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Afhandlingen analyserer i hvilket omfang Traktatfrihederne forpligter medlemsstaterne til at yde kompensation for underskud til koncerner og til selskaber med faste driftssteder. Afhandlingen er inddelt i otte kapitler. Afhandlingens kapitel 1 præsenterer emnet, problemformulering samt metode.Afhandlingens kapitel 2 introducerer emnet på medlemsstabsniveau. Dette kapitelintroducerer de udfordringer, som - på den ene side - den asymmetriske behandling af overskud og underskud og - på den anden side - de grundlæggende principper for beskatning skaber i relation til fradrag, som skaber et underskud. Herudover beskriver kapitlet de mest almindelige metoder, som anvendes for at yde underskudskompensation. Endelige beskriver kapitlet de udfordringer, som opstår i relation til underskudskompensation, når selskaber og koncerner udøver grænseoverskridende virksomhed. Afhandlingens kapitel 3-5 introducerer de fire friheder og redegør for, hvordan EU domstolen vurderer, om en national skattelovgivning er i uoverensstemmelse med en traktatfrihed. Kapitel 3 introducerer de fire traktatfriheder og redegør for traktatfrihedernes restriktionsbegreb, som dette fortolkes i relation til nationale regler på området for direkte beskatning. På grundlag af dette indledende kapitel uddyber kapitel 4 restriktionstesten, som består af henholdsvis ulempetesten of sammenlignelighedstesten, mens kapitel 5 uddyber justifikationstesten.Afhandlingens kapitel 6-7 analyserer EU-domstolens praksis vedrørende underskudskompensation. Kapitel 6 analyserer i hvilket omfang en medlemsstat er forpligtet til at yde kompensation for underskud lidt af koncerner i grænseoverskridende situationer. Dette afsnit analyserer således EU-domstolens praksis vedrørende horisontalekompensationsordninger samt underskudsanvendelse i forlængelse af en fusion. Kapitel 7 analyserer i hvilket omfang en medlemsstat er forpligtet til at yder kompensation for underskud lidt af et selskab med et fast driftssted. Dette afsnit analyserer EU-domstolens praksis vedrørende fradrag for underskud i det underskudsgivende indkomstår, fradrag for underskud i medfør af vertikale kompensationsordninger, genbeskatning af underskud som allerede er taget i betragtning og udskydelse af beskatning som følge af underskud. The thesis analyses to what extent the Treaty freedoms require the EU Member State to provide loss compensation to corporate groups and to companies with permanent establishments in the European Union. The thesis is divided into eight chapters. The first part of the thesis presents the subject, the research questions, the motivation for the choice of subject, delimitation and legal philosophy and methods.Chapter 2 introduces the subject on Member State-level. This chapter introduces the challenges that are caused by - on the one hand - the asymmetrical treatment of profits and loss and - on the other hand - the fundamental principles of taxation in respect of losses. This chapter further introduces the most common methods adopted in order to provide loss compensation. Finally, the chapter elaborates on the challenges that arise in relation to loss compensation when corporate groups and companies exercise cross-border activity.Chapter 3-5 introduces the four Treaty freedoms and explain how the European Court of justice examines whether a nation legislation on direct taxation violates a Treaty freedom. Chapter 3 introduces the four Treaty freedoms and explains how the European Court of Justice interprets the concept of restriction in respect of national legislation on direct taxation. On that basis, chapter 4 elaborates on the restriction test, which comprises the disadvantage test and the comparability test, while chapter 5 elaborates on the justification test.Chapters 6-7 analyses the case law of the European Court of Justice on loss compensation. Chapter 6 analyses to what extent the Treaty freedoms require a Member State to provide loss compensation to corporate groups in cross-border situations. This chapter analyses the case law on horizontal loss compensation schemes and national provisions providing for loss compensation in the context of a merger. Chapter 7 analyses to what extent a Member State is required to provide loss compensation to a company with a permanent establishment. This chapter analyses the case law concerning deductions of losses during the loss-making income year, deduction of losses by means of horizontal loss compensation schemes, reincorporation of losses previously deduction and the deferral of taxation as a consequence of losses.Chapter 8 contains the conclusion on the thesis. This chapter concludes to what extent the Treaty freedoms require the Member States to provide loss compensation to corporate groups in cross-border situations and to a company with a permanent establishment.

Kontekstuelle faktorer (Eng. contextual factors) er vigtige for at få en dybere forståelse af resultaterne fra kliniske forsøg. Gennem det globale Outcome Measures in Rheumatology (OMERACT)-initiativ er der et presserende behov for vejledning i at identificere kontekstuelle faktorer, når der udvikles såkaldte core outcome sets (dvs. et minimum set af målinger der skal foretages i kliniske forsøg). Dette førte til dannelsen af OMERACT-arbejdsgruppen, Contextual Factors Working Group.1. Først præciserede vi det overordnede formål for arbejdsgruppen og udviklede en forskningsplan (artikel I). Hovedformålet var at udvikle en operationel definition og vejledning i at håndtere kontekstuelle faktorer i forsøg indenfor reumatologi, når der udvikles core outcome sets. Derudover ønskede vi at udvikle et generisk sæt af vigtige kontekstuelle faktorer for reumatologiske forsøg.2. Vi undersøgte forskellige forståelser af begrebet kontekstuelle faktorer (artikel II). Ved hjælp af semistrukturerede interviews med 12 forskere/klinikere og 7 patienter, samt kvalitativ indholdsanalyse af interviewdataene, fandt vi to overordnede temaer, der tilsammen beskriver fire forskellige typer af kontekstuelle faktorer, hvoraf tre var relevante indenfor OMERACT.3. Vi udviklede en operationel definition af kontekstuelle faktorer (artikel III). Beskrivelserne for de tre typer blev finpudset, og vi gennemførte et Delphi-studie med 33 patienter og 128 klinikere/øvrige. Efter to Delphi-runder var der opnået konsensus. De tre faktortyper blev kaldt effect modifying -, outcome influencing - og measurement affecting contextual factors, som på dansk kan formidles som hhv. effekt-modificerende -, udfalds-influerende og målings-påvirkende kontekstuelle faktorer.4. Vi undersøgte en række patientkarakteristika for, om de kunne ændre behandlingseffekten på tværs af forsøg indenfor reumatologi, og dermed ville være effect modifying contextual factors (artikel IV). Vi inkluderede 187 randomiserede forsøg i en meta-epidemiologisk undersøgelse og fandt begrænsede data og få, potentielt misvisende, indikationer på effektmodifikation.5. Til sidst leverede vi en simpel vejledning i statistiske tests af interaktion til at identificere effektmodifikation (subgruppeeffekter) i randomiserede forsøg (artikel V). I vejledningen foreslår vi, at forsøgsrapporter i fremtiden skal estimere behandlingseffekten i forskellige subgrupper for at facilitere nuancerede opsummeringer af evidens, der på sigt kan fremme stratificeret patientbehandling.Vores operationelle definition af kontekstuelle faktorer beskriver tre typer, effect modifying -, outcome influencing - og measurement affecting contextual factors. Vi undersøgte potentielle effect modifying contextual factors på tværs af forsøg, men fandt begrænset evidens, særligt på grund af manglende data. Der er behov for konsekvent og ensartet rapportering af patientkarakteristika i forsøg og gerne estimater for behandlingseffekten i subgrupper. Vores biostatistiske vejledning kan bruges som inspiration. Dette arbejde forventes at fortsætte som tre initiativer, for at udvikle en liste med vigtige faktorer og vejledning for hver type af de kontekstuelle faktorer. Contextual factors are important for understanding trial results. Through the global Outcome Measures in Rheumatology (OMERACT) initiative of international stakeholders interested in outcome measurements and trial design, there is an urgent need for guidance on how to identify contextual factors as part of core outcome set development. This led to the formation of the OMERACT Contextual Factors Working Group.First, we clarified the overall aim of the effort and developed a research plan (paper I). Our main goal was to provide an operational definition and guidance on how to address contextual factors in rheumatology trials as part of developing core outcome sets. Further, we aimed to provide a generic set of important contextual factors that should always be considered in rheumatology trials.Second, we explored perspectives on contextual factors (paper II). Through semi-structured interviews of 12 researchers/clinicians and 7 patients, and qualitative content analysis, we found two overarching themes describing four types of contextual factors, of which three were relevant within OMERACT.Third, we developed a consensus-based operational definition of contextual factors (paper III). We refined the descriptions of the three contextual factor types and involved 33 patients and 128 clinicians/others in a Delphi survey, reaching consensus after two rounds. The contextual factor types were termed effect modifying -, outcome influencing -, and measurement affecting contextual factors.Fourth, we explored whether population characteristics modify treatment response across trials within rheumatology and, hence, may be effect modifying contextual factors (paper IV). We included 187 trials in a meta-epidemiological study and found limited data and few, potentially spurious, indications of effect modification.Finally, we provided a concise and nontechnical (biostatistics) tutorial on the use of statistical tests for interaction to identify effect modifiers (subgroup effects) in randomized trials (paper V). We propose that trial reports in the future should include treatment effect estimates for subgroups to facilitate better evidence synthesis on stratified medicine.In conclusion, our consensus-based operational definition of contextual factors describes three types, effect modifying -, outcome influencing -, and measurement affecting contextual factors. When exploring potential effect modifying contextual factors across trials, we found limited evidence, mainly due to lack of data. There is an urgent need for consistent reporting of population characteristics in trials and, preferably, treatment effect estimates for subgroups. Our simple hands-on guide for investigating effect modifiers may be used as inspiration. This work is expected to continue as three separate workstreams for developing consensus-based generic lists of important factors and guidance for each contextual factor type.

Blærebetændelse er en hyppig infektionssygdom i Danmark og rammer personer i alle aldersgrupper. Selvom blærebetændelse let kan behandles med antibiotika vil sygdommen ofte vende tilbage og vi ved ikke meget om hvorfor nogle personer, som er ellers sunde og raske, bliver ramt og ikke andre. På hospitalerne er blærebetændelse også den hyppigste hospitals-erhvervet infektionssygdom som i høj grad kan tilskrives det store forbrug af urinvejskatetre. Blærebetændelse udgør således et stort problem både i samfundet og på hospitalerne.Målet med dette ph.d.-projekt var at udvikle og optimere en blærebetændelse-model i grise og karakterisere infektionsforløbet og patogenesen i dette dyr mhp. at afdække grisens muligheder som translationel dyremodel inden for denne sygdom.I modellen anvendtes konventionelle hun-grise (Landrace x Yorkshire) på ca. 40 kg. Infektionen blev induceret via transurethral inokulation (via blærekateter) med uropatogene E. coli (UPEC). Grisene blev inokuleret med aftagende mængder bakterier for at identificere det mindste nødvendige inokulum og derved karakterisere grisensfølsom over for blærebetændelse. Ved at bruge en ΔFimH mutant blev betydningen af type-1 fimbriae undersøgt. Tilstedeværelsen af intracellulære bakterier blev undersøgt ved at behandle (med antibiotika) inficerede griseblærer ex vivo eller in vivo og herefter mikroskopere med konfokal laser scanning mikroskopi samt ved udpladning af homogeniseret blærevæv. Grisemodellen blev også tilpasset til at facilitere et studie med et nyt antimikrobielt blærekateter.Resultaterne er sammenskrevet i 5 manuskripter (3 publikationer og 2 manuskripter under fagfællebedømmelse) og viser at grise er meget følsomme for UVI og at kun ganske få bakterier er tilstrækkeligt til at give ophav til blærebetændelse. infektionspotentialet er meget afhængigt at type-1 fimbriae, da ΔFimH mutanten var betydeligt svækket. Intracellulære bakterier kunne ikke påvises I blærevæv. I katetermodellen var det antimikrobielle kateter I stand til at forhindre infektion i alle grise til sammenligning med kontrol grise som alle udviklede blærebetændelse.Konklusionen er, at blærebetændelses-modellen i grise er en pålidelig model som afspejler mange vigtige parametre ved human infektion. Derfor er grisen velegnet til patogenese-studier og som præ-klinisk model til at validerer nye behandlinger mod blærebetændelse. Herudover viser studierne at der er betydeligeforskelle i patogenesen, særligt i forhold til den intracellulære kolonisering, mellem mus og grise og indikerer herved at resultater fra mus ikke altid kan ekstrapoleres direkte til større dyr. Urinary tract infection (UTI), in particular cystitis, is a widespread disease in Denmark and the whole world and occurs in all age groups [1]. UTIs constitutes the most common nosocomial infection, the most common cause of sepsis and accounts for approximately 3000 deaths every year in Denmark alone [3, 133]. Community-acquired UTIs are characterized by a high frequency of recurrence, even in otherwise healthy women with no apparent risk factors [1].A part from epidemiological data, much of what we know about the pathogenesis of UTI comes from experimental studies in cell-culture based assays and murine models of cystitis. In these models, uropathogenic Escherichia coli (UPEC), the most common etiological agent of UTI, has been shown to invade bladder epithelial cells forming intracellular dormant reservoir [134]. In mice, these reservoirs can survive antibiotic treatment and seed re-infections [121]. The intracellular pathogenic cascade has been suggested as a plausible explanation to recurrent UTIs in humans as well. However, despite being extensively demonstrated in mice through the last 20 years, only very few studies has indicated a similar pathogenesis in humans and the hypothesis have struggled to become accepted in clinical societies [134-137]. This may in part be explained by an increasing skepticism towards the translatability of murine models to human disease [4].To bridge the gap between mice and humans, this Ph.D project aimed to investigate UPEC pathogenesis, including the intracellular pathogenic cascade, in a new large animal model of UTI in pigs. Pigs have been highlighted as excellent models of infectious diseases and share more similarities to humans in terms of genetics, immune physiology and urinary tract anatomy compared to their rodent counterpart [7]. Female domestic pigs (Landrace x Yorkshire, mix) of roughly 40 kg were used here. The pigs were inoculated through a urinary catheter with UPEC to induce cystitis. Pigs were inoculated with varying concentrations of bacteria to determine minimal infectious inoculum, i.e. the susceptibility to infection. Furthermore, by using a mutant lacking the T1F, one of the most well-described virulence factors of UPEC, the influence of thisfimbriae on infectious outcome was assessed in the porcine model. To investigate the intracellular pathogenic cascade, whole-bladders from infected pigs were investigated for the presence of intracellular bacteria following ex vivo and in vivo antibiotic treatment by analyzing splayed bladders with confocal laser scanning microscopy and plating homogenized tissue samples. Lastly, the model was adapted to facilitate studies of catheter-associated UTI (CAUTI), and with this, an efficacy study of a novel antimicrobial catheter was performed. The results are consolidated in 5 manuscripts (3 published papers, 2 in peer-review) and show that pigs are highly susceptible to UTI, with only a few single bacteria of UPEC capable of successfully infecting this animal. This infectious potential is largely dependent on T1F, as the T1F-deficient mutant was strongly attenuated. Surprisingly, we found no evidence of intracellular persistence upon antibiotic treatment. In the CAUTImodel, we demonstrate proof-of-concept of an antimicrobial bladder catheter that effectively prevented CAUTI in all pigs.In conclusion, the pig represents a robust model that recapitulates important aspects of human UTI. Thereby, the model is appropriate for studies of UTI pathogenesis as well as pre-clinical efficacy studies of new therapeutic treatments or interventions against UTI. Furthermore, the results of these studies show important differences in UTI pathogenesis between mice and pigs, particular in relation to intracellular persistence and thereby support that results from experiments in mice should be interpreted with caution.

Conduct problems in adolescence is a well-known phenomenon where a range of negative behaviors can have multiple detrimental effects on the youth themselves, their family members and surroundings. Callous-unemotional (CU) traits have been linked to more severe and persistent antisocial behaviors and are characterized by a lack of empathy, a lack of remorse and guilt, a lack of concern in performance and shallow affect (Frick et al., 2014). Research suggests that there might be a distinct developmental pathway for conduct problems in children with CU traits, evidenced by both neurobiological and -psychological indicators (Frick et al., 2014). This has warranted the addition of the CU-specifier “with limited prosocial emotions” to the conduct disorder. CU traits might thereby provide a more nuanced assessment of risk factors associated with conduct problems and could assist in providing more optimal treatments for youth with these characteristics.This PhD-dissertation had three aims related to CU traits in adolescents. The first aim was to assess the construct validity of a commonly used measure of CU traits, the Inventory of CallousUnemotional traits (ICU), in a Norwegian sample of at-risk adolescents. The second aim was to assess the degree to which CU traits are linked to treatment outcomes among adolescents with behavior problems who receive Functional Family Therapy (FFT). The third aim was to assess the degree of change in CU traits for adolescents participating in FFT. The analyses were based on data from a single group pre-post evaluation of FFT in Denmark (N=407), and a randomized controlled trial of FFT in Norway (N=159-160). Aim 1: The construct validity of the Norwegian translation of the ICU. Previous research is somewhat inconsistent regarding the factorial structure of the ICU and the items on the Unemotional subscale have been particularly scrutinized. The first paper included in this thesis (Paper 1) thus studied the construct validity of the Norwegian translation of the ICU. A multi-informant sample of 160 adolescents and their parents and teachers provided the data for this study. The results from Paper 1 showed that a two-factor solution of a Callousness factor and an Uncaring factor provided the best fit to the model across respondent groups. The Callousness factor was most strongly related to anti-social behavior, while the Uncaring factor was most strongly related to the lack of fear. Despite these distinct correlational patterns, the two-factor structure could be the result of a common method-variance effects related to whether items were standard- or reverse-scored. It is therefore likely that CU traits are best operationalized as a unidimensional measure. Aim 2: The relationship between CU traits and treatment outcomes. The degree to which CU traits impact treatment outcomes for adolescents with behavior problems was the focus of the remaining papers of this thesis (Paper 2 and Paper 3). In both of these there was little evidence to suggest that CU traits were linked to diminished treatment outcomes. On the contrary, CU traits were linked to steeper decreases in anti-social behavior and steeper increases in prosocial behavior in Paper 2. In Paper 3, the relationships between CU traits and treatment outcomes became non-significant when controlling for baseline levels of behavior problems. One possible explanation for these findings is that adolescents with CU traits have more problems at baseline and thereby a greater potential range of improvement. Importantly, the results in Paper 3 showed that although CU traits were either neutrally or positively related to treatment outcomes, baseline CU traits were still predictive of problematic behavior at the end of treatment. This suggests that adolescents with elevated levels of CU traits could be in need of more tailored and long-term services to sustain behavioral improvements over time. The impact of CU traits on treatment outcomes was not different when comparing FFT treatment to an active control condition, when only looking at those with clinical levels of externalizing problems at the start of treatment or when comparing primary to secondary CU subtypologies.Aim 3: The malleability of CU traits. With respect to whether CU traits change over the course of treatment, the results from Paper 2 and Paper 3 were somewhat mixed. In both papers the overall change in CU traits across treatment was small, and a reliable decline in CU traits was observed in relatively few adolescents. At the same time, both papers found more pronounced reductions in CU with respect to both magnitude and the proportion of participants with reliable decreases in CU traits among the subset of adolescents with increased CU traits at baseline. This suggests that CU traits could act as a moderator of the malleability of CU traits. There were no differences in the malleability of CU traits when comparing FFT treatment to an active control condition and when comparing primary to secondary CU sub-typologies.Conclusion: The results from this PhD-dissertation point to the need for continued development of measures of CU traits in both research and clinical settings. Furthermore, the results suggest that adolescents with behavior problems and CU traits do benefit from evidence-based and high-quality treatment, through observed declines in aggressive and rule breaking behavior as well as increases in social skills. Such behavioral improvements seem obtainable without a reduction in the CU traits themselves, as the results indicate that CU traits seem to be relatively stable across time even in the context of treatment. Future work should study the possible benefits of prolonged interventions that specifically target CU-associated risk factors in adolescents, to see if behavioral improvements beyond those obtainable in evidence-based programs and high-quality treatments can be reached. The way in which a reduction in CU traits can be achieved and lead to long-term positive outcomes is also of great importance.

Hvad kan bibelsk eksegese og acceleratorfysik bruge hinanden til? For at øge forståelsen af Dødehavsrullerne er det afgørende med et håndtryk henover kløften mellem humaniora og naturvidenskab

Baggrund: Ved primær implantat-baseret rekonstruktion af brystet anvendes hovedsageligt to kirurgiske metoder: implantatet kan placeres over eller under m. pektoralis major. Placering under m. pektoralis major har gennem tiden været den mest anvendte metode. Årsagen til dette er, at implantatet herved beskyttes af den overliggende muskel hvilket både aflaster den overliggende hud samt nedsætter raten af kapseldannelse. Den submuskulære placering af implantat kan dog også være forbundet med forskellige risici, bl.a. forvrængning af brystet, et fænomen der på engelsk kaldes ”breast animation deformity” (BAD). Denne forvrængning opstår pga. en ufrivillig sammentrækning af brystmusklen som herved trykker på det underliggende implantat. Denne sammentrækning og følger heraf, kan medføre muskelspasmer, smerte og kosmetiske generherunder displacering af enten brystvorten, forvrængning af huden over implantatet eller en unaturlig forskydning af hele brystet. Bryst forvrængning, BAD, kan sandsynligvis undgås hvisman i stedet lægger implantatet over m. pektoralis major. Denne metode er mere skånsom idet man undgår at fridissekere musklen fra thorax væggen og i stedet beskytter og fastholder implantatet ved brug af et syntetisk eller biologisk net. Selvom præmuskulær placering af implantatet synes at minimere udviklingen og graden af BAD, er metoden dog ikke uden risici og komplikationer. Det tyndere vævs dække over implantat kan bl.a. medføre synlige implantat kanter og måske en øget risiko for udvikling af ptose. Målet med dette Ph.d.-projekt har været at undersøge og sammenligne hyppigheden og sværhedsgraden af BAD imellem to grupper som har fået foretaget primær implantat-baseret brystrekonstruktion med enten submuskulær eller præmuskulær placering af implantatet. Materiale & metode: Vi gennemførte tre studier der hver især havde til formål at undersøge hyppigheden af BAD efter brystrekonstruktion; et litteraturstudie, et retrospektivt studie og et prospektivt randomiseret klinisk forsøg. Hovedfokus i det retrospektive- og prospektive studie var at estimere hyppigheden og sværhedsgraden af BAD ved brug af vores dertil nyudvikledegraderingsskala kaldet ” the Nipple, Surrounding skin, Entire breast (NSE) grading scale”. Sekundært hertil undersøgte og sammenlignede vi i det randomiserede studie også forekomsten af postoperativ smerte, komplikationer, kvindernes livskvalitet og den patientrapporterede tilfredshed, samt en sammenligning af patient rapporteret kosmetisk evaluering af operationsresultater.Resultater: Overordnet set viste alle tre studier det samme; alle patienter rekonstrueret med submuskulær placering af implantatet havde en eller anden grad af BAD. Patienter rekonstrueret med præmuskulær placering havde signifikant mindre forekomst af BAD men forekomsten blev ikke fuldstændig elimineret. De patienter som var rekonstrueret med præmuskulær placering af implantatet og som blev vurderet til at have BAD, havde en mild grad BAD (grad 1-2). Patienterne i den submuskulære gruppe scorede en højere grad af smerte de første tre postoperative døgn, men der var ingen forskel i smerteniveau mellem grupperne efter 3 måneder. Antallet og graden afpostoperative komplikationer var sammenlignelige imellem grupperne. Patienternes vurdering af livskvalitet og tilfredshed efter indgrebet var høj uanset om implantatet var placeret sub- eller præmuskulært. Ved anvendelse af BREAST-Q fandt vi ingen signifikante forskelle mellem præoperativ og postoperativ livskvalitet og tilfredshed pånær i det domæne der omhandlede seksuel livskvalitet. Ligeså fandt vi ingen forskel mellem den præ- og submuskulære gruppe i den patientrapporterede kosmetiske evaluering. Ved kosmetisk evaluering udført af kirurgerne var derdog en tendens til, at den præmuskulære gruppe scorede højere efter 12 måneder. Konklusion: Alle patienter i den submuskulært rekonstruerede gruppe blev vurderet til at have en eller anden grad af BAD. Komplikationsrater og kosmetiske resultater var sammenligneligeimellem grupperne og ligeså, fandt vi en høj patient tilfredshed og en høj livskvalitet uafhængigt af implantatets placering. Forekomsten af BAD virker altså ikke til at have de gener for patienterne som vi tidligere har troet de havde, og set fra et klinisk perspektiv danner de præsenterede data et fundament for at kunne anvende og tilbyde begge metoder til implantatbaseret brystrekonstruktion. For med sikkerhed at kunne fastslå relevansen af vores fund ville en større patientkohorte og enlængere opfølgning dog være at foretrække. Ligeså var vores delmål sekundære og et studie primært designet til at undersøge bl.a. livskvalitet og tilfredshed ved brug af BREAST-Q ville væreat foretrække. Background: When performing direct-to-implant breast reconstruction (DIR) two methods are mainly used. The dual plane subpectoral implant pocket is well described and considered reliable due to a thick vascularized tissue cover protecting the implant. The submuscular plane is however associated with a risk of developing breast animation deformity (BAD), an unwillingly contraction of the pectoralis major muscle (PMM). This contraction can lead to muscle spasms, pain, and an aesthetically unattractive distortion of the nipple areolar complex (NAC), breast skin and/ormovement of the entire breast. The prepectoral plane is less invasive and has in combination with a biological or synthetic mesh shown outcomes comparable to reconstruction using subpectoral implant placement. The avoidance of muscular release might mitigate BAD, however new challenges may occur due to the thinner implant cover. The primary aim of this PhD project was to assess and compare the incidence and degree of BAD in women reconstructed by either subpectoral or prepectoral DIR.Material and methods: We conducted three separate studies investigating the incidence of BAD; A systematic literature review, a retrospective study, and a randomized clinical trial (RCT). The focus of the retrospective study and the RCT was to assess the incidence and degree of BAD between sub- and prepectorally reconstructed women utilizing our novel developed BAD grading scale: the Nipple, Surrounding skin, Entire breast (NSE) grading scale. The secondary outcome measures in the RCT included pain and complications, health-related quality of life (HRQOL) and patient satisfaction as well cosmetic evaluation. Results: The combined results showed that all patients reconstructed by subpectoral implant placement had some degree of BAD. Patients reconstructed by prepectoral implant placement were less prone to suffer from BAD, however the incidence of BAD was not totally mitigated. All the prepectorally reconstructed women which were assessed to have a degree of BAD, were graded with a mild degree of BAD. We found comparable complication rates between the sub- and prepectoral reconstructed groups. The level of postoperative pain was higher in the subpectoral group the first three postoperativedays, but there were no differences three months postoperative. Likewise, patients had a high HRQOL, and overall satisfaction assessed by the BREAST-Q. We found no differences betweengroups at any timepoint besides in the domain sexual well-being. Lastly, regardless of pocket plane, patients evaluated their cosmetic outcome equally high. When evaluation was done by the surgeon, we found a significant difference in cosmetic outcome at twelve months in favor of the prepectoral group.Conclusion: All patients reconstructed by the subpectoral implant placement showed some degree of BAD, whereas the majority of the prepectoral group did not reveal any degree of BAD. Ourresults furthermore demonstrated equal complications rates and comparable cosmetic outcomes between groups. Likewise, we found a high patient satisfaction showing no difference in HRQOLbetween groups. It seems BAD might not bother the patients as much as we have previously thought. From a clinical perspective, we believe the presented data allows us to offer both methodsfor DIR. Studies with larger cohorts and a longer follow-up are however warranted to fully determine the clinical significance of these findings. Furthermore, HRQOL was a secondary outcome measure in our study and a RCT utilizing the BREAST-Q to investigate HRQOL between sub- and prepectorally reconstructed groups as the primary outcome would be preferable.

10.1 BaggrundAlvorligt syge og/eller svækkede patienter bliver ofte indlagt på danske sygehuse uden dokumentation for ønsker om behandlingsniveau. Dette kan føre til potentielt byrdefuld, ikke-gavnlig og/eller uønsket behandling.10.2 FormålDette studie sigter mod at udvikle og teste et dansk POLST-dokument for at forbedre samtalerne mellem patienten og den behandlende læge om præferencer for behandlingsniveau. Dette er for at sikre, at patientens ønsker er kendte og dokumenterede. Dokumentet er baseret på et amerikansk POLST-dokument og adresserer patienters ønsker vedrørende genoplivning, medicinsk behandling og ernæring.10.3 MetodeDette multi-method studie udvikler og tester et Dansk POLST dokument. Indsamler og analyserer resultaterne fra POLST dokumenter og spørgeskemaer, fulgt op af semistrukturerede individuelle interviews. Kvantitative data analyseres ved hjælp af deskriptiv statistik. Tematisk analyse er den analytiske strategi for kvalitative data. I den kritiske fortolkning og diskussion af data blev resultaterne og temaerne der var udledt af studiet yderligere fortolket og diskuteret i forhold til relevant forskning og teorier.10.4 Resultater10.4.1 Artikel IDen danske version af POLST dokumentet blev af patienter, pårørende, læger og sygeplejersker vurderet som læsevenlig, forståelig og brugbar til at diskutere og dokumentere danske patienters præferencer for behandlingsniveau. De fleste patienter ønskede ikke et genoplivningsforsøg og valgte udvalgt behandling, samt ingen ernæring i sonde eller drop. Dette skal dog bekræftes i en større undersøgelse. For at kunne diskutere ønsker for behandlingsniveau blev et anvendeligt og overskueligt dokument opfattet som vigtigt af deltagerne. 10.4.1 Artikel IIDe fleste alvorligt syge patienter ønskede ikke et genoplivningsforsøg og valgte udvalgt behandling, samt ingen ernæring i sonde eller drop. Ønskerne for behandlingsniveau var ens inden for aldersgrupper, køn og projektsteder, men med en tendens til, at yngre patienter foretrak fuld behandling og plejehjemsbeboere foretrak genoplivning. Flertallet af deltagerne fandt, at den danske POLST var brugbar til diskussion og beslutningstagning for behandlingsniveau i høj eller meget høj grad, og at POLST-dokumentet gjorde det muligt at tale åbent om ønsker for behandlingsniveau.10.4.1 Artikel IIIPatienter og læger fandt det værdifuldt at have en samtale om niveauer for behandling. Pårørende blev betragtet som nøglepersoner. De vigtigste udfordringer var tidspunktet for samtalen, samt at sikre sig tilstrækkelig viden til fælles beslutningstagning. Det vigtigste perspektiv ved samtalen var at styrke patientens autonomi.10.5 KonklusionDen danske version af POLST dokumentet blev af patienter, læger, pårørende og sygeplejersker vurderet som læsevenlig, forståelig og brugbar til at diskutere og dokumentere danske patienters præferencer for behandlingsniveau. Flertallet af deltagerne fandt, i høj eller meget høj grad, at den danske POLST var brugbar til diskussion og beslutningstagning om behandlingsniveau i den sidste tid.De fleste alvorligt syge patienter ønskede ikke et genoplivningsforsøg og valgte udvalgte behandlinger, samt ingen ernæring i sonde eller drop. Ønskerne om behandlingsniveau var ens inden for aldersgrupper, køn og projektsteder, men med en tendens til, at yngre patienter foretrak fuld behandling og plejehjemsbeboere foretrak genoplivning. Pårørende blev betragtet som nøglepersoner. De vigtigste udfordringer var tidspunktet for samtalen, samt at sikre sig tilstrækkelig viden til fælles beslutningstagning. POLST dokumentet gjorde det muligt at tale åbent om ønsker for behandlingsniveau. Det vigtigste perspektiv ved samtalen var at styrke patientens autonomi. 9.1 BackgroundSeriously ill or frail patients are often admitted to Danish hospitals without documentation of wishes for levels of treatment. This may lead to potentially burdensome, non-beneficial, and/or unwanted treatment. 9.2 AimThis study aims to develop and test a Danish POLST form to enhance conversations between the patient and their treating physician about preferences for life-sustaining treatment and ensure the patient´s wishes are known and documented. The form is based on the US POLST form, and addresses patients´ preferences regarding cardiopulmonary resuscitation, medical treatment, and nutrition.9.3 MethodsThis multi-method study collects and analyses the results from POLST forms and questionnaires, followed up by semi-structured individual interviews. Quantitative data will be analysed using descriptive statistics. Thematic analysis is the analytic strategy for qualitative data. In the critical interpretation and discussion of the data, the results and themes derived from the study were further interpreted and discussed relative to relevant research and theories. 9.4 Results9.4.1 Paper IThe Danish version of the POLST form was assessed as readable, understandable, and useful in obtaining and documenting Danish patients’ preferences for life-sustaining treatment by patients, relatives, physicians, and nurses. The majority patients did not want a resuscitation attempt, opted for selected treatments and no artificial nutrition. However, this needs to be confirmed in a larger scale study. To be able to discuss wishes for life-sustaining treatment, a manageable and clear document was perceived as important by the participants. 9.4.1 Paper IIThe majority of seriously ill patients did not want a resuscitation attempt, opted for selected treatments and no artificial nutrition. The wishes for life-sustaining treatment were similar within age groups, genders, and locations, apart from younger patients being more in favour of a ‘full treatment’ and nursing home residents mostly preferring cardiopulmonary resuscitation. The majority of participants found that the Danish POLST was usable for conversations and decision-making about life-sustaining treatment to either a high or very high degree, and reported that the POLST form facilitated an opportunity to openly discuss life-sustaining treatment.9.4.1 Paper IIIPatients and physicians found having a conversation about levels of life-sustaining treatment valuable, especially for strengthening patient autonomy. Relatives were considered key persons. The timing of the conversation and securing sufficient knowledge for shared decision-making and documentation of the wishes was the main perceived challenges. The most important aspect of the conversation was strengthening patient autonomy. 9.5 ConclusionThe majority of participants found that the Danish POLST form was readable, understandable and useful for facilitating conversations and make decisions about life-sustaining treatment to either a high or very high degree. The POLST form facilitated an opportunity to openly discuss life-sustaining treatment.The majority of seriously ill patients did not want a resuscitation attempt and opted for selected treatments and no artificial nutrition. The wishes for life-sustaining treatment were similar within age groups, genders and locations, but with a tendency toward younger patients in favor of full treatment and nursing home residents more in favor of cardiopulmonary resuscitation. Relatives were considered key persons. The main challenges perceived were timing of the conversation and securing sufficient knowledge for shared decision-making and documentation of the wishes. The most important aspect of the conversation was strengthening patient autonomy.