| 31. |
- Boman, Erika, 1975-
(författare)
-
Inner strength as a health resource among older women
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Long life does not inevitably mean more healthy years; older women have an increased risk of disabilities, diseases and adverse life events. Nevertheless, many older women experience health. This may be explained by possessing resources that promote health, despite adversities. Inner strength is seen as a resource as such. In this thesis inner strength is interpreted according to a theoretical model where inner strength comprises four interrelated and interacting dimensions: connectedness, creativity, flexibility and firmness, and being rated by the Inner Strength Scale (ISS).Aim and methods The overall purpose of this thesis was to explore inner strength as a health resource among older women. In study I six focus group interviews were performed with older women (66-84 years; n = 29) and the interviews were analysed by a concept driven approach and by means of qualitative content analysis. Studies II–IV had a quantitative, cross-sectional design. A questionnaire was sent to all older women (65 years and older) living in Åland, an autonomous island community in the Baltic Sea, and 1555 (57%) women responded. The data was analysed using descriptive and inferential statistics.Results In study I, exploring how inner strength and its dimensions can be identified in narratives of older women, connectedness was interpreted as a striving to be in communion, creativity as the ability to make the best of the situation, firmness as having a spirit of determination – “it is all up to you”, and flexibility as a balancing act. The results of study II showed that strong inner strength was associated with better mental health, but not physical health. In exploring factors associated with health-related quality of life, fewer symptoms of depressive disorders was the strongest explanatory variable, and together with not feeling lonely associated with better both physical health and mental health. Better physical health was also explained by not having a diagnosed disease, being of lower age and the opportunity to engage in meaningful leisure activities. Better mental health was additionally explained by having enough money for personal needs. In study III the result showed that non-depressed women were likely to have a strong inner strength, as well as never or seldom feeling lonely, taking fewer prescribed drugs, feeling needed and having the opportunity to engage in meaningful leisure activities. In study IV poorer mental health was associated with weaker inner strength in total, and in all four dimensions of inner strength. Symptoms of depressive disorders and feeling lonely were related to lower scores in three of the dimensions (except firmness and creativity, respectively) and poorer physical health was associated with lower scores in two of the dimensions (firmness and flexibility). Some other health threats were significantly associated with only one of the dimensions (connectedness or creativity), and others were not significantly associated at all.Conclusion The results add nuance to the notion of inner strength and deepen empirical knowledge about the phenomenon. It is elucidated that the ISS can be used not only to rate inner strength but also to offer guidance as to the areas (i.e. dimensions) in which interventions may be profitable. It is further shown that inner strengths can be identified in narratives of older women. Mental ill health has shown to have overall the strongest association with weakened inner strength among community-dwelling older women. The causality can, though, not be studied due to the cross-sectional design; therefore, longitudinal studies are recommended. Notwithstanding that limitation, the findings can be used as a knowledge base in further research within this field.
|
|
| 32. |
- Boman, Niklas, 1984-
(författare)
-
Building muscle : a translation of training adaptation
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Training is preparation for what is expected to come through utilization of the plastic and resistive features of nature, known as adaptation. As such, training in humans may have a number of desired goals. These are typically related to sports performance or education. Whatever the goal, a plan needs to be made for reaching it. One needs to identify or select which activities and environments constitute the event or events to which adaptation is sought. Adaptations occurs by imposing something similar to said environment and practicing the selected activities in preparation for the events that can ultimately lead to goal fulfillment.One quite common goal of physical training is to achieve a more lean and muscular physique, be it for reasons of performance or esthetics. A leaner and more muscular physique can have many advantages for health and quality of life. If we are to prepare the body’s physical capabilities and properties, they should be utilized in the preparation. By proper design and execution of a program for physical preparation, we set out on the path to achieve the goal.A factor that is often highlighted as an important key to building muscle in the human body is the steroid hormone testosterone. According to the hormone hypothesis, increases in muscle mass are achieved through transient elevations in anabolic hormones, such as testosterone and IGF1, induced by physical training. To achieve hypertrophy of the muscles through physical training, one must ensure sure that the muscles get the correct signal, the growth signal, as a result of the training.The work presented in this thesis is, in part, an examination of the hormone hypothesis, with both empirical and theoretical elements. The empirical foundations are results of an experiment in which a group of young men were subjected to a program of physical training, designed for all intents and purposes in accordance with contemporary knowledge, to result in muscular hypertrophy in the subjects. The goal was achieved, with an average 4.6% increase in lean body mass in the subjects after the training program. However, there was no evidence that anabolic hormones were elevated at any time during the measurement period.The major part of this thesis details a model for explaining the collected observations. It is not intended to merely provide a guide for achieving a leaner more muscular physique but rather is aimed at formulating the problem of inducing the desired adaptations and difficulties involved in approaching the problem. For reasons discussed in this thesis, I do not claim that this is the full and final word on the matter. However, it goes some way toward explaining why, and perhaps how, desired goals should be formulated so that the muscles may understand them.
|
|
| 33. |
- Bonde, Mari, 1982-
(författare)
-
Structure and Function of the Borrelia burgdorferi Porins, P13 and P66
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Borrelia burgdorferi is an elongated and helically shaped bacterium that is the causal agent of the tick-borne illness Lyme disease. The disease manifests with initial flu-like symptoms and, in many cases, the appearance of a skin rash called erythema migrans at the site of the tick bite. If left untreated the disease might cause impairment of various organs such as the skin, heart, joints and the nervous system. The bacteria have a parasitic lifestyle and are always present within a host. Hosts are usually ticks or different animals and birds that serve as reservoirs for infection. B. burgdorferi are unable to synthesize building blocks for many vital cellular processes and are therefore highly dependent on their surroundings to obtain nutrients. Because of this, porins situated in the outer membrane, involved in nutrient uptake, are believed to be very important for B. burgdorferi. Except for a role in nutrient acquisition, porins can also have a function in binding extracellular matrix proteins, such as integrins, and have also been implicated in bacterial adaptation to new environments with variations in osmotic pressure.P13 and P66 are two integral outer membrane proteins in B. burgdorferi previously shown to have porin activities. In addition to its porin function, P66 also has integrin binding activity. In this thesis, oligomeric structures formed by the P13 and P66 protein complexes were studied using the Black lipid bilayer technique in combination with nonelectrolytes. Initial attempts were also made to study the structure of P13 in Nanodiscs, whereby membrane proteins can insert into artificial lipid bilayers in their native state and the structure can be analyzed by electron microscopy. In addition, the role of P13 and P66 in B. burgdorferi osmotic stress adaptation was examined and also the importance and role of the integrin-binding activity of P66 in B. burgdorferi infections in mice.Using Black lipid bilayer studies, the pore forming activity of P13 was shown to be much smaller than previously thought, exhibiting activity at 0.6 nS. The complex formed by P13 was approximately 300 kDa and solely composed of P13 monomers. The channel size was calculated to be roughly 1.4 nm. Initial Nanodisc experiments showed a pore size of 1.3 nm, confirming the pore size determined by Black lipid bilayer experiments. P66 form pores with a single channel conductance of 11 nS and a channel size of 1.9 nm. The porin assembles in the outer membrane into a large protein complex of 420 kDa, containing exclusively P66 monomers. The integrin-binding function of P66 was found to be important for efficient bacterial dissemination in the murine host but was not essential for B. burgdorferi infectivity. Neither P13 nor P66 had an active role in osmotic stress adaptation. Instead, two p13 paralogs were up-regulated at the transcript level in B. burgdorferi cultured under glycerol-induced osmotic stress.
|
|
| 34. |
- Borssén, Magnus, 1977-
(författare)
-
DNA methylation as a prognostic marker i acute lymphoblastic leukemia
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Most ALL cases originate from immature B-cells (BCP-ALL) and are characterized by reoccurring structural genetic aberrations. These aberrations hold information of the pathogenesis of ALL and are used for risk stratification in treatment. Despite increased knowledge of genetic aberrations in pediatric T-cell ALL (T-ALL), no reliable molecular genetic markers exist for identifying patients with higher risk of relapse. The lack of molecular prognostic markers is also evident in patients with relapsed ALL. During the last decades, aberrant epigenetic mechanisms including DNA methylation have emerged as important components in cancer development. Telomere maintenance is another important factor in malignant transformation and is crucial for long-term cell survival. Like DNA methylation, telomere length maintenance has also been implicated to reflect outcomes for patients with leukemia.In this thesis, the prognostic relevance of DNA methylation and telomere length was investigated in pediatric ALL at diagnosis and relapse. The telomere length (TL) was significantly shorter in diagnostic ALL samples compared to normal bone marrow samples collected at cessation of therapy, reflecting the proliferation associated telomere length shortening. Prognostic relevance of TL was shown in low-risk BCP-ALL patients where longer telomeres at diagnosis were associated with higher risk of relapse.Genome-wide methylation characterization by arrays in diagnostic T-ALL samples identified two distinct methylation subgroups denoted CIMP+ (CpG Island Methylator Phenotype high) and CIMP- (low). CIMP- T-ALL patients had significantly worse outcome compared to CIMP+ cases. These results were confirmed in a Nordic cohort treated according to the current NOPHO-ALL2008 protocol. By combining minimal residual disease (MRD) status at treatment day 29 and CIMP status at diagnosis we could further separate T-ALL patients into risk groups.Likewise, the CIMP profile could separate relapsed BCP-ALL patients into risk groups, where the CIMP- cases had a significantly worse outcome compared to CIMP+ cases. From these data we conclude that DNA methylation subgrouping is a promising prognostic marker in T-ALL, as well as in relapsed BCP-ALL two groups where reliable prognostic markers are currently missing. By elucidating the biology behind the different CIMP profiles, the pathogenesis of ALL will be further understood and may contribute to new treatment strategies.
|
|
| 35. |
- Boström, Gustaf
(författare)
-
Depression in older people with and without dementia : non-pharmacological interventions and associations between psychotropic drugs and mortality
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate associations between psychotropic drug use and death, associations between functional capacity, dependency in ADL and depression, and to evaluate a non-pharmacological intervention to reduce depressive symptoms, among older people with and without dementia.There is limited knowledge about the risk of death associated with psychotropic drug use among those aged ≥85 years, those with dementia, or those living in residential care facilities; groups that have a higher intake of psychotropic drugs and who are also more prone to adverse drug reactions. In a representative sample of people ≥85 years (n = 992), baseline antidepressant use was not associated with an increased 5-year mortality risk when adjusting for confounding factors. A significant interaction between gender and antidepressant use was found, with a higher mortality risk in women, than in men. When analyzing men and women separately, no significant associations were found. In a sample of older people (i.e. ≥65 years) with dementia (n = 1037), there was a significant gender difference in 2-year mortality associated with the baseline use of antidepressant drugs, with a lower mortality risk in men, than in women. In men, the mortality risk was significantly reduced with antidepressant use, while there was no significant association in women. The association between baseline use of benzodiazepines and mortality had a tendency toward an increased risk during the first year of follow-up, although this became non-significant after adjustments. In this time period, the interaction term for sex was significant, with a higher mortality risk among men than women. When the sexes were analyzed separately, no significant associations were found. No significant associations were found between baseline use of antipsychotic drugs and mortality.Drug treatment for depression seems to have a limited effect in older people and may have no effect in people with dementia. In order to find alternative ways of treating or preventing depression in older age, it is important to increase our knowledge about factors associated with this condition. Functional capacity and dependency in activities of daily living (ADL) are associated with depression in community-dwelling older people. However, it is uncertain whether the same associations are to be found in very old people (i.e. ≥80 years), including those with severe cognitive or physical impairments. In a heterogeneous sample (n = 392) with a high mean age, a large range of cognitive and functional capacity, a wide spectrum of dependency in ADL, and a high prevalence of comorbidities, depressive symptoms were significantly associated with functional balance capacity, but not with overall dependency in ADL. Among individual ADL tasks, dependency in transfer and dressing were associated with depressive symptoms.Physical exercise has shown effect sizes similar to those of antidepressants in reducing depressive symptoms among older people without dementia, with moderate–high-intensity exercise being more effective than low-intensity exercise. However, these effects are unclear among older people with dementia. Care-facility residents with dementia (n = 186) were cluster-randomized to a high-intensity functional exercise program or a non-exercise control activity conducted for 45 minutes every other weekday for 4 months. No significant difference between the exercise and control activity was found in depressive symptoms at 4 or 7 months. Among participants with high levels of depressive symptoms, reductions were observed in both the exercise and control groups at 4 and 7 months.In conclusion, ongoing treatment at baseline with any of the three psychotropic drug classes antidepressants, antipsychotics and benzodiazepines did not increase the risk of mortality in older people with dementia. Neither did antidepressant drugs in very old people. In both samples, gender differences were found in the mortality risk due to antidepressant use. In those with dementia, the mortality risk due to benzodiazepine use also differed by gender. The potential risk from initial treatment and gender differences regarding mortality risk require further investigation in randomized controlled trials or in large cohort studies properly controlled for confounding factors. In older people, living in community and residential care facilities, functional capacity seems to be independently associated with depressive symptoms whereas overall ADL performance may not be associated. Dependency in the individual ADL tasks of transfer and dressing appear to be independently associated with depressive symptoms and may be an important focus for future interdisciplinary multifactorial intervention studies. Among older people with dementia living in residential care facilities, a 4-month high-intensity functional exercise program has no superior effect on depressive symptoms than a control activity. Both exercise and non-exercise group activities may reduce high levels of depressive symptoms. However, this finding must be confirmed in three-armed randomized controlled trials including control groups receiving standard care.
|
|
| 36. |
- Bovinder Ylitalo, Erik, 1985-
(författare)
-
Molecular heterogeneity of prostate cancer bone metastasis
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Castration-resistant prostate cancer (CRPC) develops after androgen deprivation therapy of advanced PC, often with metastatic growth in bone. Patients with metastatic CRPC have very poor prognosis. Growth of CRPC, in most but not all patients, seems to involve androgen receptor (AR) activity, despite castrate levels of serum testosterone. Multiple mechanisms behind AR activation in castrated patients have been described, such as AR amplification, AR mutations, expression of constitutively active AR variants, and intra-tumoral steroid synthesis. However, other mechanisms beside AR activation are also involved and CRPC patients with tumors circumventing the need for AR stimulation will probably not benefit from AR targeting therapies but will need alternative treatments.Available treatments for CRPC are chemotherapy, AR antagonists or inhibition of androgen-synthesis. Novel drugs are constantly under development and several new therapies has recently been approved for clinical use. These include, in addition to new AR targeting therapies also immunotherapy, osteoclast inhibitors and bone-targeting radiopharmaceuticals. Due to heterogeneous mechanisms behind CRPC and that newly developed therapies are based on different mechanisms of action, there are reasons to believe that CRPC patients show different therapy responses due to diverse molecular properties of individual tumors. Although there are promising prospects, no biomarkers are used today for patient stratification into different treatments. Another important aspect is that, when effective, any therapy will probably induce tumor responses that subsequently cause further molecular diversities and alternative paths for development of tumor relapse and castration-resistance. Such mechanisms are important to understand in order to develop new treatment strategies.In this thesis, global gene expression and methylation patterns were studied in bone metastases obtained from PC patients going through metastasis surgery for spinal cord compression. Gene expression patterns were analyzed by multivariate statistics and ontology analysis with the aim to identify subgroups of biological/pathological relevance. Interesting findings from array analysis were verified using qRT-PCR and immunohistochemical analysis. In addition, a xenograft mouse model was used to study the effects of abiraterone (steroidogenesis inhibitor) and cabazitaxel (taxane), and subsequently developed resistance mechanisms in the 22Rv1 PC cell line expressing high levels of AR-V7; a constitutively active AR splice variant associated with a poor prognosis and resistance to AR targeting therapies.In summary, results showed that the majority of CRPC bone metastases were AR-driven, defined from high levels of AR-regulated gene transcripts, while a smaller sub-group was non-AR-driven (paper I). AR-driven bone metastases had high metabolic activity in combination with downregulated immune responses while non-AR-driven cases had a more pronounced immune response (paper I) and higher bone cell activity (paper II). Paper III identified pronounced hypermethylation in primary prostate tumors probably causing a suppressed anti-tumor immune-response whereas metastases showed a different methylation pattern related to increased AR activity and patient outcome. In paper IV, 22Rv1 xenografts showed poor response to abiraterone and initially excellent response to cabazitaxel, but eventually resistance occurred probably due to an upregulation of the ABCB1 transporter protein. Anti-androgens partly reversed the resistance.In conclusion, we have identified molecular heterogeneities in clinical bone metastases associated with biological characteristics, which could perhaps be used both for stratifying patients into treatment modalities, and to aid in further development of effective therapies for CRPC.
|
|
| 37. |
- Brunström, Mattias, 1988-
(författare)
-
Effect of antihypertensive treatment at different blood pressure levels
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundHigh blood pressure is associated with an increased risk of cardiovascular disease and premature death. The shape of association between blood pressure and the risk of cardiovascular events is debated. Some researchers suggest that the association is linear or log-linear, whereas others suggest it is J-shaped. Randomized controlled trials of antihypertensive treatment have been successful in hypertension, but ambiguous in the high normal blood pressure range. Previous systematic reviews have not found any interaction between baseline systolic blood pressure and treatment effect, with beneficial effects at systolic blood pressure levels well below what is currently recommended. These reviews, however, use a method to standardize treatment effects and study weights according to within-trial blood pressure differences that may introduce bias.MethodsWe performed two systematic reviews to assess the effect of antihypertensive treatment on cardiovascular disease and mortality at different blood pressure levels. The first review was limited to people with diabetes mellitus. The second review included all patient categories except those with heart failure and acute myocardial infarction. Both reviews were designed with guidance from Cochrane Collaborations Handbook for Systematic Reviews of Interventions, and are reported according to PRISMA guidelines. We included randomized controlled trials assessing any antihypertensive agent against placebo or any blood pressure targets against each other. Results were combined in random-effects meta-analyses, stratified by baseline systolic blood pressure. Non-stratified analyses were performed for coronary heart disease trials and post-stroke trials. Interaction between blood pressure level and treatment effect was assessed with Cochran’s Q in the first review, and multivariable-adjusted metaregression in the second review.The third paper builds on data from the second paper, and assesses the effect of standardization according to within-trial blood pressure differences on the results of meta-analyses. We performed non-standardized analyses, analyses with standardized treatment effects, and analyses with standardized treatment effects and standard errors. We compared treatment effect measures and heterogeneity across different methods of standardization. We also compared treatment effect estimates between fixed-effects and random-effects meta-analyses within each method of standardization. Lastly, we assessed the association between number of events and study weights, using linear regression.ResultsForty-nine trials assessed the effect of antihypertensive treatment in people with diabetes mellitus. Treatment effect on cardiovascular mortality and myocardial infarction decreased with lower baseline systolic blood pressure. Treatment reduced the risk of death and cardiovascular disease if baseline systolic blood pressure was 140 mm Hg or higher. If baseline systolic blood pressure was below 140 mm Hg, however, treatment increased the risk of cardiovascular death by 15 % (0-32 %).Fifty-one trials assessed the effect of antihypertensive treatment in primary prevention. Treatment effect on cardiovascular mortality, major cardiovascular events, and heart failure decreased with lower baseline systolic blood pressure. If baseline systolic blood pressure was 160 mm Hg or higher treatment reduced the risk of major cardiovascular events by 22 % (95 % confidence interval 13-30 %). If systolic blood pressure was 140-159 mm Hg treatment reduced the risk by 12 % (4-20 %), whereas if systolic blood pressure was below 140 mm Hg, treatment effect was neutral (4 % increase to 10 % reduction). All-cause mortality was reduced if systolic blood pressure was 140 mm Hg or higher, with neutral effect at lower levels.Twelve trials compared antihypertensive treatment against placebo in people with coronary heart disease. Mean baseline systolic blood pressure was 138 mm Hg. Treatment reduced the risk of major cardiovascular events by 10 % (3-16 %), whereas the effect on mortality was neutral (7 % increase to 11 % reduction).Standardization of treatment effects resulted in more extreme effect estimates for individual trials. This caused increased between-study heterogeneity, and different results with fixed- and random-effects model. Standardization of standard errors shifted weights from trials with many events to trials with large blood pressure differences. This caused biased overall effect estimates. Standardization of standard errors also resulted in wider confidence intervals, masking the previously increased heterogeneity. This reduced the possibility to find different treatment effects at different blood pressure levels.Conclusion The effect of antihypertensive treatment depends on blood pressure level before treatment. Treatment reduces the risk of death and cardiovascular disease if baseline systolic blood pressure is 140 mm Hg or higher. Below this level, treatment is potentially harmful in people with diabetes, has neutral effect in primary prevention, but might offer additional protection in people with coronary heart disease. Standardization should generally be avoided in meta-analyses of antihypertensive treatment. Previous meta-analyses using standardized methods should be interpreted with caution.
|
|
| 38. |
- Brynolfsson, Patrik, 1981-
(författare)
-
Applications of statistical methods in quantitative magnetic resonance imaging
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Magnetic resonance imaging, MRI, offers a vast range of imaging methods that can be employed in the characterization of tumors. MRI is generally used in a qualitative way, where radiologists interpret the images for e.g. diagnosis, follow ups, or assessment of treatment response. In the past decade, there has been an increasing interest for quantitative imaging, which give repeatable measurements of the anatomy. Quantitative imaging allows for objective analysis of the images, which are grounded in physical properties of the underlying tissues. The aim of this thesis was to improve quantitative measurements of Dynamic contrast enhanced MRI (DCE-MRI), and the texture analysis of diffusion weighted MRI (DW-MRI).DCE-MRI measures perfusion, which is the delivery of blood, oxygen and nutrients to the tissues. The exam involves continuously imaging the region of interest, e.g. a tumor, while injecting a contrast agent (CA) in the blood stream. By analyzing how fast and how much CA leaks out into the tissues, the cell density and the permeability of the capillaries can be estimated. Tumors often have an irregular and broken vasculature, and DCE-MRI can aid in tumor grading or treatment assessment. One step is crucial when performing DCE-MRI analysis, the quantification of CA in the tissue. The CA concentration is difficult to measure accurately due to uncertainties in the imaging, properties of the CA, and physiology of the patient. Paper I, the possibility of using two aspects of the MRI data, phase and magnitude, for improved CA quantification, is explored. We found that the combination of phase and magnitude information improved the CA quantification in regions with high CA concentration, and was more advantageous for high field strength scanners.DW-MRI measures the diffusion of water in and between cells, which reflects the cell density and structure of the tissue. The structure of a tumor can give insights into the prognosis of the disease. Tumors are heterogeneous, both genetically and in the distribution of cells, and tumors with high intratumoral heterogeneity have poorer prognosis. This heterogeneity can be measured using texture analysis. In 1973, Haralick et al. presented a texture analysis method using a gray level co-occurrence matrix, GLCM, to gauge the spatial distribution of gray levels in the image. This method of assessing texture in images has been successfully applied in many areas of research, from satellite images to medical applications. Texture analysis in treatment outcome assessment is studied in Paper II, where we showed that texture can distinguish between groups of patients with different survival times, in images acquired prior to treatment start.However, this type of texture analysis is not inherently quantitative in the way it is calculated today. This was studied in Paper III, where we investigated how texture features were affected by five parameters related to image acquisition and pre-processing. We found that the texture feature values were dependent on the choice of these imaging and preprocessing parameters. In Paper IV, a novel method for calculating Haralick texture features was presented, which makes the texture features asymptotically invariant to the size of the GLCM. This method allows for comparison of textures between images that have been analyzed in different ways.In conclusion, the work in this thesis has been aimed at improving quantitative analysis of tumors using MRI and texture analysis.
|
|
| 39. |
- Bråndal, Anna, 1966-
(författare)
-
Rehabilitation after stroke with focus on early supported discharge and post-stroke fatigue
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Stroke is a major cause of disability worldwide. After treatment in a specialized stroke unit, early supported discharge (ESD) followed by home rehabilitation has shown to be an effective way to improve patient outcome and quality of care for persons with mild to moderate stroke. ESD service is recommended in the national and international guidelines for stroke care, but has only partially been implemented in Sweden. Following stroke, fatigue is a common consequence that often becomes more evident when the patient comes home. Currently, there is insufficient evidence about how to measure, treat and handle post-stroke fatigue. The overall aim of this thesis was to evaluate and implement early supported discharge (ESD) based on stroke patients experience after discharge from the stroke unit and local conditions. The aim was also to evaluate post-stroke fatigue with a potentially valid and reliable scale and finally to prepare for a study to evaluate cardiorespiratory training as a part of ESD service for patients with post-stroke fatigue.Methods In paper I, nine strategically chosen patients were interviewed of their experience of falling ill, the hospital stay, discharge, contact with health care after discharge and their request of support. Papers II-III describe and evaluate the development, content, implementation and effects of a locally adopted method for early supported discharge (Umeå Stroke Center ESD) in modern stroke care. Paper II included 153 consecutive patients and paper III, 30 232 patients with first-ever stroke registered in the Riksstroke registry in Sweden. Paper II evaluated number of patients/year, clinical and functional health status, satisfaction in relation to needs, accidental falls/other injuries and resources with the result summarized in a value compass. The implementation process was evaluated retrospectively by means of Consolidated Framework for Implementation (CFIR). Paper III evaluated patient reported outcome measurements (PROMs) at 3 months. The primary outcome in paper III was satisfaction with the rehabilitation after discharge. Secondary outcomes were information about stroke provided, tiredness/fatigue, pain, dysthymia/depression, general health status and dependence in activities of daily living (mobility, toilet hygiene and dressing). Multivariable logistic regression models for each PROM was used to analyze associations between PROMs and ESD/no ESD. In Paper IV, the Fatigue Assessment scale (FAS) was translated into Swedish and evaluated regarding psychometric properties when self-administered by persons with mild to moderate stroke. 72 consecutively patients selected from the stroke unit admission register received a letter including three questionnaires: the FAS, the Short Form Health Survey (SF-36) subscale for vitality and the Geriatric Depression Scale GDS-15. A second letter with FAS was sent within 2 weeks, for re-test evaluation. Paper V is a study protocol for a planned randomized controlled trial (RCT) of 50 consecutive stroke patients will who receive stroke unit care followed by ESD-service at Umeå Stroke Center, University Hospital, Umeå, Sweden. Paper V will investigate if a structured cardiorespiratory interval training program (CITP) added to the ESD-service may result in relieved post-stroke fatigue and increased oxygen uptake.Results The interviews in Paper I revealed three main categories with subcategories: “Responsible and implicated”, “Depersonalized object for caring measures” and “The striving for repersonalization and autonomy”. The findings indicate that coming home gave the informants’ important insights and understanding of the stroke, its consequences and was also an important factor for the recovery. Paper II-III showed that it is possible to develop and implement an adapted ESD service for stroke patients based on the patients’ experiences and requests, evidence-based recommendations and local conditions. The ESD service reduced dependence of activity, increased mobility with seemingly no increased risk of accidental falls or other injuries. The patient satisfaction in relation to needs regarding the ESD was high. Paper III showed that patients that received ESD were more satisfied with rehabilitation after discharge, had less need for assistance with ADL and less dysthymia/depression compared to patients that did not receive ESD. Study IV showed that the Swedish FAS used at home as a selfadministered questionnaire is a reliable and valid questionnaire for measuring fatigue in persons with mild to moderate stroke. The internal consistency was good, the agreement between the test and retest reliability for individual items (weighted kappa) was for the majority of items good or moderate. The relative reliability for total scores was good and the absolute reliability was 9 points. The Swedish FAS had no floor nor ceiling effects and correlated both with the SF-36, subscale for vitality and the GDS-15 indicating convergent construct validity, but not divergent construct validity.Conclusion It is possible to develop and implement ESD care for stroke patients based on patients’ experience and needs, evidence-based principles and local conditions. Early supported discharge (ESD) in the setting of modern stroke unit care appears to have positive effects on rehabilitation in the subacute phase. The Swedish FAS used at home as a self-administered questionnaire is reliable and valid for measuring fatigue in persons with mild to moderate stroke.
|
|
| 40. |
- Buckland, Robert, 1976-
(författare)
-
DNA precursor asymmetries, Mismatch Repair and their effect on mutation specificity
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In order to build any structure, a good supply of materials, accurate workers and quality control are needed. This is even the case when constructing DNA, the so-called “Code of Life.” For a species to continue to exist, this DNA code must be copied with incredibly high accuracy when each and every cell replicates. In fact, just one mistake in the 12 million bases that comprise the genome of budding yeast, Saccharomyces cerevisiae, can be fatal. DNA is composed of a double strand helix made up of just four different bases repeated millions of times. The building blocks of DNA are the deoxyribonucleotides (dNTPs); dCTP, dTTP, dATP and dGTP. Their production and balance are carefully controlled within each cell, largely by the key enzyme Ribonucleotide Reductase (RNR). Here, we studied how the enzymes that copy DNA, the replicative polymerases α, δ and ε, cope with the effects of an altered dNTP pool balance. An introduced mutation in the allosteric specificity site of RNR in a strain of S. cerevisiae, rnr1-Y285A, leads to elevated dCTP and dTTP levels and has been shown to have a 14-fold increase in mutation rate compared to wild type. To ascertain the full effects of the dNTP pool imbalance upon the replicative polymerases, we disabled one of the major quality control systems in a cell that corrects replication errors, the post-replicative Mismatch Repair system. Using both the CAN1 reporter assay and whole genome sequencing, we found that, despite inherent differences between the polymerases, their replication fidelity was affected very similarly by this dNTP pool imbalance. Hence, the high dCTP and dTTP forced Pol ε and Pol α/δ to make the same mistakes. In addition, the mismatch repair machinery was found to correct replication errors driven by this dNTP pool imbalance with highly variable efficiencies. Another mechanism to protect cells from DNA damage during replication is a checkpoint that can be activated to delay the cell cycle and activate repair mechanisms. In yeast, Mec1 and Rad53 (human ATR and Chk1/Chk2) are two key S-phase checkpoint proteins. They are essential as they are also required for normal DNA replication and dNTP pool regulation. However the reason why they are essential is not well understood. We investigated this by mutating RAD53 and analyzing dNTP pools and gene interactions. We show that Rad53 is essential in S-phase due to its role in regulating basal dNTP levels by action in the Dun1 pathway that regulates RNR and Rad53’s compensatory kinase function if dNTP levels are perturbed.In conclusion we present further evidence of the importance of dNTP pools in the maintenance of genome integrity and shed more light on the complex regulation of dNTP levels.
|
|
