Doctoral Theses from Sahlgrenska Academy

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Combining Action Research and System Dynamics to facilitate change and improvement processes in healthcare
(2022-09-30) Holmström, Paul
Background 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.
Acquired Epilepsy with a Focus on Stroke: Treatment and Prognosis
(2022-02-23) Larsson, David
The 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.
lmprovement in perioperative care of the day case patient; logistics and quality of care.
(2022-02-23) Sellbrant, Irén
Background: 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.
On the role of Natural Killer cell immunogenetics for the outcome of immunotherapy in acute myeloid leukemia
(2022-02-14) Hussein, Brwa
Numerous 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.
Blood Vessels, Biomarkers, and Broken Barriers: lnvestigations of the Brain Vasculature in Models of Neonatal Brain lnjuries
(2022-02-10) Andersson, Axel
Brain 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.
Prerequisites for palliative care provision in intensive care
(2022-02-08) Hamdan Alshehri, Hanan
Palliative 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.
Metabolic alterations and adipose tissue dysfunction in individuals with a family history of type 2 diabetes
(2022-02-08) Henninger, Josefin
ABSTRACT 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.
Promoting the Clinical Relevance of 3D Bioprinting
(2022-02-03) Apelgren, Peter
This 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-compatibility
Human iPSC-derived neuronal networks. Development and application for compound evaluation
(2022-02-03) Izsak, Julia
Research 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.
Unmet need for mental healthcare among men Sweden: Gendered pathways to care
(2022-02-02) Blom, Sara
Aim: 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.
Process and economic evaluation of a transition program for adolescents with congenital heart disease: the Stepstones project
(2022-01-28) Saarijärvi, Markus
Transition 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.
Genomic mutational heterogeneity in cancer. lmproved models and tools for driver gene detection
(2022-01-19) Boström, Martin
Cancer 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.
Pelvic floor dysfunction in nulliparous women
(2022-01-18) Al-Mukhtar Othman, Jwan
Background: Pelvic floor dysfunction (PFD) is a public health problem affecting millions of women worldwide. In addition to personal suffering, it also creates an economic burden for health care systems and society. Parity and mode of delivery are well known risk factors for PFDs. Therefore, examining the prevalence of PFDs in women not exposed to childbirth provides insight into the natural history of the condition without the confounding effect of obstetric injury. Aim: To obtain a detailed description of the age-related prevalence and predictors of PFDs in a large, national, randomly selected cohort of nulliparous women aged 25 to 64 years. This knowledge is necessary for comparisons with parous women to demonstrate the effect of pregnancy and the effect of vaginal delivery on future PFD. Material and methods: This was a national cohort study where the study population was drawn from the Total Population Register by Statistics Sweden. The final study population consisted of 9,197 women registered in Sweden, with no births aged 25 and 64 years. Self-reported information regarding possible PFD was obtained via the web and by mail in 2014 using a 40-item questionnaire. Results: Paper I: Urinary function in nulliparous women deteriorated during the four most active decades of adult life. However, 75% remained continent by age 65. In women with a normal BMI this applied to >80%. Almost all aspects of urinary dysfunction increased with age. The most significant increase was observed for nocturia ≥2, mixed urinary incontinence (MUI), leakage ≥ 1/week, leakage of more than a few drops of urine, and bothersome UI. Paper II: Symptoms indicating pelvic organ prolapse (sPOP) were experienced in all ages but surgical procedures for POP were rare. Bothersome sPOP was more prevalent in older women. The symptom of "bulging" was strongly associated with other irritative conditions from the genital area. These co-occurring symptoms increased with increasing frequency of "bulging". Paper III: In nulliparous women with a history of childhood nocturnal enuresis (CNE), all the studied parameters of lower urinary tract symptoms and PFD were approximately doubled and acted as a strong marker for later PFDs. Paper IV: The predominant component of leakage in nullipara with faecal incontinence (FI) was liquid stool, which occurred in >90%. Solid stool leakage was rare. The pattern of distribution of different types of leakage was similar in all age groups. BMI and age were interacting risk factors for FI. Conclusion: Over a 40-year period from age 25, the prevalence of all UI parameters increased in nulliparous women. Bothersome prolapse symptoms were rare in women who have not undergone childbirth. The strongest risk factor for fecal incontinence was abnormal stool consistency. Age, BMI and CNE were important risk factors for almost all PFDs.
On HIV in the elderly and vitamin B metabolism in HIV infection
(2022-01-17) Tyrberg, Erika
The evolution of the human deficiency virus (HIV) field is unparalleled in the history of infectious diseases. From the first cases in the beginning of the 1980s, when an HIV diagnosis was a death sentence, through the discovery of the first effective medicines, up till today when people living with HIV (PLHIV) with access to antiretroviral therapy (ART) can lead a near normal life. The aim of this thesis was to investigate further into two areas where knowledge is still lacking, and important questions remain. We investigated HIV in the elderly and the role of vitamin B metabolism in HIV-associated central nervous system (CNS) disease. In paper I and II we studied HIV infection in the elderly ( 65 years of age) compared to a control group ( 49 years of age). In a study of cross-sectional design 100 elderly PLHIV and 99 controls, on ART regimens containing atazanavir, darunavir, or efavirenz were included. In paper I we showed that elderly had a higher number of concomitant medications, comorbidities, and potential drug-drug interactions, than the younger controls. In the darunavir arm, the elderly had higher steady-state concentrations. This was also found in the atazanavir arm, although not statistically different, but suggesting a possible class effect of protease inhibitors. Paper II investigated the role of ART regimen on markers of inflammation and immune activation in elderly PLHIV. The regimens had different inflammatory profiles with lower interleukin-6 levels in the atazanavir arm, and lower ICAM-1 in the efavirenz arm. The darunavir arm had higher CXCL10 levels compared to the efavirenz arm. Paper III and IV studied the role of homocysteine and vitamin B metabolism in CNS injury in HIV infection. Paper III describes an association between plasma homocysteine, a marker of vitamin B12 and folate deficiency, and cerebrospinal fluid neurofilament light protein (NfL), a sensitive marker of neuroaxonal damage in HIV infection. In paper IV this association was further studied in a randomised controlled clinical trial. Sixty-one virally suppressed PLHIV were randomised either to the active treatment arm (treatment with vitamin B12, B6, and folate) or control arm. After 12 months the levels of homocysteine had decreased, and the plasma B12 and folate levels had increased in individuals in the treatment arm. However, no difference in plasma levels of NfL was found compared to the control arm at 12 months. Furthermore, in the treatment arm, no difference in NfL was found after 24 months, compared to baseline plasma NfL levels. In conclusion, we found that elderly PLHIV are at risk of adverse drug events through a high prevalence of concomitant medications, potential drug-drug interactions, and higher drug concentrations of protease inhibitors. In addition, we found different inflammatory profiles of efavirenz, atazanavir, and darunavir, a finding that needs to be confirmed in future studies. Furthermore, a novel finding of an association between homocysteine and NfL was made. However, supplementation with B vitamins did not decrease NfL, suggesting a non-vitamin B dependent cause of the association.
The role of the alpha 7 nicotinic acetylcholine receptor in inflammation and brain injury
(2022-01-13) Hammarlund, Maria
The alpha 7 nicotinic acetylcholine receptors (α7nAChR) are expressed in the nervous system as well as on peripheral immune cells where it participates in the cholinergic anti-inflammatory pathway. Inflammation is a common component in the pathology of many diseases and injuries, including brain damage. Stroke and neonatal encephalopathy are common causes of mortality and morbidity worldwide in adults and infants, respectively, but lack sufficient treatment strategies. This thesis aims to deepen the knowledge of α7nAChR involvement in immune regulation in human immune cells, and to investigate the treatment effect of α7nAChR stimulation in experimental models of adult and neonatal brain injury. In Paper I, expression of the α7nAChR encoding gene CHRNA7 and its partially duplicated gene CHRFAM7A were investigated in human peripheral blood mononuclear cells (PBMCs) from the healthy Swedish SciLifeLab SCAPIS Wellness Profiling (S3WP) cohort, and whether single nucleotide polymorphisms (SNPs) in these genes could affect clinical parameters as well as the immune response. Gene expression of CHRNA7 and CHRFAM7A was positively correlated, and CHRFAM7A expression was four times higher than CHRNA7 expression. Furthermore, one SNP, rs34007223, was associated with high sensitivity CRP (hsCRP) levels and nine SNPs in CHRNA7 and/or CHRFAM7A were associated with altered PBMC cytokine response. In Paper II, the expression of Chrna7 was investigated in different regions of the naïve adult mouse brain, and the treatment effect of the α7nAChR agonist AR-R17779 on stroke-induced injury was investigate using the middle cerebral artery occlusion (MCAO) model in mice. Chrna7 was shown to be expressed in all investigated brain regions with the highest expression in hippocampus and cortex. Although a small effect on white blood cell count was observed, the agonist had no effect on injury outcome in the MCAO model. In Paper III, the effect of α7nAChR stimulation on neonatal encephalopathy was investigated using a mouse model of hypoxia-ischemia, and whether this effect might be sex dependent. No effect was observed on injury outcome seven days after insult. However, cytokines CCL2, CCL5 and IL-6 were shown to be decreased in the injured brain hemisphere 24 hours after insult in male, but not female, α7nAChR-stimulated mice. The findings in this thesis support the role of both CHRNA7 and CHRFAM7A as important regulators of the immune system in humans. Although α7nAChR stimulation had no effect on outcome in adult or neonatal brain injury models, minor effects on immune response were observed by the treatment. Notably, the immunomodulatory effect in the neonatal model was sex dependent and suggests that inclusion of both male and female subjects is of importance when evaluating α7nAChR function.
Atrial fibrillation in aging; methodological aspects and the relation to dementia and cerebral vascular disease
(2022-01-12) Lina, Rydén
Emerging evidence suggest an increased risk of dementia in individuals with atrial fibrillation (AF). However, until recently, few studies have investigated the relation between AF and dementia taking both prevalent and incident stroke into account. Therefore, this thesis aims to examine if AF increase the risk of dementia in a sample free from a history of stroke at baseline and incident stroke during follow-up. Further, the mechanisms behind an association between AF and dementia in the absence of symptomatic stroke is not elucidated. Therefore, this thesis also aims to examine if AF is associated to silent brain infarcts (SBIs) and small vessel disease on brain MRI. Since epidemiological studies often are accompanied with biases, we also analyzed differential attrition during follow-up and agreement between self- and proxy-reported diagnoses. Data were obtained from the Gothenburg H70 Birth Cohort (H70) studies and the Prospective Population Study of Women (PPSW) in Gothenburg. The samples used in this thesis include the cohorts born 1930 (followed from age 70 to 88) and 1944 (examined at age 70). The H70 and PPSW studies are comprehensive population-based studies aiming to be representative of older adults living in Gothenburg, Sweden. We found that a history of AF at age 70 increased the risk of dementia during follow-up in the 1930 cohort. Further, we found that AF was cross-sectionally associated to symptomatic stroke, SBIs, and lacunes among 70-year-olds in the 1944 cohort. There were no associations between AF and global white matter hyperintensity (WMH) volumes or the presence of any cerebral microbleed. However, among participants with symptomatic stroke, AF was associated with larger WMH volumes. In the 1930 cohort, both AF and dementia were associated with attrition due to death. Further, agreement between self- and proxy-reported diagnoses was substantial for AF, myocardial infarction, angina pectoris, hypertension, and diabetes mellitus, but only fair for heart failure and intermittent claudication. Further research is needed to investigate the mechanism(s) behind the association between AF and dementia, the optimal treatment regimens for AF in relation to dementia prevention, and possibilities to include brain MRI in treatment guidelines to further personalize anticoagulation treatment in AF patients. In addition, analyzing differential attrition and diagnostic accuracy in epidemiologic research is necessary to evaluate and generalize results.
Bioabsorbable Screws for Pelvic Osteotomies in Children
(2022-01-07) Hedelin, Henrik
Multiple conditions, with developmental dysplasia of the hip being a prime example, affect the congruity of the pediatric hip joint. A Salter osteotomy (SO) or a triple pelvic osteotomy (TPO) can be used to address suboptimal biomechanical conditions in the hip joint by improving containment and load distribution. Traditionally these osteotomies use metal implants to stabilize the osteotomy of the ilium, necessitating a second surgery for implant removal. If Kirschner-wires are used there are also risks related to wire migration and lack of stability. The general aim of this thesis was to explore the novel use of poly lactic-co-glycolic acid (PLGA) screws for osteotomy fixation in SO and TPO. The feasibility of this concept was examined regarding the stability of fixation as well as the biocompatibility of the implants. Bioabsorbable screws negate the need for implant removal which would be a major benefit for children. Study I reported on a novel surgical method for SO using PLGA screws instead of metal implants. A case series of 21 patients was reported on and the stability of the osteotomy fixation was evaluated using the post-operative radiographs. Migration percentage, acetabular index and center-edge angle were used to decide if an osteotomy collapsed or remained stable. In all patients but one the osteotomy remained stable and healed with maintained perioperative correction. There were no local reactions to the bioabsorption of the screws. Study II presented a retrospective analysis of the bioabsorption of 4.5mm PLGA screws as interpreted on Magnetic Resonance Imaging (MRI). Twelve patients who had undergone a SO or TPO with PLGA screws as the method of fixation were included. Eighteen MRIs were performed 0.5-4.5 years postoperatively and were analyzed according to eight parameters. After 2-4.5 years all screw canals were replaced with >90% bone with one exception where most, but not 90%, was replaced with bone. The local reactions seen during the bioabsorption were minor. Study III described a modified surgical method for TPO utilizing PLGA screws for the ilium osteotomy. A case series of 11 patients was reported on and the postoperative stability of the osteotomy was evaluated using migration percentage, acetabular index, center-edge angle as well as Sharp’s angle. The osteotomy angle (OA) was, as an addendum, suggested as a parameter to evaluate the integrity of an osteotomy. All patients maintained the initial correction and there were no signs of implant failure nor any local reactions to the implants. In Study IV the finite element method was used to analyze how different screw configurations affect stability in a TPO. Relative flexibility for loads in all translational degrees of freedom was calculated for five different screw configurations in a standardized hemi-pelvis. In two of these configurations the entry points used are only viable options if bioabsorbable implants are used. The screw configurations with a more perpendicular angle to the osteotomy and with a greater spread in the osteotomy plane between the screws resulted in increased stability. The use of bioabsorbable implants enables entry points that can provide improved biomechanical stability in a TPO. In summary, the presented studies support that 4.5 mm PLGA screws provide sufficient stability in SO and TPO in children with no major local reactions to the implants. After bioabsorption the screw canals were mostly replaced by bone and the use of bioabsorbable implants enables fixation configurations that seems to improve stability of the osteotomy. The use of bioabsorbable screws for pelvic osteotomies can eliminate suffering associated with a second surgery and save resources.
On the biological behavior of barrier membranes: implications for Guided Bone Regeneration. Clinical and Experimental studies
(2021-12-21) Turri, Alberto
There is a continuous development of bone augmentation solutions to meet the rising demand for effective dental implant rehabilitations. One of the most used techniques is Guided Bone Regeneration (GBR). Although successful in the clinic, there is still scarce knowledge of the biological mechanisms behind bone regeneration, which therefore, turns out to be the appropriate aim of this project. The clinical Study I was a retrospective investigation on the long-term outcome of single implant treatment in the anterior maxilla, in conjunction with or immediately after Guided Bone Regeneration (GBR). The study on 74 included patients indicated the presence of factors negatively influencing marginal bone level, such as small defects, simultaneous GBR-implant placement, short healing time and onset of early and late complications. In Studies II and IV, resorbable and nonresorbable barrier membranes with different topographical features, were used to protect bone defects created in the rat femur and were compared with untreated sham defects. After different time points, samples were collected and processed for qPCR, histology, histomorphometry, electron microscopy, Western blot, and immunohistochemistry. In both studies, the protective role of the membranes as “physical barriers” was confirmed by the absence of soft tissue ingrowth inside the defects. Additionally, the membranes held an active role in wound healing dynamics. In Study II, the extracellular matrix-derived collagen membrane showed direct bone regenerative effects on the strength of attracting cells that release signals linked to bone formation and bone remodeling (BMP-2, FGF-2, TGF-β, ALP, CatK). In Study IV, the effect of two types of PTFE membranes in promoting favorable healing in the underlying bone defects was verified. The qPCR findings demonstrated comparable bone formation for the two barriers applied, and a superior “bioactive role” of the dual e-PTFE in the soft tissue compartment as revealed by high expression of tissue regeneration (FGF-2, FOXO1, COLL1A1) and vascularization (VEGF) genes as well as a downregulation of pro-inflammatory cytokines (IL-6 and TNF-). Finally, Study III was conducted to develop a methodological clinical platform to advance our scientific knowledge of the early bacterial colonization of barrier membranes. By employing CLSM imaging, it was shown that a dual expanded configuration of PTFE membrane resulted in less biofilm accumulation compared to solid dense PTFE. In conclusion, the present thesis provides a first line of information on molecular and cellular pathways, as well as microbiological response, triggered during GBR by different membranes, featuring a plausible active role in would healing dynamics along with the traditional barrier effect. Keywords: Guided bone regeneration, Resorbable membrane, Nonresorbable membrane, Gene expression, Histomorphometry, Soft tissue regeneration, Biofilm.
Predictors of bone fragility in older women. Associations in older women between risk medications and measurements of physical function, bone microstructure and fracture risk
(2021-12-20) Larsson, Berit
Bone fragility with fractures constitutes a growing public health concern, resulting in suffering and major health care cost. This thesis project has been carried out by means of studies based on the SUPERB cohort of 75–80-year-old women from Gothenburg. Bone fragility has been addressed in relation to the commonly used selective serotonin reuptake inhibitors (SSRIs) and statins, as well as in relation to physical functional ability, measured using TUG (timed up and go) and OLST (one leg stand-ing time). Bone geometry and microstructure were measured at the distal site of radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT). Associations between TUG, OLST and the risk of incident fractures were analysed. Treatment with SSRIs was linked to lower physical functioning regarding grip strength, walking speed, and number of chair stand rises. Independently of covariates, treatment with SSRIs was associated with worse physical function but was without any association with skeletal micro-structure or bone geometry. In a cohort of 803 women, the use of statins was associated with better cortical bone character-istics. Statin users had lower cortical porosity, higher cortical bone density, and greater cortical area than nonusers. Regarding physical function variables, a slow TUG >12 s and a short OLST <10 s were both associated with an increased risk of fracture independently of clinical risk factors and bone mineral density (BMD). A slow TUG (> 12 s) was associated with an increased risk of major osteoporotic (MOF) fracture and hip fracture. In a 75-year-old woman with slow TUG, the 4-year fracture probability of MOF increased by a factor of 1.5–1.9, depending on BMD. In Cox regression analyses adjusted for age, height and weight, a one leg standing test (OLST) time of less than 10 s was associated with a threefold increase in the risk for incident hip fracture, MOF and non-vertebral fracture. In a 75-year-old woman with a low OLST (< 10 s), the 4-year fracture probability increased by a factor of 1.3–1.5, depending on BMD. Treatment with SSRIs was associated with normal bone microstructure and density but worse physical function. The use of statins was associated with better cortical bone character-istics in older women. The physical function tests TUG and OLST have substantial impact on fracture probabilities, indicating that inclusion of these tests in patient evaluation should be considered in order to improve fracture prediction in older women.
T cells in colon cancer; migration and effector functions
(2021-12-16) Szeponik, Louis
Immune cells are recognised as one of the main players in the tumor microenvironment and targeted by many new cancer therapies. Regulatory T cells (Treg) can suppress tumor infiltrating lymphocytes which are associated with a better patient outcome. Additionally, unconventional T cells have the potential to kill tumor cells through T cell receptor-independent mechanisms and also in a non- major histocompatibility complex restricted manner. The aim of this thesis was to investigate how Treg can supress the T cell migration into intestinal tumors and what type of T cell populations are affected. Furthermore, we characterized different unconventional T cell populations in human colon cancer samples using mass cytometry. We used APCMin/+/DEREG mice to deplete Treg in intestinal tumors. We demonstrated that Treg inhibit the transendothelial migration of T cells into tumors dependent on the interaction of CXCR3 with its ligand CXCL10. Endothelial cells increased expression of CXCL10 when Treg were depleted in tumors. Furthermore, Treg inhibited the expression of endothelial neutral sphingomyelinase 2 (nSMase2) through TGF-β and other unknown soluble factors which resulted in reduced expression of adhesion molecules and chemokines, and decreased tumor infiltration of T cells. CD8αβ T cells were specifically affected by Treg depletion which increased their expression of Th1 related molecules, activation, and proliferation, while CD8αα T cells and γδ T cells were unaffected. In human tumors, exhausted mucosal associated invariant T (MAIT) cells were increased compared to unaffected tissue and none of the MAIT cell populations expressed high levels of activating natural killer cell receptors. In addition, γδ T cell subpopulations showed a great diversity, and some populations were patient specific. In conclusions, this thesis demonstrates that Treg depletion increases the migration of tumor infiltrating T cells associated with a Th1 response. This is partly mediated by nSMase2 inhibition in endothelial cells. Treg depletion could be a viable option to increase beneficial effector T cells in colorectal cancer patients.

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