Background In patients with diabetes mellitus (DM) or chronic kidney disease (CKD), established cardiovascular disease (CVD) is associated with an increased risk of recurrent events and poor outcome. Ischemic stroke after an acute myocardial infarction (AMI) is a devastating event that carries high risks of decreased patient independence and death. Among patients with DM or CKD, the risk of an ischemic stroke within a year following an AMI is not known. Improved risk factor control is required to reduce the likelihood of CVD recurrence. Guidelines recommend target lipid profile and blood pressure values; however, data show that these targets are often not met. Therefore, there remains an urgent need for improved cardiovascular secondary preventive follow- up. Aims The aims of the present studies were to define trends in the incidence and predictors of ischemic stroke after an AMI in patients with DM or CKD. Furthermore to assess whether secondary preventive follow-up with nurse-based telephone follow-up including medication titration after CVD improves risk factor values in patients with DM or CKD and to investigate if this method performs better than usual care to implement a new treatment guideline in diabetic patients. Methods To assess the risk of post-AMI ischemic stroke, patient data were obtained from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). In separate studies, we compared a total of 173 233 AMI patients with and without DM, and 118 434 AMI patients with and without CKD. Within the nurse-based age-independent intervention to limit evolution of disease (NAILED) trial, we investigated a nurse-based cardiovascular secondary preventive follow-up protocol. Patients with acute coronary syndrome, stroke, or transient ischemic attack were randomized to receive either nurse-based telephone follow-up (intervention) or usual care (control). Low-density lipoprotein (LDL-C) levels and blood pressure (BP) were measured at 1 month (baseline) and 12 months post- discharge. Intervention patients with above-target baseline values received medication titration to achieve treatment goals, while the measurements for control patients were forwarded to their general practitioners for assessment. We calculated the changes in LDL-C level and BP between baseline and 12 months post-discharge, and compared  these changes between 225 intervention patients and 215 control patients with concurrent DM or CKD. During the course of the NAILED trial, new secondary preventive guidelines for DM patients were released, including a new LDL-C target value. To assess adherence to the new guidelines within the NAILED trial, we compared LDL-C levels in the 101 intervention patients and 100 control patients with DM. Results Ischemic stroke after AMI The rates of ischemic stroke within one-year after admission for an AMI decreased over time, from 7.1% in 1998–2000 to 4.7% in 2007–2008 among DM patients, and from 4.2% to 3.7% during the same time periods for non-diabetic patients. Lower stroke risk was associated with percutaneous coronary intervention (PCI) and initiation of secondary preventive treatments in-hospital. In-hospital ischemic stroke occurred in 2.3% of CKD patients and 1.2% of non-CKD patients, with no change in these incidences over time. The rates of one-year post- discharge ischemic stroke decreased between 2003–2004 and 2009–2010 from 4.1% to 2.5% among CKD patients, and from 2.0% to 1.3% among non-CKD patients. Lower rates of post-discharge stroke were associated with PCI and statins. Cardiovascular secondary preventive follow-up Among DM and CKD patients with above-target baseline values in the NAILED trial, the median LDL-C value at 12 months was 2.2 versus 3.0 mmol/L (p<0.001) and median systolic BP was 140 versus 145 mmHg (p=0.26) for intervention and control patients, respectively. Before the guideline change, 96% of the intervention and 70% of the control patients reached the target LDL-C value (p<0.001). After the guideline change, the corresponding respective proportions were 65% and 36% (p<0.001). Conclusion Ischemic stroke is a fairly common post-AMI complication among patients with DM and CKD. This risk of stroke has decreased during recent years, possibly due to the increased use of evidence-based therapies. Compared with usual care, cardiovascular secondary prevention including nurse-based telephone follow-up improved LDL-C values at 12 months after discharge in patients with DM or CVD, and led to more efficient implementation of new secondary preventive guidelines.

This thesis analyses the fabled public exchange of letters that occurred between political theorist Hannah Arendt and historian of Jewish religion Gershom Scholem in 1964 following the historic trial of Adolf Eichmann and Arendt's subsequent publication of her report of the event, Eichmann in Jerusalem. The thesis covers the historical issues that form the contextual background to the exchange. It involves the introduction of the two participants as defining Jewish intellectuals of the past century, the course of the trial itself and the political and ideological problems it entailed as well as the turbulent history of the reception of Arendt's book. It is down to these four factors that guaranteed the eminence of the exchange of letters analysed in the thesis. Oft-quoted as the exchange is, there has been no proper analysis of it to this date. To accomplish this task, the thesis adopts the theoretical-methodological framework of discourse analysis in general, and the version of rhetorically oriented discursive psychology, proposed mainly in the publications of Potter and Wetherell (1987) and Billig (1996), in particular. This approach allows the thesis to provide a fine-grained analysis of the various ways of textual construction. Firstly, the ways examined concern the significance, worth and value of the debate itself, as formulated by both of the participants. Secondly, they involve the construction of the attempt to establish definite versions of the content of the book. Thirdly, they cover the textual acts of accounting for that content, or the practice of misinterpretation of that content, respectively. What all these three aspects have in common is the positioning of the problems touched upon in a moral and political context, and ultimately approaching them in terms of the identities of the participants. In this sense, versions of the events and ways of accounting for it will not only aim at producing accurate descriptions of events but in the forms of an implied morality or politics an implied "action-plan" for the future as well. The construction of Arendt and Scholem is, hence, analysed in terms of its argumentative organisation in order to undermine the other's counterversion and to establish its own as the definite one. While, structurally, there are many similarities in the two letters, what distinguishes them is that they conceive of their objects (i.e. the text), subject positions, and political or moral values according to which they should be assessed in quite diametrically opposite ways. This thesis not only registers the various rhetorical ways the participants fashion their versions as definite ones, but also accounts for the differences in their contents.

Background: Although physical inactivity has been linked with numerous chronic health conditions and overall mortality, the majority of English adults report insufficient physical activity. To increase population physical activity levels, researchers have called for more community-level interventions. To evaluate these complex public health interventions, innovative study designs are required. The aim of this thesis was to evaluate whether a community-level physical activity intervention—‘Devon Active Villages’—increased the activity levels of rural communities. Methods: The Devon Active Villages intervention provided villages with 12 weeks of physical activity opportunities for all age groups. Community engagement helped tailor activity programmes for each village; communities were then supported for a further 12 months. 128 rural villages from south-west England were randomised to receive the intervention in one of four time periods, as part of a stepped wedge cluster randomised controlled trial. Data collection consisted of a postal survey of a random sample of adults (≥18 years), at baseline, and after each of the four intervention periods. The primary outcome of interest was the proportion of adults who reported sufficient physical activity to meet the current guidelines (≥150mins of moderate-and-vigorous, or ≥75mins of vigorous-intensity activity per week). The number of minutes spent in moderate-and-vigorous activity per week was analysed as a secondary outcome. Using data from all five periods, a comparison of study outcomes between intervention and control arms was performed, allowing for time period (as a fixed effect), and the random effect induced by correlation of outcomes (clustering) within villages. Additionally, the baseline data were analysed separately using logistic and linear regression models to examine the correlates of physical activity behaviour in rural adults. Results: Baseline study: 2415 adults completed the postal survey (response rate 37.7%). The following factors both increased the odds of meeting the recommended activity guidelines and were associated with more leisure-time physical activity: being male, in good health, greater commitment to being more active, favourable activity social norms, greater physical activity habit, and recent use of recreational facilities. In addition, there was evidence that younger age, lower body mass index, having a physical occupation, dog ownership, inconvenience of public transport, and using recreational facilities outside the local village were associated with greater reported leisure-time physical activity. Main study: 10,412 adults (4693 intervention, 5719 control) completed the postal survey (response rate 32.2%). The intervention did not increase the odds of adults meeting the physical activity guideline, although there was weak evidence of an increase in the minutes of moderate-and-vigorous-intensity activity per week. The ineffectiveness of the intervention may have been due to its low penetration—only 16% of intervention participants reported being aware of the intervention, and just 4% reported participating in intervention events. Conclusions: Baseline study: This study highlights potentially important correlates of physical activity that could be the focus of interventions targeting rural populations, and demonstrates the need to examine rural adults separately from their urban counterparts. Main study: A community-level physical activity intervention providing tailored physical activity opportunities to rural villages did not improve physical activity levels in adults. Greater penetration of such interventions needs to be achieved for them to have any chance of increasing the prevalence of physical activity at the community level.

Background Patients who experience a stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke, but little is known about temporal trends in unselected populations. Reports of low adherence to recommended treatments indicate a need for enhanced secondary preventive follow-up to achieve the full potential of evidence-based treatments. In addition, socioeconomic factors have been associated with poor health outcomes in a variety of contexts. Therefore, it is important to assess the implementation and results of secondary prevention in different socioeconomic groups. Aims The aims of this thesis were to assess temporal trends in ischemic stroke recurrence and evaluate the implementation and results of a nurse-led, telephone-based follow-up program to improve blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels after stroke/TIA. Methods In study I, we collected baseline data for unique patients with an ischemic stroke event between 1998 and 2009 (n=196 765) from the Swedish Stroke Register (Riksstroke). Recurrent ischemic stroke events within 1 year were collected from the Swedish National Inpatient Register (IPR) and the cumulative incidence was compared between four time periods using the Kaplan-Meier survival analysis and the logrank test. Implementation (study II) and 1-year results (study III-IV) for the secondary preventive follow-up were studied in the NAILED (Nurse-based Age-independent Intervention to Limit Evolution of Disease) study. Between 1 Jan 2010 and 31 Dec 2013, the baseline characteristics of consecutive patients admitted to Östersund Hospital for acute stroke or TIA were collected prospectively (n=1776). Consenting patients in a condition permitting telephone-based follow-up were randomized to nurse-led, telephone-based follow-up or follow-up according to usual care. Follow-up was cunducted at 1 and 12 months after discharge and the intervention included BP and LDL-C measurements, titration of medication, and lifestyle counseling. In study II, we analyzed factors associated with non-participation in the randomized phase of the NAILED study, including association with education level. In addition, we compared the 1-year prognosis in terms of cumulative survival between participants and non-participants. In study III, we compared differences in BP and LDL-C levels between the intervention and control groups during the first year of follow-up and, in study IV, in relation to level of education (low, ≤10 years; high, >10 years). Results The cumulative 1-year incidence of recurrent ischemic stroke decreased from 15.0% to 12.0%. Among surviving stroke and TIA patients, 53.1% were included for randomization, 35.7% were excluded mainly due to physical or cognitive disability, and 11.2% declined participation in the randomized phase. A low level of education was independently associated with exclusion, as well as the patient’s decision to abstain from randomization. Excluded patients had a more than 12-times higher risk of death within 1 year than patients who were randomized. After 1 year of follow-up, the mean systolic BP, diastolic BP, and LDL-C levels were 3.3 mmHg (95% CI 0.3 to 6.3), 2.3 mmHg (95% CI 0.5 to 4.2), and 0.3 mmol/L (95% CI 0.1 to 0.4) lower in the intervention group than among controls. Among participants with values above the treatment goal at baseline, the differences in systolic BP and LDL-C levels were more pronounced (8.0 mmHg, 95% CI 4.0 to 12.1; 0.6 mmol/L, 95% CI 0.4 to 0.9). In the intervention group, participants with a low level of education achieved similar or larger improvements in BP and LDL-C than participants with a high level of education. In the control group, BP remained unaltered and the LDL-C levels increased among participants with a low level of education. Conclusion The 1-year risk of ischemic stroke recurrence decreased in Sweden between 1998 and 2010. Nurse-led, telephone-based secondary preventive follow-up is feasible in just over half of the survivors of acute stroke and TIA and achieve better than usual care in terms of BP and LDL-C levels, and equality in BP improvements across groups defined by education level. However, a large proportion of stroke survivors are in a general condition precluding this form of follow-up, and their prognosis in terms of 1-year survival is poor. Patients with a low education level are over-represented within this group and among patients declining randomization for secondary preventive follow-up.

Bakgrund: Placebo finns i en mängd olika former, allt från läkemedel till manipulation av utrsutning. Hur placebo fungerar i kroppen är svårt att fastslå, trots detta har positiva effekter påvisats genom minskad kronisk smärta (Finnis et al., 2010), sömnlöshet (Belanger et al., 2007) och depression (Kirsch et al., 2008). Tidigare studier visar även att styrkelyftare ökar sin maximala styrka med hjälp av placebo. Metod: Studien är en cross-over experimentell design där totalt 19 deltagare medverkat. Två stycken kapslar, en på 300 mg och en större på 450 mg används för att se skillnader i ett trial making test och ett beeptest. Syftet med studien är att undersöka och kvantifiera placeboeffekten. Studien baseras på hypotsen att priset på, och mängden av ett placebopreparat påverkar resultatet i ett test för fysisk prestation (beeptest) och i ett test som mäter koncentrationsförmågan (Trial making test). Resultat: Trial making test del a visade ingen signifikant skillnad mellan kapsel a och kapsel b (p=0,699). Trial making test del b rapporterade inte någon signifikant skillnad mellan kapsel a och b (p=0,161). Vid beeptestet rapporterades det även här ingen signifikant skillnad mellan kapsel a och b (p=0.839). Slutsats: Det är svårt att dra en slutsats om vi lyckats övertala deltagarna tillräckligt för att bevisa att en placeboeffekt påverkar resultatet i ett beeptest och i ett trial making test. En annan fråga vi ställer oss är om beeptestet är rätt val av test för att testa placebons effekt eftersom mycket runt omkring kan ha påverkat deltagarna, exempelvis av varandra och hur de presterar. Detta är något som vi tror kan ha påverkat resultatet.

Infertility is a frequently occurring chronic health condition, which often persists throughout the reproductive years. Heightened anxiety symptoms often are comorbid with infertility diagnoses. Women experiencing infertility, and particularly those with anxiety symptoms, characterize an emerging population that deserves special attention. However, women experiencing infertility have identified barriers to seeking psychotherapy (e.g., fears of being dismissed from fertility treatment and/or stigmatized). Consequently, women diagnosed with infertility need a psychotherapy that not only can reduce these symptoms, but can also be private and convenient. The current study translated an empirically tested in-person mind/body protocol into an internet-based intervention to suit the needs of this population. Seventy-one women were randomly assigned to the intervention or a wait-list control. At the close of the study, only three participants had completed the intervention. At mid-assessment, relative to the wait-list group, the intervention group had a lower level of depressive symptoms and, for those with elevated anxiety symptoms at baseline, a lower level of anxiety symptoms. The findings suggest that even a partially completed internet-based intervention can reduce the anxiety and depressive symptoms of women with a diagnosis of infertility.

Insofar as forgiveness of oneself enables one to responsibly manage the consequences of wrongdoing, the practice of self-forgiveness may be essential to the preservation of one’s physical, psychological, relational, and spiritual health. In the present thesis, an intervention wait-list design was employed to investigate the efficacy of a 6-hour self-directed workbook designed to promote self-forgiveness. University students (N = 204) who reported perpetrating an interpersonal offense and who experienced some sense of remorse were randomly assigned to either an immediate treatment or wait-list control condition, and assessments were administered on three occasions. Participants’ self-forgiveness ratings increased in conjunction with completion of the workbook, and the effect of treatment depended upon self-administered dose and baseline levels of dispositional self-compassion in some cases. In summary, the workbook appeared to facilitate the process of responsible self-forgiveness among perpetrators of interpersonal wrongdoing, though replication trials are needed in which lower rates of attrition reduce the possibility of biased results.

First-in-man (FIM) Phase I clinical trials are part of the critical path in the development of a new compound entity (NCE). Since FIM clinical trials are the first time that an NCE is dosed in human subjects, the designs used in these trials are unique and geared toward patient safety. We develop a method for obtaining the desired response using an adaptive non-linear approach. This method is applicable for studies in which MTD, NOEL,NOAEL, PK, PD effects or other such endpoints are evaluated to determine the desired dose. The method has application whenever a measurable PD marker is an indicator of potential efficacy and could be particularly useful for dose finding studies. The advantages in the adaptive non-linear methodology is that the actual range of dose response and lowest non-effective dose levels are more quickly and accurately determined using fewer subjects than typically needed for a conventional early phase clinical trial. Using the nonlinear logistic model, we demonstrate, with simulations, that the DOSEFIND approach has better asymptotic relative efficiency than a fixed-dose approach. Further, we demonstrate that, on average, this method is consistent in reproducing .the target dose, that it has very little bias. This is an indicator of reproducibility of the method, showing that the long-run average error is quite small. Additionally, DOSEFIND is more cost effective because the sample size needed to obtain the desired target dose is much smaller than that needed in the fixed dose approach.

Classical phase II trial designs assume a patient population with a homogeneous tumor type and yield an estimate of a stochastic probability of tumor response. Clinically, however, oncology is moving towards identifying patients who are likely to respond to therapy using tumor subtyping based upon predictive markers. Such designs are called targeted designs (Simon, 2004). For a given phase I1 trial predictive markers may be defined prospectively (on the basis of previous results) or identified retrospectively on the basis of analysis of responding and non-responding tumors. For the prospective case we propose two Phase I1 targeted designs in which a) the trial is powered to detect the presence of responding subtype(s) as identified either prospectively or retrospectively by predictive markers or b) the trial is powered to achieve a desired precision in the smallest subtype. Relevant parameters in such a design include the prevalence of the smallest subtype of interest, the hypothesized response rate within that subtype, the expected total response rate, and the targeted probabilities of type I and II errors (α and β). (The expected total response rate is needed for design a) but not for b)). Extensions of this design to simultaneous or sequential multiple subtyping and imperfect assays for predictive markers will also be considered. The Phase II targeted design could be formulated as a single stage or Simon two-stage design. For multiple subtyping corrections to the significance level will be considered. Sample size calculations for different scenarios will be presented. An implication of this approach is that Phase II trials based upon classical designs are too small. On the other hand, trials involving "reasonable" numbers of patients must target relatively high threshold response rates within tumor subtypes. For the retrospective case we will provide the power to detect desired rates in the subtypes and provide the sample sizes required to achieve desired power. Retrospective analysis has the advantages that the analysis can be "supervised" by grouping responding and non-responding tumors; and multiple hypotheses, including hypotheses not formulated at the time of trial design, can be tested.

The goal of this escalating single-dose phase I research study was to determine the safety, tolerability, pharmacokinetics, pharmacodynamics as well as in vitro metabolism and plasma protein binding of MS-275, a novel histone deacetylase inhibitor, in patients with solid tumors and lymphomas. A validated LC/MS assay was developed to quantitate MS-275 in plasma, human liver microsomes and urine. The pharmacokinetic (PK) evaluation was done using a non-compartmental approach. In-vitro plasma protein binding profile of MS-275 was characterized by a validated micro-equilibrium dialysis method. In vitro phase I and phase II hepatic metabolism of MS-275 were evaluated using human liver microsomes. A correlative covariate analysis was performed in an effort to explain the wide inter-individual variability among patients.Results from the study demonstrate that the validated LC-MS assay is specific, accurate, precise and sensitive. MS-275 demonstrates a substantial inter-individual PK variability in systemic exposure and clearance; exposures increase in near-proportion, while peak concentrations increase more than-proportionally with an increase in dose. Mean apparent oral clearance (CL/F) is independent of dose and exhibits apparent dose-independent PK behavior over the studied dose range. Oral absorption is highly variable. MS-275 has a 50-fold longer half-life in humans compared to pre-clinical species. PK/PD analysis showed significant correlation between occurrence of DLT and higher systemic exposures. Although there was an increase in the acetylation of histone H3 and H4 over time, preliminary analysis showed no significant correlation between PK parameters and change in % histone acetylation after 24 hours. MS-275 is moderately bound to plasma proteins. Hepatic phase I and II metabolic pathways are only minor routes of elimination, and MS-275 is neither a substrate for liver-specific organic anion transporting proteins, OATP1B1 and OATP1B3, nor a substrate for gastrointestinal efflux transporters ABCB1 (P-gp) or ABCG2. No significant correlation was found between CL/F and demographic, body measures and other clinical covariates, and inter-patient variability in CL/F remained similar in magnitude even after correcting dose for body surface area (BSA) or other body measures. BSA is not a significant predictor of MS-275 PK, and flat-fixed dosing can be used in the future.