Doctoral Theses from University of Gothenburg / Doktorsavhandlingar från Göteborgs universitet
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Item Combining Action Research and System Dynamics to facilitate change and improvement processes in healthcare(2022-09-30) Holmström, PaulBackground The healthcare sector is under considerable pressure for cost savings and to increase efficiency. Healthcare is complex with staff of multiple professions and a variety of patient care pathways. Time pressure and minimal margins for errors, as well as tension between the hierarchical structure and the power of the professions, can make it challenging to implement new policies or procedures. Action Research (AR) is frequently used to engage staff in change processes. Outside Sweden, System Dynamics (SD) is often used to model and simulate complex issues in healthcare. Group Model Building using SD has been established to engage staff in the modelling but requires learning of the basics of SD by the participants. To overcome this barrier, it is desirable to develop methods to use SD modelling integrated into AR projects, but little research has been published about this. The overall purpose of this thesis is to deepen the understanding of using SD, by itself or combined with AR, to support groups of healthcare professionals and researchers working with change and improvement processes. Materials and methods Two research projects and five improvement cases in healthcare were studied. The research projects used SD methodology to study disease characteristics and preventive effects by different interventions. Epidemiological data from disease-specific quality registers, scientific publications, and hospital systems were used. The cases were re-analysed in depth by a multidisciplinary work group (SD, AR, medical sciences) using iterative abductive qualitative methodology. A structure for studying consultative projects was used to identify steps in the workflows of the cases. Socioanalytical questions were used to bridge between the AR and SD perspectives. Results The two research projects were epidemiological in nature and the simulations made it possible to study phenomena which were difficult to isolate and examine in reality. The projects resulted in models depicting disease trajectories which were used to test different scenarios and suggest relevant clinical interventions. In the five improvement cases, AR contributed to high levels of engagement among the participants and to the building of confidence in and ownership of the results. AR also ensured that the SD models were adequate, relevant, and rooted in reality. SD provided a coherent and consistent systems overview of the complex and complicated structure of each improvement case, offered causal rigor, and provided ample opportunities for reality checks. During the cases, the two methods were deeply integrated and always present in experiential learning processes. In both the research projects and the improvement cases, workflows and model development were adapted to each group. All cases went through divergent and convergent phases leading to shared points of reference, “project and case specific multiprofessional knowledge repositories”. It was ensured that the voice of each participant was heard and that this inspired engagement, interaction, and exploratory mutual learning activities. The facilitator had an intermediary role, acting as an "interpreter" between the group and the simulation model, ensuring that the model elucidated the issues at hand. Mutually agreed solutions were tested in silico. Conclusions The two research projects demonstrated that SD is well-suited for policy planning of disease prevention in Swedish healthcare. The methodology is cost effective and allows simulations to be carried out in silico for testing without risk to patients or organisational efficiency. It also increases the understanding of systemic interdependencies between various patient-related and intervention-related factors for different diseases. Policymakers can for instance be assisted in choosing the intervention with greatest preventive impact by being presented with likely effects from expected or plausible scenarios. The five improvement cases showed that integrating SD into AR for problems in healthcare can achieve useful, comprehensive, and robust outcomes. Results by this methodology will, by design, be calibrated to local needs and circumstances and is thereby likely to improve chances of sustained actualisation. The addition of simulations will increase certainty about expected results and speed up the problem-solving process.Item Digitala sexuella trakasserier i skolan: Elevperspektiv på sexting, utsatthet och jämställdhet.(2022-02-24) Hunehäll Berndtsson, KristinaAtt sexta, innebär att dela självproducerade foton eller videoklipp med naket eller halvnaket innehåll av sexuell karaktär. Delningen sker genom att en person själv skickar, tar emot eller vidarebefordra sexuella foton eller videoklipp. Samhällsfenomenet ”dickpics” är en specifik form av sexting och handlar om när pojkar skickar bilder av könsorgan. När flickor skickar nakenbilder på motsvarande sätt benämns dessa bilder oftast som ”nudes”. Sexting kan upplevas som kränkande om samtycke saknas. Digitala sexuella trakasserier definieras i avhandlingen som bild- eller filmbaserade sexuella trakasserier. Avhandling är en sammanläggningsavhandling bestående av tre fackgranskade artiklar och ett fackgranskat bokkapitel. Delstudierna syftar till att undersöka elevers erfarenheter av sexting och digitala sexuella trakasserier i årskurs 9 och hur dessa erfarenheter påverkar ungdomarna, både individuellt och som grupp. Studien är designad som en fallstudie innehållande tre grundskolor, belägna i olika socioekonomiska och geografiska områden i Sverige. Elevernas berättelser av forskningsämnet har samlats in genom fokusgruppsintervjuer, parintervjuer och individuella intervjuer. Teoretiska perspektiv på kön, klass, sexualitet, sexuella trakasserier och sårbarhet används för att undersöka maktförhållanden i ungdomars sociala relationer inom skolan. Avhandlingen visar att både flickor och pojkar utsätts för digitala sexuella trakasserier i skolvardagen. Problematiken är komplex, beroende på att sexting missbrukas på ett flertal olika sätt. Via Snapchat får elever oönskade dickpics och nudes skickade till sig från skolkamrater. Nakenbilder eller videoklipp som först skickats i samförstånd mellan två personer, kan senare missbrukas genom att de olovandes delas med andra. Elever blir också lurade eller hotade av skolkamrater till att skicka nakenbilder eller sexuella videoklipp; explicita sextingmeddelanden som sedan visas upp bland kamrater eller sprids på skolan. Resultatet indikerar att elevernas erfarenheter av sextingproblematik tar sig delvis skilda uttryck på de olika skolorna. Skillnaderna kan förstås utifrån dominerande klass- och könsnormer inom de lokala skolkulturerna. Ungdomar saknar däremot ofta både socialt stöd och tillfredställande strategier för att bemöta och hantera digitala sexuella trakasserier i skolvardagen. För utsatta elever kan följderna bli svåra, både emotionellt och socialt, de löper risker som slutshaming, mobbning och psykisk ohälsa.Item Excited state dynamics in the strong coupling regime(2022-02-24) Mony, JürgenStrong exciton-photon coupling exhibits the possibility to modify photophysical and photochemical properties of organic molecules without changing their structure. This is due to the formation of hybrid light-matter states, called polaritons, which are created when the strong coupling regime is achieved. The polaritons inherit properties from both parts, light and matter, resulting in unique properties. In this thesis, the excited state dynamics of different strongly coupled systems are presented. The emission lifetime of polaritons were explored by optical spectroscopy. Their emission lifetime showed to be independent of both their excitonic/photonic constitution and the measuring angle. These findings support the theory of the exciton reservoir theory. Furthermore, the impact of strong light-matter interactions on the photoisomerization quantum yield of a photoswitch was examined. The photoisomerization quantum yield showed a dependence whether the system was excited at the lower or upper polariton and on the photonic/excitonic constitution of the polariton. When exciting the upper polariton, the quantum yield was unperturbed whereas it dropped significantly when exciting the lower polariton. Finally, the formation of aggregated states in the strong coupling regime were studied. It was observed that the emission can be controlled by simply altering the photonic and excitonic contribution to the lower polariton. A higher excimer emission was seen for samples, whose lower polariton have a higher excitonic character, whereas a higher photonic contribution resulted in an enhanced polariton emission. The deeper understanding of the excited state dynamics in the strong cou- pling regime might result in higher performances in optical applications such as TTA upconversion or singlet fission. Furthermore, the deepened knowledge can unveil the potential of the arising field of polaritonic chemistry.Item Acquired Epilepsy with a Focus on Stroke: Treatment and Prognosis(2022-02-23) Larsson, DavidThe relationship between epilepsy and stroke is complicated. While stroke is a major cause of epilepsy after middle age, there is also evidence that the risk of stroke is increased in persons with epilepsy. The overall aim of this dissertation is to elaborate on the prognosis and treatment of epilepsy in older adults and its association to stroke. It is based on four studies which have been conducted using information from linked national registers, which offer unique opportunities to follow thousands of patients over a long period of time. The results from Papers I-II indicate that a significant proportion of all new-onset seizures after middle age will herald a subsequent stroke. Using incidence data and population statistics, we estimated the 10-year risk of stroke to be between 5-20%, depending on age group. In relative terms, the risk appears to be almost two-fold (odds ratio [OR] 1.77; 95% confidence interval [95%CI] 1.65-1.89) compared with age-matched controls from the general population – and highest during the first year after seizure onset (OR 2.21; 95 % CI 1.79–2.72). The studies described in Papers III-IV examined prognostic aspects of antiseizure medication (ASM) therapy in poststroke epilepsy. Paper III found the 5-year retention rate to be highest for lamotrigine (0.75, 95%CI 0.70–0.79) and levetiracetam (0.69, 95%CI 0.63–0.74), suggesting these drugs are well tolerated in this patient group. Paper IV used a similar methodology but investigated if mortality varied with different ASMs in monotherapy. Patients treated with lamotrigine had lower mortality (hazard ratio [HR] 0.72, 95%CI 0.60-0.86) than the reference group treated with carbamazepine, while patients treated with valproic acid had higher mortality (HR 1.40, 95%CI 1.23-1.59). Treatment with levetiracetam was associated with a reduced risk of cardiovascular death compared to carbamazepine (HR 0.77, 95%CI 0.60-0.99). In conclusion, this thesis supports a tailored management approach in adults with new-onset seizures late in life, particularly in those with a history of stroke. Persons with late-onset seizures have high vascular risk, potentially warranting screening and treatment for vascular risk factors. Moreover, the association between ASM selection and mortality raises concerns about clinically relevant drug-drug or drug-disease interactions that may modify vascular risk. Overall, lamotrigine and levetiracetam seem sensible initial treatment options in this patient group.Item lmprovement in perioperative care of the day case patient; logistics and quality of care.(2022-02-23) Sellbrant, IrénBackground: The “Day surgery concept” is increasing and nowadays numerous of surgical procedures in patients of all ages, with different comorbidities are performed as day case surgery. Day surgery (DS) is a process; not a procedure. Anaesthetic method, multi-modal analgesia, new surgical minimally invasive techniques and a mind-set to facilitate a rapid recovery are all of importance. Thus, multiple factors influence a safe, effective and successful perioperative course combining high quality of care with rapid recovery, enabling patients to be safely discharged on the day of surgery. Aim: To investigate how different parts of the perioperative care per se affects resource utilisation, logistics and quality of recovery in three common DS procedures. Methods: Paper I; A retrospective observational study in patients scheduled for pelvic organ prolapse (POP) surgery assessing discharge on day of surgery, impact of “annual changes” (2012-14) and anaesthetic techniques in 4 different hospitals. Paper II; A prospective randomised study in male patients scheduled for open hernia repair assessing the impact of surgical scrub/sterile covering before vs. after induction of general anaesthesia on haemodynamic changes, medication, logistics and quality of care. Paper III; A prospective randomised study performed on patients scheduled for surgery of distal radial fractures (DRF) investigating the impact of 3 different anaesthetic methods on postoperative pain, postoperative opioid consumption and logistics the first postoperative week. Paper IV; A subgroup of study III patients, prospectively randomised to 2 different immobilisation methods, brace vs cast, assessing patients self-assessed Quality of recovery (QoR-15), postoperative opioid use and logistics the first postoperative week. Results: Paper I; The use of local anaesthesia and sedation (LAS) significantly increased the by-passing of PACU to a step-down unit and discharge day of surgery during the study period. Paper II; No differences in vasoactive medications was found between groups, but there was a significant decrease in PACU-time in awake patients. Both patients and surgical nurses found the awake procedure acceptable. Paper III; The pain scores and postoperative opioid consumption were significantly higher in the supraclavicular block (SCB) group with long-acting local anaesthetic agent (long-LA) compared to short-acting (short-LA) 24-hours post-surgery and during the first 3 postoperative days. The long-LA-group also had most unplanned healthcare contacts postoperatively. Most SCB-patients could by-pass PACU. Paper IV; The median QoR-15 score increased over time from baseline to 1 week post-surgery with no significant differences between brace/cast-groups of patients. Conclusion: The use of LAS in POP-surgery improved both theatre and PACU efficacy and increased discharge on day of surgery. Surgical scrub/sterile covering before induction can be performed without jeopardizing patient´ quality of care and probably improve the perioperative care. SCB with long-LA for surgical repair of DRF provide effective analgesia during early postoperative course, but the patients that received SCB with short-LA had less pain at 24-hours post-surgery, a better pain profile and consumed less opioids during the first 72 hours postoperatively. An immobilisation with brace instead of cast directly after DRF-surgery appears to be a feasible and attractive option.Item Parasite host interaction between the freshwater pearl mussel (Margaritifera margaritifera) and brown trout (Salmo trutta) – the impact from glochidia larvae on the host(2022-02-17) Wengström, NiklasParasites can modulate the physiology and behavior of the hosts to enhance their chances to complete their life cycle. The numerous freshwater bivalves of the order Unionoida all have a parasitic larval stage, also known as glochidia, parasitizing fish hosts. The freshwater pearl mussel Margaritifera margaritifera is a host specialist and their glochidia can only metamorphose on salmonid fish (Salmonidae), and in Europe the glochidia has only been shown to develop into juvenile mussels on Atlantic salmon Salmo salar and brown trout S. trutta. In this thesis, the interaction between the parasitic freshwater pearl mussel and its salmonid host, the brown trout have been studied in five papers. The overall aim was both to investigate if host behavior can increase the risk of being infected by glochidia (paper I), to what extent glochidia infection alters the behavior and physiology of the host (paper II, III and IV) and finally how infection in a natural stream correlates with movement patterns, growth, and habitat use (paper V). My results show that more active trout had an increased risk of being infected, competitive ability decreased with elevated infection intensity, prey handling time were longer for infected fish and growth rate was lower in infected fish. Standard and maximum metabolic rate as well as levels of hematocrit was elevated in infected fish compared to non-infected fish. In a natural stream infected fish was smaller than non-infected which agrees with other studies, and the infected fish cover larger areas than non-infected suggesting they could not hold a territory, and finally there was a difference in habitat use that we cannot explain now. In summary, all the results suggest that the glochidia infection is a burden to the fish host that will hinder the individual to compete for resources on equal terms as non-infected fish. These patterns have also been seen in previous studies performed in laboratory with hatchery reared and artificially infected fish. The glochidia is a potent parasite, and when they come in high numbers, they cause a disease state to its host. The symptoms can be seen both physiological and behavioral but subdued behavior symptoms seem to be seen only when the infection intensity is high. In the future I would like to see more studies investigating behavioral and physiological effects from glochidia infections on the fish host. In my future work with propagating freshwater pearl mussels, I will have the opportunity to test new hypothesis derived from this thesis.Item On the role of Natural Killer cell immunogenetics for the outcome of immunotherapy in acute myeloid leukemia(2022-02-14) Hussein, BrwaNumerous studies have revealed that natural killer cells have fundamental roles as effector cells in myeloid leukemias. Thus, understanding NK cell-related biomarkers that influence clinical outcome are warranted. This thesis comprises in-depth dissection of how NK cell biology impacts on survival during histamine dihydrochloride/IL-2 therapy in acute myeloid leukemia (AML), with an emphasis on role of genetics of NK cell receptors and HLA. We studied AML samples from the Re:Mission trial using flow cytometry and PCR-based techniques. In addition, various in vitro NK cell functional assays have been performed using healthy donors and CRISPR-edited cell lines. In paper I, we sought to examine the effects of an HLA-B dimorphism, which affects HLA-E presentation, on NK cell function and on NK cell responses to leukemic cells. Results suggested that individuals with a presentable HLA-B variant harbored better-educated NKG2A+ cells. Furthermore, AML patients with this variant showed superior clinical outcome after HDC/IL-2 therapy in comparison to patients with non-presentable HLA-B leader peptides. In paper II, we investigated the potential impact of gene variants of NKG2D, DNAM-1 and NKp30 on receptor expression and survival of AML. Findings demonstrated that an NKG2D SNP was associated with increased expression and better clinical outcome of HDC/IL-2 immunotherapy. However, this polymorphism is in linkage disequilibrium with other polymorphisms in adjacent genes. Thus, in paper III, we first aimed to determine the clinical impact of NKG2A variants on outcome of AML after immunotherapy; secondly, to define whether the NKG2A gene variants affect function of NK cells. AML patients with high-expressing NKG2A alleles had a more immature NK cell repertoire, higher granzyme B content and superior clinical outcome. Taken together, this thesis provides new insights into NK cell biology, and their potential applicability to predict outcome of immunotherapy in AML.Item Blood Vessels, Biomarkers, and Broken Barriers: lnvestigations of the Brain Vasculature in Models of Neonatal Brain lnjuries(2022-02-10) Andersson, AxelBrain injury during the perinatal period can lead to lifelong impairment in cognitive and motor function, or an early death. Term neonatal encephalopathy and preterm germinal matrix haemorrhage are two conditions that can irreversibly injure the brain, but clinical tools for diagnosing and treating these pathologies are lacking. It is known that the cerebrovasculature, i.e. the blood vessels of the brain and blood/brain barrier (BBB) plays a role during the course and recovery of injury. This thesis investigated the cerebrovascular involvement in two animal models of neonatal brain injury in an attempt to elucidate injury mechanisms, find potential new treatments, and identify biomarkers for brain vascular dysfunction. Using rodent models for hypoxic/ischemic encephalopathy (HIE) and germinal matrix‐intraventricular haemorrhage (GM‐IVH) we found raised levels of tight‐junction proteins claudin‐5 and occludin, two integral components of the BBB, in blood plasma and cerebrospinal fluid at different time points. In the HIE model, levels of tight‐junction proteins in the circulation were sex‐dependent and the amount of claudin‐5 in CSF correlated with the severity of brain injury. These proteins thus have potential as biomarkers for early detection of cerebrovascular insults. In addition, we did in‐depth assessments of the BBB function in both models and detailed the temporal and regional increases of barrier permeability after injury by measuring the extravasation of radiolabelled sucrose, visible dyes, and molecular tracers. Studies of the cerebral vasculature and angiogenesis after HI showed that the density of proliferating endothelial cells were largely unaffected after injury, but the number of growing endothelial tip cells were strongly reduced in the entire brain, accompanied by changes in the expression of angiogenesis genes. The thesis also includes the first trial of endogenous RNAse A as a neuroprotective treatment for neonatal brain injury, a treatment that has shown promise in adult models of other pathologies with cardiovascular aspects. We found significant reductions of grey and white matter tissue loss after RNAse A administration in HI animals, but no protection of BBB function or evidence for a reduced neuroinflammatory response. Taken together, this thesis contains new insights into several aspects of the vascular mechanisms involved in the pathogenesis of two major forms of injury that can occur in the neonatal brain.Item In Search of the Self: A Study of the International Scene of Modern Advaitic Satsang in Present-Day Rishikesh(2022-02-10) Thorsén, ElinThe north Indian pilgrimage town Rishikesh has since the late 1990’s become something of a center for the international scene of Modern Advaita. An increasing number of teachers and adherents from mainly Western countries have started to gather there for a few weeks each spring to engage in satsang, a form of dialogical lectures, in these cases based on contemporary interpretations of the classical Indian philosophical system Advaita (“nondual”) Vedānta. At the heart of Advaita Vedāntic philosophy lies the postulation that the inner Self (ātman) is identical with Ultimate Reality (Brahman), and in its essence is nondual awareness. In contemporary versions, “awakening” to such nondual awareness is usually presented as being within reach “here and now”, rather than as a goal in a distant future. Modern Advaita can be characterized as an “internalist” form of spirituality, as focus is put on the practitioner’s gradual realization of nondual tenets through techniques such as meditation and self-inquiry. Salvific space, hence, is thought of as being located within rather than outside of the practitioner’s body. At the same time, Modern Advaita is an ambulating movement, as teachers regularly go on tours to give satsang and offer retreats, and their followers often travel far to join these activities. As such, this is an inherently transnational phenomenon where mobility and locations play a crucial role. Taking its starting point in Thomas Tweed’s theory of religion as entailing “crossing and dwelling”, In Search of the Self is an ethnographic work that investigates the aspects of movement and position within Rishikesh’s Modern Advaitic satsang scene. It follows a group of satsang participants on their journeys to Rishikesh; their reported alternation between dual and nondual “space” during satsang; and their attempts to implement nondual teachings, partly by recreating satsang as a symbolic space, in day-to-day life at home.Item Prerequisites for palliative care provision in intensive care(2022-02-08) Hamdan Alshehri, HananPalliative care provision is aimed at improving patients’ quality of life when cure no longer possible through healthcare systems, including intensive care. It has been ob-served that ongoing challenges exist concerning integration of palliative care into inten-sive care contexts. This necessitates an understanding of the contextual facilitators and barriers. The overall aim of this thesis therefore was to explore the prerequisites of palli-ative care provision in intensive care contexts. A multimethod approach was employed, including a systematic review, intensive care professionals and managers interviews, as well as a psychometric evaluation of an instrument with potential to be used for as-sessing intensive care professionals’ attitudes in a future evaluation of a knowledge translation strategy. Study I is a mixed-method systematic review identifying factors influencing the integration of palliative approaches in intensive care units. The review included a total of 24 qualitative and quantitative studies and the findings indicated that the prerequisite factors were (a) an organizational structure that facilitates policies and environmental dimensions, and (b) interpersonal factors/barriers, related to the patient and the patient’s family, including decision making, multidisciplinary team communi-cation, and prognostication. Study II is an interpretive description design study in-volving interviews with 36 intensive care professionals, and was designed to explore their perspectives on the provision of palliative care within intensive care settings. The findings illuminated intensive care professionals’ perceptions of palliative care within intensive care contexts, their decision-making related to goals for care strategies, and the challenges pertaining to family involvement in care goals. Study III is an interpretive description study exploring the association of organizational structures when integrating palliative care within an intensive care units. The study included interviews with 15 managers and 36 intensive care professionals. The findings show a ‘do not resuscitate’ policy as a gateway to palliative care, facilitating family members to enable to participa-tion and support, while barriers to palliative care in the intensive care units exists in the way intensive care is organized. In study IV, a cross-sectional design was applied to measure the differential item functioning of the Frommelt Attitudes Toward Care of the Dying (FATCOD) scale. A convenience sampling method was used, recruiting partici-pants from both Sweden and Saudi Arabia professionally working in intensive care contexts. Ordinal logistic regression was undertaken to investigate potential differences in the perceptions of the items between different professional groups and in different geographical locations. The results establish that 12 out of 30 items in the FATCOD had significant differential item functioning among the groups. The conclusion derived from this thesis enhances our understanding of the facilitators and barriers of palliative care initiatives, as it illuminates the importance of acknowledging attitudes of death and dying within the professional groups in ways that go beyond the “do not resuscitate (DNR)” decision making as a gatekeeping process and considers the potential of inte-grating a palliative approach in intensive care.Item Metabolic alterations and adipose tissue dysfunction in individuals with a family history of type 2 diabetes(2022-02-08) Henninger, JosefinABSTRACT Aims The overall aim of this doctoral thesis was to further examine the anthropometric, metabolic and adipose tissue dysfunctions, as well as explore novel metabolites, associated with type 2 diabetes mellitus (T2D), examining individuals both with and without known genetic predisposition to T2D. This thesis is part of the research conducted at Lundberg laboratory for diabetes research, Institute of Medicine, Sahlgrenska Academy, at Gothenburg University. In study I, we aimed to investigate if markers of adipose tissue dysfunction, as well as anthropometric and biochemical markers of glucose metabolism dysfunction, were present in subjects with a family history of T2D and controls. In study II, we aimed to identify predictive factors of deteriorating glucose tolerance in individuals with known genetic predisposition to T2D, using similar measures as in study I. In study III, we aimed to compare individuals with and without genetic predisposition to T2D. In study IV, we aimed to examine how, in addition to anthropometric and biochemical variables, adipose tissue distribution and morphology and non-targeted serum metabolites predict cardiometabolic profile. In study V, we further examined non-targeted serum metabolites and its associations to markers of glucose and insulin metabolism, as well as to adipose tissue morphology and distribution. Materials and methods (study I-V) In study I, we examined 17 first-degree relatives (FDR) and compared them to 17 controls without known genetic predisposition using anthropometric data, OGTT data and subcutaneous adipose tissue biopsy data. In study II, we explored predictive factors of deteriorating glucose tolerance in 138 FDR using anthropometric data, OGTT, IVGTT euglycemic clamp data as well as adipose tissue cell size. In study III, we compared 200 FDR to 73 controls in a cross-sectional manner, examining the same variables as described in study II. In study IV and V, we examine 53 male individuals with extensive clinical, biochemical and magnetic resonance imaging phenotyping, as well as targeted and non-targeted serum metabolites. Machine learning methods were used. Results (study I-V) In study I we found that FDR displayed adipocyte dysfunction and impaired insulin sensitivity, compared to controls. In study II, we found that the FDR that developed IGT and T2D at baseline displayed both markers of impaired insulin sensitivity and impaired insulin secretion, as well as adipose tissue dysfunction. In study III we found differences in several OGTT measurements between groups, indicating that OGTT can be an easy yet effective measure to assess glucose tolerance in high risk individuals. In study IV we found that visceral fat accumulation and age predicted ectopic fat storage in heart and liver, and found metabolites associated with a family history of T2D. In study V, we presented metabolites predicting markers of glucose and insulin metabolism, as well as markers of adipose tissue morphology and distribution. Conclusion In this doctoral thesis we further characterized the development of T2D in individuals genetically predisposed to the condition, with a focus on adipose tissue dysfunction and the usefulness of the OGTT. We finally explore novel metabolomic markers of T2D.Item Electromagnetic Field Induced Out-of-Equilibrium Structural Dynamics in Protein Crystals: From Picoseconds to Milliseconds(2022-02-04) Ahlberg Gagnér, ViktorLight-induced interactions in biomolecules are strongly varying over different model systems. Most amino acids and proteins absorb ultraviolet light, but only a few with specialised chromophores or fluorophores, are able to absorb light in the visible spectrum. In the terahertz frequency spectrum, spectroscopy have revealed protein-light interactions which are attributed to low-frequency protein vibrations. Despite the fact that questions regarding a protein’s structure and function are integrally connected, only a small fraction have been answered. With the develop ment of ultra-fast facilities, the possibility to answer these questions at picosecond and sub-picosecond time scales are possible. The aim of this thesis is to demonstrate results from different aspects of the structural dynamics research field. This thesis show induced structural dynamics in the model protein bovine trypsin, while irradiated by a terahertz electromagnetic field at millisecond and at femtosecond timescales, during two different X-ray crystallography experiments. At millisecond timescales, differences in averages over the model parameters B-factors and anisotropy (’ANISO’) reveal structural dynamics which are not attributed to thermal vibrations. A clustering of the individual components of the anisotropic displacement parameter tensor, group atoms which have seemingly no spatial correlation. This indicates long range vibrations, oscillating over the entire protein scaffold. At femtosecond timescales, averages of distances of individual atom positions and individual B-factors, show structural differences which are distributed over the entire protein model, but localised to specific residues, or nearest neighbours. In addition, the structural dynamics in photosyntetic reaction center protein were demonstrated in a femtosecond optical pump-X-ray probe experiment. Average distance ratios of individual Cα atoms from photo-activated and ”dark” datasets were compared. The distances reveal a structural difference upon excitation with infrared light, attributed to an electron charge transfer from the special pair of chlorophyll molecules, to the menaquinone, via the cofactors of the L-subunit. The structural differences are supported by electron difference maps, time-resolved infrared spectroscopy and molecular modelling. Finally, this thesis demonstrate X-ray data, collected at a commissioning beamtime at the FemtoMAX beamline, of the short-pulse facility at MAX IV. Despite technical and practical difficulties, high resolution X-ray diffraction data were collected with good data reduction and refinement statistics. From this data, a satisfactory protein model was obtainedItem Promoting the Clinical Relevance of 3D Bioprinting(2022-02-03) Apelgren, PeterThis thesis focuses on the development of methodologies enabling the reconstruction of autologous, functional, and long-term-stable cartilage-like tissue using 3D bioprinting technology and animal experiments. The stability, resilience, and in vivo viability of the printed cells and tissue vascularization, as well as the observed immunogenicity and safety, represent the main issues evaluated and discussed in this thesis. Furthermore, the mechanical properties of the applied biomaterials are evaluated in detail. Study I Background: This study quantitatively assessed the proliferative capacity of chondrocytes in the presence and absence of stem cells in the 3D bioprinting setting. Results: We observed significant increases in the number of chondrocytes and cluster formations during the study period. Compared with pure human nasal chondrocyte (hNC) group, we identified a significant additional proliferative effect in the group containing both hNCs and stem cells, and histologic analysis confirmed the expected production of collagen type II in the extracellular matrix, as well as the distribution of glycosaminoglycans in the cartilage-like tissue. Additionally, fluorescence in situ hybridization analysis confirmed that the chondrocytes were of human origin, and their male phenotype verified the male chon-drocyte-donor source. Study II Background: In this study, we evaluated the results of subcutaneous implantation of 3D-bioprinted constructs mixed with human chondrocytes and stem cells over the course of 10 months. Results: We observed no signs of necrosis, tumors, ossification, or other adverse effects. Moreover, the constructs remained well-preserved, and histologic analyses showed thriving, proliferating chondrocytes in cartilage-like formations. Study III Background: This study mapped the vascularization of gridded 3D-bioprinted constructs. Results: Perfusion data from magnetic resonance imaging revealed progressive vascularization inside of grid holes that were confirmed as being filled with blood vessels connected to host circulation according to histologic analysis. Additionally, immunohistochemical analysis of endothelial cells confirmed the vascular arrangement, with collagen II production further indi-cating chondrocyte proliferation and cartilage formation. Study IV Background: In this study, we evaluated the biocompatibility (according to ISO standards) and mechanical properties of tunicate-derived nanocellulose (TNC) as a novel biomaterial. Results: We determined TNC biocompatibility as equivalent to that of expanded polytetrafluoroethylene while also exhibiting excellent mechanical properties. Keywords 3D bioprinting, cartilage, chondrocytes, stem cells, tissue engineering, nanocellulose, hydrogel, bioink, vascularization, bio-compatibilityItem Human iPSC-derived neuronal networks. Development and application for compound evaluation(2022-02-03) Izsak, JuliaResearch on human brain development and function in health and disease has been hampered by limited access to primary human tissue and limited translatability of animal studies. This knowledge gap is encouraging the use of human induced pluripotent stem cell (hiPSC)-derived neural in vitro models. The current hope is that person-specific hiPSC-based in vitro models for human brain development and neuronal network function will increase the success in translating research results from bench to bedside. The aim of this thesis was to characterize and validate a person-specific human iPSC-based neural in vitro model to study the development, properties, and pharmacological modulation of human neuronal networks. In the first article we presented a procedure to generate 3D neural aggregates comprising astrocytes, oligodendrocytes and highly functional neurons that generated synchronous neuronal networks in less than three weeks. Further, by culturing hiPSC-derived 3D neural aggregates in human cerebrospinal fluid (hCSF), we demonstrated in article II that this adult brain-like milieu promotes morphological and functional maturation. Although hCSF is superior to currently used cell culture media, it has very limited availability for routine cell culturing purposes. This motivated the search for soluble factors that can mimic the observed maturational effects. In article III, we identified TGF-β1 as a physiologically relevant factor that can suppress proliferation and enhance neuronal and glial differentiation in a human 3D neural in vitro model. In article IV, we utilized this optimized model to provide insights in how therapeutically effective and overdose concentrations of lithium influence human single neuronal and network function. We showed that epileptiform discharges caused by overdose concentrations of lithium were suppressed by the antiepileptic drug Perampanel. The demonstrated functional impact of clinically relevant pharmacological compounds on human neuronal network function represents a proof-of-concept for the enhanced translational value of the human 3D neural aggregate in vitro model. The work presented in this thesis advances the field with a fast functional isogenic in vitro hiPSC-derived neuronal network model with improved physiological relevance and applicability for drug evaluation. Hopefully, our findings will bring the field of neuroscience closer to more translatable modeling and more successful clinical trials in the future.Item Unmet need for mental healthcare among men Sweden: Gendered pathways to care(2022-02-02) Blom, SaraAim: Depression and anxiety disorders have a lifetime prevalence of about 10% among men in high-income countries but many do not seek and receive the care that they need. The aim of this thesis was to explore gendered pathways to care focusing on unmet need for mental healthcare among men in Sweden at three steps: 1) not perceiving a need for mental healthcare despite symptoms indicating a clinical need for care, 2) refraining from seeking mental healthcare when perceiving a need for it, 3) perceiving care as insufficient when seeking it. Methods: Unmet need for mental healthcare, at any time in life, was investigated using cross-sectional and longitudinal questionnaire data from population-based samples (n=3987, n=1240, n=1563). Thoughts on sick leave for depression were investigated using a vignette study in a self-recruited sample (n=3147). Bivariate and multivariable regression analyses were conducted to investigate group differences. Results: Men were more likely than women to 1) not perceive a need for mental healthcare despite symptoms indicating a clinical need for care, 2) refrain from seeking care, and 3) perceive the care as insufficient. Those with secondary education were more likely than those with university education to refrain from seeking care. Men who had refrained from seeking care, or perceived the care as insufficient, had poorer mental well-being than men who had not, but the difference did not persist after one year. Men with low mental health literacy were most likely to not perceive a need for mental healthcare, and refrain from seeking care, followed by both men with high mental health literacy and women with low mental health literacy. Least likely were women with high mental health literacy (reference). The vignette study showed that men were more likely than women to think that sick leave for a person with symptoms of depression was not reasonable, and the gender difference was partly explained by more stigmatizing attitudes towards depression among men. Conclusion: The results indicate that men have a higher risk of unmet need for mental healthcare at multiple steps on the pathway to care. Men with low mental health literacy and secondary education seem particularly vulnerable. This indicates that pathways to mental healthcare are gendered, i.e., impacted by gendered structures related to masculinities, and that some groups of men face greater barriers at these pathways. The healthcare system should review how its design and communication can contribute to mitigate these gendered inequalities. There is especially a need for outreach strategies considering that not perceiving a need for mental healthcare seems to be a major barrier.Item Process and economic evaluation of a transition program for adolescents with congenital heart disease: the Stepstones project(2022-01-28) Saarijärvi, MarkusTransition programs have been developed for adolescents with chronic conditions and evaluated through randomized controlled trials. However, knowledge is lacking on what barriers and facilitators to implementation exist, how change is created, and the cost-effectiveness of these programs. The overall aim of this thesis was to perform a process evaluation and health economic analysis of the STEPSTONES transition program for adolescents with congenital heart disease in transition to adulthood and transfer to adult care. The methods used in this thesis were process evaluations (Studies I – III) and a health economic evaluation (Study IV). Mixed methods were used to design, collect, and analyze data according to the methodological guidance for process evaluation of complex interventions by Moore et al (2015). The findings showed that the transition program was implemented with high fidelity, although some components were more difficult to implement. Factors affecting the implementation process were the participants’ and healthcare professionals’ responsiveness and willingness to engage in the program, organizational factors, recruitment and retention, and the parents’ process of achieving balance between becoming a support system and managing their own information and support needs. Key change mechanisms were the opportunity to meet a transition coordinator trained in person-centered care and adolescent-friendly communication, the creation of a safe space that was built on confidentiality, a learning process starting from the adolescents’ needs, and goal setting beyond the heart defect. The health economic evaluations showed that the intervention group had higher costs due to receiving the transition program. No differences in health outcomes with the EQ-5D were observed in this study. The conclusion is that the transition program was largely implemented as it was intended. Implications from these findings are that transition programs have prerequisites for implementation but tailoring to other conditions and contexts needs to be taken into consideration. Knowledge is needed on the longitudinal impact of transition programs to provide decision makers with evidence on the future benefits of transition programs for adolescents with chronic conditions.Item Perceptions of Political Competition and the Integrity of Elections(2022-01-26) Dawson, StephenPolitical competition is generally regarded as one of the hallmarks of a well-functioning democracy. Competitive elections hold politicians to account, thereby increasing government performance to the benefit of citizens. However, the uncertainty generated by close elections can also create perverse incentives for political actors to undermine the integrity of the contest to improve their chances of victory. Yet we still know relatively little about when and in what ways close elections can be detrimental to democracy. This dissertation suggests that the relationship between electoral integrity and political competition is best understood from the perspective that there are two primary dimensions of this competition: the intensity of electoral competitiveness and the credibility of the information that portrays it. While political elites may be incentivised to manipulate elections in different ways to improve or consolidate their chances of victory, voters may also consider portrayals of competition along these two dimensions when deciding whether and for whom to vote. Four research articles study different aspects of this relationship across a range of institutional contexts and using several methodological approaches. First, a cross-national study of presidential elections across two levels of democracy finds that electoral fraud increases with electoral competition in democratic contexts. Second, a study on the 2016 municipal elections in South Africa reveals a strategic political economy of targeted vote-buying. Third, a qualitative comparison of falling participation levels in Central Asia and the Caucasus reconsiders the cyclical nature of the relationship between political competition and electoral integrity. Fourth, a survey experiment in Turkey attempts to gauge whether the perceived credibility of opinion polls can have adverse consequences for voting behaviour. The findings of this dissertation suggest that political competition – and importantly how it is perceived – can have significant consequences for the conduct of elections. It is therefore of great importance to pay close attention to how information relating to competition is interacted with by political actors during elections.Item Dynamics of particles in fluids: effects of correlations and interactions(2022-01-24) Dubey, AnshumanParticles suspended in turbulent fluid flows are common in Nature and in technological applications. In some cases, the relative dynamics of spherical particles may be of interest. One example is small rain droplets in turbulent clouds. The dynamics of nearby droplets is correlated because they experience a correlated airflow. But their relative dynamics is influenced also by fluid-mediated droplet-droplet interactions, or by electrical forces due to charges which the droplets may carry. Heavy particles may detach from the fluid streamlines due to inertia and show inhomogeneities in their spatial distributions, known as clustering. In other cases, the angular dynamics of aspherical particles may be of interest, an example being long and slender fibres in wood pulp used for papermaking. In this thesis, we start by studying the separations and relative angles of non-interacting particles in turbulent flows. This is followed by two studies on the relative dynamics of interacting droplets in steady flows. First, we analyse a discrete-time, toy model of inertial particles in turbulence. The simplicity of the model allows us to understand in detail how the distribution of inertial particles in turbulence depends on the particle inertia. Second, we use a statistical model to study how slender rods align with the Lagrangian stretching direction in a turbulent channel flow. We show that the alignment is stronger near the channel wall, than near the channel center. Nevertheless, the rods show large excursions away from alignment. Our model explains the dynamics qualitatively near the channel center but quantitatively near the channel wall. Third, we use dynamical systems theory to unravel the mechanisms leading to collisions of small, charged droplets in still air. We find that a saddle point with its associated stable manifold determines whether droplets collide or not. This mechanism causes the collision outcomes of droplets with large charges to become independent of non-continuum effects. Finally, we perform a bifurcation analysis of hydrodynamically interacting neutral droplets settling in a straining flow. Our analysis explains a non-monotonic dependence of their collision rate upon the strength of the strain and that of gravity. We find that even for neutral droplets, there is a regime where the steady-state collision rate becomes independent of non-continuum effects. In addition, our analysis predicts strong inhomogeneities in the distribution of separations.Item Carpe Diem or Seize your Health? The Economics of Time Preferences, Health, and Education(2022-01-20) Norrgren, LisaWho is more likely to follow medical recommendations, invest in their health and pursue higher degrees of schooling? Behavioral economic theory provides a clear answer to this question: more patient individuals (who discount future outcomes less heavily) should be more likely to choose costs and forgo utility now, in order to get better long-run outcomes. But does this behavioral theory match up with peoples' real choices? If so, can it be used to predict important future life events? In four different chapters, this thesis shed new light on education, illness, and death outcomes. It does so using the information on people’s time preferences, i.e., the relative weight a person gives to future utility compared with present utility. Based on extensive information for people born in 1953 in Stockholm and their mothers, as well as contemporary data from pregnant women in South Africa , the thesis shows that time preferences is an important factor in understanding everyday health investments, social mobility, and long-run health outcomes. Most striking are the results in chapter one, which shows that patient adolescents, compared with their less patient peers, are about 20% less likely to die before age 65.Item Genomic mutational heterogeneity in cancer. lmproved models and tools for driver gene detection(2022-01-19) Boström, MartinCancer is a disease that is strongly related to evolution, as mutations that confer a benefit to individual cells face positive selection and eventually lead to tumorigenesis. As such, the search for genes that drive cancer development entails distinguishing positive selection from other sources of increased mutation rates, which requires detailed knowledge of how normal mutation rates vary across the genome. This thesis aims to improve that knowledge, as well as to provide novel methods of driver detection. In cutaneous melanoma, there are mutational hotspots in promoters that coincide with the sequence motif “TTCCG”. These hotspots could easily be misinterpreted as cancer drivers, but in the first paper of this thesis we show that they are in fact caused by increased UV damage susceptibility upon transcription factor binding, with some contribution from impaired DNA repair. In the second paper, we study how the UV mutational signature varies between different genomic regions and show that the main difference is caused by the level of cytosine methylation, owing to its effect on UV damage formation. We also improve the traditional trinucleotide mutational signature by incorporating longer patterns, capturing the effect of TTCCG-related promoter mutations. In the third paper, we demonstrate a novel method for driver detection that ignores recurrence signals, instead testing the likelihood of observing a particular combination of mutated tumours in a patient cohort. In addition to providing an orthogonal perspective on driver detection, this method is less sensitive to flaws in modelling some forms of mutational heterogeneity, such as the TTCCG hotspots. In summary, this thesis improves our knowledge of mutational heterogeneity in cancer, in addition to describing a new driver detection test that is less sensitive to situations where that knowledge falls short. Both of these advances contribute to the search for genes that drive cancer development.