorer forat opnå de gode repræsentationer, og dette er ofte udfordrende for beregning og lagring af både upstream og downstream applikationer. Derfor adresserer denne afhandling ovenstående udfordringer og yder bidrag til repræsentationslæring på tekst- og tekstbaserede netværksdata.Til tekstrepræsentation læring foreslås en multi-label-læringsmodel baseret på semantisk etiketlæring for at kategorisere tekstbaserede publikationer med hierarkiskkategoristruktur. Denne model lærer først repræsentationer af publikationer og kategorier. Derefter genkender og videregiver modellen den matchende information hierarkisk. Endelig opnår denne model bedre forudsigelser i hierarkisk kategori af publikationer.Til tekstbaserede netværksdata foreslås først en metapath-baseret repræsentationsmodel. Denne model kan lære lavdimensionelle repræsentationer for målknuder fra deres tekstattributter og topologiske strukturer ved hjælp af en kaskadestyret selvovervåget læring mekanisme. For at overvinde begrænsningen af metapath og reducere de ekstra omkostninger, foreslår vi også en selvovervåget metapath-fri algoritme med relationsbaseret nabo-graf kontrastlæring. Denne model kan producere globale repræsentationer ved at lære alle knudepunkter og links. Repræsentationerne kan bruges til mange downstream-opgaver. Modellen udkonkurrerer de nyeste metoder.Samlet set giver afhandlingen en omfattende gennemgang af eksisterende repræsentation læringsmetoder og foreslår nye metoder baseret på dyb læring for at producere meget mere effektive og effektive repræsentationer til tekst og netværk. Bidragene er empirisk valideret på adskillige datasæt og opgaver i den virkelige verden. Text and networks, as two common forms of data, always appear cooperatively in describing diverse applications in the real world, such as review systems, social networks, and citation networks. As the demand of data analytics continues to grow, how to effectively and efficiently represent text and network data has become a critical research issue. To resolve this problem, various machine learning models have been proposed for text and network representation learning, but most of them mainly rely on tons of manually labeled training samples, complex systems, and/or high-dimensional vectors to improve the accuracy and precision of representations, which often bring new challenges to computation and storage costs in both upstream and downstream applications. Thus, this thesis addresses the above challengesand makes contributions to representation learning on the text and text-attributed network data.For text representation learning, a label-semantic augmented multi-label-learning model is proposed to categorize text-based publications with hierarchical category structure, which creatively learns representations of publications and categories, recognizes and passes their matching information hierarchically, and as a result, achieves better hierarchical-category predictions.For text-attributed network representation learning, a meta-path-based embedding method is first developed, which is able to learn low-dimensional representations for target-typed nodes from their text attributes and topological structures by a cascaded self-supervised mechanism. Moreover, in order to overcome the limitation of preset meta-paths and reduce the extra learning cost, we also propose a selfsupervised meta-path-free algorithm with relation-based neighbor-graph contrast learning, which could produce global node representations by encoding all-typednodes and relations. These representations can be used for a variety of downstream tasks and outperform state-of-the-art baselines.Overall, this thesis provides a comprehensive review of existing representation learning methods and proposes several novel approaches based on deep learning to produce much more effective and efficient representations for text and networks.The contributions are empirically validated on several real-world datasets and tasks.

  • Other research product . Other ORP type . 2022
    Open Access English
    Authors: 
    Raadal Skov, Inge;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    Steroidtabletter er en effektiv behandling til ukontrolleret astma, men behandlingen er desværre også associeret med en lang række bivirkninger. Gennem de sidste årtier er der tilkommet mange nye behandlingsmuligheder til astma, men internationale studier viser, at steroidtabletter fortsat bliver brugt i stort omfang. Der er dog endnu ingen studier, der har belyst omfanget i Danmark. Denne afhandling er baseret på tre landsdækkende register-baserede observationsstudier af unge voksne i alderen 18-45 år i aktiv behandling for astma i perioden 1999-2018.I studie I undersøgte vi medicinforbrugsmønstre ved hjælp af årlige tværsnitsundersøgelser og fandt, at næsten én ud af tyve personer med aktivt behandlet astma indløste en recept påsteroidtabletter i løbet af ét år, og at dette stort set ikke havde ændret sig over den 20-årige periode. Når vi opdelte forbrugerne efter mængden af steroid, de havde indløst i løbet af et år, fandt vi, at storforbrug (svarende til ≥5 mg prednisolon per dag over et år) var sjældent forekommende og at den samlede mængde steroid per person generelt var faldende over perioden. Desuden blev der indløst færre lavdosis-steroidtabletter med ≤10 mg per tablet som et tegn på et faldende forbrug af lavdosisvedligeholdelsesbehandling. I studie II sammenlignede vi steroidtabletforbrugere med ikkeforbrugere og fandt, at steroidtabletforbrugerne udviklede flere sygdomme, såsom osteoporose, type 2 diabetes, hjertesvigt, med flere, og at denne risiko steg, desto højere forbrug de havde. Interessant nok så vi, at risikoen allerede steg efter lave doser svarede til ≤500 mg, hvilket svarer til kun en eller to steroidtablet-kure for akut astmaforværring. I studie III fandt vi, at 70% af personer med gentagne behandlinger med steroidtabletter ikke har kontakt med en speciallæge. Dog steg antallet af årlige nyhenviste fra 6,3% i 1999 til 18% i 2018. Patienter med ekstremt højt forbrug af anfaldsmedicin samt nylige akutte skadestuebesøg og indlæggelser blev i højere grad henvist til speciallæge. Samlet set har forekomsten af astmapatienter, der bruger steroidtabletter, været uændret gennem 20 år, men den mængde steroid, de udsættes for per år, er faldende. Forbrug af steroidtabletter er associeret med øget risiko for at udvikle en lang række sygdomme - selv ved lave doser. Kun et mindretal af forbrugerne opnår speciallægevurdering. I betragtning af de seneste årtiers store fremskridt inden for diagnostik og behandling af astma er det essentielt at sikre en optimeret ogindividualiseret håndtering af patienter med behov for steroidtabletbehandling, herunder øget fokus på steroidbesparende tiltag, tidlig håndtering af associerede følgesygdomme, og rettidig henvisning til speciallæge når indikeret. Oral corticosteroids (OCS) are effective in treating uncontrolled inflammatory diseases such as asthma, but they are unfortunately associated with serious adverse effects. Many efforts have beenmade to reduce the use of OCS in asthma over the decades, but international studies suggest OCS continue to be frequently used, and overused, in asthma management. However, limited information has been available on the OCS use among individuals with asthma in Denmark. In this thesis we have conducted three nationwide, registry-based observational studies among cohorts of young adult users of asthma medication aged 18-45 years during 1999 to 2018.In study I, we performed annual cross-sectional drug analyses and found that almost one in twenty among the annual asthma population would fill a prescription for OCS within a given year,and that this had essentially not changed over the 20-year period. However, we found that the annual cumulative exposure per user decreased. High use ≥5 mg/day (prednisolone equivalents) was rare and decreased by almost 40%. Furthermore, the usage of low-dose tablets ≤10 mg/tablet decreased markedly, indicating a reduction in low-dose maintenance use. In study II, we performed a propensity score matched study of incident OCS users compared to nonusers. We found OCS users to have an increased risk of all prespecified comorbidities with evidence of positive dose-response relationships. Interestingly, the increased risks were evident at even low cumulative exposures of ≤500 mg (equivalent to only one or two OCS exacerbation courses). Mortality rates and rates of unscheduled hospital visits similarly increased with increasing OCS exposure. In study III, we investigated thefrequency and predictors of receiving specialist care among individuals with repeated OCS use (i.e., two prescriptions within 12 months). We found that 70% of repeated OCS users did not have contact to specialised care. However, the annual frequency of referrals for specialist care almost tripled from 6.3% in 1999 to 18% in 2018. Patients with excessive use of reliever medication and recent acute asthma-related hospital visits were more likely to receive specialist care. In conclusion, the frequency of OCS use in asthma management of young adults has remained stable over a 20-year-period, but the cumulative exposure per person has decreased. OCS use isassociated with increased risk of incident comorbidities, mortality, and health care utilisation even at low cumulative doses. Only a minority of repeated OCS users are assessed by a specialist.Considering recent advances in both diagnostic tools and available treatments, it is pivotal to ensure optimised management of patients exposed to OCS with focus on OCS sparing initiatives, managing of comorbidities, and early referral for specialist care when appropriate.

  • Open Access English
    Authors: 
    Duch Kiilerich Andresen, Andreas;
    Publisher: Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
    Country: Denmark

    På grund af uoverensstemmelser i litteraturen og ingen klare retningslinjer for lumbal fusion hos ældre, havde dette ph.d.-studie til formål at undersøge resultatet og omkostningseffektiviteten af at tilføje instrumentering i lumbal fusions kirurgi hos ændre, ved behandling af degenerativt led skred med samtidig forsnævring i rygmarvskanalen. Yderligere ville vi undersøge vigtigheden af balance i sagittal planet, når der foretages stivøgrende operation på et niveau, uanset valgt fusionsmetode.MetodeEt kontrolleret lodtrækningsforsøg blev udført, her blev 108 patienter inkluderet og ved lodtrækning opdelt i to grupper. Gruppe 1 gennemgik standard midtlinjebesparende frilægning af nerverne og en uinstrumenteret stivgørende opeation med egen knogle fra frilægningen samt donorknogle udtaget i forbindelsemed hoftekirurgi Gruppe 2 gennemgik den samme standard-midtlinjebesparende frilægning af nerverne, og udover knogletransplantatet blev der udført instrumenteret operation med pedikel skruer Ved operationen besvarede patienterne et standardbatteri af spørgeskemaer, inklusive Oswestry Disability Index, EuroQoL-5D-3L, VAS-ryg og -ben, Zurich ClaudicationQuestionnaire og ShortForm36. Et lateralt 36" røntgenbillede blev taget før operationen for at måle den sagittale balance.Patienterne blev fulgt i to år efter operationen, med patientrapporterede resultater og 36" røntgenbilleder ved et- og toårs opfølgning. Ved et års opfølgning blev der udførten CT-scanning for at undersøge succesen af den stivgørende operation.Resultater Vi fandt ingen forskel mellem grupperne i funktion, livskvalitet eller smerter ved etog toårs opfølgning. Der var en markant forskel i fusionssucces til fordel for den instrumenterede fusion (94% vs. 31%) Syv patienter gennemgik reoperation i den uinstrumenterede gruppe versus én patient i den instrumenterede gruppe efter to års opfølgning. Sideløbende med lodtrækningsforsøget forsøg blev der udført en økonomisk evaluering. De samlede omkostninger for behandlingen var baseret på en journalrevision, og generering af omkostninger blev konstrueret fra bunden og op. Med en moderat stigning i kvalitetsjusterede leveår i den instrumenterede gruppe på 0.095 og en øget omkostning på €146 fandt vi et trinvis omkostningseffektivitetsforhold (ICER) på €1536, hvilket tydede på, at den instrumenteret fusion var omkostningseffektiv. Ved udførelse af sensitivitetsanalyse baseret på alle reoperationer eller når beregningen baseres på hospitalets standardtilskud for operationerne, dominerede den instrumenterede fusion med både et bedre resultat og lavere omkostninger, hvilket tyder på en moderat omkostningsbesparelse ved instrumentering. Ved undersøgelse af effekten af en præoperativ sagittale ubalance fandt vi en sammenhæng mellem balancen før operationen, og de patientbesvarede spørgeskemaer udfyldt før operationen, men der var ingen sammenhæng mellem balancen og det patient rapporterede udfald af operationen ved hverken et- eller toårs opfølgning.Konklusion Som konklusion fandt vi, at selvom der ikke var statistisk signifikante forskelle mellem grupper baseret på patientrapporterede resultater, havde patienter i den instrumenterede gruppe færre reoperationer og en højere fusionssucces sammenlignet med den uinstrumenterede gruppe. Omkostningsanalysen tyder på, at instrumenteret fusion er omkostningseffektiv med en ICER på 1536. Det konkluderes derfor at ved behandling af degenerativt led skred med spinalstenose hos ældre vil instrumenteret stivgørende operation være tilrådeligt hos patienter, hvor den stivgørende operation vurderes nødvendig. Due to inconsistencies in the literature, and no clear guidelines for lumbar fusion in the elderly, this PhD study aimed to investigated the outcome and cost effectiveness of added instrumentation in lumbar spinal fusion in the elderly, when treating degenerative spondylolisthesis. Further, we aimed to investigate the importance of a preoperative sagittal imbalance in one-level in-situ fusion, regardless of fusion method.MethodsA randomized controlled trial was performed, 108 were included and by randomization divided into two groups. Group 1 underwent standard midline sparing decompression and uninstrumented fusion, with allograft mixed with local autograftfrom the decompression, due to degenerative spondylolisthesis and spinal stenosis. Group 2 underwent the same standard midline sparing decompression, and in addition to the bone graft, pedicle screw instrumentation was performed at the index level.At surgery, patients answered a standard battery of questionnaire, including Oswestry Disability Index, EuroQoL-5D-3L, VAS-back and -leg, Zurich Claudication Questionnaire and ShortForm-36. A lateral 36” X-ray was taken before surgery, to measures preoperative sagittal balance. Patients were followed for two years after surgery, with patient reported outcomes and 36” X-rays at one- and two-year follow-up. At one-year follow up, a CT-scan was performed to investigate fusion status.Results We found no difference in disability, quality of life or pain at one- and two- year follow up. There was a marked difference in fusion rates in favor of the instrumented fusion (94% vs 31%) Seven patients underwent reoperation in the uninstrumented group versus one patient in the instrumented group, at two-year follow up. Alongside the randomized trial, a micro-adjusted economical evaluation was performed. The accumulated costs were based on a journal audit, and generation of costs were done from a bottom-up perspective. With a moderate increase in quality adjusted life years in the instrumented group of 0.095, and an increased cost of €146, we found an incremental cost effectiveness ratio of €1536, suggesting that instrumented fusion was cost-effective. When performing sensitivity analysis based on all reoperations or based on standard hospital reimbursement rates, instrumented fusion dominated uninstrumented fusion with better outcome and lower costs, suggesting a moderate cost saving with instrumentation. When investigating the effect of a preoperative sagittal imbalance, we found a correlation between preoperative sagittal vertical axis and preoperative patient reported outcomes, but there were no correlations to sagittal vertical axis and outcome at either one- or two-year follow up. Conclusion In conclusion, we found that, although there were no statistically significant differences between groups based on patient reported outcomes, patients in the instrumented group had fewer reoperations and a higher fusion rate compared to the uninstrumented group. The cost analysis suggest that instrumented fusion is cost effective with an ICER of 1536. Concluding that, in treating degenerative spondylolisthesis in the elderly, instrumented fusion would be advisable in patients where fusion is needed. 

  • Restricted English
    Authors: 
    Møller, Merete; Roos, Ewa Maria; Andersen, Lotte Nygaard; Juhl, Carsten; Kongsted, Alice; Villumsen, Martin Dalgaard;
    Publisher: Syddansk Universitet
    Country: Denmark
Send a message
How can we help?
We usually respond in a few hours.