Background: In research, patient participation in medical decision-making has been shown to be associated with higher patient satisfaction and improvement of treatment outcomes. But when it comes to patient participation when being old and frail there are pitfalls and the research in this area is sparse. The aim of this thesis is to explore participation in medical decision making of the frail elderly patient in hospital from the perspectives of patients themselves and the health care staff. In this thesis frail, elderly patients is defined as individuals 75 years old or older, who during the past 12 months have received inpatient hospital care three or more times and who have three or more diagnoses in three or more diagnostic groups according to the classification system ICD-10. The participants were frail patients’ in hospital or newly discharged and it was health care personnel working with frail elderly patients. In three of the studies the method was mainly qualitative (Paper I, III, IV) and in one (Paper II) quantitative. The qualitative methods were one-to-one tape-recorded interviews of 25 patients (Paper I and IV), 18 personnel (III and IV), 5 focus group interviews of physicians (Paper III) and 26 days of observations in hospital wards (IV). Chosen methodologies of analysis were content analysis and Grounded Theory. The quantitative study (II) was a cross-sectional survey using telephone interviews with patients (n= 156). This material was descriptively analysed and examined using weighted kappa statistics. Results: The results reported in Paper II show that elderly patients generally want to participate more in medical decision making than they do, though preferences for degree of participation are highly individualized – both findings important to consider in clinical practice. According to the patients important key concepts of patient participation in medical decision making are to be listened to and to be informed (Paper I). The main reasons for not being able to participate included having many illnesses and generally, overall bad medical condition (Paper II). Also, cited as a problem was difficulty in understanding medical information, for example when given by a foreign-speaking physician (Paper I, II and IV). Frail, elderly patients complained that they were less informed than was their preference (Paper I, II and IV). Moderate agreement was obtained between patient’s preferred and actual roles in medical decision making. Patients often expressed gratitude and confidence in their health care (Paper I and IV), but also, sympathy for stressed health care personnel who had so much to do. The frail elderly patients do sometimes feel like a burden to the health care (Paper I and IV). The professionals gave expressions of trying to avoid taking care of frail elderly patients and at the same time expressions of frustration and bad conscience not being able to take good care of them due to lack of time and lack of beds (Paper III, IV). Especially the physicians felt they were trapped between the needs of the patients’ and the remunerations system rewarding time-constricted health care production (number of investigations, operations, easy accessibility) – not a time-consuming holistic view on all illnesses and medications including communication with the patients and all caregivers involved (Paper III). Both patients and the professionals perceive the hospital as some kind of “institution of power”, difficult to challenge, and the decisions of which one has to accept. Conclusion: In this thesis there are shown a number of challenges to participation in medical decision making by frail, elderly patients, which thus limits quality of care for this patient group. Health care is revealed as not well adapted to meet these patients’ complex needs. A model is presented that explains how the organisation of health care, and the reimbursement system, does not facilitate a holistic view. The health care professionals appear to adapt to the organisation and the remuneration system, which leads to practices, such as, rapid discharges and a tendency to examine the patient for only one or a few problems. Finally a suggestion for a model to improve care of frail elderly patients is presented. This model includes the need of more hospital wards being able to work with a holistic view, better skills in gerontology and geriatrics and a more adapted remuneration system for the frail, elderly patients.

Acute myeloid leukemia (AML) is a severe disease, which originates in blood-forming cells. Although major advances in understanding the biology of AML, the majority of patients eventually succumb to the disease. The tyrosine kinase receptor FLT3 has become an attractive therapeutic target AML for two major reasons; 1) It is one of the most frequently mutated genes in AML (about 30%). 2) Most of these mutations (FLT3-ITDs) correlate with an increased risk of relapse and poor overall survival. Small targeting inhibitors towards FLT3 have been designed and evaluated in clinical trials. However, the experiences from clinical trials are that drug resistance develops in a substantial number of patients. To overcome these resistance-associated problems it its important to improve the understanding of how FLT3 mutations function and how they respond to targeting drugs. This was addressed in this thesis by elucidating FLT3-ITD cell transformation mechanisms, identifying key downstream target molecules of mutated FLT3 and exploring the effect of various targeting inhibitors. The major finding of my thesis is that FLT3-targeting drugs elicit apoptosis through a FOXO3a-dependent upregulation of proapoptotic BH3-only protein Bim via inactivation of the PI3K/AKT signaling pathway. Furthermore, we have identified an interesting apoptotic mechanism, linked to increased ROS levels caused by expressing hyperactivated AKT in hematopoietic stem cells and bone marrow progenitor cells from FLT3-ITD transgenic mice. These findings are interesting from a therapeutic point of view. We have also shown that canertinib, an inhibitor of the ERBB receptor family, targets mutated FLT3 in vitro and in vivo. The irreversible binding mechanism of canertinib, as well as its multikinase activity, is attractive features. Overall, the results presented herein could provide basis for future directions in treatment of FLT3 mutant positive AML patients. Finally, we studied nine different FLT3-ITD mutations ranging in length from 6-33 amino acids. Data from this study suggest that different FLT3-ITDs may induce distinct degrees of transformation and that they respond differentially to FLT3-targeting drugs. These differences were not associated with size of the duplication but rather the mutational composition. In conclusion, this thesis explores the biologic features of FLT3 mutations and therapeutic targeting opportunities.

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Introduktion: Hälsa är hos människan något ursprungligt och naturligt. För att främja befolkningens hälsa görs ett så kallat hälsofrämjande och förebyggande arbete. Distriktssköterskan är en av de professioner som har i uppdrag att arbeta hälsofrämjande. Syfte: Studiens syfte var att undersöka distriktssköterskans hälsofrämjande arbete på vårdcentral. Metod: Studien genomfördes med kvalitativ metod. Tio distriktssköterskor, verksamma inom offentliga vårdcentraler, intervjuades med hjälp av en semistrukturerad intervjuguide. Data analyserades utifrån en modifierad variant av kvalitativ innehållsanalys enligt Graneheim och Lundman. Resultat: Distriktssköterskans hälsofrämjande arbete på vårdcentral presenteras i form av tre kategorier: Att se helheten i mötet med patienten, Att använda olika verktyg och Hälsofrämjande arbete i glesbygd. Konklusion: Distriktssköterskan betraktar det hälsofrämjande arbetet som en naturlig del i sitt yrkesutövande. Mötet med patienten och att samtala är distriktssköterskans centrala uppgift. Samarbete med andra professioner främjar hälsan för patienten. Genom att arbeta med en mer konsekvent uppföljning samt utveckling av riktlinjer kan ett mer strukturerat arbetssätt skapas. Detta arbetssätt skulle kunna bidra till att distriktssköterskans hälsofrämjande arbete blir mer effektivt.