| 1. |
- af Geijerstam, Peder, Doktorand, 1983-
(författare)
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Home Blood Pressure in Health and Disease
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hypertension is the most common preventable cause of premature all-cause mortality, primarily from cardiovascular disease (CVD). Individuals with dysglycemia, including prediabetes and diabetes, are at increased risk. Licorice intake raises blood pressure (BP) through the effects of glycyrrhizic acid (GA), but the true limit of safe intake is uncertain. Home BP has several benefits over BP measured at a clinic, including a higher predictive value for CVD. By combining office and home BP, it is possible to diagnose masked hypertension (MH), in which home but not office BP is elevated, and white coat hypertension (WCH), in which office but not home BP is elevated. The aim of this thesis was to advance our knowledge on home BP in relation to dysglycemia, markers of CVD, and licorice intake. The first 3 papers used data from the Linköping cohort of the prospective Swedish CArdioPulmonary bioImage Study (SCAPIS). Study IV was a randomized controlled cross-over study. Data was obtained from questionnaires, blood samples and office and home BP measurements. In studies I-III, pulse wave velocity (PWV), coronary artery calcium score (CACS), and carotid artery plaques as markers of CVD were also included. In Study I, we examined 5025 men and women aged 50-64 years old for the relation between dysglycemia and home BP. Both the systolic office and home BP measurements were positively as-sociated with dysglycemia. Participants with dysglycemia vs normoglycemia more often had MH. The findings were in line with previous research and strengthened the association between dysglycemia and MH. In Study II, we examined the associations between MH and markers of CVD in 4122 individuals without BP-lowering treatment. Of participants, 4.2% had MH, and these were more often men and had higher BMI than those with normotension. Participants with MH also had higher odds for CACS ≥100, an as-sociation which has previously been suggested as a trend.In Study III, we examined the relation between soluble P-se-lectin (sP-selectin) as a measure of thrombotic activity, plasma high-sensitivity C-reactive protein (hsCRP) as a measure of inflammation, and home BP in 4548 participants. Both markers were higher in each hypertension phenotype compared with sustained normotension. The quartile of participants with the highest sP-se-lectin values had higher odds for CACS ≥100 and carotid artery plaques. The association between sP-selectin and sustained hyper-tension was novel and not affected by adjustments for hsCRP. In Study IV, 28 healthy participants aged 18-30 years old were evaluated for the effects of a daily intake of licorice containing 100 mg of GA compared with a control product for 2 weeks. During the licorice intake period, the systolic home BP increased with 3.1 mmHg, and the suppression of serum aldosterone and plasma renin levels indicated that this was due to the licorice intake. In conclusion, this thesis further strengthens the idea that both home and office BP measurements have values beyond that of the other, and that home BP may be most valuable in individuals with dysglycemia and obesity, and in men. Finally, licorice may be more potent than previously known, suggesting the need for increased awareness.
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| 2. |
- Ahlbeck, Lars, 1964-
(författare)
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Intralymphatic Immunotherapy : A Novel Route to Ameliorate Allergic Rhinitis Due to Pollen
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allergy to pollen and animal dander is a major public health problem. Close to 30% of the population have symptoms from the upper and/or lower respiratory tract when they meet fur animals or pollen. Whereas symptom-relieving medications have a good to sufficient effect on about 80% of those affected, a large group of 10–20% have severe symptoms, despite medication, with an impact on well-being and ability to work. In Sweden, the annual cost of allergy was calculated at €1.3 billion in 2014.Immunotherapy is effective in treating and preventing pollen allergy and allergic asthma, but is expensive, complicated, requiring 40 injections, and takes more than three years to complete if subcutaneous injections are used. Tablets placed under the tongue are another method, with one tablet taken every day for three years. Only 1.5‰ receive such treatment, yet just over 3% would need it.With intralymphatic immunotherapy, a small dose of allergen is given in a lymph node in the groin on 3 occasions, one month apart. As this method takes only eight weeks, it is a much faster and less costly treatment. However, although several studies have shown that the treatment is safe, its efficacy remains the subject of doubt.Our pilot study in 2012, with a 3-year follow-up to 2015, showed encouraging results, and was followed by a double-blind randomised study with 72 participants from 2014 to 2018. The research subjects then received treatment with birch and grass pollen extract or one extract and a placebo. Regardless of treatment, symptoms, quality of life and medication consumption improved during the birch and grass pollen seasons in the 3 years after treatment. Increased frequencies of T-regulatory lymphocytes may explain the non-specific effects.In 2017 to 2018, we conducted a double-blind study with 38 participants, half of whom received placebo and half, active treatment. In this study, we saw no difference between the treatment groups in the first year after treatment. However, after discontinuation and unblinding in 2019, i.e., two years after treatment, the actively treated group improved in terms of symptoms, and quality of life was improved compared with the placebo group despite less need for medication. T-regulatory lymphocytes increased one year after treatment only in the actively treated group.A long-term follow-up of the research subjects from our two larger studies in 2022, i.e., five to eight years after treatment, showed in the double-blind study without a pure placebo that the scores for symptoms, medication use, and quality of life remained as low as after the first three years. In the placebo-controlled study, a statistically significant improvement in symptoms remained during the grass pollen season. Analysing the two studies together, symptom improvement was significant even during the birch pollen season. Thus, although the effect does not seem to diminish, those who did not receive birch, but only grass, needed to use more medication during the birch pollen season in 2022, seven to eight years after treatment. Moreover, those who did not receive grass but only birch needed more medication during the grass pollen season. This may suggest that the non-specific effect begins to wane after seven to eight years.Allergy to pollen is a major problem for individuals and society, where symptom-relieving treatment with drugs is not enough for many. They can be helped with immunotherapy, which takes at least three years, is expensive and fraught with side effects. In contrast, intralymphatic immunotherapy involves three injections over eight weeks. Our three studies show that the treatment is safe and indicate that it has a clinical effect up to eight years after treatment. T-regulatory cells appear to be important to the immunological mechanism, leading to tolerance to pollen.
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| 3. |
- Ahlberg, Mona, 1966-
(författare)
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Being cared for in an Intensive Care Unit – family functioning and support
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- When COVID-19 came as an uninvited guest into our everyday lives, nursing in intensive care was affected and thus the studies contain data from both before and during the COVID-19 pandemic.Before the pandemic, most intensive care units, which care for patients with critical illness in a technical setting, allowed family members to visit the patient 24 hours a day. The intensive care unit is a stressful and frightening environment for both the patient and their family. They can be affected both mentally and physically, showing symptoms such as difficulty sleeping, stress and depression. The intensive cared patient often does not remember anything from the time they were cared for in the intensive care unit, and the family needs to explain and recount this unconscious time. During the pandemic, this changed, with restrictions and limited opportunities to visit the hospital and patient due to virus outbreaks. Family members received information about the patient's medical condition by phone from a physician. The overall aim of this thesis was to explore and conceptualise the family functioning of families with a family member treated in the intensive care unit. There was also an intention to describe and evaluate how an intervention affects the family and individual family members in families where a family member received intensive care.In these studies, qualitative, quantitative, as well as mixed methods were utilised. Participants were adult intensive cared patients from seven intensive care clinics, and their families. The results examined between families are based on the patient and family characteristics. The results from study I show that families who have experienced COVID-19 and with a family member who was cared for in an intensive care unit, have existential thoughts. Study II shows no major impact on family function between families, but the answers differ within the families who experienced intensive care. In study III, concerning families experiencing intensive care and attending family health conversations, there was an awareness of family function. The conversations brought the family closer together, through improved understanding of each other. In study IV family functioning, hope and sense of coherence were com-pared among the participants in two intervention groups: Family health conversations and support group conversations. Family functioning and hope were higher in the group that participated in the family health conversations and comprehensibility, meaningfulness and vitality were higher among the participants in the support group conversation. By exploring how family function affects the individual family member and the family as a unit during critical illness and intensive care, new ways of working can be strengthened in the care of patients and their families.
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| 4. |
- Ahmad, Awais, 1987-
(författare)
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Autoantibodies in healthy blood donors, rheumatic and autoimmune liver diseases
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmunity is a common phenomenon where the immune system recognises the body's own tissues. Autoimmunity can lead to disease if tissue damage occurs. Autoimmune diseases affect 5–10% of the global population and in many of these autoantibodies can be detected. The autoantibodies can be detected with several different methods. In this thesis, line immunoassays and fluorescence enzyme immunoassay were used to investigate the presence of autoantibodies in blood donors and various disease groups. Line immunoassays use strips while fluorescence enzyme immunoassay uses wells. The strips and wells are coated with proteins that are allowed to react with serum samples from the patient. In the presence of autoantibodies, either a color change (line immunoassay) or a light reaction (fluorescence enzyme immunoassay) occurs.Study I and II: With the EuroLine -Autoimmune Liver Diseases- (IgG) line immunoassay, the presence of autoantibodies associated with autoimmune liver diseases was analysed in blood donors, patients with autoimmune liver diseases and patients with SLE. Autoantibodies could be detected in several blood donors. A very rare autoantibody, anti-LC- 1, was more common in blood donors than in patients with autoimmune liver diseases. Despite the presence of the autoantibodies, no association was seen with abnormal liver values in blood donors or patients with SLE. By raising the cut-off, the number of "false positive" results decreased. However, this could not correct the problem with anti-LC-1, which seems to indicate that there is a problem with the LC-1 antigen so that non-specific reactions are detected. The risk of developing autoimmune liver disease was considered to be low in the SLE patients, as none of these patients developed autoimmune liver disease despite several years of follow-up. Most of the positive findings with the EuroLine immunoassay could not be confirmed with other methods, indicating that this method is very sensitive.Study III: With the EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) line immunoassay, the rare autoantibodies anti-Th/To and anti-NOR90 could be detected as frequently in blood donors as in patients with systemic sclerosis. Most of the other autoantibodies were more common in patients with systemic sclerosis compared to blood donors and other disease groups. Some of these autoantibodies were associated with specific clinical manifestations, including renal involvement in patients with SLE. These findings need to be verified.Study IV: Autoantibodies that bind the U1-RNP protein (anti-U1-RNP) can be detected in patients with SLE. Patients with anti-U1-RNP can be further analysed for the presence of autoantibodies against the protein RNP 70kDa (anti-RNP70). However, the clinical value of further analysis of anti-RNP70 is uncertain. In this study, fluorescence enzyme immunoassay was used to analyse anti-U1-RNP positive samples for anti-RNP70 to evaluate whether it added anything of clinical value in SLE patients. Presence of anti-U1-RNP was associated with low white blood cell counts and less organ damage. However, analysis of anti-RNP70 in patients with SLE did not add any additional clinical information.Conclusion: Euroline -Autoimmune Liver Diseases- (IgG) and EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) are tools that are of value in the diagnosis of autoimmune liver diseases and systemic sclerosis, but the methods have high sensitivity which can lead to false positive results. By raising the cut-off, the risk of this can be reduced. Some rare antibodies were found more frequently in blood donors than in patients with the different disease groups, suggesting potential problems with the antigen source. Subtyping of anti-RNP70 in SLE patients with anti-U1-RNP did not add anything of clinical value.
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| 5. |
- Al-Hawasi, Abbas, 1976-
(författare)
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Retinal ganglion cell examination with Optical Coherence Tomography reflects physiological and pathological changes in the eye and the brain.
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The retinal ganglion cell is situated in the inner retina and its axons, composing the retinal nerve fiber layer (RNFL), leave the eye to form the optic nerve. These cells develop embryologically from the forebrain and later during development re-establish connections with different parts of the brain serving different purposes. This unique position and connections make it possible to be investigated with different methods. Optical Coherence Tomography (OCT) is an accessible and easily operated clinical device that can provide a detailed image of this layer at a few micrometers level of precision in measurements. In this thesis we aimed to see whether examining these cells with OCT could reflect physiological and pathological changes in the eye and brain.In cases of optic neuritis (Paper I), the OCT examination showed early thickening of the peripapillary (pRNFL) followed by thinning which takes 6-9 months to reduce to below normal thickness without the ability to distinguish between the real from pseudo thinning. The ganglion cell -inner plexiform layer (GCL-IPL) layer, however, showed a thickness reduction within a few weeks to 3 months without pseudo thinning. In cases of Idiopathic Intracranial Hypertension (IIH) (Paper II), the GCL-IPL remained unchanged and there was no difference in pRNFL thickness compared to healthy controls, whereas the optic disc parameters of rim thickness, rim area, cup volume and cup/disc ratio differed significantly (P<0.05).In cases of benign multiple sclerosis (Paper IV), the OCT could detect that eyes which are not affected by optic neuritis had an annual thinning rate of the RNFL and GCL-IPL similar to a healthy population (P>0.05) which may indicate the benign course of the disease. In cases of physiological factors affecting the GCL in healthy population (Paper III) the OCT examination showed that there was a significant thinning rate of the layer with age (P<0.05), but the thinning was not significant when sex and axial length of the eye were taken into consideration. Males had a thicker GCL volume than females and with age a significant reduction in GCL volume was noted in females but not in males. A Longer axial length of the eye found to be associated with thinner GCL volume. In conclusion retinal ganglion cell changes detected with OCT can reflect physiological and pathological changes in the eye and brain.
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| 6. |
- Alexandrou, Christina, 1981-
(författare)
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MINISTOP 2.0 : a smartphone app integrated in primary child health care to promote healthy diet and physical activity behaviors and prevent obesity in preschool-aged children
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundChildhood overweight and obesity is currently estimated to affect 39 million children under the age of five worldwide. After the COVID-19 pandemic, further increases have been observed in several countries including Sweden, where an increased incidence was observed in 3- and 4-year-old children, especially in disadvantaged areas. This development emphasizes the urgent need for population-based childhood obesity prevention interventions, and Swedish primary child health care provides an ideal setting for primary preventive efforts during the preschool years. However, thus far, previous child health care-based obesity prevention interventions have demonstrated limited effectiveness. As previous interventions also have been face-to-face delivered and thus resource-demanding; new, and scalable ways of delivering interventions also need to be evaluated. Mobile health or mHealth refers to the use of mobile devices for medical and public health practice and provides opportunity for development and dissemination of digital interventions for various purposes and populations at scale. This thesis reports the results of the MINISTOP 2.0 project, which covers the development and evaluation of the MINISTOP 2.0 digital intervention, from adaptation and translation of the intervention to Somali, Arabic and English (Paper I), to evaluation of real-world effectiveness within the Swedish primary child health care setting (Paper II) followed by exploration of user experiences and implementation aspects (Paper III) and a cost-consequence analysis of the intervention costs (Paper IV). AimThe overall aim of this thesis was to evaluate whether a 6-month parent-oriented mHealth intervention (MINISTOP 2.0 app), embedded in the routine services of Swedish primary child health care, can be used to improve diet and physical activity behaviors, and decrease the prevalence of over-weight and obesity in 2.5-to-3-year-old children. MethodsThe MINISTOP 2.0 project utilized a hybrid type 1 effectiveness-implementation study design to enable simultaneous evaluation and exploration of intervention effectiveness, user experiences and implementation aspects. Paper I: A qualitative exploration of user requirements in an app-based parental support intervention was conducted through three focus group interviews with Somali- (n = 5), Arabic- (n = 4), and Swedish-speaking parents (n = 6), and individual interviews with child health care nurses (n = 15). Data was analyzed using thematic analysis. Paper II: A two-arm parallel randomized controlled trial was conducted at 19 child health care centers located in six Swedish regions. Participating parents (n = 552) were invited during their routine visit at 2.5/3-years at their primary child health care center. All baseline and follow-up procedures were conducted by the nurses. Parents that were randomized to the control group received standard care, while the intervention group received access to the MINISTOP 2.0 app for six months, alongside standard care. Prior to randomization, nurses measured the child’s height and weight for assessment of BMI, and parents answered a questionnaire about their child’s intake of fruit and vegetables, sweet and savory treats, and sweet drinks; time spent in moderate-to-vigorous physical activity (MVPA) and screen time; and parental self-efficacy (PSE) for promoting healthy diet, physical activity, and screen time behaviors. These baseline procedures were then repeated at a 6-month follow-up visit to the child health care center. Paper III: A qualitative exploration of user experiences, acceptability, and feasibility of the MINISTOP 2.0 intervention was conducted through individual interviews with parents (n = 24) with diverse backgrounds, and with child health care nurses (n = 15). Data was analyzed using content analysis. Paper IV: Data on all costs related to the MINISTOP 2.0 intervention, including costs for app and interface upkeep as well as salary costs for introduction and dissemination of the app by nurses, was collected retrospectively. A cost-consequence analysis was then performed to estimate the costs of the intervention. ResultsPaper I: Parents expressed several challenges related to promoting healthy eating behaviors, such as worrying about their child not eating enough, and difficulties balancing different food cultures. There were also requests for the app content to be accessible through alternative modes of delivery (e.g., audio/video) for parents with low literacy. Nurses underlined the importance of supporting parents early with health behavior interventions, and the value of a shared digital platform, available in several languages, to facilitate communication with parents. Paper II: Seventy-nine percent of the participating parents (n = 552) were mothers and 62% had a university degree. Among the children, 24% had two foreign-born parents. Children in the intervention group had lower in-takes of sweet and savory treats (-6.97 g/day; p = 0.001), sweet drinks (-31.52 g/day; p < 0.001), and screen time (-7.00 min/day; p = 0.012) com-pared to the control group at follow-up. Parents in the intervention group also reported higher total PSE (0.91; p = 0.006), PSE for promoting healthy diet behaviors (0.34; p = 0.008) and PSE for promoting healthy physical activity behaviors (0.31; p = 0.009) compared to the control group. For children’s MVPA or BMI z-score, no statistically significant effect was observed between groups. Finally, parents also reported high satisfaction with the app, and 54% reported using the app once a week or more. Paper III: Findings indicated that the app was well accepted and appreciated, as it increased knowledge and awareness around current health behaviors. Furthermore, evidence-based information available in one place and from a trusted source, was highly valued, especially when living in a country with a different culture than your own. The app was also acknowledged as a feasible support tool and a suitable complement to the standard care offered during visits. Finally, due to the accessibility in different languages and the possibility of disseminating the app at scale, both nurses and parents described the app as an appropriate tool for reaching larger populations of parents as well as parents in need of additional support. Paper IV: The total cost for the MINISTOP 2.0 intervention was 437 439 SEK based on the 277 families in the intervention group. The cost for child health care nurses introducing and registering families for the app represented only 9% of the total cost per family, which was considerably lower in comparison to other similar childhood obesity prevention interventions. Also, notably, for upscaling, sharing running costs for the user interface for larger populations of children, would result in much lower total costs per family. ConclusionsOverall, qualitative findings for adapting the intervention highlighted the need for early access to information, as well as the importance of adapting interventions to also be accessible for parents with migrant background and parents with lower literacy. When disseminated through primary child health care, the MINISTOP 2.0 intervention resulted in statistically significant reduced intakes of sweet and savory treats, sweet drinks, and screen time in children (primary outcomes) as well as increased PSE for promoting healthy diet and activity behaviors (secondary outcome). The app was well accepted and perceived as a feasible support tool for parents. Furthermore, accessibility in different languages was also appreciated. Finally, the relatively low salary costs in comparison to face-to-face interventions suggest that the MINISTOP 2.0 app and caregiver interface may be an affordable preventive effort for early promotion of healthy lifestyle behaviors in children when scaled up on a population level. Altogether, the results from the papers in this thesis support the large-scale implementation of the MINISTOP 2.0 app within the Swedish primary child health care setting for promotion of healthy lifestyle behaviours in 2.5-to-3-year-old children.
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| 7. |
- Alfredsson Ågren, Kristin, PhD Student, lecturer, 1971-
(författare)
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Internet use and digital participation in everyday life : Adolescents and young adults with intellectual disabilities
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Internet use is an integral part of everyday life in contemporary society, especially among young people. It is used to perform activities in everyday life by an increasing proportion of the population. However, knowledge about access to and use of the internet by adolescents and young adults with intellectual disabilities (ID) is scarce. More knowledge is needed about digital competencies and digital participation in their everyday lives.Aim: The overall aim of this thesis was to explore and describe internet access and use, and digital participation in everyday life among adolescents and young adults with intellectual disabilities.Designs and Methods: The thesis is based on results from three studies. In study I, the focus was on access to and use of the internet in the everyday settings of school/work, at home or during free time. Data was collected through observations, conversations, and follow-up interviews with 15 participants with ID, aged 13–24 years. The data was analysed using qualitative content analysis. In studies II and III, the design was cross-sectional and comparative, using national surveys on media and internet use from the Swedish Media Council, from which comparative data from reference groups could be gained. In study II, the national survey of adolescents on internet access and use was cognitively adapted for adolescents with intellectual disabilities, aged 13–20 years, in several steps. This made it accessible to a total selection of pupils from all the special schools in four diverse municipalities in two different regions of Sweden. In study III, the national survey of parents about opportunities and risks of internet use by their adolescents was used. The surveys were sent to a sample of n=318 adolescents with ID and their caregivers/parents. The responses were higher for the adolescents (n=114) than for the parents (n=99), and the response rate of the adolescents with ID was equivalent as that of the reference group, at 36% and 38% respectively. In study II, chi-square tests were used and, when necessary, Fisher’s exact test to analyse the data. In study III, analyses were carried out using Fisher’s exact test and logistic regression to control for confounding factors.Results: This thesis show that access to internet-enabled devices is lower for adolescents with ID than for the general population, except for tablets (study II). All internet activities, except playing games, are performed by fewer adolescents with ID compared to the reference group (study II) and the time spent on the internet activities is less (study III). Both environmental challenges and personal abilities present difficulties in internet access and use (study I) and affect digital participation for adolescents and young adults with ID. Furthermore, a significantly higher proportion of parents of adolescents with ID perceive opportunities associated with internet use and playing games, and a lower proportion perceive risks with negative consequences, or have concerns about online risks, compared with the reference group (study III). Significantly more parents of adolescents with ID state that their adolescent never uses smartphones or social media compared with the reference group. Strategies used to handle the digital environment and take part in internet activities were found and described, such as getting support from others, reducing the number of internet-enabled devices used and personalising them. Gaining access to internet content and performing internet activities was facilitated by picture-, word- and voice-based strategies, which were used by adolescents and young adults with both mild and moderate ID (study I).Conclusions: The conclusions are that the results show a lag in internet access and use and in digital participation by adolescents and young adults with ID. Adolescents and young adults with ID were accessing and using the internet in similar ways to the reference group, but to a lesser extent. The impact of the participants’ environment, together with their lack of certain abilities, make the development of digital competencies difficult for them. The result that parents of adolescents with ID perceive more opportunities and fewer risks associated with the internet provides new knowledge to support positive risk-taking in internet use and enable digital participation by adolescents and young adults with ID. Support can be developed in collaboration between the adolescent/young adult, their parents and teachers, and staff in community-based services and should involve physical, social and digital environmental adaptations. These can enable the development of digital competencies and minimise the lag in digital participation in everyday life, which is needed for participation in today’s digitalised society.
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| 8. |
- Allemann, Hanna, 1979-
(författare)
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Online support for informal carers of persons with heart failure : Focus on perceptions, development and experiences
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Heart failure (HF) is a common condition, and its prevalence is expected to increase. The illness trajectory is unpredictable, and its effects will include a potential impact on informal carers, i.e., family, friends, and significant others. Sometimes these persons are affected by the help and care they provide in such a way that they might themselves need support. However, they may be unrecognised in their endeavours, and might also experience a lack of support, especially from healthcare. Online solutions are considered to have the potential to provide accessible support to carers that is also anticipated to be cost-effective. Aim: This thesis focuses on support to informal carers to persons living with HF, but also take the viewpoint of the person with HF by exploring social supports associations with their health and well-being. The overall aim was to explore perceptions, development, and experiences of online support for informal carers. Method: This thesis comprises four studies. Study I had a cross-sectional design using self-reported data and data from the Swedish Pace-maker and ICD Registry. Data from 1,550 persons with HF who were living with an ICD and who had complete data on the outcome variable were utilised for both descriptive analysis and logistic regression. The outcome variable, perceived social support, was measured using the questionnaire Multidimensional Scale of Perceived Social Support (MSPSS), which includes measuring support from significant others, family, and friends. The logistic regression was conducted to compare those dichotomised as having low/medium perceived social support to those having high levels of support. Study II had a qualitative design, and data were collected through 8 focus groups with 23 informal carers of persons with HF to explore their perceptions of how online solutions could be of value for support. Data were analysed using qualitative content analysis. Study III had a descriptive design. It describes the co-design process of an online support pro-gramme for carers through three phases. In phase I, topics and content that reflected carers needs and preferences were identified. In phase II, the content for the support programme was developed and through phase III the content was refined and finalised. Informal carers participated in every phase, and the co-design process also involved professionals with expertise in, for example, HF and caregiving, for the development of content. It was an iterative process, moving back and forth between phases, and the re-search group acted as coordinators and ensured that carers’ voices were kept central to the process. Study IV had a qualitative design, and data were collected through individual semi-structured interviews with 15 carers. Interviews were analysed using qualitative content analysis. The study focused on informal carers' experiences of online, co-designed support pro-gramme while being participants in a randomised controlled trial (RCT) that has the aim of studying the effects of engaging with the programme. Results: The findings show that one in five diagnosed with HF and living with an ICD reported low/medium levels of social support and that these persons had higher odds of negative psychosocial outcomes. This un-derscores the value and importance of support from informal carers for the well-being of those with HF. The thesis focused on perceptions, development, and experiences of online support for informal carers. The findings suggest that a co-designed support programme has the potential to be usable and useful for carers considering the online format and its content. It may provide insights, preparedness, and validation in relation to being a carer of a person with HF. However, carers may have an ‘ambiguous stance’ towards the online format and going online for support may not be the preferred form of support for all carers. Conclusion: A co-designed online support programme, when built on a trusted platform within a healthcare context, may be considered both usable and useful for carers. The online format and content also provide the potential to offer timely and adaptable support. The content, developed in a collaboration between carers and professionals, offers evidence-based, relevant information, thereby possibly avoiding seeming impersonal, which can also be beneficial. The programme acknowledges the intertwined lives of carers and those with HF, and its content reflects this, potentially also enhancing its perception as usable and useful for carers. Still, the potential of the support programme depends on carers being aware of its existence, or being made aware, and can further recognise its value. The support programme is considered to have the capacity to be relevant for a broad group of carers, and therefore efforts may be of importance to ensure it is accessed and utilised. However, it is also important to take into account that not everyone may be willing or able to go online for support, or may wish to stay in a caring role. Healthcare also needs to recognise this when offering support to carers and the online support may be regarded an option among several.
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| 9. |
- Andersen, Pia, 1958-
(författare)
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Physical activity on prescription with access to counsellor support implemented in routine care : Healthcare and patient perspectives
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The Swedish PAP (physical activity on prescription) programme FaR®, introduced in 2001, has been adopted by all Swedish regions, which are responsible for provision of healthcare in Sweden. Several studies have shown positive outcomes of the Swedish PAP on patients’ physical activity and other health-related outcomes. There are no guidelines for best practises of the Swedish PAP, which has led to the development of different organizational structures for its delivery. This thesis project was developed with the ambition of providing knowledge for further development of PAP in clinical practise.Aim: The overall aim was to investigate and generate improved understanding of a structure for physical activity on prescription with access to physical activity counsellors, implemented in routine healthcare.Methods: To address the overall aim, four real-world studies with different design and analysis methods were carried out. The study population consisted of patients 18 years or older prescribed PAP in primary and secondary care in Region Kronoberg’s healthcare organization. Study I investigated characteristics of healthcare delivery of PAP over a four-year period, including all patients prescribed PAP in these years. Study II explored factors that influenced patient’s long-term engagement in physical activity after prescription. Study III investigated differences in physical activity and health-related quality of life (HRQoL) at one-year follow-up between patients who used versus patients who did not use counsellor support after prescription. Study IV investigated factors associated with patients increase in physical activity at one-year follow-up. Data sources for the studies were electronic medical records (Studies I, II, III and IV), individual interviews (Study II) and a baseline and a follow-up questionnaire (Studies III and IV). Different statistical analyses were performed in Studies I, III and IV. Study II used qualitative content analysis based on an approach including both inductive and deductive analysis. The final study samples of PAP recipients were N = 4,879 (Study I), n = 13 (Study II), n = 400 (Study = III) and n = 355 (Study IV).Results: Study I: 4,879 PAP recipients were identified, one-third had used the offer of counsellor support. PAP recipients had a high frequency of diagnosis and healthcare consumption prior to PAP. Counsellor users had higher frequency of multiple diagnoses and healthcare visits than non-counsellor users. The main prescriber of PAP was physicians and the main prescribing setting was primary care. Study II: PAP recipients’ long-term engagement with physical activity was influenced by the determinants of capability, opportunity, and motivation. Receiving a prescription of physical activity, and professional counselling and follow up from a physical activity counsellor, and adaption of PAP to the individual’s capacity were important for patients change of physical activity. Study III: Counsellor users had better outcomes in both physical activity and HRQoL than non-users of this support. Study IV: Nearly half of the PAP recipients had increased physical activity one year after prescription. Increased physical activity was positively associated with lower baseline activity, counsellor use, and positive perception of given support after PAP.Conclusions: Patients who were prescribed PAP had a high frequency of diagnoses and high healthcare consumption in the year prior to the prescription. Due to the positive findings regarding patient outcomes on physical activity, and patient experiences of counsellor support, it could be suggested that individualized counselling and follow up by a physical activity counsellor is of importance for patients’ engagement in physical activity, especially for patients with lower baseline activity. Since increased activity was also seen among nonusers of counsellor support, a general recommendation for physical activity counsellor support for all PAP recipients could not be suggested.
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| 10. |
- Andersson White, Pär, 1983-
(författare)
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Social Inequalities in Child Health : Type 1 Diabetes, Obesity, Cardiovascular Risk Factors and the Role of Self-control
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Swedish Commission on Health Inequality defined health inequality as systematic differences in health between groups in society with different social positions. All avoidable socioeconomic health inequalities are unfair, and as stated by WHO's Commission on the Social Determinants of Health, we have a moral obligation to try to reduce them. "Putting these inequities right is a matter of social justice. Reducing health inequities is, for the Commission on Social Determinants of Health, an ethical imperative." This ethical imperative is especially apparent regarding the health of children and adolescents. Children’s right to the highest attainable standard of health is also enshrined in Article 24 of the Convention on the Rights of the Child. To reach the goal of a reduction of health inequalities, research is necessary to describe the social gradients of health. Research is also needed to better understand why these gradients occur. A better understanding and knowledge about health inequalities can lead to policies that reduce these inequalities and ensure children’s right to health.This thesis investigates social inequality in child health using data from a Swedish population-based prospective birth cohort, the All Babies in Southeast Sweden (ABIS) cohort. Social inequality in obesity in the ABIS cohort is also compared with other birth cohorts participating in the Elucidating Pathways to Child Health Inequality (EPOCH) collaboration which includes cohorts from six high-income countries; Sweden, the Netherlands, Canada (one national and one cohort from Quebec), UK, Australia, and USA.In Paper 1 we show that health inequalities in overweight and obesity are detectable already at two years of age and that these inequalities increase during childhood. In adolescents, low socioeconomic status increases the risk of becoming overweight and the risk of components of the metabolic syndrome, including high blood pressure and dyslipidemia (low high-density cholesterol).The level of inequality in obesity in the Swedish ABIS cohort was lower than in the other participating countries in the EPOCH collaboration (Paper 2). Inequality was lower in absolute and relative terms when SES was measured by household income. Inequality was also lower in absolute, but not relative, terms when SES was measured by maternal education. This finding indicates that some of the policies implemented in Sweden may attenuate social inequalities in obesity in children. Examples of such policies with evidence for reducing social inequality in obesity implemented in Sweden include universal preschools and free school meals.This thesis also investigates health inequalities in autoimmune disease (Paper 3). In this study, we found that low socioeconomic status increased the risk of Type 1 Diabetes but not the other autoimmune diseases investigated. Path analysis indicated that part of the increased risk in children with low SES of Type 1 Diabetes might be mediated by a higher body mass index and an elevated risk of serious life events.In the final paper, this thesis tests the hypothesis that differences in maternal and child self-control mediate social inequalities in obesity. Two measures of self-control were used; for mothers, the self-control variable was based on behaviors related to self-control (smoking during pregnancy, smoking during the child’s first year of life, breastfeeding duration, and participating in the ABIS study with biological samples). For the children, the self-control variable was based on questionnaire data on the impulsivity subscale of the Strengths and Difficulties Questionnaire (SDQ). The results showed that the two measures of self-control mediated 87.5 % of the increased risk of obesity at age 19 years in children with low maternal education and 93 % of the risk if maternal BMI was also included in the selfcontrol variable.In the discussion part of this thesis, the conclusions that can be deduced from understanding the mechanisms of social inequality in child health are discussed. A theory with a central role of self-control for health inequality predicts that social inequality will increase without interventions. In an environment with rising numbers of stimuli of the human reward system, stimuli that also have negative long-term consequences (socalled Limbic traps), child and adolescent health, in general, will decrease. Because of the mechanisms related to SES and self-control, children with low SES will be disproportionally affected. The result of this development will be increasing levels of social inequalities in child health.The discussion also includes implications for policies that may improve health and reduce inequalities. These policies should reduce the exposure of children and adolescents to harmful behaviors/limbic traps. Examples of policies that have this effect include universal preschools for all children, free healthy meals in preschools and schools, increased after-school activities for all children, and longer school days for adolescents with increased hours for physical activity, music, and art. Mobile phones and social media restrictions in schools and policies to reduce use at home should also be implemented. Finally, policies should be implemented to reduce residential and school segregation in the community.
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| 11. |
- Anderzén, Johan
(författare)
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Differences in glycemic control in type 1 diabetes children and adolescents : in a national and international perspective and the effect on microvascular complications in young adults
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on glycemic control measured as HbA1c in type 1 diabetes (T1D) patients during childhood and especially during adolescence, both in a Swedish and an international context, and relates the glycemic control to the risk of complications in young adults. In studies I and II, the Swedish Pediatric Diabetes Quality Register (SWEDIABKIDS) and the Swedish National Diabetes Register (NDR) were used. More than 4000 young adults with T1D and data on HbA1c in NDR both in 2011 and 2012 as well as data on HbA1c in SWEDIABKIDS were used. The T1D patients with poor glycemic control during their teenage period had a risk for retinopathy several times higher than those with good glycemic control. The risk for micro- and macroalbuminuria was also higher in those with poor glycemic control and was most pronounced in the T1D patients with high HbA1c in both registers. Females had worse glycemic control than males during the teenage period and an increased risk of retinopathy as young adults. In studies III and IV, pediatric diabetes quality register data from, respectively, eight and seven Western high-income countries were collected in the year 2013. Data on about 60 000 T1D patients were analyzed according to mean HbA1c levels in the countries and related to actual age and T1D duration to determine if there were differences in glycemic control between the countries. There were large differences in mean HbA1c between the countries, both when related to age and T1D duration. Despite the differences in mean HbA1c, the increase in mean HbA1c with increasing age and T1D duration was very similar in all countries. The overall picture of these studies is that good glycemic control is very important to avoid complications of T1D as young adults, and it seems particularly important to maintain a good glycemic control during adolescence. Furthermore large differences in glycemic control in T1D patients in Western high-income countries were found. Despite the differences in glycemic control, the pattern of rising HbA1c with increasing age and duration of T1D was very similar in all countries. Females have worse glycemic control than males during their teenage period, both in Sweden and internationally, and they also have more retinopathy as young adults. This thesis shows that it is of the utmost importance to treat T1D patients intensively directly after diagnosis, to treat the young T1D patients intensely and to reduce the rise in HbA1c with increasing age and duration of T1D in order to avoid complications early in life. Diabetes quality registers give the opportunity to compare results and share experiences, both within and between countries, so treatment of T1D can be designed in the best possible way and thereby minimize T1D complications.
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| 12. |
- Andreassen, Maria, 1966-
(författare)
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Digital support for people with cognitive impairment : An intervention to increase the occupational performance in everyday life
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Senior people with cognitive impairment may experience an inability to manage everyday life due to difficulties related to time management, and planning and structuring everyday life. These difficulties can affect people negatively, for example not remembering to carry out future planned activities. Interventions that compensate for lost cognitive ability often include using assistive technology for cognition (ATC). By investigating the feasibility and potential effects of an intervention with the interactive digital calendar with active reminders, RemindMe, knowledge can be generated about aspects of learning to use and using digital support. Further, knowledge can also be generated about occupations in everyday life that people need to receive reminders for, both during the rehabilitation period and two years after the rehabilitation period. This knowledge can support building evidence-based interventions in rehabilitation for people with cognitive impairment using digital technology. Aim: The overall aim of this thesis was to study an interactive digital calendar with mobile phone reminders (RemindMe) for people with cognitive impairment, as support to increase the occupational performance in everyday life. Methods: This thesis includes four studies, using both qualitative and quantitative data collection methods. Study I was a focus group interview, exploring twenty senior people aged between 66 and 85 and their experiences of learning to use and using RemindMe in everyday life. The seniors had used RemindMe for six weeks and had received weekly support calls from a research assistant during the study period. After six weeks, the participants took part in focus group interviews. Four focus group interviews were conducted, analysed with content analyses. The use of RemindMe and feasibility aspects were also investigated in study II with a mixed-methods design. Eight patients with cognitive impairment, aged between 26–68, and seven occupational therapists participated. The occupational therapists were experienced in occupational therapy and were working at three different outpatient rehabilitation clinics in southeast Sweden. They had a median of 20 years of experience (range of 2–25 years). The patients received an introduction to using RemindMe, as well as weekly support calls from occupational therapists or a research assistant for eight weeks. Quantitative data was collected using the Quebec User Evaluation of Satisfaction with Assistive Technology 2.0 (QUEST 2.0). The frequency of and the actual use of RemindMe was generated by RemindMe. Qualitative data was collected via face-to-face interviews with occupational therapists, via field notes from the weekly support conversations, and during the assessments with patients with cognitive impairment. Analyses were conducted using descriptive statistics and directive deductive content analyses. Study III investigated the intervention with RemindMe, addressing plausible outcome measures by investigating changes in outcomes, impact on occupational performance, independence, health-related quality of life, and the psychosocial impact of support used for people with cognitive impairment. The design was a pilot randomized controlled trial with fifteen patients, with cognitive impairment, aged between 26–79, randomized to either an intervention group or a control group. The intervention group consisted of eight patients and the control group of seven patients. The outcome measures were assessed using the Canadian Occupational Performance Measure (COPM), the Functional Independence Measure (FIM), the EuroQol 5-Dimension Visual Analog Scale (EQ-5D-VAS), and the Psychosocial Impact of Assistive Devices Scale (PIADS). Study III was registered at ClinicalTrails.gov, identifier: NCT04470219. Study IV explored seven patients, aged between 51–71, experiences of strategies and support used to establish a new everyday life and their experience of support for time management and planning and structuring everyday life due to cognitive impairment. The study was a qualitative, semi-structured, face-to-face interview. The interviews were analysed with inductive content analysis. Results: The results of this thesis address learning to use and using assistive technology for cognition (ATC) in everyday life and outcomes from using RemindMe. The participants were accustomed to using calendars. However, there were differences in terms of whether they preferred to use “low tech” calendars (such as paper calendars), or “high tech” calendars (for example, digital calendars with reminders), or whether a combination of “low and high tech” was preferred (Studies I and IV). Other support strategies were also described, for example, the conscious use of objects as reminders in the home environment or everyday life routines (Study IV). Participants were positive towards the use of digital technology, especially mobile phones/smartphones that they easily can carry with them (Studies I and IV). Participants also described the advantage of using digital technology with active reminders and audio prompts, signalling, and telling them when to do something. This was described as the reminder “talks to me” (Study I). The actual use of RemindMe showed that reminders were for example used for taking medication, do exercises, or meeting family or friends (Study II). Occupational therapists in Study II described that their patients benefited from using reminders and that patients have to be active in their everyday life and perceive a need for reminders. The outcomes from measurements of occupational performance (COPM) indicate that patients in the intervention group increased their occupational performance and their satisfaction with their performance compared with the control group. The intervention group also increased their independence (FIM) in the communication and social and intellectual abilities subscales (Study III). Conclusions: The results indicate the importance of choosing a reminder that is suited to the patient’s needs, and this reminder can be either “low tech” or “high tech”. The important thing is that the reminder matches the patient’s needs. The result also indicates that for people with cognitive impairment to make full use of the reminder in everyday life, support with learning to use and using the device for a longer period is needed. Participants (Studies II, III, and IV) described scheduling and receiving active reminders as important for achieving a feeling of comfort and security. Another technique was to find habits and routines or objects to support time management and planning and structuring everyday life. Having a sense of comfort and security involved being in control of everyday life. It can be understood as people talking about being fully involved in their life situations, and in that sense as experiencing participation. However, this was s not investigated in the present studies. Two years after the rehabilitation period, digital or paper calendars were used to establish a new everyday life. Active reminders were trusted and resulted in a feeling of comfort and security as well as a sense of control and independence in everyday life.
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| 13. |
- Arbring, Kerstin, 1961-
(författare)
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Two worlds, one goal : A Clinician’s Perspective on Laboratory Analyses in Anticoagulant Treatment
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Almost precisely a century ago, in the 1920s and 1930s, cattle bled to death in North America after being fed moldy hay containing sweet clover, the yellow Melilotus officinalis, and the white Melilotus albus. The toxic substance in the hay inhibiting blood coagulation was identified and named dicumarol. Further development resulted in warfarin, an oral anticoagulant that has been used for over 70 years and still is, even though newer direct-acting oral anticoagulants (DOACs) are mainly replacing it. For some patients, warfarin is still the drug of choice. A safe warfarin treatment needs repeated blood sample analysis (PT-INR), and with the new DOACs come new laboratory challenges. The aim of this thesis was to investigate ways laboratory methods can contribute to improving oral anticoagulant treatment. Paper I explores genetic variants of the enzyme targeted by warfarin, VKORC1. The result shows that the haplotype VKORC1*2 is the most important of the VKORC1 haplotypes for warfarin dosage, with a lower dose requirement. The VKORC1*2 haplotype was also related to more unstable PT-INR levels. Paper II describes a cross-section study comparing warfarin treatment control, as PT-INRs within the intended therapeutic range, in primary health care centers (PHCCs) and specialized anticoagulation clinics (ACCs). Both settings showed good therapeutic control, with at least as good therapeutic control in the PHCCs as in the ACCs. Today, almost all warfarin treatment in our region is centralized to ACCs. Paper III focuses on the modification of a point-of-care PT method. A ratio of PT from two different dilutions of each patient sample was calculated and used as an indirect measure of DOAC activity. There were close correlations between the PT ratio and drug concentrations measured at the hospital laboratory. The detection level varies between DOACs and may limit its use in some situations. Paper IV evaluated the MRX PT DOAC, an assay based on the PT ratio principle. It was found to be able to detect potentially interfering DOAC levels in plasma samples. Confirmatory testing is recommended, as is sensitivity improvement for the detection of specific interferences.
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| 14. |
- Ax, Anna-Karin, 1980-
(författare)
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Exercise in patients with cancer : Effects on health-related quality of life, costs, and cost-effectiveness during oncological treatment
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Short and long-term side effects of oncological treatment negatively affect daily living and health-related quality of life (HRQoL) in patient with cancer. Exercise during treatment is beneficial for HRQoL, however evidence as to what exercise intensity is most optimal for improving HRQoL and cost-effectiveness is lacking. Cost-effectiveness is important information for decisionmakers when implementing healthcare interventions, such as exercise programmes. The overall aim of this thesis was to study functioning in daily life, HRQoL, costs, and cost-effectiveness of an exercise intervention of different exercise intensities in patients with cancer receiving oncological treatment. Method: Study I was qualitative and explored how individuals with cancer receiving curative treatment and participating in an exercise intervention experienced their functioning in daily life. Semi-structured individual interviews (n =21) were performed and analysed with thematic analysis. Studies II–IV were quantitative and used data from a randomised controlled trial (RCT) of high-intensity (HI) and low-to-moderate-intensity (LMI) exercise of combined resistance and endurance training with or without self-regulatory behaviour change support. The RCT was preceded by a descriptive longitudinal study with usual care (UC). Participants were diagnosed with breast, prostate, or colon cancer and received (neo)adjuvant oncological treatment. Study II evaluated the effects on HRQoL of exercising at HI (n =288) and LMI (n =289) versus UC (n =89) up to 18 months after start of oncological treatment, using the EORTC QLQ-C30 questionnaire. Data were analysed using descriptive and multivariate statistics. Study III evaluated resource utilisation and societal costs of the exercise intervention in the RCT (n =534) versus UC (n =85), and of HI (n =269) versus LMI (n =265) exercise 18 months after start of oncological treatment. Societal costs included costs of healthcare resource utilisation (healthcare visits, hospitalisation, prescribed medication), productivity loss (disability pensions and sick leave), and the exercise intervention. Study IV evaluated the cost-effectiveness of the exercise intensities in the RCT (HI: n =99 and LMI: n =90) at 1-year follow-up post intervention. Cost data were retrieved from Study III and health outcome were collected using the EQ-5D-5L questionnaire and calculated for quality-adjusted life-years. Cost-effectiveness was evaluated as the incremental cost-effectiveness ratio (ICER). Results: Participants experienced impairments from oncological treatment but strove to maintain function in daily life. The exercise programme improved physical and psychological wellbeing during treatment (Study I). There were no significant differences in HRQoL between exercise intensities up to 1 year after the exercise intervention. The exercise groups scored significant better HRQoL compared to UC over time (Study II). There was no significant difference in mean societal costs between the exercise intervention and UC, nor between the exercise intensities (Study III). There was no significant difference in cost or in effect between the exercise intensities. Although the mean ICER indicated that HI was cost-effective compared to LMI, the uncertainty was large (Study IV). Conclusion: Participating in an exercise programme during oncological treatment was a positive and supportive experience that contributed to increase physical and psychological wellbeing. Exercise of HI and LMI during oncological treatment had similar effect on HRQoL and societal costs. In addition, the exercise group had beneficial effects on HRQoL and no significant difference in societal costs compared to UC, meaning the exercise programme did not save or add societal cost. Thus, based on cost-effectiveness we suggest decisionmakers and clinicians implement exercise programmes including both HI and LMI in cancer care and recommend exercise regardless of intensity according to the patient’s preferences to improve or to maintain aspects of HRQoL during oncological treatment.
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| 15. |
- Bang, Peter, 1992-
(författare)
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Beyond Categories : A Dimensional Approach to Autism and Sensorimotor Differences
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autism spectrum conditions (ASC) encompass a range of sensory, motor, and social-communicative differences, reflecting the considerable heterogeneity within the autism spectrum. This diversity underscores the limitations of categorical diagnostic approaches, which often fail to capture the individualized manifestations of autism. Advances in genetics and neuroscience have driven a shift towards dimensional frameworks that emphasize the spectrum nature of autism and the broad autism phenotype (BAP). BAP encapsulates subclinical traits that mirror those of autism in the general population, challenging the conventional boundaries between clinical and non-clinical populations. Furthermore, sensorimotor differences, which are particularly prevalent in individuals with ASC, follow a spectrum-like pattern similar to the BAP and are predictive of developmental outcomes related to social participation, communication, and overall quality of life in people with and without ASC. However, specific descriptions of these relationships are lacking.This dissertation investigated the complex relationships between sensorimotor differences and autistic traits (ATs). Through a series of five interconnected studies, we examined broad sensory processing patterns and specific sensory modalities, namely auditory processing and motor/proprioception, to explore their roles in autistic phenotypes.Study 1 of the dissertation validated a Swedish translation of the Broad Autism Phenotype Questionnaire (BAPQ). By examining parents' BAP traits, the study highlighted significant associations between higher ATs and having a child with ASC. Furthermore, it confirmed the presence of all three AT domains—social interaction (ATSOC), communication (ATCOM), and cognitive rigidity (ATRIG), reinforcing the genetic and phenotypic continuity between clinical and subclinical ATs.Study 2 and Study 3 served as broader investigations into all seven sensory modalities and their associations with ATs. Study 2 explored these modality-specific associations, using Bayesian stochastic search variable selection (SSVS) and dominance analysis. This study highlighted auditory processing difficulties as the most consistent predictor of all three AT domains. Additionally, proprioceptive and tactile processing difficulties were specifically associated with ATCOM and ATSOC, respectively.Study 3 extended this analysis to a developing population, focusing on the relationship between sensorimotor processing, ATs, and anxiety in children aged 6-11 years. Identical to Study 2, we found tactile symptoms as a predictor of ATSOC, proprioceptive symptoms for ATCOM, and auditory symptoms for ATRIG. In addition, olfactory symptoms were selected as a predictor of ATCOM, and motor coordination was a consistent predictor of all AT domains. Using SSVS, this study also identified that auditory and olfactory processing difficulties were strong predictors of anxiety symptoms.Building on the previous studies, Study 4 narrowed the focus to auditory processing differences, investigating specific auditory problems and their associations with the AT domains. All AT domains significantly predicted affective reactions to sounds, while difficulties with speech perception, spatial perception, and auditory stream segregation were most strongly predicted by ATCOM.Study 5 focused on the previously found links between motor coordination and proprioceptive processing and ATCOM. Using causal mediation analysis within a counterfactual framework, this study found that cerebellar error correction deficits, measured through a finger tapping task, significantly impacted ATCOM through motor skills in childhood.Together, this dissertation provides a comprehensive overview of the sensory processing dimensions related to the core AT domains. Specifically, the studies underscored the clinical significance of monitoring auditory and olfactory complaints in children, as these were predictive of anxiety, and emphasized that early motor deficits impact social communication development. The findings advocate for the inclusion of detailed sensory and motor assessments in neurodevelopmental evaluations to identify children at risk for poor mental health outcomes. Future research should continue to explore the mechanisms underlying sensory processing differences. Particular focus should be placed on auditory and motor/proprioceptive functions and their contributions to ATs and clinical outcomes, such as anxiety. Emphasis should also be given to longitudinal studies that track these relationships over time.
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| 16. |
- Bauer, Susanne
(författare)
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Cell type-specific translatome analysis of mouse models of three genetic neurodegenerative diseases
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The burden neurodegenerative diseases place on patients, their loved ones, and the healthcare system is significant, and despite extensive research efforts, there is currently no cure. Since degenerative changes in the brain can begin years before symptoms appear, early intervention is critical. Additionally, neurodegenerative diseases target certain brain regions and neuron types early on. A more comprehensive understanding of the affected cells during the presymptomatic phase is therefore crucial for an effective and targeted intervention. Herein, we isolated, sequenced, and analyzed translatome samples from six neuronal cell types in knock-in mouse models of three monogenic neurodegenerative diseases at a presymptomatic stage: genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Huntington’s disease (HD). To obtain the translatome samples, we used RiboTag to immunoprecipitate HA-tagged ribosomes with their translating mRNAs from targeted cell types. We analyzed six cell types across two brain regions: cerebral and cerebellar glutamatergic and GABAergic neurons, and cerebral parvalbumin (PV) and somatostatin (SST)-expressing neurons. In the first paper, we focused our analysis on the prion diseases, gCJD (E200K) and FFI (D178N). Here observed a similar response of SST+ neurons, a cell type not previously reported as affected, in both disease models. This was characterized by upregulation of ribosomeassociated genes, and downregulation of cytoskeleton and synapse-associated genes in FFI. Weighted gene co-expression network analysis of SST+ neurons pointed towards the downregulation of mTOR inhibition as a potential mechanism underlying the observed gene expression changes. In the second paper, we analyzed a 129S4-HdhQ200 knock-in mouse model of HD. Histological and behavioral assessment revealed pathological changes in the striatum and cerebellum at 9 months and a later, mild behavioral phenotype. Translatome analysis indicated a surprisingly strong response in reportedly resistant glutamatergic neurons of the cerebellum, marked by upregulation of cell cycle regulators Ccnd1 and chromobox protein genes. In the third paper, we aimed to compare disease-specific responses of PV+ neurons across the three disease models. This analysis revealed a milder response in HD compared to prion disease at comparable disease stages. Functional analysis further indicated PV+ neurons may respond differently in the investigated diseases, showing upregulation of immune response-associated pathways in gCJD, neurodegenerative-disease pathways in FFI, and autophagy in HD. Lastly, the generation of mouse models such as were used in papers I-III requires stable and predictable transgene expression without interfering with the expression of endogenous genes. In the fourth paper, we conducted a pilot study to compare three potential loci, Rpl6, Rpl7, and Eef1a1, as potential safe harbors for transgene integration. Preliminary results indicated that the Rpl6 locus may be best suited for our purposes. Furthermore, this work generated a novel dataset consisting of translatome profiles of six cell types in three neurodegenerative disease models. This provides gene expression data at a previously unavailable level of cellular resolution, especially in prion disease. We believe that this data will serve as a valuable resource for future research and help expand our understanding of the early molecular mechanisms in neurodegenerative disease beyond the scope of this thesis.
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| 17. |
- Bendelin, Nina, 1980-
(författare)
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Internet-Delivered Acceptance and Commitment Therapy for Chronic Pain : Feasibility, patients’ experiences and implementation process
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic pain represents a major burden for individuals and society. Internet-delivered psychological interventions are evidence-based treatments that enable patients to access qualified care at a time and place convenient for them. Internet-delivered Acceptance and commitment therapy (IACT) has shown promising treatment effects for chronic pain patients on pain-related outcomes such as disability, pain intensity, and interference, and on psychological outcomes such as catastrophizing, fear-avoidance and acceptance. Interdisciplinary pain rehabilitation programs (IPRP) are multimodal interventions given by synchronized teams of health care professionals from different disciplines. With moderate treatment effects on many outcomes, IPRP is the best evidence treatment for chronic pain to date. IACT may add to IPRP’s effectiveness by providing individual psychological treatment via the internet. However, IACT has not yet been implemented in routine care in a larger scale. In this thesis, the aim was to study if IACT may be acceptable for chronic pain patients and if it is feasible and effective as an addition to IPRP. Three methodological approaches were used: qualitative analysis, implementation science and a controlled trial of effectiveness in a clinical context. Study I showed that an internet-delivered aftercare intervention enabled chronic pain patients to change their perception of their body and pain and their attitude about their future and self. Furthermore, self-motivating goals and acceptance strategies appeared to influence autonomy. The results gave promise to the feasibility of IACT as aftercare following IPRP. Study II showed that chronic pain patients’ experiences of IACT vary, with respect to being in treatment and the consequences of treatment. Specifically, e-therapist feedback and deadlines for homework may have an impact on autonomy and change. Patients’ expectations, motivations, and restraints could explain treatment engagement and experiences. In Study III, IACT added during IPRP enhanced the treatment effects on pain acceptance and affective distress. Furthermore, IACT added as aftercare strengthened the long-term effect of IPRP on psychological flexibility and self-efficacy. However, unsatisfactory completion rates complicated the interpretation of the findings. Study IV showed that implementing IACT in an IPRP setting may be facilitated by contextual alinement and modifications based on patients’ needs. Thorough testing of the application and matching the intervention’s aim with the host’s needs are important not to challenge the process. An implementation framework may ease planning and evaluation of implementation processes. In conclusion, IACT could be feasible as an addition to IPRP. IACT can help chronic pain patients self-manage their pain and improve pain acceptance and self-efficacy. However, chronic pain patients’ varying experiences may need to be considered to improve treatment engagement and help patients benefit from treatment. In addition, implementation of IACT in IPRP settings is likely to depend on both flexibility to changing host needs and continuity of known pivotal components in IACT.
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| 18. |
- Bengtsson, Daniel, 1975-
(författare)
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Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing’s disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).One of the patients in study I and III had a corticotroph pituitary carcinoma and in addition, Lynch syndrome (LS), a hereditary cancer-predisposing syndrome caused by germline mutations in DNA mismatch repair (MMR) genes and primarily associated with colon and endometrial carcinomas. In study II, we investigated the characteristics of the pituitary carcinoma and found loss of MSH2 and MSH6 protein expression, consistent with the patient’s germline mutation in MSH2. This was the first published case of a pituitary tumour associated with LS. In addition, we identified all known Swedish patients with LS (n=910) and searched for diagnostic codes consistent with a pituitary tumour in the Swedish national patient register. We found in total three patients with clinically relevant pituitary tumours, the reported prevalence in the background population is around 1:1000.The last two studies in the thesis focused on Cushing’s disease (CD), i.e. an ACTH-secreting pituitary tumour resulting in excess levels of cortisol. CD is associated with multiple comorbidities and increased mortality. The reversibility of comorbidities and mortality risk after remission of cortisol levels have been under debate. Study IV examined psychiatric consequences of CD, measured by the use of psychotropic drugs. 179 patients with CD and a quadrupled matched control group were followed from diagnosis and at 5- and 10-year follow-up. We found that use of antidepressants remained at around 25% of patients with CD, regardless of remission status, at diagnosis and follow-up, whereas drugs for somatic comorbidities decreased. Use of antidepressants, sleeping pills and anxiolytics was higher in patients with CD compared to controls at diagnosis and 5-year follow-up. A cross-sectional analysis of 76 patients in sustained biochemical remission for median 9.3 years showed that 25% were taking antidepressants, a significantly higher use than controls, OR 2.0 (95% CI 1.1-3.8). In addition, patients with CD had a higher use of psychotropic drugs, already in the 5-year period before diagnosis.Study V investigated mortality and causes of death in 371 patients with CD, compared to a quadrupled matched control group. Follow-up was median 10.6 years (IQR 5.7-18.2) after time of diagnosis. Overall mortality was increased in patients with CD, HR 2.1 (95% CI 1.5-2.8) and remained elevated for patients in remission at last follow-up (n=303), HR 1.5 (1.02-2.2). For patients not in remission (n=31), HR was 5.6 (2.7-11.6). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death in patients with CD. Main conclusions of the thesis:Temozolomide improves outcome in patients with aggressive pituitary tumours/carcinomas and a low MGMT expression in the tumour predicts a favourable outcome. As additional therapies evolve, MGMT may help to tailor the treatment.Germline mutations in MMR genes may contribute to the development and clinical course of pituitary tumours and may be a novel cause of hereditary pituitary tumours.Patients with Cushing’s disease have a high use of psychotropic drugs that remains elevated despite achievement of biochemical remission, suggesting persisting negative effects on mental health and highlighting the need for long-term monitoring of psychiatric symptoms. In addition, psychiatric symptoms may be early and important signs of CD.Efforts to achieve biochemical remission are crucial to reduce mortality in CD. However, patients in remission still have an increased mortality compared to controls. This underscores the need for life-long monitoring and treatment of associated comorbidities in patients with CD.
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| 19. |
- Bensberg, Maike, 1993-
(författare)
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DNA methylation in T cell leukaemia
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- T cell acute lymphoblastic leukaemia (T-ALL) is a predominantly paediatric cancer that stems from malignant transformation of developing T cells. While the disease has an overall survival rate of 80%, the intense chemotherapy treatment causes severe toxicity and long-term side effects. Furthermore, the survival rate for patients in relapse is less than 25%. Consequently, there is a need for improved therapy options to reduce treatment-related side effects and improve the survival rate of relapsed patients. Targeting aberrant DNA methylation with hypomethylating agents (HMAs) has been successful in the treatment of myelodysplastic syndromes and acute myeloid leukaemia but has not been routinely used in the treatment of T-ALL, despite DNA hypomethylation being observed in T-ALL patients. In this work, we employed a comprehensive set of molecular and sequencing-based techniques to explore the possibilities of HMAs as a treatment option for T-ALL.We made the discovery that the DNA demethylating enzyme ten-eleven translocation 2, TET2, is downregulated or completely silenced in primary T-ALL. Moreover, the TET2 promoter was highly methylated in a group of patients, suggesting that TET2 itself can be silenced through DNA methylation in T-ALL. By treatment with HMAs, TET2 was demethylated in T-ALL cell lines and was one of few genes that was activated upon loss of DNA methylation, indicating that TET2 expression is regulated by DNA methylation in T-ALL cell lines. The development of a novel HMA, the DNMT1-specific inhibitor GSK-3685032, offers a tool to reveal the mechanism of action of the traditional HMAs, 5- azacytidine and decitabine, and to study the effects of acute loss of DNA methylation on cancer cells. We found that 5-azacytidine and decitabine are cytotoxic to T-ALL cells primarily by creating DNA double strand breaks. In contrast, GSK did not prompt a DNA damage response and instead reduced global DNA methylation to as little as 18% with limited cytotoxicity only occurring after levels of DNA methylation had dropped below 30%, a level of demethylation not achieved with DEC or AZA.T-ALL is more than two times more common in boys than girls and mutations in X-linked tumour suppressor genes that escape X inactivation, have been suggested as an underlying cause for the observed sex-bias. In theory, these aberrations would be more detrimental in XYmale cells than in XX-female cells due to the presence of an extra protective copy of the gene in females. We profiled DNA methylation during T cell development and created a map of sex-specific gene expression and expression from the inactive X chromosome, finding that some, but not all, suggested tumour suppressor genes in fact escape X inactivation. These results highlight the importance of profiling the healthy cells that T-ALL arises from to correctly judge the functional impact of gene dysregulation in cancer.In the last study, we aimed to investigate the role of N6-adenine methylation (6mdA) during T cell differentiation. While 6mdA is common in bacteria it is much rarer in humans. Nevertheless, 6mdA has previously been associated with several cellular processes, including cancer progression. Our study calls the presence of 6mdA in mammals into question by exposing limitations of the techniques used in its analysis. We show that contamination with bacterial DNA or 6mAcontaining RNA, nonspecific antibody binding, and low precision of third-generation sequencing techniques all hinder the detection and investigation of rare DNA modifications, such as 6mdA.Together, this work is an in-depth study of the function and the potential of DNA methylation in the biology of healthy and malignant T cells.
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| 20. |
- Bergström, Maria, 1983-
(författare)
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Participation and support in everyday life over a decade : perspectives of persons with rheumatoid arthritis and their significant others
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: The treatment of rheumatoid arthritis (RA) has evolved over recent decades. Today, many previous limitations related to, for example, joint damage have become rare, and persons with RA can often continue to work and engage in different aspects of everyday life. Nonetheless, persons with RA still report restrictions in everyday life, as they can be negatively impacted by symptoms like pain, stiffness and fatigue. As these symptoms might be invisible to others, the significant others of persons with RA can find it difficult to comprehend the effect of the disease. As a consequence, both the person with RA and the significant other may be affected, despite today’s effective treatment.As participation is a central concept within healthcare, it is also a prominent factor within rehabilitation and its goals. Despite access to contemporary treatment during the whole disease course, persons with RA still report participation restrictions. Since RA is a chronic disease, these remaining restrictions are of particular interest from a longitudinal perspective. However, support from the social environment, such as significant others, has the possibility to positively influence participation in everyday life. Therefore, it is essential to explore the influence of significant others and their support with the goal of enhanced participation in the everyday life of persons with RA, from a longitudinal perspective.Aim: The general aim of this thesis is to explore participation in the everyday life of persons with RA over a decade, and in relation to this investigate the influence of significant others and their support.Methods: This thesis consists of four studies that used different methodological approaches: qualitative, quantitative and mixed methods.Study I was a qualitative study where 59 persons with RA participated in semi-structured interviews approximately three years after diagnosis. Questions covered experiences in everyday life and participation. The material was analysed through content analysis.In Study II, longitudinal data from 274 persons with RA were analysed regarding disease activity (assessed by DAS28), grip force (assessed by Grippit), pain intensity (VAS mm) and activity limitations (assessed by HAQ). The data were collected at inclusion, year one and year two after diagnosis. Data related to sickness absence were also obtained, as well as self-assessed perceptions of experienced support. Through regression analyses, associations between disease-related variables and sickness absence were investigated, with support as a moderator.The data in Study III comprise semi-structured individual interviews with 16 persons with RA and their significant others, conducted approximately a decade after diagnosis. The interview guide was developed with Study I in mind and included similar topics, with the addition of support. This material was analysed using dyadic analysis, where a person with RA and the significant other comprised a dyad.Finally, in Study IV, a convergent mixed methods approach was used. Longitudinal data regarding disease-related variables (same as Study II) were collected during the first decade after diagnosis and analysed through linear mixed models. The qualitative material consisted of individual interviews conducted three and ten years after diagnosis and analysed by directed content analysis. The quantitative and qualitative results were integrated in accordance with the chosen method.Results: Significant others of persons with RA could encompass both facilitators and hinders to participation in the everyday life of persons with RA. Through the provision of support and helpful attitudes towards needed adaptations, they had a positive influence on participation in the everyday life of persons with RA. This was a continuous process since the persons with RA were still affected by the disease a decade after diagnosis, and adaptations by the significant others might also still be needed.Experiences of RA were found to differ between men and women over the first decade after diagnosis. Moreover, through a mixed methods design, discrepancies were found between the persons’ own descriptions in interviews and the quantitative results. For instance, women expressed issues related to grip force and disease activity in the interviews, but these issues were not detected in the same way in the quantitative results. These discrepancies were additionally not seen in men; however, both men and women still showed signs of disability a decade after RA diagnosis. Nevertheless, over time, the persons with RA and their significant others had learned to live with the disease and there was a sense of togetherness in everyday life with RA. Namely, they approached the disease together as a unit.Support was identified as a positive aspect that facilitated everyday life. It entailed both the support between the person with RA and the significant other, as well as the support from others outside of the dyad. Support could also come in different forms. For example, the person with RA could receive emotional support from a significant other, or healthcare professionals (HCPs) could provide informational support to either or both of the parties. In connection to the latter, a continuous need for knowledge was identified in both the persons with RA and the significant others. Support from significant others also proved to have an impact on work life specifically, as more perceived support was associated with an increased risk of sickness absence.Conclusively, significant others and their support can influence participation in the everyday life of persons with RA, and this influence can be facilitated through positive attitudes and different types of support during the first decade after diagnosis.Conclusions: Significant others are essential providers of support as facilitators for participation in the everyday life of persons with RA, including many years after diagnosis. However, they must also be attentive towards the further need for adaptations and possible emotional burden in the persons with RA. It is also important for significant others to find a balance between overprotecting and contributing to independence.The significant others in their turn might need support in understanding the impact of the disease. In this case, HCPs should be providers of support to both persons with RA and their significant others and consult with both of them as a unit in the rehabilitation process. This also exemplifies the need for support from outside the dyads of persons with RA and their significant others.Support is requested both at an early stage and throughout the disease course. Different types of support from significant others can therefore preferably be part of the rehabilitation process as a way to enhance participation in the everyday life of persons with RA.
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| 21. |
- Berin, Emilia, 1992-
(författare)
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Resistance Training and Physical Activity in Postmenopausal Women : Effects on Vasomotor Symptoms, Quality of Life and Microcirculation
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Menopause is a physiological event, but is associated with bothersome symptoms as well as physical changes that affect women’s health. About 75 % of women experience vasomotor symptoms (hot flushes and night sweats) related to menopause that often reduce quality of life. The vasomotor symptoms may be attributed to dysfunctional temperature regulation centrally in the hypothalamus and peripherally in the skin’s circulation. The most effective treatment for vasomotor symptoms is menopausal hormone therapy, but not all women are able to, or want to, use it. In addition to the impact on quality of life, studies have associated vasomotor symptoms and menopause with macrovascular endothelial dysfunction. Previous studies on the association of these factors with the skin’s microcirculatory function are small and few. Observational studies have associated physical activity and exercise with less vasomotor symptoms, but the evidence from intervention trials is of low quality and the results are ambiguous. Physical activity has established general health effects, and could potentially decrease vasomotor symptoms by effects on endogenous opioids centrally, and by more efficient thermoregulation peripherally. The aim of this thesis was to investigate the effect of resistance training on vasomotor symptoms and health-related quality of life in postmenopausal women, and to explore the women’s experiences of the training to find barriers and facilitators. We also aimed to investigate whether the skin’s microcirculatory function differed between women regarding menopausal status, vasomotor symptoms, menopausal hormone therapy, and physical activity. Material and methods The first study was an open randomized controlled trial including 65 postmenopausal women with moderate to severe vasomotor symptoms and low physical activity levels. We randomized the women to 15 weeks of resistance training (intervention) or unchanged physical activity (control). The participants registered vasomotor symptoms daily in a diary, and answered health-related quality of life questionnaires at baseline and at 15 weeks. The first 15 women to finish the intervention were recruited to a qualitative study. The women’s experiences of the resistance training intervention were explored in individual interviews after the intervention period, and all were followed-up with telephone interviews after one year. The third study was cross-sectional, including 1148 women from Linköping, 50-64 years old, who participated in the Swedish CArdioPulmonary bioImage Study (SCAPIS). These women answered a questionnaire about menopausal status, vasomotor symptoms and menopausal hormone therapy use, and wore accelerometers for seven days to assess physical activity. The skin’s microcirculation was assessed at rest and during post-occlusive reactive hyperemia. Results Moderate to severe vasomotor symptoms per 24 hours decreased significantly more in the group of women randomized to resistance training compared with the control group (mean difference -2.7, 95% CI -4.2 to -1.3). The resistance training group improved in domains of menopause-specific health-related quality of life compared with the control group but there was little impact on generic health-related quality of life. In the qualitative study we found that the vasomotor symptoms acted as a “trigger” for the women to become motivated to exercise. Their motivation then evolved from being driven by hopes of symptom relief into being driven by a wish for general well-being, which was still a driving force after one year. Microvascular function did not differ between postmenopausal and premenopausal women, or between women with or without vasomotor symptoms or menopausal hormone therapy. Women with higher levels of objectively measured and self-reported physical activity had a better reactivity of the skin’s microcirculation. The differences remained significant after adjusting for BMI, smoking, hypertension, diabetes, and education. Conclusions Resistance training could be effective for decreasing vasomotor symptoms and improving some aspects of health-related quality of life in motivated postmenopausal women. The vasomotor symptoms themselves spurred motivation to exercise, indicating they present an opportunity to increase physical activity. When a woman seeks medical advice for vasomotor symptoms, this could be a chance for health care professionals to help her initiate or increase exercise. Women who performed more physical activity and exercise had better skin microvascular function, but no association with VMS was found. Future studies are needed to investigate what type and dose of exercise is the most effective to reduce vasomotor symptoms and whether there is a way to predict for whom exercise will or will not be an effective intervention.
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| 22. |
- Bielsten, Therése, 1978-
(författare)
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“Doing things together” : Towards a health promoting approach to couples’ relationships and everyday life in dementia
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Most people with dementia live in their own homes, often together with their partners, who become informal caregivers. Relationship quality and sense of couplehood can be threatened as a result of the transition from a mutually interdependent relationship to a caregiver-care-receiver relationship. This, in turn, may lead to many negative consequences for both partners. Support provided for couples is often divided into different types for the person with dementia and for the partner without dementia and lacks couple-based support that targets the relationship, resources and the couple’s everyday life together. Aim: The overall aim of this thesis is to explore couple-centred interventions in dementia and to develop and test a salutogenic, resource-oriented and couple-based intervention among couples in which one partner has dementia living at home. Methods and findings: This thesis comprises three parts: The first part Exploring involves two linked reviews, one narrative review (study I A) and one scoping review (study I B) that aim to identify and describe what previous couple-centred interventions comprised and why they were conducted. The results of the reviews revealed a knowledge gap in and a need for easily accessible support that targets couple relationships, resources and everyday life. The second part Developing (study II) refers to the development of an easily accessible resource-oriented couple-management intervention. The first step was to identify priority topics for such an intervention through a co-researcher process with couples living with dementia. This included a comprehensive literature review, interviews with couples in which one partner has dementia, and consultation meetings with expert groups of people with dementia and partners in both Sweden and the UK. The co-researcher process and the expert meetings informed four main themes with corresponding sub-themes that couples with dementia considered as important to their wellbeing in their everyday lives: (1) Home and Neighbourhood, (2) Meaningful Activities and Relationships, (3) Approach and Empowerment, and (4) Couplehood. The themes were further developed and integrated into the multimedia application DemPower, which was developed for the delivery of the intervention. The third part Testing and Evaluating describes a feasibility study (study III) in which the DemPower application was tested for feasibility and acceptability among couples in Sweden and the UK. The results of the feasibility study indicated that the DemPower intervention was feasible and acceptable among couples in which one partner has dementia living at home. The testing and evaluating part also comprise a qualitative study (study IV) that explores the experiences of engaging with DemPower together as a couple living with dementia in Sweden. The findings resulted in the three themes: (1) Growth of the relationship, (2) We are not alone, and (3) Positive approach, which the couples appreciated and associated with the resource-oriented and salutogenic approach of DemPower. The overall findings of the thesis are presented in a concluding synthesis at the end of the thesis. The concluding synthesis, focused on “Meaningfulness”, “Empowering health promotion”, “Normalization” and “Transitions and couplehood”, represents the core findings of this thesis. What this thesis adds: This thesis contributes to research, healthcare and the public by highlighting the need for a salutogenic approach toward couples living with dementia. The DemPower application, with its focus on couples’ relationships, resource-orientation and everyday life, has proven feasibility and acceptability and has meaningfully addressed a gap in the literature and in practice. As researchers, healthcare professionals and the public, we need to support couples where one partner has dementia to continue to live as normal life as possible. This can best be achieved by focusing on what couples can do, by inclusion and by valuing them as the experts within dementia research and of their life experiences.
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| 23. |
- Blomdahl, Julia, 1991-
(författare)
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Non-Alcoholic Fatty Liver Disease : Insights into Alcohol Consumption, Genetics, and Proteomics
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- NAFLD (Non-Alcoholic Fatty Liver Disease) affects approximately a quarter of the global population and is closely linked to type 2 diabetes mellitus and obesity. The disease spectrum ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular cancer. However, accurately predicting which patients will experience a progressive disease course remains a significant challenge. The variant gene of PNPLA3 is known to be associated with NAFLD and a more progressive disease, although its precise function remains unclear. Patients with NAFLD typically consume small to moderate amounts of alcohol, with recommended thresholds set at a maximum of 210 gram per week for males and 140 grams per week in females. However, the impact of alcohol consumption on liver disease in NAFLD remains disputed, with conflicting research findings. Liver biopsy is considered the gold standard for diagnosing NAFLD. However, due to its impracticality for such a large population with the condition, various non-invasive methods have been explored for diagnosing and evaluating NAFLD. This thesis aimed to investigate the potential effects of moderate alcohol consumption on NAFLD histology, explore the potential role of variant PNPLA3 in NAFLD, and assess the use of proteomics in classifying fibrosis. In Papers I and II, moderate alcohol consumption was assessed through questionnaires, clinical interviews, and measurement of the direct alcohol biomarker phosphatidylethanol (PEth). Paper I, a cross-sectional study including 86 participants, showed an association between moderate consumption and advanced fibrosis. Moderate consumption was defined as consuming more than 66 grams of ethanol per week or a PEth-value over 50 ng/mL. Notably, individuals with both moderate alcohol consumption and a diagnosis of type 2 diabetes exhibited significantly more advanced fibrosis. Paper II was a cohort study where 82 participants were followed over 17.2 years. Similarly, participants with moderate alcohol consumption displayed significant fibrosis progression. The strongest association was observed in participants with PEth-value of 48 ng/mL or higher, or those with binge drinking. In Paper III, the potential role of variant PNPLA3 was explored, exhibiting impaired autophagic flux and reduced lipophagy in variant PNPLA3 cells. Liver biopsies of NAFLD individuals with variant PNPLA3 displayed an accumulation of lipid droplets positive for both PNPLA3 and LC3 (a common marker of the autophagosome). This suggests that PNPLA3 is part of the lipophagy process, which is impaired in the variant gene and contributes to steatosis. Paper IV examined two independent NAFLD cohorts. In the discovery cohort, 60 participants with biopsy-proven NAFLD were included, while 59 participants were included in the validation cohort. The study evaluated 266 proteins and found that a biomarker model combining ACE2, HGF, and IGFBP-7 distinguished between different fibrosis stages (F0–1 and F2–4) in both cohorts. In summary, measuring phosphatidylethanol is advisable in NAFLD patient evaluations. Elevated PEth-levels (≥48 ng/mL) or alcohol consumption exceeding 66 grams per week should warrant advice to abstain from alcohol. PNPLA3 is implicated in NAFLD pathophysiology, potentially through impaired lipophagy. While its clinical application remains uncertain, genetic profiling for NAFLD risk assessment may become part of future non-invasive approaches. Additionally, proteomics holds promise for non-invasive NAFLD assessment, with the combination of ACE2, HGF, and IGFBP-7 identifying significant fibrosis in two separate cohorts.
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| 24. |
- Boano, Gabriella, 1974-
(författare)
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Surgical Ablation of Atrial Fibrillation with Cryo and Radiofrequency Concomitant to Mitral Valve Surgery : Clinical, Biochemical and Echocardiography Outcomes
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. In cardiac surgery, the negative influence of AF on short- and long-term outcomes has made concomitant ablation procedures more common. The indications, clinical aspects, results, risks, and benefits of the additional surgical ablation are still valuable topics for discussion. This compilation thesis consists of four papers aiming to investigate some of the clinical, biochemical, and echocardiographic aspects of surgical ablation for AF (Cox-Maze IV) when performed concomitant to mitral valve surgery (MVS).Through a retrospective, case-control, single-center study, we described the impact of the Cox-Maze IV procedure added to MVS with focus on postoperative heart failure (paper I).Cryoenergy (cryo) and radiofrequency (RF) are the two different energy sources mainly used in Cox-Maze IV for AF ablation. To achieve linear scars in the atrial wall, the RF procedure uses heat damage, whereas the cryo method freezes down to -150°C. Through a prospective, randomized, longitudinal, controlled study, we compared the biochemical responses of the two ablative methods in concomitant MVS and the release of enzymes expressing myocardial injury, as well as inflammatory, cell stress, and apoptosis-specific proteins. We could show that cryo results in a larger release of markers for myocardial damage but has no impact on the early inflammatory response (paper II).Extended scar lesions resulting after maze may influence atrial function. As the left atrium plays a key role in the altered cardiac hemodynamics in AF, an echocardiographic analysis of the effects of the Cox-Maze IV procedure concomitant to MVS on the left atrium was carried out. The impacts of the two energy sources (cryo and RF) on left atrial remodeling and function had not been compared previously. Their direct effect on left atrial remodeling and mechanical function were assessed 1 year after surgery in patients with restored sinus rhythm. Sinus rhythm restoration after MVS concomitant to Cox-Maze IV results in a reduced left atrium size regardless of the energy source used. Three-dimensional echocardiography showed that, compared to RF, the extension of the ablation area produced by cryo implies major left atrium structural remodeling affecting systolic function. The negative effect on left atrium remodeling seems to be linear with the duration of the AF (paper III).An overview of the pacemaker implantation rate after the Cox-Maze IV procedure concomitant to MVS was obtained in a multicenter study using national qualitative registers (SWEDHEART, Carath, Svenska ICD- och Pacemakerregistret) (paper IV, sumbitted).Our results contribute to optimizing surgical indications and patient selection, providing a deeper understanding of the biochemical and echocardiographic changes during and after surgical ablation.
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| 25. |
- Braian, Clara, 1981-
(författare)
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Innate immune responses to Mycobacterium tuberculosis infection : How extracellular traps and trained immunity can restrict bacterial growth.
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis, and the cause of 1.5 million deaths in 2018. During a pulmonary TB infection, the bacterium reaches the lungs and is phagocytosed by cells of the innate immune system, primarily macrophages. The macrophages are either able to eradicate the bacteria or the bacteria start to replicate, and the following immune response leads to the formation of a large cluster of different cell types called a granuloma. In the granuloma the mycobacteria are contained in a latent infection, or they can start to replicate causing rupture of the granuloma and spread of the disease. Neutrophils are also innate immune cells that are rapidly recruited to the site of infection. They are phagocytes, but they also exert extracellular effector mechanisms by their release of microbicidal granule proteins, reactive oxygen species and neutrophil extracellular traps. M. tuberculosis has co-evolved and adapted to the human host making it ingenious at exploiting the human immune response, promoting its survival and replication in human host cells. The human immune system has also evolved mechanisms to limit M. tuberculosisreplication and spread. This thesis covers work on the innate immune response to TB and how neutrophils and macrophages respond to a mycobacterial infection and can control M. tuberculosis-replication.Neutrophils and macrophages can respond to M. tuberculosis by releasing extracellular traps. We demonstrated that neutrophil extracellular traps contain the danger signal heat-shock protein 72 when induced by mycobacteria, which subsequently mediate a proinflammatory activation of adjacent macrophages. Macrophages can also release extracellular traps, and we observed the release of macrophage extracellular traps in response to M. tuberculosis that grow in cord-structures. We further demonstrated that the induction of extracellular traps also required the mycobacterial virulence factor ESAT-6.Trained immunity is an epigenetically regulated memory of the innate immune system that results in a heightened response to a later encounter of the same or different pathogen. β-glucans are structural components of microbial cell walls and known inducers of trained immunity. We studied the effects of β-glucan from a bacterial source (curdlan from Alcaligenes faecalis), from yeast (WGP dispersible from Saccharomyces cerevisiae) and from the supernatant of a multicellular fungi (Alternaria) in search of functional changes in human macrophages which enhanced their anti-mycobacterial capacity. M. tuberculosis growth reduction was observed in WGP dispersible-trained macrophages when co-cultured with neutrophils. We also discovered that the interferon-gamma (IFNγ) signaling pathway, which is important for mycobacterial control, is hypomethylated in the WGP dispersible-trained macrophages. Since hypomethylation of genes typically is associated with gene activation, this suggests a more active IFNγ signaling in response to β-glucan innate immune training.Most of our studies were performed using in vitro culturing of primary human macrophages and neutrophils. However, an in vitro 3D tissue model is a valuable tool when studying complex events that occur during a TB infection that involves both multiple cell types and requires knowledge of the spatial movement of cells. In this thesis we also describe an in vitro lung tissue model, which we could use to observe the clustering of monocytes around mycobacteria and quantify the size and number of macrophage clusters.In conclusion, this thesis comprises work on innate immune functions during tuberculosis infection. We describe extracellular trap formation in macrophages and neutrophils in response to M. tuberculosis. We also explore trained immunity and how β-glucan training can enhance mycobacterial growth restriction.
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| 26. |
- Bruno, Valentina, 1986-
(författare)
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Clinical and immunological aspects on recurrent pregnancy loss
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Paper I. Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro. Sci Rep 2018. In paper I low molecular weight heparin (LMWH) in vitro effects on activation and polarization of central regulatory immune cells, such as Th cells and macrophages, were assessed, since LMWH has been widely used as an empiric treatment in recurrent pregnancy loss (RPL) and its immunological effects are not fully known. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured without or with LMWH at different concentrations. LMWH exposure induced an activated phenotype of macrophages, with high expression of HLA-DR and CD206 assessed by flow cytometry, associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory Tcells, and intensified IFN-γ secretion. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells, suggesting that potential immunological effects of LMWH may be effective mainly at an earlier gestational age to provide an appropriate implantation process in women with recurrent miscarriage. Paper II. Low-molecular-weight-heparin increases Th1- and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomized controlled trial. Sci Rep 2019.In paper II we investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomized controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analyzed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p < 0.001) and the Th17- associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Significantly higher plasma levels of CXCL10 and CXCL11 in treated women were detected at gw 28 and 34, compared to the untreated ones. Thus, a potential proinflammatory effect, linked mainly to Th1 immunity, was shown, suggesting an unfavorable effect of LMWH treatment, since Th1 responsea are responsible for breaking the fetal-maternal immune tolerance. Paper III. First-trimester trophoblasts obtained by chorionic villus sampling maintain tolerogenic and proteomic features in successful pregnancies despite a history of unexplained recurrent pregnancy loss. Am J Reprod Immunol. 2020.In paper III we investigate the “local” immune changes in women with RPL, since they potentially could reveal important mechanisms in RPL. Supernatants from superfluous chorionic villus sampling material culture was used in an ex vivo model, to determinate the immune proteomics profile and to perform functional assays for M2 like macrophages and regulatory T cells polarization, assessed by flow cytometry technique. Chorionic villi, human fetally derived placental tissue, were shown to induce an M2 like-phenotype and an expansion of Treg cells in an ex vivo model, and these immunological properties were maintained despite a history of RPL. Accordingly, no differences in the inflammation proteomic profile were found in RPL, compared to controls. Trophoblasts in an ex vivo model thus maintain tolerogenic and proteomic profile features in successful pregnancies, despite a history of RPL.
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| 27. |
- Bögl, Hans Peter, 1969-
(författare)
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Atypical femoral fractures: Another brick in the wall : On aspects of healing, treatment strategies and surveillance
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atypical femoral fractures are stress fractures of the femoral subtrochanteric and diaphyseal region. It is a common notion that these fractures heal poorly, if at all. In this thesis we show that patients with atypical femoral fractures have a good capacity to generate bone and therefore heal fractures. In daily practice, these patients have a higher risk for reoperation when compared with patients with a normal femoral fracture. However, this risk is less likely to be dependent on the type of fracture than other factors such as age, gender, comorbidities and survival. Using an implant that protects the fragile proximal femur, the risk for reoperations can be attenuated dramatically. An intramedullary nail with fixation of the femoral neck protects the femur from subsequent hip fractures – the most common complication in elderly patients with any type of femoral shaft fracture.Atypical femoral fractures are difficult to identify in the population. Erroneous diagnosis coding, poor reporting of adverse drug reactions and low accuracy of radiology reports make the identification and surveillance a difficult task. The Swedish Fracture Register has provided the option to register this special fracture since 2015. With its physician-based registration process, it enables researchers and treating physicians to identify and follow these rare fractures longitudinally.
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| 28. |
- Carlsson, Hanna, 1978-
(författare)
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Laboratory methods for investigation of the immunological orchestra in response to pathogens
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Laboratory methods used for investigation of immune response often involve collection of whole blood and analysis of different biomarkers in blood components or generated from pathogen stimulation of whole blood or peripheral blood mononuclear cells (PBMC). Methods used to measure biomarkers are for example enzyme-linked immunosorbent assay (ELISA) which measures one biomarker at a time or multiplex assays for example x-unknown, multi-analyte profiling (xMAP) by Luminex or proximity extension assay (PEA), which can measure up to just over 3000 biomarkers at a time. Analysis of one biomarker at a time are time consuming, costly, and dependent of a large sample size to enable repeated measurements of different analytes. Therefore, multiplex assays that are time saving, more cost effective and measures multiple bi-omarkers at once in a small sample can be applied. The aim of this thesis was to evaluate multiplex laboratory methods for investigation of the immunological orchestra in response to Borrelia infection and influenza immunisation and if possible, further characterize individuals with different clinical outcomes or serological response, respectively. In our studies (paper I-III) we included 1113 blood donors of which 66 were found to previously have had a subclinical borreliosis (defined as presence of Borrelia-specific antibodies without recall of previous Lyme borreliosis), of the 66 individuals 60 were available for participation. We also included 22 patients previously diagnosed with Lyme neuroborreliosis (LNB). In paper IV we included in total 73 individuals consisting of healthcare workers and patients attending seasonal influenza vaccination. We applied whole blood, PBMC and plasma stimulations and measured a range of cytokines, chemokines and complement factors with ELISA, nephelometry, xMAP and PEA. Our results show that subclinical Lyme borreliosis (SB) individuals display the following pattern, low age, male sex, low amount of secreted interleukin (IL)-17, CCL20 and higher secretion of IL-10 by PBMCs stimulated three days with Borrelia garinii compared to patients with previous Lyme neuroborreliosis (LNB). The subclinical individuals also show higher activation of the complement system in response to Borrelia afzelii. We performed multiplex analysis of complement factors in attempt to further characterize our SB individuals and LNB patient but found the results to deviate largely from reference values retrieved with other standardized methods. This highlights the importance of critical review of generated results from all form of assays. To investigate immune responses after influenza immunisation and further characterize serological responders and nonresponders we included measurement of influenza-specific antibodies and total immunoglobulins (Ig) in blood serum, influenza-specific mucosal IgA (nasal-swabs) and cell-mediated immune response in supernatants from PBMCs stimulated with influenza vaccine using PEA. We found the serological responders to be characterised by lower levels of total IgM, Granzyme B (GZMB) and IL-12 together with higher levels of CXCL13 compared with nonresponders. To conclude, xMAP and PEA are two valuable methods that can be applied together with multivariate statistical methods in the investigation of both innate and adaptive immunity characteristics and association to clinical outcome or serological response after Borrelia infection and influenza immunisation, respectively.
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| 29. |
- Casado Bedmar, Maria Teresa, 1990-
(författare)
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Neuro-immuno-regulation of inflammation in the colonic mucosa : Focus on mast cells and eosinophils in bowel disorders
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Intestinal homeostasis is key to control uptake across the mucosa and protect from harmful substances. Disturbances in the bidirectional communication between the gut and the brain are implicated in irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD), being Crohn’s disease (CD) and ulcerative colitis (UC) the two most common IBD subtypes. Although these chronic bowel-relapsing inflammatory disorders present different histopathology, they share similar pathological features. Both IBS and IBD are characterized by a disrupted intestinal barrier function, a pro-inflammatory chronic condition, and an altered gut-brain axis. Despite all the scientific effort, the sequence or exact combination of events that drive these diseases are still unknown, and so is the exact role of every single component. Growing evidence suggests altered neuro-immune interactions as a pathogenic factor.The general aim of this thesis was to elucidate the potential involvement of mast cells and eosinophils in IBS and IBD, and the neuro-immune intercellular circuit via vasoactive intestinal polypeptide (VIP) that might exacerbate mucosal inflammation and intestinal barrier disruption.Intestinal tissues from IBS, inactive IBD, healthy controls (HC), and murine colitis were collected. Electrophysiological and permeability studies were performed using the ex vivo Ussing chamber technique. Tissues were processed with immunohistological procedures to study cell numbers, activation, location, and interactions in relation to VIP.We demonstrated for the very first time an increased transcellular passage of live commensal and pathogenic bacteria through the colonic mucosa of IBS, identifying VIP as a key regulatory molecule together with mast cells activation. In vitro experiments revealed the ability of VIP to activate mast cells. Image analysis identified VIP-mast cells in closer proximity in IBD patients and murine colitis compared to controls. Communication between mast cells and VIP was shown upregulated in IBD and mice colitis via VIP receptor (VPAC)1. Similarities and differences between HC, IBS, and IBD were further studied. Results indicated a pronounced increased intestinal permeability in UC, even during remission, followed by IBS, compared to healthy controls. Surprisingly, permeability results did not correlate with mast cells, but with eosinophil number and activation. A further image analysis suggested an inhibitory effect of eosinophils and VIP on mast cells and an altered interaction between them under inflammatory conditions. Lastly, intestinal VIP levels were shown to increase in IBD patients after the treatment with biological agents and were suggested as a possible biomarker for biological treatment outcome.This thesis presents novel insights into the regulation of intestinal permeability, as well as into the pathophysiology of IBD and IBS by demonstrating the importance of neuro-immune interactions between mast cells, VIP, and eosinophils.Altogether, our findings have broadened the knowledge of neuro-immune interactions in IBS and IBD and might have the potential to onsight lead to new therapeutic approaches thereby improving the outcomes for patients suffering from these diseases.
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| 30. |
- Druvefors, Emma, 1985-
(författare)
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Fertility in Inflammatory Bowel Disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammatory bowel diseases (IBD) often present in adolescence or early adulthood and is thus frequently diagnosed in men and women in their reproductive age. Previous population-based studies of fertility in patients with IBD are scarce.From the Swedish National Patient Register (NPR) all patients diagnosed with IBD of fertile age between 1964–2014 were identified. Statistics Sweden identified a matched reference cohort (ratio 1:5) from the general population matched for sex, age and place of birth. Children born were identified through the Medical Birth Register and the Swedish Multigeneration Register. For subgroup analyses information about medication was collected through Medical Drug Register and information about socioeconomic status from Longitudinal Integrated Database for Health Insurance and Labour Market Studies. From the SWedish Inflammatory Bowel disease quality REGister (SWIBREG) a cohort of women with UC who underwent colectomy 2000–2020 was identified. Demographic data from SWIBREG and information from a study specific questionnaire regarding reproductive history and voluntary childlessness were analysed.From the NPR 27,331 women and 29,104 men with IBD were identified, corresponding to 272,793 matched individuals.The fertility rate in women with IBD was 1.52 (standard deviation [SD] 1.22) births per 1000 person-years, compared with 1.62 (SD 1.28) (p <0.001) in the matched reference cohort. Fertility was negatively affected mainly in women with Crohn's disease (CD) and IBD-unclassified (IBD-U) and to a lesser extent in ulcerative colitis (UC). Disease activity, bowel resections and, in the case of CD, also perianal disease further adversely affected fertility. For women with UC and IBD-U, but not for women with CD, fertility improved throughout the study period. Contraceptive use was higher in female IBD patients, both before and after the diagnosis.In total 2,989 women underwent colectomy during the study period. Reconstruction with ileal pouch anal anastomosis (IPAA) and ileorectal anastomosis (IRA) was used to about the same extent in UC and IBD-U, although this was rare in CD. Compared with the matched reference cohort, women with IBD had lower fertility overall after colectomy (HR 0.65, CI 0.61–0.69), with least impact for operations that left the rectum intact (HR 0.79, CI 0.70–0.90). When the comparison was made within the group of patients undergoing colectomy, fertility in female patients remained nearly unaffected after IRA in all subtypes of IBD, but was impaired after IPAA, especially in UC (HR 0.67 CI 0.50–0.88), and after completion proctectomy in all subtypes of IBD (CD 0.61 CI 0.38–0.96), UC HR 0.65, CI 0.49–0.85 and IBD-U0.68, 0.55–0.85).The survey regarding reproductive behavior after colectomy was completed by 214 (73%) out of 294 eligible women identified in SWIBREG. The desire to have children was negatively affected by disease onset in 59% of the women, colectomy in 44% and by reconstruction in 37%. Altogether, 39% women with UC estimated that they chose to have fewer children in the end because of the disease, but only 10% expressed that the disease made them completely restrain from having children. On the contrary 37% of the women reported that they had experienced difficulties to conceive and 19% expressed that they could not conceive at all. Of the women undergoing reconstruction post colectomy, 37% reported that the choice of reconstruction method was influenced by their desire to have children. Difficulty conceiving was more commonly reported after reconstruction with IPAA (odds ratio [OR] 5.54) than IRA (OR 2.57).Men with IBD also had lower fertility rate compared with the matched reference population, although the impact on parity was limited; 1.28 (SD 1.27) versus 1.35 (SD 1.31) (p < 0.001). Fertility in men was nevertheless impaired in all IBD subtypes. The disease severity measured as order of hospital admissions (UC and IBD-U), intensity of medical treatment (CD), and bowel surgery (IBD-U) were further associated with impaired fertility in men. In the 3,771 men undergoing colectomy during the study period, fertility was only marginally (HR 0.89, CI 0.85–0.94) impaired, regardless of reconstruction.In conclusion, women with IBD have only slightly reduced fertility rates compared with the matched reference population with some exceptions. In non-surgically treated patients, the impact was most pronounced in female patients with CD. Women post colectomy have a particularly marked impact on fertility independent of IBD subtype. Bowel reconstruction with IPAA and proctectomy had a pronounced negative impact on fertility, while fertility was not further affected after IRA. More than half of the women with UC post colectomy reported that developing UC has affected their desire to have children, but difficulty to conceiving is also commonly reported. The impact of IBD in men was only minor.
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| 31. |
- Dufvenberg, Marlene, 1961-
(författare)
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Adolescent Idiopathic Scoliosis : Postural Stability, Prognostic factors and Impact of Conservative Treatments on Radiologic, Clinical and Self-Reported Outcomes
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Adolescent idiopathic scoliosis (AIS) is a three-dimensional distortion of spinal curvature of unknown cause that develops during puberty. If the frontal plane curvature exceeds a Cobb angle of 24°, full-time bracing is recommended to prevent curve progression, negative health consequences or need for surgery. However, many patients decline full-time bracing, and limited evidence exists regarding alternative conservative treatments. Increasing knowledge of risk factors enables better identification of high-risk patients, thereby reducing the risk of over- or undertreatment. The overall aim of this thesis was to evaluate evidence of association between scoliosis and postural stability to inform a potential treatment target, to investigate the effectiveness of three alternative conservative treatments for patients who declined full-time bracing, and to develop a prognostic model for future risk of increased curvature in AIS. Methods: Data collection is based on one systematic literature review and meta-analysis, and one randomised controlled trial (RCT) for patients with AIS. In Paper I, literature was reviewed, and utilized posturography data to assess static postural stability to identify potential differences between patients with AIS and the control group (CON). In Papers II and III, patients were randomly assigned to either physical activity combined with hypercorrective Boston scoliosis night brace (NB), scoliosis-specific exercises (SSE), or a control group with physical activity alone (PA). Effects on trunk rotation, Cobb angle, self-reported physical activity, spinal appearance, and health-related quality of life were evaluated. Likewise, adherence, capability, and motivation in performing self-managed treatment were assessed. Follow-up was conducted at 6 months intervals until endpoint. The endpoint was defined as non-progression if the curvature increased by 6° or less at skeletal maturity, i.e., less than 1cm of growth over 6 months, or progression if the curvature increased by more than 6° before skeletal maturity. In Paper IV, data from the RCT were used for a longitudinal cohort analysis, developing and validating a prognostic model using Cox Proportional Hazards survival analysis. Results: Paper I found reduced postural stability in AIS patients compared to CON with increased sway area, mediolateral and anteroposterior range, and a posterior shift in the sagittal plane. The RCT included 135 individuals, mean age of 12.7 years (SD1.4) and Cobb angle of 31° (SD5.3). At 6 months, patients reported high adherence (72-95%) and motivation (65-92%) to the treatment, particularly in the NB group. Both the SSE and PA groups increased physical activity levels compared to the NB group. At endpoint, adherence remained adequate, but better in the NB and PA groups compared with the SSE group (50-89%). Adherence increased with higher capability and motivation, which explained 53% of the variance in adherence at endpoint. The SSE group had higher proportion of moderate problems in mobility and usual activities than the NB and PA groups, with no other clinically relevant between-group differences. The prognostic model (n=127) for curve progression showed acceptable discriminative ability (0.791), with risk factors including skeletal immaturity, larger major curve, and worsening spinal appearance. The model was adjusted for treatment exposure, as NB reduced the risk of curve progression. Conclusions: Patients with AIS have decreased postural stability with a posterior positional shift. Treatment evaluation at endpoint showed few between-group differences. However, the SSE group had higher proportion of moderate problems in mobility and usual activities compared to the other groups. Treatment adherence was adequate, but better in the NB and PA groups. Higher capability and motivation increased long-term adherence to the treatment. The treatment alternatives could be considered as the first option following a clinical decision on treatment. Including self-reported spinal appearance as a risk factor in the prognostic model may be clinically important for predicting which patients are at risk of curve progression.
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| 32. |
- Dutta, Ravi Kumar, 1983-
(författare)
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Genetic and molecular alterations in aldosterone producing adenomas
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aldosterone producing tumors (APA, also known as Conn tumors) are adrenal tumors that overproduce aldosterone, a hormone that regulates the sodium levels in blood and contributes to blood pressure (BP) regulation. Excessive production of aldosterone causes hypertension and approximately 5-15% of hypertensive patients have hyperaldosteronism, known as primary aldosteronism (PA). Major causes of PA are bilateral adrenal hyperplasia (BAH) or aldosterone producing adenoma (APA) and about 30% of PA patients have APAs. In most cases, the disease is unilateral, in rare case bilateral. Patients with APA are often detected when they have elevated blood pressure (BP>160/100mmHg) or when BP cannot be controlled with drugs. Surgery dramatically normalizes or lowers BP in patients with APA.In this thesis, we first explored the mutation frequency in susceptibility genes in sporadic APAs. About 60% of APAs displayed complementary mutations in the KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNAID and CLCN2 genes (Paper I, II & III). Copy number variation analysis of 35 APAs identified amplification of chromosome 10q24.31 in two tumors, where CALHM1-3- genes encoding for potential calcium ion channels are located. Only CALHM2 is expressed in adrenals and sequencing of CALHM2 revealed three different heterozygous sequence variants; c.341_42delCT (CALHM2P114Rfs*12), c.286G>A (CALHM2A96T) and c.580G>A (CALHM2V194M) in 5 APAs. CALHM2 is expressed in the mitochondrial membranes and Ca2+ imaging revealed that CALHM2 has selection of another ion rather than Ca2+. The genetic variant CALHM2V194M converts CALHM2 into a non-selective channel and results in higher Ca2+ conductance in mitochondria. We further found that loss of CALHM2 function upregulates REELIN/LRP8 signaling activating β-catenin dependent transcription of target genes (Paper II). In Paper IV, we investigated Scandinavian APA cases (n=35) and Swedish controls (n=60) for GWAS and discovered a susceptibility locus on chromosome Xq13.3 in a 4 Mb region to be significantly associated with APAs. Significance level was still same after genotyping the sentinel SNP rs2224095 in a replication cohort of APAs (n=52) and controls (n=740). Sequencing of an adjacent gene of the sentinel SNP, MAGEE1, identified a rare variant in one APA, which is complementary to other mutations in our primary cohort. In Summary, our studies have increased the knowledge of molecular genetic events in APAs. The results may contribute to find future non-surgical treatments for APAs.
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| 33. |
- Duvetorp, Albert, 1980-
(författare)
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Different Aspects of Psoriasis : Comorbidity, Comedication and Disease Biomarkers
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is a common heterogeneous inflammatory disease with its predominant manifestation occurring in the skin. The impact of this disease, however, extends far beyond the skin surface. During the last decades, mounting scientific evidence of psoriasis disease impact on quality of life, stigmatization and comorbidity has led to the predominant view that psoriasis care needs a holistic approach. Epidemiological research is needed to visualize the greater picture whereas research on disease pathomechanisms can provide answers to disease evaluation challenges, facilitate development of new treatments, and provide insights into mechanistical bridges explaining comorbidity occurrence. In study I of this thesis, serum S100A8/A9 was evaluated as a possible biomarker of psoriasis skin disease activity. Dramatic reductions in S100A8 and S100A9 and S100A8/A9 heterocomplex levels were found in lesional psoriasis skin after NB-UVB treatment without any significant reduction occurring in serum. Study II was designed as a retrospective, cross-sectional population study including the adult population of the county of Jönköping. The odds of having pharmacologically treated depression among individuals with psoriasis was compared to the odds of the background population. Psoriasis was associated with an elevated depression risk. Depression was more prevalent among women (both in the background population and among individuals with psoriasis). Young age was associated with higher odds for depression among individuals with psoriasis. Study III was based on the same study population as study II. In this study the comedication burden of individuals with psoriasis was compared to the background population. Comedication assessed were prescription drugs used to treat comorbidity associated with psoriasis in previous scientific publications. Patients with psoriasis were found to have a high comedication burden. Patients receiving systemic treatment for psoriasis had a higher number of different dispensed drugs suggesting that severe disease implies a higher risk of comorbid disease. Study IV was an exploratory study assessing numerous potential biomarkers for psoriasis disease activity. Extensive Luminex analysis of skin and serum samples collected during study I was performed. No serum mediator (potential biomarker of disease activity) showed a significant change after NB-UVB (following correction for multiple testing). In skin, NB-UVB had effects on mediators of the Th17 pathway and multiple chemokines but also previously undescribed or less explored disease mediators. Study II and III suggest that comorbidity and its comedication is common among Swedish psoriasis patients in contact with the health care system. This research reinforces the perception that a holistic approach is needed when treating patients with psoriasis. Behind the failure to identify a biomarker for skin disease activity in study I and IV lurks the questions to how, if or when inflammation in the skin affects systemic inflammation and in extension comorbid disease.
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| 34. |
- Elawa, Sherif, 1988-
(författare)
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Microvascular Function Assessment after Mastectomy and Radiation Therapy in Breast Cancer Patients : From Methodology to Clinical Application
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Post-mastectomy radiotherapy (PMRT) is an important part of the treatment of breast cancer. It reduces the risk of recurrence and improves overall survival. Scaring and fibrotization of the skin and subcutaneous tissue of the chest wall or remaining breast are among its side-effects. These late side-effects of PMRT may in turn affect skin microcirculation and oxygenation, although this connection is not completely established. In patients that later require breast reconstruction, it is difficult as a plastic surgeon to evaluate if the microcirculatory changes have been affected by PMRT, and how such effects should have an impact on the choice of reconstructive method. In the work presented in this thesis, laser speckle contrast imaging (LSCI), laser-doppler flowmetry (LDF) and diffuse reflectance spectroscopy (DRS) have been used with a strong vasodilator, methyl nicotinate (MN) to study the microcirculatory changes after PMRT.In studies I and II, we aimed to find the optimal concentration of MN and its main mechanisms of action. In healthy volunteers, the microvascular response to different concentrations of MN was evaluated on the forearm using LSCI. It was found that a concentration of 20 mmol/l resulted in a quick vasodilatory response with a long plateau phase, minimal tissue edema and no non-responders. In study II, we utilized locally administered drugs to block the three main pathways responsible for skin vasodilation. Subsequently, we provoked the skin with MN and assessed its effect with LSCI. From this study we could conclude that MN’s mechanism of action is largely mediated by prostaglandins and partly by local sensory nerves.In study III, we examined the skin microcirculatory response in breast cancer patients before, immediately after, and at two and six months following unilateral PMRT, using the contralateral breast as a control. A significant increase in basal skin perfusion and perfusion after application of MN was observed on the irradiated chest wall immediately after RT compared to the contralateral breast and compared to before RT. At six months after RT, there was no longer a difference in basal skin perfusion or after application of MN in the irradiated chest wall compared to the contralateral breast and compared to before RT was given. The results from this study concluded that skin perfusion in the irradiated chest wall had returned to normal when measured six months after RT.In study IV, the late effects on skin microvascular function were studied in women who had undergone mastectomy and PMRT several years prior to the study. Skin perfusion and oxygen saturation was measured with white light diffuse reflectance spectroscopy (DRS) combined with Laser Doppler Flowmetry (LDF) before and after application of MN on the irradiated chest wall with the contralateral non-irradiated breast as control. In this study we found that skin perfusion and oxygenation in the breast are affected several years after radiotherapy and that our method could be a valuable clinical tool prior to deciding surgical procedures after PMRT.To conclude, MN can be topically applied to the skin to reliably assess microvascular function and the microvascular capacity. LSCI and LDF have different strengths and drawbacks, with LSCI having the advantage of having a large spatial resolution that allows for measurements of control areas in the same field of view as the provoked areas. LDF in combination with DRS enabled us to further assess perfusion and oxygenation simultaneously which could be an advantage in fibrotic skin where skin perfusion and oxygen saturation may not correlate with each other. Although the study groups differed between the study examining the early effects of PMRT with the late effects of PMRT, we have been able to non-invasively visualize changes in microcirculation in relation to the acute and chronic phase after PMRT. Future studies are needed to investigate the value of pre-operative measurements with MN provocation for predicting surgical outcome.
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| 35. |
- Ellegård, Sander, 1985-
(författare)
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HER2-positive breast cancer : Clinical and molecular aspects
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundHuman Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer is notable for its aggressive behavior, however with the introduction of trastuzumab in the early 2000’s, prognosis has improved. This thesis investigates the efficacy of trastuzumab in real-world settings after its introduction and evaluates the prognostic value of molecular biomarkers, aiming to optimize treatment approaches and improve patient outcomes.Material and MethodsHER2-positive patients treated in the advanced and early stages of breast cancer were retrospectively identified using Swedish patient registries and through the review of medical records.Study I included 46 patients with advanced breast cancer treated with trastuzumab between 2000 and 2007. Immunohistochemical analysis of several proteins hypothesized to be involved in trastuzumab resistance were evaluated. Additionally, gene copy number variations were analyzed using droplet digital PCR.Study II include 599 patients who received adjuvant trastuzumab between 2006 and 2014 in the Southeastern health care region, in order to evaluate the implementation of trastuzumab after its approval and to evaluate patient outcomes with regard to clinicopathological variables.Study III conducted quantitative analyses of stromal tumor-infiltrating lymphocytes (sTILs) in patients with available tumor material from the same cohort identified in study II. Additionally, a case-control study of 21 cases with 21 matched controls treated with trastuzumab were analyzed with RNA-sequencing in order to identify important differentially expressed genes.ResultsStudy I demonstrated that trastuzumab treatment in a real-world setting had similar survival as in pivotal clinical trials. Additionally, high amplification of HER2 correlated with improved progression-free survival (PFS) and overall survival (OS) in advanced breast cancer patients and PTPN2 gain was correlated with reduced PFS and OS.Study II confirmed trastuzumab's efficacy in a large real-world cohort. Trastuzumab treatment, estrogen receptor (ER) status and number of metastatic lymph nodes were the most important prognostic factors for breast cancer-specific survival and distant recurrence-free survival.Study III identified a significant association between high levels of sTILs and improved overall survival. Additionally, several G-protein coupled receptors (GPCRs) involved in EGFR and Wnt signaling were found to be upregulated in cases vs controls.ConclusionsTrastuzumab maintains its efficacy in clinical practice, affirming its role in current treatment regimens for HER2-positive breast cancer. The findings support the prognostic significance of sTILs and suggest HER2-amplification levels as a relevant prognostic factor. We propose PTPN2 and several GPCRs as areas for future research.
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| 36. |
- Engvall, Kristina, 1978-
(författare)
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Taxane-Induced Peripheral Neuropathy among Early-Stage Breast Cancer Survivors : Prevalence, Risk Factors, Quality of Life and Genetic Prediction Models
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Taxane-induced peripheral neuropathy (TIPN) is a common and distressful side effect. Little is known on how long TIPN persist and its effect on health-related quality of life (HRQL). The overall aim of this thesis was to study the prevalence and severity of persistent TIPN, to investigate its impact on HRQL and to explore the clinical and genetic risk factors for TIPN among early-stage breast cancer survivors (ESBCS). Methods: A population-based cohort of 884 recurrence-free ESBCS diagnosed 2010-2015 in the Southeast Health Care region, Sweden and 1768 control women without prior cancer, who received a postal questionnaire including EORTC chemotherapy-induced peripheral neuropathy (CIPN20) and QLQ-C30 instruments. Prevalence of TIPN symptoms and clinical risk factors were explored. Adjusted relative risks (RR) were estimated for ESBCS compared to control women. For impact on HRQL, adjusted mean scores of QLQ-C30 scales among ESBCS with and without TIPN were calculated. Blood samples from 362 ESBCS were whole-exome sequenced. We leveraged logistic regression models to develop and validate polygenic prediction models to estimate the risk of persistent PN symptoms in a training and test cohort. Results: The response rate was 79% for ESBCS and 59% for controls. The median time post-taxane was 3.6 years. The adjusted RR for ESBCS vs. controls was highest (RR 1.8) for tingling in feet and numbness in feet. Individual sensory symptoms occurred in 9%-48% and motor symptoms in 7%-61% of ESBCS. The most prevalent symptoms were difficulty opening jar and cramps in feet. Paclitaxel, older age, overweight, diabetes mellitus, vibrating hand tools, smoking and autoimmune disease were independent risk factors (Study I). All 13 sensory and motor TIPN symptoms at increased risks among ESBCS had a significant impact on global health status, which worsened with increased severity of TIPN. Between 30%-93% of ESBCS with moderate-severe TIPN reported a clinically important impairment of functioning and personal finances. Moderate-severe difficulty climbing stairs and problems standing/walking were associated with medium-large clinically important differences (Study II). In the explorative sub-study, two of five prediction models based on genetic and clinical risk factors obtained AUC results above 60% in the test cohort. Using the model for numbness in feet (35 SNVs) in the test cohort, 73% survivors were correctly predicted. For tingling in feet (55 SNVs) 70% were correctly predicted (Study III).Conclusions: Most sensory and motor symptoms are more common among taxane-treated ESBC survivors than in women from the general population, many symptoms persist ≥3.6 years. Persistent TIPN symptoms are associated with clinically relevant impairment of HRQL. Polygenic prediction models including clinical risk factors may be used to estimate the risk of persistent taxane-induced numbness in feet and tingling in feet.
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| 37. |
- Ennab Vogel, Nicklas, 1981-
(författare)
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Optimizing prehospital acute stroke care in the presence of economic constraints
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mechanical thrombectomy (MT) has become standard of care for acute anterior circulation ischaemic stroke due to large vessel occlusion since the launch of second-generation stent retrievers for clinical use nearly a decade ago. Up until recently, the treatment was exclusively performed at university hospitals in Sweden. Sundsvall Regional Hospital joined as the eighth treatment facility in late 2023. Scarce resources of healthcare systems across the world hamper the complete implementation of MT in acute stroke care. Hence, efforts to improve patients’ accessibility to and healthcare providers’ utilization of MT remain prioritized. Methods for determining the optimal number and locations of treatment facilities for MT in economically constrained healthcare systems remain unstudied. The optimal number and locations of ambulance helicopters for prehospital transportation of patients with presumed acute stroke too. The aim of the thesis is to solve constrained optimization problems within the framework of cost-effectiveness analysis for prehospital acute stroke care management of patients with AIS. To fill these knowledge gaps, this thesis takes on an interdisciplinary research approach, and combines health economics, operations research, and medicine to identify cost-effective solutions for location problems with respect to the implementation of MT in the Swedish healthcare system. A comprehensive set of consolidated data based on anonymized, patient-level, nation-wide registry data for a study period of six years underlies analyses. This thesis employs predictive modelling, geographic network analysis, optimization, and decision modelling for economic evaluation within the framework of cost-effectiveness analysis to identify the most cost-effective solutions to implement. The fitting of predictive generalized linear models to four treatment modalities in acute stroke care for patients with acute ischaemic stroke established the linear associations in absolute effect measures between the modified Rankin Scale score at 90 days post-stroke and the time from symptom onset to treatment start with intravenous thrombolysis only, MT only and intravenous thrombolysis plus MT, respectively. With imposed economic constraints, the analysis identified the optimal number and locations of thrombectomy centres for the Swedish healthcare system. Furthermore, it identified the optimal number and locations of ambulance helicopters too. Finally, it was possible to determine the combination of optimally located thrombectomy centres and ambulance helicopters that comprises the most cost-effective solution to implement into the Swedish stroke system of care. This thesis demonstrates that economically constrained optimization of thrombectomy centres and ambulance helicopters in acute stroke systems of care comprises highly cost-effective solutions that entail immense health gains in patients with acute ischaemic stroke. Health economics, operational research and medicine can be combined to create a powerful decision-modelling tool in the evaluation of implementation strategies for prehospital acute stroke systems of care.
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| 38. |
- Ericsson, Maria, 1970-
(författare)
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No time to waste : Pre-hospital actions and time delays in patients with ST elevation myocardial infarction – temporal trends and prognostic impact on short- and long-term survival
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: In ST-elevation myocardial infarction (STEMI) patients, a rapid diagnosis is imperative to reduce total ischaemic time minimizing risk for heart failure, serious arrhythmias, or death. Prehospital context is complex, and the patient delay constitute major part of the pre-hospital phase. Patient delay has been prone hard to impact but the system delay has had major transformation during the years. Aim: The overall aim was to explore pre-hospital actions and time delays in STEMI patients, investigating temporal trends and estimate prognostic impact on short- and long-term survival. Methods: Study I, was a multicentre survey study, exploring decisions, and actions in relation to the choice of first medical contact (FMC). Study II was a sub-study to the multicentre survey, exploring the interaction between tele nurses and callers in authentic calls when the caller with an evolving myocardial infarction (MI) chose to call Swedish health care direct (SHD) as FMC. Study III, was based on the same database as study I, exploring early (< 20 minutes) and late (> 90 minutes) response from symptom onset in STEMI patients. Study IV, was based on SWEDEHEART-registry, investigating temporal trends in pre-specified risk groups for pro-longed pre-hospital delay times (PHDT), estimating cumulative survival in short and long term stratified in six different PHDT groups. Results: Study I, only half of the patients’ contacted emergency medical services (EMS) as their FMC. Choice of FMC prolonged time to diagnosis in relation of calling EMS. Choosing SHD pro-longed delay to diagnosis with 38 minutes. Study II, four interactions were found between tele-nurses and callers, reasoning, distinct, irrational, and indecisive, and type of interaction could lead or mislead the call moving progressively forward or not. Study III, bystanders calling EMS, men, intensive and alarming symptoms such as dyspnoea and weakness and to interpret symptoms attributed from the heart was associated with a rapid action calling an ambulance within 20 minutes, which was performed by one of five patients. Study IV, trend curves for median PHDT was hump shaped for the 20 years studied. Women, older age, and patients with diabetes had consistent pro-longed PHDT, except for the oldest patients (> 80 years). PHDT was an independent risk for short- and long-term survival. Patients with the shortest PHDT 0-1 hour had the highest mortality up to five days. In five-year follow up this group accompanied with the group within 1-2 hours had highest estimated survival. Conclusion: Pre-hospital delay is an independent predictor of short- and long-term survival. To interpret symptom correctly and knowledge in how to act, calling an ambulance rapidly, impact time to diagnosis and diminish time delays. Pre-hospital delay merits further attention regarding future interventions.
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| 39. |
- Eriksson, Ida, 1985-
(författare)
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Dealing with damaged lysosomes : Impact of lysosomal membrane stability in health and disease
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The lysosome is the main unit for degradation and plays important roles in various cellular processes, such as nutrient sensing, cholesterol regulation and cell death. Consequently, altered lysosomal function contributes to, or even causes, several diseases. Lysosomal membrane permeabilization (LMP) and release of lysosomal content to the cytosol can induce cell death, and is implicated in inflammation and neuronal decline in several neurodegenerative diseases. It has also emerged as a potential target in cancer therapy. Due to the detrimental effects of LMP, cells harbor several mechanisms to protect and prevent lysosomal membrane damage. The aim of this thesis was to elucidate how lysosomal membrane stability and repair mechanisms affect cell death and survival. We find that lysosomal cholesterol is upregulated in response to an increased load of reactive oxygen species in a Parkinson’s disease cell model, and that augmented cholesterol protects from LMP. However, cholesterol also induces accumulation of α-synuclein and inhibits lysosome-mediated degradation, which can destabilize the lysosomal membrane and accelerate the course of disease. Further, we demonstrate that lysosomal membrane damage is counteracted by a calcium-dependent repair mechanism to prevent LMP. Lysosomes damaged beyond repair are instead sequestered in an autophagosome and degraded by intact lysosomes in a process called lysophagy. As a result, small vesicles containing lysosomal membrane proteins are generated, which we believe are used to restore lysosomal function. We show that malignant cells are more sensitive to LMP, and that they differ in their activation of damage-response mechanisms compared to normal cells. Moreover, in malignant cells, the intracellular position of the lysosomes determines the susceptibility to lysosomal damage. Peripherally located lysosomes are less sensitive, and by relocating lysosomes to the perinuclear area in the cell, we can sensitize lysosomes to LMP induction. In summary, this thesis demonstrates the importance of damage-response mechanisms to protect from lysosomal membrane damage and maintain cellular function. It also indicates that targeting of lysosomal stability and repair is a potential therapeutic strategy in both neurodegenerative diseases and in cancer.
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| 40. |
- Eriksson-Liebon, Magda, 1986-
(författare)
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The effects and experiences of internet-delivered cognitive behavioural therapy : The perspectives of patients with non-cardiac chest pain and healthcare professionals in the emergency and cardiac care
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundNon-cardiac chest pain (NCCP) is a common issue, accounting for roughly half of all emergency department visits related to chest pain. Patients afflicted with NCCP often endure cardiac anxiety, misinterpreting the pain as heart-related and fearing it, despite the absence of any life-threatening cardiac issues. This anxiety often leads to the avoidance of physical activities, negatively impacting their quality of life. Cognitive behavioural therapy (CBT) has been shown to be effective in managing psychological distress such as anxiety and depression. CBT is a structured process that helps patients identify and restructure their negative thoughts, get a corrected and more realistic perception of their symptoms, and learn to manage their thoughts about chest pain. Despite its effectiveness, CBT is resource-intensive, and therefore internet-delivered cognitive behavioural therapy (iCBT) may be an alternative as it increases accessibility and is more cost-effective compared to traditional therapy methods. However, there is a lack of re-search on the effectiveness of this treatment approach for patients with NCCP and cardiac anxiety. Moreover, digital care technologies are still relatively unfamiliar in clinical practice, particularly in emergency departments, and the successful implementation of iCBT relies on healthcare professionals' acceptance and integration of digital care into clinical practice. Aim The overall aim of this dissertation was to evaluate the short- and long-term effects of a nurse-led iCBT program on psychological distress in patients with NCCP, and to explore their experiences participating in the iCBT program. In addition, the study aimed to describe healthcare professionals' perceptions of digital care in the emergency and cardiac care for patients with NCCP. Methods This dissertation comprises two quantitative and two qualitative studies. A randomised clinical trial (RCT) (studies I, II, and III) was conducted to evaluate cardiac anxiety, measured with the Cardiac Anxiety Questionnaire (CAQ); and secondary outcomes such as fear of body sensations, measured with The Body Sensations Questionnaire (BSQ); depressive symptoms, assessed with the Patient Health Questionnaire-9 (PHQ-9); health-related quality of life (HRQoL), measured using the EuroQol Visual Analog Scale (EQ-VAS); and chest pain frequency with a self-developed question. The RCT cohort consisted of 109 patients who had at least two healthcare consultations for NCCP in the past 6 months, experienced cardiac anxiety (CAQ score ≥24), and were randomised into a 5-week iCBT program (n=54) or psychoeducation (n=55). An intention-to-treat analysis was conducted, and linear mixed model analysis was used to assess between-group differences in primary and secondary outcomes. The iCBT program included psychoeducation, mindfulness, and exposure to physical activity, with weekly homework assignments and feedback, while the control (psychoeducation) group received readable psychoeducation program aimed to increase knowledge about their mental health, symptoms, and the strategies that can be used to manage chest pain and improve their well-being. Study I was a short-term follow-up with a three-month duration. Study III was a longitudinal study with a 12-month follow-up. Additionally, factors impacting the treatment effect of iCBT on cardiac anxiety were also explored. Study II was a semi-structured qualitative study utilising an inductive approach with content analysis following Patton (2015). Face-to-face interviews were conducted with 16 participants from the iCBT group. Study IV was a qualitative descriptive study involving individual, digital/face-to-face semi-structured interviews with 17 licensed healthcare professionals (physicians and nurses) working in emergency care or cardiology. Data were analysed using inductive thematic analysis based on Braun and Clarke (2006). Result In Study I, no significant differences were found between the iCBT and control (psychoeducation) groups regarding cardiac anxiety or any of the secondary outcomes in terms of the interaction effect of time and group over the 3-month follow-up. iCBT demonstrated a small effect size on cardiac anxiety (Cohen’s d=0.31). A positive change score (≥11 points on the CAQ) was reported by 16 patients in the iCBT group (36%) compared to 13 patients (27%) in the control (psychoeducation) group, indicating a slightly greater improvement in cardiac anxiety in the iCBT group. However, the difference between the groups was non-significant (p=.213). Within-group analysis showed significant improvement in cardiac anxiety (p=.037) at the 3-month follow-up compared to the 5-week follow-up in the iCBT group, but not in the control (psychoeducation) group. In Study III, there was no statistically significant interaction effect of time and group between the iCBT and control (psychoeducation) groups regarding cardiac anxiety over the 12-month follow-up. However, there was a statistically significant interaction effect of time and group (p=.009) regarding chest pain frequency for the iCBT group and a group effect on health-related quality of life (p=.03) for the iCBT group. Furthermore, the regression analysis showed that higher scores of "avoidance" on the CAQ at baseline were associated with improvement in cardiac anxiety at the 12-month follow-up in both groups. In Study II, participants described their experiences, leading to three main categories: "driving factors for participation in the iCBT program", "the program as a catalyst" and "learning to live with chest pain." Participants described how pain impacted their lives, the struggle that led them to participate in the program, and how they found the program helpful, trustworthy, and viewed it as a tool for gaining the strength and skills they needed to live a normal life despite chest pain. In Study IV, healthcare professionals described their perception of digital care, resulting in four themes: "new ground to walk on”, "a challenge for the current healthcare system", "digital care has its potential" and "prerequisites for use in clinical practice". These themes describe healthcare professionals' knowledge and experience with digital care, the challenges associated with implementing digital care in the current healthcare system, the opportunities it presents, and identify facilitators for the implementation of digital care in clinical practice.ConclusionsIn studies I and III, iCBT was not superior to psychoeducation in reducing cardiac anxiety in patients with NCCP. However, both iCBT and psychoeducation have demonstrated utility as interventions for reducing cardiac anxiety in these patients. Moreover, patients with an increased propensity to avoid activities or situations they believe may trigger cardiac -related symptoms, were found to have reduced cardiac anxiety. Patients generally perceived the iCBT program positively, viewing it as a tailored and effective tool for confronting fears and restoring normalcy in their lives. Healthcare professionals express a mixture of caution and optimism towards digital care, emphasising the importance of clear leadership, education, technical competence, and positive attitudes to ensure successful implementation and maximise benefits for patients with NCCP.
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| 41. |
- Eskilsson, Anna, 1986-
(författare)
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Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fever is a cardinal sign of inflammation and is evolutionary conserved. Fever is known to be beneficial during acute inflammation, but over time and if very high it can be detrimental. The signaling pathways by which fever is initiated by the brain and the peripheral mechanisms through which the temperature increase is generated were studied from several point of views. Fever is known to be dependent on prostaglandin E2 (PGE2) binding to its receptors in the median preoptic nucleus of the hypothalamus, which signals to the brainstem and through sympathetic nerves to heat conserving and heat producing effector organs. This thesis focuses on identifying the cells that produce the PGE2 critical for the fever response; showing where in the brain the critical PGE2 production takes place; demonstrating how peripheral inflammation activates these cells to produce PGE2; and finally, identifying the effector mechanisms behind the temperature elevation in fever. By using a newly developed specific antibody we showed that the enzyme responsible for the terminal step in the production of PGE2, microsomal prostaglandin E-synthase 1 (mPGES-1), is expressed in endothelial cells of brain blood vessels in mice where it is co-expressed with the enzyme cyclooxygenase-2 (Cox-2), which is known to be induced in these cells and to be rate limiting for the PGE2 production. The mPGES-1 enzyme was also expressed in several other cell types and structures which however did not express Cox-2, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. The role of the mPGES-1 in these other cells/structures remains unknown. Next, by using mice with selective deletion of Cox-2 in brain endothelial cells, we showed that local PGE2 production in deep brain areas, such as the hypothalamus, is critical for the febrile response to peripheral inflammation. In contrast, PGE2 production in other brain areas and the overall PGE2 level in the brain were not critical for the febrile response. Partly restoring the PGE2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to an intraperitoneal injection of bacterial wall lipopolysaccharide (LPS). The data show that the febrile response is dependent on the local release of PGE2 onto its target neurons, possibly by a paracrine mechanism. Deletion of the receptor for the pyrogenic cytokine IL-6 on brain endothelial cells, but not on neurons or peripheral nerves, strongly attenuated the febrile response to LPS and reduced the induction of the Cox-2 expression in the hypothalamus. Furthermore, mice deficient of the IL- 6Rα gene in the brain endothelial cells showed a reduced SOCS3 mRNA induction, whereas IκB mRNA-levels were unaffected, suggesting that the IL-6 signaling occurs via STAT3 activation and not signaling through the transcription factor NF-κB. This idea was confirmed by the observation of attenuated fever in mice deficient of STAT3 in brain endothelial cells. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R on brain endothelial cells to induce prostaglandin synthesis in these cells. Finally, we demonstrate that mice with genetic deletion of uncoupling protein-1 (UCP-1), hence lacking functional brown adipose tissue, had a normal fever response to LPS, and that LPS caused no activation of brown adipose tissue in wild type mice. However, blocking peripheral cutaneous vasoconstriction resulted in a blunted fever response to LPS, suggesting that heat conservation, possibly together with shivering or non-shivering thermogenesis in the musculature, is responsible for the generation of immune-induced fever, whereas brown adipose tissue thermogenesis is not involved.
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| 42. |
- Fornander, Liselott, 1981-
(författare)
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How we talk : aspects of communication and team cognition of trauma resuscitation teams
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A trauma team consists of professionals assembling in an ad hoc manner to resuscitate a patient with life-threatening injuries. In such a team, how the team manages to use non-technical skills, such as communication is important to achieve task management and decision making. Communication is practised in simulations, and the simulation environment has also been used in research to understand teamwork processes. This thesis is based on video observations of trauma teams working in real life (IRL) and in situ simulations of trauma resuscitations. The aim was to assess the creation of team cognition IRL and in simulation, to analyse verbal communication in the teams and the effects of real-time communication on team structure. In Study I, a grounded theory analysis was undertaken to understand how verbal and non-verbal interactions create team cognition. The analysis resulted in a theory pointing to “split vision” as a team’s ability to alter process modes between team positioning and sensitivity to the patient that was dependent on patient and situational values absorbed from team members’ implicit actions. In Study II, the verbal response modes taxonomy was applied to analyse both the grammatical and pragmatic meaning of verbal interactions that were compared between team roles. In the six most communicative team roles in the context of IRL trauma teamwork, pure mode communication dominated the way of delivering messages. In Study III, the structures of four IRL and four simulated trauma teams were analysed using a social network analysis of real-time communication. Overall, the teams were highly centralised, with the examining physician functioning as an information hub. In Study IV, communication from the same teams was categorised according to information and task management, as well as different coordination behaviours. We compared the IRL and simulation domains based on the proportions of utterances of each category/code, and found that “Give information after request” and closed-loop communication were more prevalent in simulation. Observing real-time communications using different methodologies gave a perspective on the conditions and possibilities for adaptation in terms of work prescriptions and team training, such as room for more communication and possible congestions of nodes in terms of occupancy and tacit communications and working modes thus far unnoticed by us and unreported. Such understanding complements established knowledge about coordination behaviours and interactive team cognition and should be taken into consideration in the practise and training of trauma teams.
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| 43. |
- Fors, Maria, 1987-
(författare)
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Best Practice Physiotherapy for Patients with Low Back Pain in Primary Care : Clinical Outcomes and Explanatory Factors
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Clinical practice guidelines provide general recommendations informing best practice physiotherapy for low back pain (LBP). Despite increased research on LBP, the recommendations have barely changed over the last few decades and the burden of LBP remains. New research strategies have been suggested to further understand the complexity of factors influencing recovery of LBP. Several mechanisms are expected to underpin the benefits of physiotherapy care. How different factors influence and explain treatment outcome in patients in different phases of primary care pathway needs to be better understood for the development of better targeted LBP interventions.The overall aim of this thesis was to investigate if and how best practice physiotherapy primary care for patients with LBP can improve clinical outcome.Methods: The four papers in the thesis are based on two randomised controlled trials (RCT) evaluating best practice physiotherapy for patients with LBP in different phases of the primary care pathway reflecting the variation of patients’ needs. Two papers investigated pre-surgery physiotherapy compared to being on a waiting-list in patients with degenerative lumbar spine disorders who are surgical candidates (n = 197). Effects on walking ability and quadriceps femoris strength were evaluated. Associations between the pre-surgery physical factors with 1-year post-surgery physical activity (PA) level were analysed using multiple linear regression. The dose-response relationship was investigated comparing the effects of attending ≤11 treatment sessions with ≥12 treatment sessions. Multiple mediation analyses and conditional process analyses were used to explore physical and psychosocial factors as mediators and patients’ treatment expectations as a moderator of the treatment’s effects on disability, back pain intensity, health-related quality of life (HRQoL), and self-rated health.Two papers were based on a stepped cluster RCT, where a physiotherapy primary healthcare model for LBP (the BetterBack MoC) was regionally implemented. Patients seeking care for LBP were allocated to either the BetterBack MoC (after implementation) or to routine care (before implementation) (n = 467). In a prospective cohort study within the RCT, the associations between patients’ initial illness perceptions and outcomes in disability, back pain intensity, HRQoL, and self-care enablement (i.e., perceived ability to understand and cope with LBP) after 3 and 12 months were explored using stepwise linear regression. Single mediation analyses were used to test whether a priori hypothesised patients’ illness perceptions and self-care enablement at 3 months mediated effects in disability and pain at 6 months of care according to the BetterBack MoC compared to routine care. Exploratory mediation analyses were also used to compare guideline-adherent care with non-adherent care. Guideline-adherent care was defined as care that included education and exercise interventions and did not include non-evidence-based interventions, referral to specialist care, or imaging.Results: Small positive effects from pre-surgery physiotherapy were seen in walking ability and quadriceps femoris strength. No clear dose-response relationship could be demonstrated when comparing the effects of ≤11 treatment sessions with ≥12. Pre-surgery physical outcome measures together explained 27.5% of the variation in PA level 1-year post-surgery, mainly explained by the pre-surgery PA level. The effect of the pre-surgery physiotherapy on patients’ PA level partly explained the treatment’s effect on self-rated health. Furthermore, among biopsychosocial factors, self-efficacy related to activities of daily living (ADL) partly explained the effect on all outcomes. PA related fear avoidance beliefs partly explained the effects on pain and self-rated health. Patients’ treatment expectations moderated the effect in all outcomes. High expectations had a positive moderating effect, while expectation of full recovery had a suppressive effect. In patients seeking physiotherapy for LBP, negative initial prognosis and treatment expectations were associated with worse scores in several outcomes at 3- and 12-month follow-ups. Patients’ illness perceptions and self-care enablement did not explain the effects of care after implementing the BetterBack MoC. This was mainly due to the BetterBack MoC not having superior effects over routine care on the hypothesised mediators. Illness perceptions and self-care enablement at 3 months were associated with disability and pain at 6 months. Further, these factors partly explained the effects of guideline-adherent care in disability and pain.Conclusions: Patients’ illness perceptions, self-care enablement, ADL self-efficacy, and PA related fear-avoidance beliefs were supported to be potential factors explaining the effect on clinical outcomes of best practice physiotherapy for LBP in primary care. Patients’ initial expectations regarding the prognosis and treatment may influence prospective outcomes including patients’ self-care enablement. More specifically, pain and disability outcomes of best practice physiotherapy for patients seeking care for LBP may improve by targeting patients’ illness perceptions and self-care enablement. Patients who are surgical candidates can increase their physical capacity and walking related performance through best practice physiotherapy. In this pre-surgery phase, the treatment should include targeting patients’ ADL self-efficacy, PA related fear-avoidance beliefs, and PA level for improved disability, pain, and HRQoL.
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| 44. |
- Giöstad, Alice, 1994-
(författare)
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Surgery for ulnar nerve compression at the elbow : Focusing on factors influencing outcome
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ulnar nerve compression at the elbow (UNE) is a common peripheral nerve compression disorder in the upper limb. The literature regarding surgical outcome is inconclusive. This thesis aims to highlight various aspects of real-life settings for patients with UNE and to increase the understanding of underlying factors influencing the outcome of surgery.Patients undergoing surgery for UNE at a tertiary referral hospital were retrospectively evaluated (Linköping cohort; n=202). Comorbidity was extensive. Patients treated with simple decompression (SD) had a lower rate of complications than those with transposition surgery. Emerging neurogenic pain was the most common complication, with a two-fold risk for smokers. Scores from the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire revealed no differences between the surgical groups. Satisfaction with surgery was relatively low (53%), however only 8% stated that they would not go through the same surgical procedure again.Images from magnetic resonance imaging (MRI), performed in conjunction with surgery (Linköping cohort; 62 patients), were re-evaluated by a neuroradiologist. Spinal nerve root pathology contributing to the ulnar nerve (C8-Th1) was rare (1/62 patients), however, nerve root affections at other levels were common (26/62). No relation between cervical pathology and patient-reported outcome was seen.The Linköping cohort was combined with two cohorts from Region Skåne to evaluate time before return to work (RTW) after surgery for UNE (n=635 in total). RTW within 6 weeks was more common among older, SD and non-manual workers. Those who were unemployed were on sick leave longer than the rest of the population. Transposition of the ulnar nerve was the only predictor for prolonged RTW in the regression model.Patients with pain in conjunction with surgery were studied both in a retrospective observational study and in a qualitative study. Questionnaires obtained from the pain management clinic revealed a high prevalence of kinesiophobia, potential depression and/or anxiety, low life satisfaction and low overall health status. Patients with severe postoperative pain were younger and more often had bilateral surgery compared to the reference population. The narratives from the qualitative study revealed that chronic pain in conjunction with surgery for UNE affects most aspects of daily life and contributes to a heavy burden for the individual.In summary, patients surgically treated for UNE in a real-life setting constitute a heterogeneous population with wide variation in comorbidity and outcome of surgery. Pain after surgery can have a great impact on the individual and should be considered as an outcome. A biopsychosocial approach should be applied when treating patients with pain.
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| 45. |
- Gjessing, Kristian, 1967-
(författare)
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Impact of medical and non-medical Factors on Quality and Costs in Primary Care : A Conscious Look at Subconcious Processes
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background / IntroductionPhysicians and patients may be influenced by more than just the medical facts of the situation at hand. The physician is a part of the sociocultural environment and is under influence of this. The physician could be afraid of making mistakes and thus choose the safest option. In addition, economic considerations may apply. The perceived continuity or quality of the communication may also influence medical decision-making. Patients may not think about what allergens they are exposed to. Differences in socioeconomy or perceived morbidity may influence the patient's or their family’s desire to see the doctor or to use medications like antibiotics.Material and MethodsIn Paper 1, referrals from two Primary Healthcare centers in Norway were compared to each other and to the other referrals that were received by the local hospital. In Paper 2, Influenza-Like Illness (ILI) for children 2-12 years old was monitored for 7 years, and costs of treatment and parental absence due to ill children were calculated using real numbers. In Paper 3, the number of antibiotic prescriptions was compared to the patient’s socioeconomic background, to investigate possible inequalities. Paper 4 compares asthma and atopy incidence to the number of antibiotic prescriptions, to investigate if asthma patients are more often treated with antibiotics than nonasthma patients are. The analyses are based on regional healthcare data and the prospective ABIS study.ResultsPaper 1 showed that locum doctors and regular General Practitioners had the same referral rates, but the locum doctors had a distribution of diagnoses that differed significantly from the regular GPs and from the other referrals.Paper 2 showed that parental absence due to children with ILI follows the seasonal influenza pattern closely. The main burden of consultations and costs is carried by Primary Care.Paper 3 showed that parent-reported infectious morbidity at age 5, is associated with a higher number of antibiotic prescriptions in later childhood (5-14 years). Family income is a factor, where children from Q1 (wealthiest) receive significantly fewer antibiotics than children from Q3-Q5.Paper 4 found that asthma/ fur allergy at age 5 was associated with more antibiotic prescriptions in later childhood, but that wide-spectrum antibiotics are rarely used. Doctors seem to adhere to national and regional guidelines.ConclusionsPrimary care physicians seem to be affected by their grade of continuity and length of employment in their referral diagnosis distribution. Influenza-like illness in children carries a substantial cost in terms of loss of production, healthcare encounters, and personal suffering for vulnerable individuals. Parents’ perceptions of morbidity seem to influence antibiotic demand in children, along with socioeconomic factors. Children with asthma or airway allergies seem to receive more antibiotic prescriptions, possibly due to increased infectious vulnerability or to allergic exposure unknown to the doctor.
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| 46. |
- Good, Elin, 1983-
(författare)
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Interrogating Atherosclerotic Plaque Biology Through Responses to Cardiovascular Risk Management and Imaging
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis causes more deaths than any other disease worldwide, and the cause of death is most commonly a rupture of a vulnerable atherosclerotic plaque, resulting in a thrombotic event in the heart or brain. The major risk factors for plaque progression are well known, but all the mechanisms that drive atherosclerotic plaques towards catastrophic events are not yet fully elucidated. This thesis revolves around the atherosclerotic plaque; how plaques can be analysed using cardiovascular magnetic resonance imaging and the study of biological responses to cardiovascular risk management. In Study I we interrogated the quality of cardiovascular risk management in patients diagnosed with high-grade carotid stenosis and found that cardiovascular risk management was deficient in all aspects, despite the very high risk for events in these patients. Thus, we designed the next two studies to address the unmet clinical need for improved cardiovascular risk management in patients with carotid atherosclerosis while at the same time asking mechanistic questions about the effect of this approach on lymphocyte phenotypes (Study II) and on plaque composition (Study III). In Study II, the effect of cardiovascular risk management on Natural Killer cell, Natural Killer T cell and T lymphocyte subpopulations were studied in patients with carotid atherosclerosis. Our results show a polarisation away from a senescent phenotype towards more naïve i.e., juvenile cell types suggesting a transition towards a possibly less pro-inflammatory lymphocyte profile. In Study III, we applied a newly developed quantitative Dixon MRI technique to the quantification of lipid rich necrotic core and hemorrhage inside atherosclerotic plaques. Employing this technique, we explored the relationships between these high-risk plaque compositional features and circulating lipoproteins as they changed over time in response to cardiovascular risk management. In the current study there was no evidence for such a linear relationship. To further study the associations between inflammation and quantitative plaque measurements we explored in Study IV the relationship between inflammation in atherosclerotic plaques as measured by 18F-FDG uptake and features of high-risk plaque as measured by quantitative Dixon MRI. To facilitate the use of carotid MRI in larger cohorts we developed in Study V a technique for the segmentation of the carotid artery using supervised machine learning. Taken together these studies describe the importance of cardiovascular risk management, the complexity of atherosclerotic plaque biology and they propose new strategies for quantitative plaque imaging.
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| 47. |
- Granström, Fredrik
(författare)
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Inequalities in Health : the Importance of Material/Structural Factors and Psychosocial Resources
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Socioeconomic inequalities in health are well-documented in most countries. Health differences have been shown to follow a gradient, where health status in average is somewhat poorer for every lower level in the social hierarchy. Notably, the welfare state Sweden is no exception. Considerable socioeconomic inequalities in health are found, and the magnitude of e.g. educational inequalities in health has even increased over recent decades. Important contributors, or “health determinants” of observed health inequalities, include material/structural factors, behavioral factors and psychosocial factors. The inequalities arise from uneven distributions of these health determinants accumulated over the life course. Whereas earlier research has focused on independent effects of different determinants, recent research has showed that health determinants interact in complex ways when contributing to health inequalities. However, the relative importance of the independent contributions of specific types of health determinants and of the shared contributions have not been assessed. The overall aim of this thesis was to examine possible explanations of inequalities in self-reported health among groups with different educational levels in a Swedish population, in particular how material/structural factors and psychosocial resources contribute to these inequalities. This thesis is based on four population-based studies. Studies I and IV used data from the Life & health study, based on crosssectional survey questionnaires, conducted in 2000, 2004 and 2008 in five counties in the central part of Sweden. Around 35,000 respondents were included each year with response rates varying from 60% to 67%. Studies II and III used data from a sub-sample of the Swedish national public health survey (HLV) from 2012, another cross-sectional survey questionnaire. The sub-sample was carried out in four counties in the central part of Sweden. The total number of respondents in the sub-sample was 26,706, with a response rate of 53%. Outcome variables were, in studies I, II and IV, self-rated health (SRH) and, in study III, psychological distress. The magnitudes of health inequalities were examined using rate ratios and rate differences. The associations between health determinants and health out-comes were examined using logistic regression, and the analysis of independent versus shared contributions of health determinants to health inequalities was conducted using structural equation modeling (SEM). Study I showed that relative educational inequalities in SRH were two-fold among men, unchanged from 2000 to 2008, while the inequalities initially were smaller among women but increased over time, from 1.7 to 2.1. This increase was mainly due to growing inequalities in the age group 25–34 years. The distributions of all observed health determinants were more unfavorable in low education groups; most prominent for lack of a financial buffer, smoking and low optimism. These educational differences were, for most health determinants, unchanged over time. Study II examined the association of adult SRH with adverse material conditions (eco-nomic stress in the family) in childhood as well as adverse psychosocial conditions (condescending treatment) in childhood. Both economic stress and condescending treatment in childhood were strongly associated with poorer adult SRH. These associations were attenuated, but still statistically significant after adjustment for economic stress and condescending treatment in adulthood and other risk factors. Study III showed, after adjustment for age, economic difficulties, employment status and social support, a moderate association between educational level and psychological dis-tress, where low and medium educational levels were related to a lower risk of psychological distress. However, current economic difficulties showed a strong, and positive, association with psychological distress. Study IV showed that the shared pathways, including both material/structural fac-tors (e.g. financial buffer and unemployment) and psychosocial resources (e.g. optimism and social participation), explained about 40% of educational inequalities in SRH for both men and women aged 25–74 years. The pathways including only the independent effects of psychosocial resources (14% in men and 20% in women) or material/structural factors (9% and 18%, respectively) explained substantial but smaller proportions of the inequalities. In conclusion, in an adult population in the central part of Sweden, prevalence of poor SRH was, among men, twice as high in the low education group compared to the high education group during the first decade of the new millennium. Among women, educational inequalities were initially smaller, but increased over time to the same level as among men. However, when using self-reported psychological distress as health outcome, no corresponding educational inequalities were found. Instead, economic difficulties were an important determinant of psychological distress. SRH in adulthood was significantly associated with economic stress and condescending treatment during childhood, also when the same conditions in adulthood were taken into account. Material/structural factors and psychosocial resources explained more than half of the educational inequalities in SRH, and the majority of this contribution was in the form of a shared effect of material/structural factors and psychosocial resources. A shared effect means that a material/structural factor and a psychosocial resource are strongly associated, and that the combination of the two has an effect on the educational inequalities in SRH. Therefore, to reduce educational inequalities in SRH, interventions need to address both material/structural conditions and psychosocial resources. This needs to be done across educational groups, using a life course perspective, but with more intensive interventions in lower education groups.
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| 48. |
- Gubat, Johannes, 1986-
(författare)
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Identifying Essential Deubiquitinase Interactions and Targeting Protein Ubiquitination in Cancer
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is the second leading cause of death globally and is one of the most pressing health issues today. While significant advances have been made in cancer treatment, drug resistance and toxicity remain formidable obstacles to successful therapy. Thus, there is a need to find novel targets that pave the way for new cancer therapeutics. Ubiquitination, the process of tagging substrate proteins with ubiquitin molecules, regulates many of the pathways that underlie cancer progression. This thesis aims to explore innovative strategies for combating cancer by focusing on crucial elements within the ubiquitination machinery, specifically the Ubiquitin-Proteasome System (UPS) and deubiquitinases (DUBs). In Paper I, we employed the Connectivity Map to discern UPS inhibitors by analyzing the gene expression patterns of various compounds in comparison to those induced by proteasome perturbation. In Paper II, we employed orthogonal methods to identify the primary mechanism for the cytotoxicity of b-AP15. Here, we showed that pharmacologic doses of b-AP15 resulted in strong proteasome inhibition and that cytotoxicity is mediated through the mitochondria and influenced by the proteasome-associated DUB, USP14. In Paper III, we explored the role of USP14 in colorectal cancer cells and evaluated its potential as a cancer target. We found that the genetic deletion of USP14 confers a quiescent phenotype to cancer cells. In Paper IV, we used CRISPR-based screens to search for new deubiquitinase targets. We identified deubiquitinase interactions essential for cancer and explored the possibility of combinatorial deubiquitinase targeting. We pinpointed highly-networked deubiquitinases (PSMD14, USP9X, USP39, and USP7) and deubiquitinase pairs represent promising drug targets. This thesis underscores the importance of the ubiquitination process in the search for novel cancer therapeutics and provides new avenues to explore in developing therapies based on the inhibition of deubiquitinases.
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| 49. |
- Gunnarsson, Stina, 1980-
(författare)
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What makes a patient satisfied with intrathecal baclofen treatment for spasticity : Expectations and experiences
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients often report reduced spasticity and/or pain, improved function and comfort, and a high level of satisfaction after treatment with intrathecal baclofen (ITB). However, dissatisfaction, complications and unmet goals are also reported. The overall aim of the thesis was to identify, describe, and analyse what makes a patient satisfied with the effect of ITB treatment for spasticity, by considering patient expectations, experience, outcome, as well as satisfaction with treatment. Four studies are included, all focusing on patients undergoing ITB treatment or about to start treatment. Study I, a qualitative interview study, describes the experiences of 14 patients on ITB from one university hospital. Study II, a cross-sectional study, includes 6 of the 7 main hospitals in Sweden working with ITB treatment. Through questionnaires and medical records, data were collected from 83 patients, on general expectations/optimism, satisfaction with treatment and reports on complications. Study III is based on data from study II on baclofen doses for 81 patients to analyse the development of dose patterns. Study IV, a prospective longitudinal study, includes 29 patients from 2 university hospitals. Data collection focused on pre-expectations, effect at 1-year follow-up and satisfaction with treatment. The results of the thesis are summarized in 3 topics: (1) variables of interest for formulation of patients’ pre-expectations; (2) pre-expectations of outcome and ongoing ITB treatment; (3) outcomes and satisfaction with ITB treatment. Together, those topics describe what makes a patient satisfied with ITB treatment. Patients reported improvements in symptoms and reduced consequences from spasticity, however improvements were not always as good as expected. Reported satisfaction with ITB treatment varied in the 4 studies, but mostly a high level of satisfaction was reported. Variables of importance for satisfaction were improved occupational performance, pre-expectations met and initial status regarding occupational performance. In conclusion, results from this thesis emphasize the need for a dialogue between the patient and health care professionals to enable the formulation of realistic individual pre-expectations and goals. In addition, unmet pre-expectations, complications and frequent hospital visits should be included in the discussion about the benefits of ITB treatment versus the disadvantages.
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| 50. |
- Guorgis, Ghassan, 1978-
(författare)
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Understanding Skin Cancer Risk and Prevention : with Emphasis on Actinic Keratosis Patients
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The rising incidence of skin cancer globally makes it important to emphasize preventive measures that promote sun protection, particularly among individuals with phenotypic predisposition and/or risky sun habits. Actinic keratosis (AK) is the predominant actinic lesion observed in fair-skinned populations, recognized as a sign of actinic skin damage and as an occasional precursor to squamous cell carcinoma (SCC). The aim of this thesis was to explore, from a primary care perspective, how an enhanced understanding of risk factors for skin cancer development can aid in identifying individuals for patient education on prevention and early detection of skin cancer. Paper I suggests that personalized sun protection advice delivered in person by the GP can result in both short-term and long-lasting improvements in sun protective behaviour. Paper II demonstrated that individuals diagnosed with AK face a significantly elevated risk of developing SCC, basal cell carcinoma (BCC), or malignant melanoma (MM) in the following decade compared to sex- and age-matched controls. Paper III highlighted the fact that the presence of chronic lymphocytic leukaemia, and to a lesser degree hypertension and Parkinson's disease, independently raises the risk of skin cancer. This underscores the importance of providing tailored preventive guidance to individuals with these conditions. Paper IV showed that both age and male gender were factors found to be associated with an increased risk of developing skin cancer in AK patients while no risk increase was identified for any of the other variables studied. In conclusion, personalized sun protection advice from general physicians (GPs) can bring about lasting improvements in sun protective behaviour. Reinforcing this advice during medical consultations, such as nevi checks, is important to sustain this effect over a long period. This is encouraging for the accepted practice of giving sun protection advice to patients with MM, SCC and BCC. A diagnosis of AK not only indicates an increased risk of skin cancer but also serves as a readily identifiable criterion for implementing personalized preventive measures. The presence of AK substantially increases the likelihood of developing future skin cancer, even more pronouncedly when combined with specific comorbidities such as chronic lymphocytic leukaemia, hypertension, and Parkinson's disease. Future research should investigate how sun protection advice interacts with other behavioural counselling and evaluate its effectiveness over time. Additionally, exploring other factors influencing skin cancer risk in individuals with AK would facilitate the provision of comprehensive preventive interventions.
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