Aim: The overarching aim of the thesis was to explore the occurrence and clinical importance of two manifestations of myocardial injury; unrecognized myocardial injury (UMI) and altered levels of cardiac biochemical markers in patients with stable coronary artery disease (CAD). Methods: A prospective multicenter cohort study investigated the prevalence, localization, size, and prognostic implication of UMI in 235 patients with stable CAD. Late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging and coronary angiography were used. The relationship between UMI and severe CAD and cardiac biochemical markers was explored. In a substudy the short- and longterm individual variation in cardiac troponins I and T (cTnI, cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were investigated. Results: The prevalence of UMI was 25%. Subjects with severe CAD were significantly more likely to exhibit UMI than subjects without CAD. There was a strong association between stenosis ≥70% and presence of UMI in the myocardial segments downstream. The presence of UMI was associated with a significant threefold risk of adverse events during follow up. After adjustments UMI was associated with a nonsignificant numerically doubled risk. The levels of cTnI, NT-proBNP, and Galacin-3 were associated with the presence of UMI in univariate analyses. The association between levels of cTnI and presence of UMI remained significant after adjustment. The individual variation in cTnI, cTnT, and NT-proBNP in subjects with stable CAD appeared similar to the biological variation in healthy individuals. Conclusions: UMI is common and is associated with significant CAD, levels of biochemical markers, and an increased risk for adverse events. A change of >50% is required for a reliable short-term change in cardiac troponins, and a rise of >76% or a fall of >43% is required to detect a long-term reliable change in NT-proBNP.

Background: For indeterminate reasons, there have been major variations in sick leave in Sweden, and many physicians have perceived sick leave assignments as burdensome. Aim: To gain more knowledge and understanding, from a perspective of primary health care, about factors in health care and patients that affect sick leave. Thereby help patients in the best way, facilitate the work of physicians and other health professionals involved in the rehabilitation process, and use the health care resources optimally. Methods: This thesis is based on a randomised controlled trial (RCT) in a primary health care centre with participants on short-term sick leave, due to pain and/or mental illness, who received a multidisciplinary assessment. Qualitative focus-group discussions with physicians in primary health care centres. A cohort of women on very long-term sick leave due to pain and/or mental illness, who lost sickness benefits due to a new time limit on sickness insurance, were randomised to multidisciplinary assessment and multimodal intervention (TEAM), or to Acceptance and Commitment Therapy (ACT). In an extended cohort, including some men on very long-term sick leave due to pain and/or mental illness, the importance of the motivation for return to work (RTW) was investigated. Results. Very early multidisciplinary assessment increased days on sick leave in the first three month period. Physicians at primary health care centres perceived sick leave assignments as burdensome, but clearer rules and cooperation with other professionals have made sick leave assignments less burdensome. TEAM intervention resulted in an increase in working hours per week as well as an increase in work-related engagements, compared to control in the RCT. Motivation for RTW was associated with RTW or increased employability in the rehabilitation of patients Conclusions: Continued studies are needed to find those who are at risk of long-term sick leave, the time when rehabilitation efforts should be started, and the content of rehabilitation. Collaboration in teams facilitates sick leave assignments for physicians at primary care health centres. Motivation for RTW might be a factor of importance for the effect of rehabilitation and needs to be studied further.

This dissertation focuses on 2 parts: 1) Whether evidence-based guidelines are recognized and integrated into clinical practice in primary care and 2) Whether a university course aimed at teaching physical therapists to identify and address evidence-based psychosocial factors in primary care might change practice behaviour and patient outcome. To this end practising clinicians were surveyed and a course for physical therapists was developed.Concerning the first part, we showed that a relatively large proportion of clinicians in primary care were unfamiliar with the content of evidence-based guidelines and/or with the concept of “Red flags”. Yet, concerning the self-reported practice behaviour, the majority indicated they followed the key points in the guidelines. To enhance the impact of guidelines, interventions or tactics for teaching and implementing guidelines should include interactive education,discussion, feedback, and reminders which in research have shown to enhance knowledge,skills and change behaviour. Furthermore, the clinical applicability of the guidelines needs to be further developed. We could also show that psychosocial factors were integrated up to a certain point and that physical therapists in primary care were well aware of the importance of psychosocial risk factors, but it seemed physical therapists lack specificity about which factors are important. Physical therapists may have heard about risk factors but probably did not have a clear model or structure about how these factors work.Concerning the second part, the results showed that we, by means of a university course, managed to change attitudes and beliefs, increase knowledge, skills and competencies towards a more biopsychosocial standpoint. But despite these changes, the results did not show a behavioural change on behalf of the physical therapists or a better outcome for patients at risk of longterm pain and disability. Several possible explanations for this are discussed. First, the content of the course should be changed so it focuses more on behavioural change on behalf of the physical therapists. This would facilitate implementation of new behaviour in clinical practice and increase the likelihood that the new behaviour is maintained and thereby the possibility of improved patient outcome. Second, treating patients at risk for long-term pain and disability may also be too difficult for a single physical therapist in a clinical setting. This would imply large changes in the way patients are directed through the health care system compared to now. The main tasks of the physical therapists in primary care would then be to select patients at risk for long-term pain and disability. They would then treat the patients not at risk and refer the patients at risk for long-term pain and disability to more suitable treatment, for example CBT treatment delivered by a psychologist or multimodal treatment delivered by a team of experts.Since risk patients experience most suffering and are the most costly for the health care system, it is important they get the appropriate treatment at the earliest possible opportunity.In summary, this dissertation shows that integrating psychosocial factors in physical therapy is not an easy task.

Background: Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women worldwide. Adenomas can be precursors to CRC, and inflammatory bowel disease (IBD) can present with the same symptoms as CRC. The majority of patients with CRC initially consult primary care. Symptoms associated with CRC are also common among primary care patients, but seldom caused by any significant disease. Reliable diagnostic aids would be helpful in deciding which patients to refer. Faecal immunochemical tests (FITs) are commonly used for this purpose in primary care in Sweden, but there is little evidence to support this use. Faecal calprotectin (FC) has been suggested as an additional test. Aim: To explore how doctors in primary care investigate patients with suspected CRC, the value of FITs, symptoms and presence of anaemia in diagnosing CRC and adenomas in primary care, and whether FC tests could contribute to diagnosis. Methods: Three studies (1-3) were carried out in Region Jämtland Härjedalen, Sweden. There was no screening programme for CRC. We used a point of care qualitative dip-stick 3-sample FIT with a cut-off of 25-50μg haemoglobin/g faeces, and a calprotectin enzyme-linked immunosorbent assay (ELISA) test with a cut-off of 100 μg/g faeces. 1: A retrospective, population-based study including all patients diagnosed with CRC or adenomas with high-grade dysplasia (HGD) during the period 2005-2009 that initially consulted primary care. Symptoms, FIT results, anaemia and time to diagnosis were retrieved from medical records. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated from FIT results at the region’s health centres 2008- 2009. (Paper I.) 2: A prospective cohort study including consecutive patients where primary care doctors requested FITs and/or FC tests, at four health centres, from 30 Jan 2013 to 31 May 2014. FITs, FC tests, haemoglobin and iron deficiency tests were analysed; patients and doctors answered questionnaires about symptoms. Patients were examined with bowel imaging or followed for two years. Findings of CRC, adenomas with HGD, adenomas with low grade dysplasia (LGD) ≥1 cm and IBD were registered. (Papers II and III.) 3: A qualitative study of interviews with eleven primary care doctors. We explored what made them suspect CRC, and their practices regarding investigation and referral with particular attention to their use of FITs. Qualitative content analysis with an inductive approach was used for the analysis. (Paper IV.) Results: 1: Paper I: Of 495 patients 323 (65.3%) started the investigation in primary care. FITs were analysed in 215. In 23 cases with CRC, FITs were negative; 15 (65.2%) had anaemia. In 33 cases with CRC, FITs were performed due to asymptomatic anaemia; 10 (30.3%) had negative FITs. The time from start of investigation, to the diagnosis of CRC or adenomas with HGD, was significantly longer for patients with negative FITs. 2: 377 patients (9 diagnosed with CRC, 10 with IBD) were included. Paper II: Concordance of positive answers about symptoms from patients and doctors was generally low. Rectal bleeding (recorded by 43.5% of patients and 25.6% of doctors) was the only symptom related to CRC and IBD. The FIT showed a better PPV than rectal bleeding for CRC and IBD. When patients recorded rectal bleeding, the FIT had a PPV of 22.6% and a NPV of 98.9% for CRC and IBD. Paper III: The best test for detecting CRC and IBD was the combination of a positive FIT and/or anaemia with a sensitivity, specificity, PPV and NPV of 100%, 61.7%, 11.7% and 100% respectively. The FC test had no additional value to the FIT alone. The sensitivity, specificity, PPV and NPV of the FIT for CRC in study 1 was estimated at 88.4%, 73.3%, 6.2% and 99.7% respectively. In study 2, corresponding figures were 88.9%, 67.4%, 6.3% and 99.6% respectively. 3: Paper IV: We identified four categories: “Careful listening – with awareness of the pit-falls”, “tests can help – the FIT can also complicate the diagnosis”, “to refer or not to refer – safety margins are necessary”, and “growing more confident – but also more humble”. All doctors had found their own way to handle FIT results in the absence of guidelines. Conclusion: The diagnostic process when suspecting CRC can be described as navigating uncertain waters with safety margins. FITs were often used by primary care doctors but with considerable variations in interpretation and handling of results. Rectal bleeding was the only symptom related to CRC and IBD, but the FIT showed a better PPV than rectal bleeding. The combination of a negative FIT and no anaemia may be useful as a rule-out test when CRC is suspected in primary care, and this potentially also applies when patients present with rectal bleeding. Further studies are needed to confirm this and to determine the optimal FIT cut-off value for this use.

Background Type 2 diabetes is a common chronic disease with a two-fold increased risk for cardiovascular morbidity and mortality and has an increasing prevalence worldwide. This thesis is based on a study conducted in primary health care in Östergötland and Jönköping, Sweden. The aim of the thesis was to evaluate new risk markers to identify patients with high risk of developing cardiovascular disease in middle-aged men and women with type 2 diabetes. Methods Data from the cohort study CArdiovascular Risk in type 2 DIabetes – a Prospective study in Primary care (CARDIPP) was used. In paper III data were also used from CARDIPP-Revisited where all participants in the CARDIPP study were invited four years after the baseline investigation for a re-investigation. In paper IV data were used from CAREFUL which is a control group of 185 subjects without diabetes. The investigation included a standard medical history including data on diabetes duration and on-going medication. Anthropometric data were recorded and both office and ambulatory blood pressure were measured. The patients filled out a detailed questionnaire and physical activity was measured by using waist-mounted pedometers. Pedometer-determined physical activity was classified in four groups: Group 1: <5000 steps/day (‘sedentary’); Group 2: 5000-7499 steps/day (‘low active’); Group 3: 7500-9999 steps/day (‘somewhat active’); Group 4: and ≥10 000 steps/day (‘active’). Blood samples were drawn for routine analyses and also frozen for later analyses. The investigations at the departments of physiology included echocardiography, measurements of the carotid intima-media thickness, applanation tonometry and measurements of  sagittal abdominal diameter. Results Paper 1: Patients with a non-dipping systolic blood pressure pattern showed higher left ventricular mass index and pulse wave velocity (PWV) compared with patients with ≥10% decline in nocturnal systolic blood pressure. Patients with <10% decline in nocturnal systolic blood pressure had higher BMI and sagittal abdominal diameter, lower GFR and higher albumin:creatinine ratio and also higher levels of NT-proBNP than patients with a dipping pattern of the nocturnal blood pressure. Paper 2: The number of steps/day were inversely significantly associated with BMI, waist circumference and sagittal abdominal diameter, levels of CRP, levels of interleukin-6 and PWV. Paper 3: At the 4-year follow-up the change in PWV (ΔPWV) from baseline was calculated. The group with the lowest steps/day had a significantly higher increase in ΔPWV compared with the group with the highest steps/day. The associations between baseline steps/day and ΔPWV remained after further adjustment in a multivariate linear regression statistically significant (p=0.005). 23% of the variation in the study could be explained by our model. Every 1000 extra steps at baseline reduced the change in ΔPWV by 0.103 m/s between baseline and follow-up. Paper 4: Low vitamin D levels were associated with significantly increased risk for premature mortality in men with type 2 diabetes. High levels of parathyroid hormone were associated with significantly increased risk for premature mortality in women with type 2 diabetes. These relationships were still statistically significant also when two other well-established risk markers for mortality, PWV and carotid intima-media thickness, were added to the analyses. Conclusions Ambulatory blood pressure recording can by addressing the issue of diurnal blood pressure variation, explore early cardiovascular organ damage and microvascular complications that goes beyond effects of standardised office blood pressure measurements. Pedometer-determined physical activity may serve as a surrogate marker for inflammation and subclinical organ damage in patients with type 2 diabetes. There is novel support for the durable vascular protective role of a high level of daily physical activity, which is independent of BMI and systolic blood pressure. The use of pedometers is feasible in clinical practice and provides objective information not only about physical activity but also the future risk for subclinical organ damage in middle-aged people with type 2 diabetes. Our results indicate that low vitamin D levels in men or high parathyroid hormone levels in women give independent prognostic information of an increased risk for total mortality.

Background Advances in medical treatment during the last 50 years have resulted in more individuals with congenital heart disease (CHD) and Marfan syndrome reaching childbearing age. The substantial physiological changes during pregnancy result in a high-risk situation, and pregnancy is a major concern in women with these conditions. Aims To describe the socio-demographic characteristics, birth characteristics and reproductive patterns of individuals with CHD and women with Marfan syndrome. To investigate obstetric and neonatal outcomes in the firstborn children of individuals with CHD and women with Marfan syndrome. To study long-term cardiovascular outcomes after childbirth in women with Marfan´syndrome. Methods The studies are population-based register studies. The study population in the first paper included all women born between 1973 and 1983 who were alive and resident in Sweden at the age of 13 (494 692 women, of whom 2 216 were women with CHD). In the second paper, the same definition of the study population was chosen, except that it involved all men born between 1973 and 1983 (522 216 men, of whom 2 689 men with CHD). The third and fourth papers involved a study population of all Swedish women born between 1973 and 1993 who were still living in Sweden at age 13. This population consisted of 1 017 538 women, 273 of whom had been diagnosed with Marfan syndrome. Results and conclusions The individuals studied were more often born preterm, and were small-for-gestational age babies. They were more likely to have been born by cesarean section. In women with CHD, these characteristics were repeated in their firstborn children. No increased risks were found in children of men with CHD or in children of women with Marfan syndrome. There was no increased risk of aortic dissection in women with Marfan syndrome during pregnancy compared to women with Marfan syndrome who did not give birth. Higher frequencies of cardiac arrhythmia and valvular heart disease were found after childbirth in women with Marfan syndrome. Pregnancy in women with CHD is a high-risk situation associated with increased risk of adverse neonatal outcomes for the expected child. Pregnancy in women without CHD, but where the father has CHD is not so associated with increased risk of adverse obstetric or neonatal outcomes. Pregnancy in women with Marfan syndrome is not associated with adverse outcomes for the expected child.

Background: Today, women constitute about half of medical students. However, women are still underrepresented in prestigious specialties such as surgery. Some suggest that this could be explained by women being more oriented towards work-life balance. Aim: The overall aim of this dissertation was to explore aspects of gender in work-life priorities, career plans, clinical experiences and negotiations of professional ideals among medical students and newly graduated doctors, all in a Swedish setting. Method: We based the analysis on data from two different sources: an extensive questionnaire exploring gender and career plans among medical students (paper I-III) and interviews with newly graduated doctors (study IV). In paper I, four classes of first- and final-year medical (N=507, response rate 85%) answered an open-ended question about their future life, 60% were women. We conducted a mixed methods design where we analyzed the answers qualitatively to create categories that could be analyzed quantitatively in the second stage. In paper II, five classes of final-year medical students  were included (N = 372, response rate 89%), and 58% were women. We studied their specialty preference and how they rated the impact that the motivational factors had for their choice. In order to evaluate the independent impact of each motivational factor for specialty preference, we used logistic regression. In paper III, final-year medical students answered two open-ended questions: “Can you recall an event that made you interested of working with a certain specialty?” and “Can you recall an event that made you uninterested of working with a certain specialty?”. The response rate was 62% (N = 250),  and 58% were women. The analysis was similar to paper I, but here we focused on the qualitative results. In paper IV, thematic interviews were conducted in 2014 and 2015. We made a purposeful sampling of 15 junior doctors, including nine women and six men from eight different hospitals. Data collection and analysis was inspired by constructivist grounded theory methodology. Results: When looking at the work-life priorities of medical students and junior doctors it is clear that both men and women want more to life than work in their ideal future. The junior doctors renounced fully devoted and loyal ideal and presented a self-narrative where family and leisure was important to cope and stay empathic throughout their professional lives. The specialty preferences and the highly rated motives for choosing them were relatively gender neutral. However, the gender neutrality came to an end when the final-year medical students described clinical experiences that affected their specialty preference. Women were more often deterred by workplace cultures, whereas men were more often deterred by knowledge area, suggesting that it is a male privilege to choose a specialty according to interest. Among the newly graduated doctors, another male privilege seemed to be that men were able to pass more swiftly as real doctors, whereas the women experienced more dissonance between their self-understanding and being perceived as more junior and self-doubting. Conclusions: The career plans and work-life priorities of doctors-to-be were relatively gender neutral. Both female and male doctors, intended to balance work not only with a family but also with leisure. This challenges the health care system to establish more adaptive and flexible work conditions. Gender segregation in specialty choice is not the result of gender-dichotomized specialty preferences starting in medical school. This calls for a re-evaluation of the understanding where gender is seen as a mere background characteristic, priming women and men for different specialties.

Obsessive-compulsive disorder (OCD), with a prevalence of 1-2 %, frequently leads a chronic course. Persons with OCD are often reluctant to seek help and, if they do, their OCD is often missed. This is unfortunate, since active treatment may substantially improve social function and quality of life. Serotonin reuptake inhibitors (SRIs) have welldocumented efficacy in OCD, but delayed response may be problematic. Methods to predict response have been lacking. Because SRIs are effective, pathophysiological research on OCD has focussed on serotonin. However, no clear aberrations of serotonin have been found, thus other mechanisms ought to be involved. Our aims were to facilitate clinical detection and assessment of OCD, to search for biochemical correlates of response and side-effects in SRI treatment of OCD and to identify any possible involvement of oxytocin in the pathophysiology of OCD. In study I, we tested in 402 psychiatric out-patients the psychometric properties of a concise rating scale, “Brief Obsessive Compulsive Scale” (BOCS). BOCS was shown to be easy to use and have excellent discriminant validity in relation to other common psychiatric diagnoses. Studies II-V were based on 36 OCD patients from a randomised controlled trial of paroxetine, clomipramine or placebo. In study II, contrary to expectation, we found that the change (decrease) of serotonin in whole blood was most pronounced in non-responders to SRI. This is likely to reflect inflammatory influence on platelet turnover rather than serotonergic processes within the central nervous system. In studies IV-V, we found relations between changes of oxytocin in plasma and the anti-obsessive response, and between oxytocin and the SRI related delay of orgasm, respectively. In both cases, the relation to central oxytocinergic mechanisms is unclear. In males, delayed orgasm predicted anti-obsessive response.

The rarity of a disease can give rise to challenges that differ from conventional diseases. For example, rarity hampers research and development of new drugs, and patients with severe, rare diseases have limited access to qualified treatments. When drugs are available, clinical evidence has higher uncertainty and the drugs can be very expensive. When setting priorities in the healthcare sector, treatments aimed at patients with rare diseases, so called orphan drugs, have become a source of concern. Orphan drugs seldom show solid evidence of effectiveness or cost-effectiveness. Still, treatments for rare disease patients, available on the European market, has increased rapidly since the adoption of a regulation offering incentives for research and development of orphan drugs. The question arises as to whether the publicly funded health care system should provide such expensive treatments, and if so, to what extent. This doctoral thesis aims to investigate healthcare priority setting and rare diseases in the context of orphan drug reimbursement. Priority setting for orphan drugs is located at the intersection of economic, ethical and psychological perspectives. This intersection is explored by studying the public’s view on the relevance of rarity when setting priorities for orphan drugs, and by examining how orphan drugs are managed when making reimbursement decisions in practice. Papers I and II in this thesis employ quantitative, experimental methods in order to investigate preferences for prioritising rare diseases, and the extent to which psychological factors influence such preferences. Papers III and IV employ qualitative methods to further explore what factors (apart from rarity) influence priority-setting decisions for orphan drugs, as well as how decisions regarding orphan drugs are made in practice in England, France, the Netherlands, Norway and Sweden. Combining quantitative and qualitative methods has provided a more comprehensive understanding of the topic explored in the thesis, and the methods have complemented each other. Paper I shows that there is no general preference for giving higher priority to rare disease patients when allocating resources between rare and common disease patients. However, results show that preferences for treating the rare patients are malleable to a set of psychological factors, in particular “proportion dominance”. Paper II shows that the identifiability of an individual has no, or a negative, influence on the share of respondents choosing to allocate resources to him/her (compared to a nonidentified individual). Paper III confirms that rarity per se is not seen as a factor that should influence priority-setting decisions (i.e. accept a greater willingness to pay for orphan drugs), however, other factors such as disease severity, treatment effect and whether there are treatment alternatives were seen as relevant for consideration. Paper IV explores the challenges with and solutions for orphan drug reimbursement, as perceived by different actors in five European countries. Perceived challenges are related to the components involved when making reimbursement decisions, to the reimbursement system, and to the acceptance of the final decision. Solutions are either specific for orphan drugs, or general measures that can be used for orphan drugs as well as for other drugs. In conclusion, priority setting for orphan drugs is complex and requires particular attention from decision makers. There are many factors to consider when making reimbursement decisions for orphan drugs. The consequences of a decision are potentially severe (both for rare disease patients and for common disease patients, depending on the decision) and psychological factors can potentially influence decisions.

The aim for this thesis was to identify prognostic factors for chronic diabetes complications that exist at the time of diabetes diagnosis. Low level of education (<12 years) and low income (<60% of median) was found to increase the risk to have high (>70 mmol/mol) HbA1c at the time of diagnosis with 34 % and 35 %, respectively. Prevalence of diabetic retinopathy (DR) was 12% in a cohort of patients newly diagnosed with diabetes. Diabetic macular edema was present in 11% of patients with type 2 diabetes (T2D) and 13% of those with Latent Autoimmune Diabetes in Adults (LADA). Low beta cell function and low level of education increased the risk for DR with 110% and 43%, respectively. For every unit of increase in body mass index, the risk for DR was reduced by 3%. The cellular immunology of LADA patients was a mixture of that observed in both type 1 (T1D) and T2D patients. Compared to patients with T1D, LADA patients had more B-regulatory lymphocytes and antigen presenting cells capable of producing interleukine-35. This indicates a higher anti-inflammatory capacity in LADA patients compared to type T1D patients. By imputing age, body mass index, HbA1c at diagnosis, beta cell function and insulin resistance in a cluster analysis, five distinct diabetes clusters were identified. The four clusters representing T2D patients differed in incidence of DR, nephropathy and non-alcoholic fatty liver disease. This was replicated with similar results in three geographically separate populations. By studying socioeconomic background and factors present at the time of diagnosis we can better predict prognosis for chronic diabetes complications. These findings may facilitate better-targeted diabetes screening programs and more individually tailored treatment regimes.