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Monocytic human leukocyte antigen-D related (mHLA-DR) expression determined by flow cytometry has been suggested as a biomarker of sepsisinduced immunosuppression. In order to facilitate use of HLA-DR in clinical practice, a quantitative real-time PCR technique measuring HLA-DR at the transcription level was developed and evalutated. Levels of HLA-DR mRNA correlated to mHLADR expression and were robustly measured, with high reproducibility, during the course of infection. Dynamics of mHLA-DR expression was studied during the first weeks of bloodstream infection (BSI) and was found to be dependent on the bacterial etiology of BSI. Moreover, mHLA-DR was shown to be inversely related to markers of inflammation. In patients with unfavourable outcome, sustained high C-reactive protein level and high neutrophil count were demonstrated along with low mHLA-DR expression and low lymphocyte count. This supports the theory of sustained inflammation in sepsis-induced immunosuppression. The association between mHLA-DR and bacterial etiology may be linked to the clinical trajectory via differences in ability to cause intractable infection. Staphylococcus aureus was the dominating etiology among cases with unfavourable outcome. With focus on patients with S. aureus BSI, those with complicated S. aureus BSI were found to have lower HLA-DR mRNA expression during the first week than those with uncomplicated S. aureus BSI. If these results can be confirmed in a larger cohort, HLA-DR measurement could possibly become an additional tool for early identification of patients who require further investigation to clear infectious foci and achieve source control. In conclusion, PCR-based measurement of HLA-DR is a promising method for measurements of the immune state in BSI, but needs further evaluation in the intensive care unit setting to define the predictive and prognostic value for deleterious immunosuppression. The etiology of infection should be taken into consideration in future studies of translational immunology in sepsis.

Vitamin D is central in calcium turnover, and adequate levels are important for skeletal health. It is not clear how large contributions from food and sunlight are in Swedish primary care patients, considering the low radiation of UVB in Sweden and fortification of some foods, and whether differences exist between patients of immigrant and Swedish origin. Increasing incidence of osteoporosis-related fractures is a major global health problem. Genetic variations in metabolising enzymes and in the Vitamin D receptor (VDR) have also been shown to be of importance to the overall effect of vitamin D. Polymorphic variation in the gene CYP2R1 encoding the 25-hydroxylase has previously been reported to correlate with circulating levels of 25(OH)D3. Results of association studies between genetic variants of the VDR and muscle strength, as well as falls have been contradictory. The purposes of this thesis were to examine possible differences in plasma-25(OH)D3 levels and intake of vitamin D between Swedish and immigrant female primary care patients, to estimate what foods contribute the most, and to identify contributors to vitamin D status (Paper I-II). Furthermore, the relationship between polymorphisms in the CYP2R1 gene and levels of 25(OH)D3 as well as other biochemical parameters (parathyroid hormone, calcium, phosphate and fibroblast growth factor 23) of skeletal homeostasis, bone mineral density and incidence of fractures was investigated (Paper III). Also, the association between genetic variations in the gene for the vitamin D receptor and measures of muscle strength, physical performance and falls (Paper IV), was investigated by using data from a Swedish multicenter study of elderly men (MrOS). Most important results: Vitamin D deficiency was common, with significant difference between Swedish born and immigrant patients (Paper I). Food intake of vitamin D is associated with circulating vitamin D, but the factors most strongly affecting vitamin D levels were reported sun holiday and origin (Paper II). CYP2R1 polymorphisms are associated with circulating levels of 25(OH)D3 and bone mineral density (Paper III). VDR genetic variants do not appear to have a direct effect on muscle strength or physical performance and incidence of falls in elderly Swedish men (Paper IV).

The overall aim of this thesis was to study epidemiological and clinical changes in the natural history of Crohn’s disease, its phenotype, the need for surgery and pharmacological therapy over time, as well as the role of faecal calprotectin as a biomarker of pathophysiology and disease course. An increased incidence and prevalence of Crohn’s disease was seen in the period 1963-2010. The proportion of patients with non-stricturing, non-penetrating disease behaviour at diagnosis increased, suggesting that either patients with Crohn’s disease are diagnosed earlier in their disease course today or that the Crohn’s disease phenotype is changing. A decrease in complicated disease behaviour, an increased use of immunomodulators, and a reduced frequency of surgical procedures five years after Crohn’s diagnosis was observed. The decrease in surgery at five years seemed to be explained mainly by a decrease in early surgery within three months from diagnosis, likely reflecting an increased proportion of patients with non-stricturing, non-penetrating disease. This suggests that the introduction of new treatment alternatives alone does not explain the reduction in surgery rates, and an increasing proportion of patients with uncomplicated disease at diagnosis may also play an important role. Subclinical mucosal inflammation, mirrored by increased NFkB activity and increased neutrophil activity (i.e. FC and MPO expression), was observed in healthy twin siblings in both discordant monozygotic and discordant dizygotic twin pairs with IBD. These findings strongly support the hypothesis of an ongoing subclinical mucosal inflammation at the molecular level in healthy first-degree relatives of IBD patients. Baseline FC as well as consecutive FC measurements predict relapse in IBD. The doubling of FC value increased the risk of relapse by 101% in the following three months. This increased risk attenuates with time by 20% for every three month period since the sample was obtained.

Parents of children with a chronic disease are usually highly involved in their child’s treatment and may be affected by the heavy demands and constant stress. This can increase the risk of developing burnout, which is an individual reaction to long-term stress consisting of symptoms associated with emotional exhaustion, as well as physical and cognitive fatigue. The overall aim was to estimate the prevalence of burnout in parents of children with Type 1 Diabetes Mellitus (T1DM) and inflammatory bowel disease (IBD) (paper I), identify the risk factors associated with parenting a child with T1DM (paper II), explore how mothers suffering from burnout describe their mothering of a child with diabetes, with special focus on their need for control and Performance-based self-esteem (PBSE) (paper IV), and to evaluate the effect of a group intervention aimed at reducing stress-related symptoms (paper III). A total of 251 parents of children with T1DM, 38 parents of children with IBD and 124 parents of healthy children participated in a population-based study (I, II). The validated Shirom-Melamed Burnout Questionnaire (SMBQ) was used to assess burnout. 16 parents (SMBQ ≥3.75) participated in a group intervention and were evaluated for changes in SMBQ and PBSE (III). A total of 21 mothers of children with T1DM who scored for clinical burnout (SMBQ) participated in a qualitative study. Semi-structured interviews were conducted and Inductive content analysis was used (IV). In the study group 36.0% parents of children with a chronic disease scored for clinical burnout (SMBQ ≥3.75) compared to 20.2% of the reference parents (p=0.001) with a preponderance of mothers compared to fathers, 42% vs. 20.5% (p=0.001), respectively (I). Less support from the social network, sleep disturbances and lack of personal leisure time and recovery seem to be important risk factors for clinical burnout in parents of children with T1DM, especially mothers (II). Mothers’ experiences of mothering a child with T1DM were interpreted as one theme; Mission impossible, illustrating the extremely difficult circumstances under which they bring up the child with diabetes to adulthood (IV). Parents’ subjective evaluation of the intervention group was mainly positive and SMBQ (p=0.01) and PBSE scale (p= 0.04) measurements were significantly reduced 6 months after completion of the intervention (III). It is important to pay attention to how parents and especially mothers experience their daily life in order to support those who are at risk of developing burnout.

Unusual responses to sensory stimuli have been reported in nearly all children with autism spectrum conditions (ASC). A few studies on adults indicate that the sensory and perceptual problems persist into adulthood. Sensory symptoms have not been included in the diagnostic criteria for ASC but in the new diagnostic manual (DSM-5, 2013) hyper- or hyporeactivity or unusual sensory interests were included in the diagnostic criteria for ASC. Sensory phenomena are mostly investigated in studies involving children and the scales used to measure sensory reactivity have been constructed on the basis of the scientific literature and parents’ reports. The experiences of adults with ASC are not well understood and have not been systematically used to develop measures. The overall aim of the thesis was to capture the first-hand experiences of and perspectives on sensory reactivity and translate them into a self-rating scale. To fulfil this overarching aim the personal sensory experiences of adults with ASC were investigated and the variations and range of atypical sensory phenomena explored and described in two qualitative studies (study I and II). The analyses of the firstperson descriptions enabled the development of items for a scale. These were reduced in steps and the final scale which was named the Sensory Reactivity in Autism Spectrum scale (SR-AS) comprised 32 items in four subscales: high awareness/ hyperreactivity, low awareness/hyporeactivity, strong sensory interests and sensory/motor. The SR-AS was validated using content and factor analyses. Its discriminative validity was then investigated as well as its reliability in the form of internal consistency (study III). In the final step the scale was used to identify clusters of atypical sensory functioning in adults with ASC by hierarchical cluster analysis (study IV). Three different sensory clusters were found. The main contribution of this thesis is its presentation of individual experience and perspectives and the creation of an clinical tool to measure atypical sensory reactivity frequently experienced by people with ASC. The ways in which the SR-AS can be used comprise assessment of individual sensory patterns for self-knowledge and awareness, to enable the development of coping strategies and to provide information on environmental adjustments required. In diagnostic processes where other criteria for ASC are fulfilled the SR-AS can be used for assessing sensory symptoms according to the DSM-5.

Improved life expectancy is a triumph of modern medicine. However, today’s senior citizens are predicted to soon consume 75% of the available health-care resources. Identifying new strategies to promote a healthy ageing process has thus become a priority. In contribution to the research field of healthy ageing this thesis is focused on the health and gut function of older adults. Paper I explored ‘optimal functionality’; a new approach to put the older adult’s own perspectives on health in focus. According to the results a plethora of factors related to the body, the self and the external environment needs to be considered in order to create a comprehensive understanding of the health experience in old age. Paper II characterised senior orienteering athletes as a new model of healthy ageing, due to their significantly better percived health as compared to other free-living older adults; in particular they report better gut health. As the gut is important to health maintenance and immune function paper III explored inflammation and oxidative stress in senior orienteering athletes, and older adults with gut problems, generally finding low levels in both groups. Subsequently, Paper IV investigated the health status of free-living older adults in Örebro County and also reports the results from a randomised controlled trial evaluating the effect of a probiotic supplement on self-reported health and gut symptoms. Two-thirds of the included older adults reported gut problems, however, the probiotic intervention failed to show any effects. This thesis provides additional perspectives on older adults health and gut function, by concluding that 1) optimal functionality may be a useful concept to map areas of importance to the older adult’s health experience, 2) senior orienteers may be regarded as a suitable model to study healthy ageing, 3) the prevalence of gut problems among the general population of Swedish older adults is high, but was not improved by probiotic supplementation with Lactobacillus reuteri.

Microscopic colitis (MC) constitutes the main entities collagenous colitis (CC) and lymphocytic colitis (LC), diseases that are relatively recently described (in 1976 and 1989, respectively). The aims of this thesis were to study the epidemiology of MC, to describe how these diseases affect patients in terms of symptom burden and health-related quality of life (HRQoL), to study potential risk factors such as familial factors, childhood circumstances, educational level, marital status, smoking and comorbidity, and to describe a cohort of patients with ulcerative colitis (UC) or Crohn’s disease (CD) and subsequent MC, and vice versa. During 1999–2008 in Sweden, the mean annual incidence of MC was 10.2 per 105 inhabitants, compared with 5.2 per 105 inhabitants for CC, and 5.0 per 105 inhabitants for LC. The prevalence of MC on 31 December 2008 was 123 per 105 inhabitants. Women appeared to be especially affected – the female:male ratio was 3.6:1 in CC and 4.6:1 in LC. Patients’ HRQoL is impaired both in active CC and in LC. Patients with CC in clinical remission have persisting symptoms: abdominal pain, fatigue, arthralgia and myalgia; LC patients in remission have persistent fatigue compared with controls. This illustrates that the longterm outcome is different in CC compared with LC. Microscopic colitis is associated with a family history of MC, indicating that familial factors may play a role in the pathogenesis of this disease. We confirm earlier reports that smoking is a risk factor in MC. In the present study population, CC was associated with rheumatic disease and previous appendicectomy. Moreover, CC and LC were associated with thyroid disease and coeliac disease and, interestingly, with a history of UC. Most patients with UC or CD and subsequent MC, or vice versa, had UC or CD first and later developed MC. The majority had extensive UC and later onset of CC. Microscopic colitis should be considered in patients with UC or CD if there is onset of chronic watery diarrhoea without endoscopic relapse of mucosal inflammation.

This thesis focused on the acute management of patients with ST-segment elevation myocardial infarction (STEMI) in an effort to provide information that may improve outcome. The aim was to evaluate the efficacy and safety of bivalirudin versus unfractionated heparin (UFH) in STEMI patients during primary PCI. Furthermore, to provide pharmacodynamic data of novel ways of ticagrelor administration compared to standard tivcagrelor. Additionally, to identify subgroups of patients, such as women who may derive greater benefit from specific antithrombotic strategies due to their risk/benefit profile. Finally, to evaluate current formulas for estimation of renal function in the acute phase of STEMI. In Paper I, all STEMI patients in Sweden between 2008 and 2014, treated with primary PCI and UFH or bivalirudin were included in our analysis. Of the total population of 23 800 patients, 8 783 (36.9%) were included in the UFH group and 15 017 (63.1%) in the bivalirudin group. Concomitant GPI administration was 68.5% in the UFH arm compared to 3.5% in the bivalirudin arm (p<0.01).The adjusted incidence of 30-day mortality was not significant different between the two groups (UFH vs bivalirudin, adjusted HR 0.94; 95% CI 0.82 -1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between the two groups. In contrast, patients treated with UFH had a significantly higher incidence of major in-hospital bleeding (adjusted OR 1.62; 95%CI 1.30 -2.03). In Paper II pharmacodynamic data of chewed or crushed ticagrelor compared to standard ticagrelor loading dose (LD) was assessed in 99 patients with stable angina. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60 minutes after LD. High Residual platelet reactivity (HRPR) was defined as > 208 P2Y12 reaction units (PRU). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60 minutes. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20 minutes whereas no difference was observed at 60 minutes. At 20 minutes, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01). In Paper III we presented a pre-specified gender analysis of the ATLANTIC trial including 1 862 STEMI patients that were randomly assigned to pre-hospital versus in-hospital administration of 180mg ticagrelor. Women were older and had higher TIMI risk score. Women had a 3-fold higher risk for all-cause mortality compared to men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 – 5.51). However, after adjustment for baseline characteristics, the difference was lesser and no longer significant (HR 1.98, 95% CI 0.97 – 4.04). Female gender was not an independent predictor of risk for bleeding after multivariable adjustments (BARC type 3-5 HR 1.52, 95% CI 0.74-3.09). There was no interaction between gender and efficacy or safety of randomised treatment. In Paper IV, forty patients with PCI- treated STEMI were included between November 2011 and February 2013. We validated the performance of the Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rGCystC) equations for estimation of GFR against measured GFR (mGFR) during the index hospitalisation for STEMI. MDRD-IDMS and CKD-EPI demonstrated a good performance to estimate GFR with accuracy within 30% (P30) 82.5% vs 82.5%, respectively. CKD was best classified by CKD-EPI (Kappa 0.83). CG showed the worst performance with the lowest P30. The rG-CystC equation had a marked bias of -17.8% and significantly underestimated mGFR (p=0.03). Conclusions – In STEMI patients treated with primary PCI, bivalirudin should be preferred in patient at high risk for bleeding. With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared with standard integral tablets. In STEMI patients, fast and potent platelet inhibition with chewed ticagrelor may reduce the risk of early stent thrombosis and patients treated with a less aggressive antithrombotic strategy, such as UFH or bivalirudin monotherapy, may derive a greater benefit. Although gender differences in adverse outcomes could mainly be explained by older age and clustering of comorbidities in women, a bleedreduction strategy in women with high risk characteristics is warranted in order to improve their outcome. Regardless the choice of antithrombotic strategy, dose adjustment of drugs cleared by kidneys based on GFR estimation is of crucial importance. MDRD and CKD-EPI should be the formulas used for estimation of GFR in STEMI patients

Acute lymphoblastic leukemia (ALL) has poor prognosis in older/elderly adults and in high-risk/relapsed disease. Recommended treatment of ALL was evaluated (study I-IV). Data was obtained from the Swedish Acute Leukemia registries and from patient records. I. We assessed ALL relapse treatment and outcome in 76 patients aged 15-65 years (y). Complete remission (CR) was achieved in 50/71 patients (70%). Of them, 29 underwent allogeneic hematopoietic stem cell transplantation (hSCT). Five year overall survival (OS) was 15%, but close to 50% in 19 patients <35y after hSCT. II. We studied outcome of treatment with the Hyper-CVAD protocol in 19 of 24 patients with T-ALL aged 18-72y. CR was reached in 89%, but 5y leukemia-free survival was only 29%, and 20% in 15 patients not transplanted in CR1. Six patients received hSCT in CR2. Finally, 5y OS in all 19 patients was 47%. The only negative prognostic factor found was age ≥35y. III. We evaluated minimal residual disease (MRD) monitoring in 35 patients with Philadelphia (Ph) negative B-ALL aged 46-79y and treated with the ABCDV protocol. The CR rate was 91%. MRD was measured by flow cytometry in 73% in CR1 (MRD1) and omitted in those >70y or with high-risk ALL. Five patients received hSCT (only one due to MRD). Five year OS in the whole cohort was 47%. Continuous CR but not OS was improved in patients with MRD1 <0.1 %. IV. We studied 155 patients with ALL (Ph+ in 35%) aged 55-85y and treated with remission induction/palliation (124/31). Both, intensive, and palliative treatment resulted in the CR rates of 70/83/16% and 3y OS of 26/32/3%. OS was negatively influenced by age and platelet count ≤35×109/L (but not Ph+). OS was not enhanced by introduction of an age-adapted protocol. We concluded that intensive treatment with subsequent allogeneic hSCT is the most reasonable option in younger patients with ALL recurrence (I). Hyper-CVAD has low relapse-preventing efficacy (II). MRD guided intensification is probably feasible in only a minority of older patients (III). Prognosis in elderly ALL is poor, but no longer impaired by Ph+ (IV).