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Aims Genetics can explain just above 10% of the observed heritability in cardiovascular diseases. Epigenetics is about to provide some further explanations, but the information needed for that is in the accumulation phase. Genome-wide DNA methylation analysis has revealed thousands of genes, which are epigenetically differentially regulated in atherosclerotic plaques. Our results point to an additional level of complexity that needs to be integrated into the aetiology of atherogenesis.We conducted a genome-wide analysis to identify differentially methylated genes in atherosclerotic lesions. Methods DNA methylation at promoters, exons and introns was identified by massive parallel sequencing. Gene expression was analysed by microarrays, qPCR, immunohistochemistry and western blots. Results Globally, hypomethylation of chromosomal DNA predominates in atherosclerotic plaques and two-thirds of genes showing over 2.5-fold differential in DNA methylation are up-regulated in comparison to healthy mammary arteries. The imprinted chromatin locus 14q32 was identified for the first time as an extensively hypomethylated area in atherosclerosis with highly induced expression of miR127, -136, -410, -431, -432, -433 and capillary formation-associated gene RTL1. The top 100 list of hypomethylated promoters exhibited over 1000-fold enrichment for miRNAs, many of which mapped to locus 14q32. Unexpectedly, also gene body hypermethylation was found to correlate with stimulated mRNA expression. Conclusion Significant changes in genomic methylation were identified in atherosclerotic lesions. The most prominent gene cluster activated via hypomethylation was detected at imprinted chromosomal locus 14q32 with several clustered miRNAs that were up-regulated. These results suggest that epigenetic changes are involved in atherogenesis and may offer new potential therapeutic targets for vascular diseases.

Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. In this study, three magnetic resonance imaging (MRI) sequences were used to quantify the anatomical distribution of lesions, to grade DAI according to the Adams grading system, and to evaluate the value of lesion localization in combination with clinical prognostic factors to improve outcome prediction. Thirty patients (mean 31.2 years ±14.3 standard deviation) with severe DAI (Glasgow Motor Score [GMS] <6) examined with MRI within 1 week post-injury were included. Diffusion-weighted (DW), T2*-weighted gradient echo and susceptibility-weighted (SWI) sequences were used. Extended Glasgow outcome score was assessed after 6 months. Number of DW lesions in the thalamus, basal ganglia, and internal capsule and number of SWI lesions in the mesencephalon correlated significantly with outcome in univariate analysis. Age, GMS at admission, GMS at discharge, and low proportion of good monitoring time with cerebral perfusion pressure <60 mm Hg correlated significantly with outcome in univariate analysis. Multivariate analysis revealed an independent relation with poor outcome for age (p = 0.005) and lesions in the mesencephalic region corresponding to substantia nigra and tegmentum on SWI (p  = 0.008). We conclude that higher age and lesions in substantia nigra and mesencephalic tegmentum indicate poor long-term outcome in DAI. We propose an extended MRI classification system based on four stages (stage I—hemispheric lesions, stage II—corpus callosum lesions, stage III—brainstem lesions, and stage IV—substantia nigra or mesencephalic tegmentum lesions); all are subdivided by age (≥/<30 years).

The general aim of this thesis was to study the prognostic clinical and biological markers of Diffuse Large B-cell Lymphoma (DLBCL).

Paper I: Utilizing population-based data for patients with DLBCL in Sweden, the study aimed to establish whether event free survival at 24 months (EFS24) was a reproducible milestone. The disease-free survival for lymphoma patients was compared with that of age and sex matched Swedish general population. We demonstrated that overall survival was similar to age and sex matched general population only for younger patients (<60 years of age) achieving ES24. Patients older than that had worse prognosis. Death was mainly linked to cardiovascular disease and secondary malignancies.

Paper II: Plasma samples collected via the bio bank U-CAN were analyzed using multiplex extension assay (PEA) utilizing preselected protein panels to examine the possibility of distinguishing lymphomas, leukemias and controls. The study confirmed that  PEA technology could be used not only to effectively screen for large number of plasma protein biomarkers in low plasma sample volumes (1 µL), but even to discriminate between controls and different haematological malignancies. 

Paper III: Plasma protein pattern evolution in DLBCL patients was highlighted by PEA analysis of plasma proteins at different time points under treatment with Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Significant distinctions in protein patterns at diagnosis compared to controls and striking differences in protein levels before and after treatment in patient who responded to treatment were evident. The three top proteins were TCL1A, CXCL13 and IL2RA. 

Paper IV: An interesting protein that emerged from the above studies was TCL1A. This plasma protein was analyzed in plasma samples by PEA. Validation by plasma enzyme immunosorbent assay (ELISA) was attempted. The cytoplasm and nucleus bound form of TCL1A were analyzed with the help of immunohistochemistry in tissue microarray samples. The study included 178 patients of which 125 received R-CHOP. Clinical risk factor analysis showed no significant correlation with tissue IHC. Significantly higher levels of plasma TCL1A were seen in male patients (measured by ELISA and PEA) and in patients with Ann Arbor stages II-IV (measured by PEA). Survival analysis showed no statistical significance. 

In the present work, the determination of omeprazole (OME) enantiomers in oral fluid and plasma samples was carried out utilizing microextraction by packed sorbent (MEPS) and liquid chromatography-tandem mass spectrometry. A chiral column with cellulose-SB phase was used for the first time for enantiomeric separation of OME with an isocratic elution system using 0.2% ammonium hydroxide in hexane-ethanol mixture (70 : 30, v/v) as the mobile phase. OME enantiomers were determined utilizing a triple quadrupole tandem mass spectrometer in positive ion mode (ESI+) monitoring mass transitions: m/z 346.3 -> 198.0 for OME and m/z 369.98 -> 252.0 for internal standard. The limits of detection and quantification of the present method for both enantiomers were 0.1 and 0.4 ng/mL, respectively. The method validation provided good accuracy and precision. The matrix effect factor was less than 5%, and no interfering peaks were observed. The interday precision values ranged from 2.2 to 7.5 (%RSD), and the accuracy of determinations varied from -9.9% to 8.3%. In addition, the pharmacokinetics (PK) of omeprazole enantiomers in healthy subjects after a single oral dose was investigated. (S)-Enantiomers showed higher levels than (R)-enantiomers throughout 24 h. It was found that the mean maximum concentrations of (R)- and (S)-omeprazole in plasma samples were about two times higher than in oral fluid.

Background: In Sweden, information on seroprevalence of tick -borne encephalitis virus (TBEV) in the population, including vaccination coverage and infection, is scattered. This is largely due to the absence of a national tick -borne encephalitis (TBE) vaccination registry, scarcity of previous serological studies and use of serological methods not distinguishing between antibodies induced by vaccination and infection. Furthermore, the number of notified TBE cases in Sweden has continued to increase in recent years despite increased vaccination.

Aim: The aim was to estimate the TBEV seroprevalence in Sweden.

Methods: In 2018 and 2019, 2,700 serum samples from blood donors in nine Swedish regions were analysed using a serological method that can distinguish antibodies induced by vaccination from antibodies elicited by infection. The regions were chosen to reflect differences in notified TBE incidence.

Results: The overall seroprevalence varied from 9.7% (95% confidence interval (CI): 6.6-13.6%) to 64.0% (95% CI: 58.3- 69.4%) between regions. The proportion of vaccinated individuals ranged from 8.7% (95% CI: 5.8-12.6) to 57.0% (95% CI: 51.2-62.6) and of infected from 1.0% (95% CI: 0.2-3.0) to 7.0% (95% CI: 4.5-10.7). Thus, more than 160,000 and 1,600,000 individuals could have been infected by TBEV and vaccinated against TBE, respectively. The mean manifestation index was 3.1%.

Conclusion: A difference was observed between low- and high -incidence TBE regions, on the overall TBEV seroprevalence and when separated into vaccinated and infected individuals. The estimated incidence and manifestation index argue that a large proportion of TBEV infections are not diagnosed.

Purpose: Adults born with intellectual disabilities (ID) and motor disabilities (MD) have higher risk of dysphagia and should be assessed to decrease risk of severe complications. However, standardised assessment tools in Swedish are lacking.

Methods: The Dysphagia Assessment Package (DAP) was cross-culturally translated from English to Swedish (DAP-SE) and tested for content validity by an expert group. Face validity was assessed by five speech and language therapist (SLT) during meal observations (n = 10), and the clinical relevance was reported in a study-specific questionnaire.

Results: The DAP-SE was culturally adapted within the process of translation and was found to contain clinically relevant aspects to assess and suggest further interventions for adults with ID and MD. Face and content validity was confirmed by the expert group.

Conclusion: This study, in which the DAP-SE was tested in a small sample size, provides the first indications of the instrument's validity with respect to evaluating mealtimes, swallowing function and swallowing safety in adults born with ID and MD. The study adds to the knowledge on how to translate and culturally adapt an assessment tool to clinically assess dysphagia on a complex and vulnerable patient group.

Key Clinical Message Contrast-enhanced echocardiography or cardiac magnetic resonance imaging is of value in the diagnosis of apical hypertrophic cardiomyopathy. Apical hypertrophic cardiomyopathy is rare in Caucasians, and gene negativity does not rule out the diagnosis. Risk stratification for sudden cardiac death and decisions about anticoagulation in cases with atrial fibrillation should be based on guidelines.

Objective: The objective of this study was to estimate the area fraction of different ratios of Bio-Oss((R)) and bone, prior to grafting in an in vitro model to demonstrate a histomorphometric baseline.

Methods: Bio-Oss((R)) particles were mixed with autogenous bone from pig jaw in three different ratios (50:50, 80:20 and 100:0) and packed in rice paper in a standardized procedure. Histomorphometric analyses were performed in 25 specimens and 74 regions of interest. The area percentage of Bio-Oss((R)), bone, and non-mineralized tissue (NMT) were calculated. Results were reported as mean values and 95% confidence interval (CI).

Results: The mean area fraction of Bio-Oss((R)) was 20.6% (CI: 18.2-23) in the 50:50 mixture, 33.6% (CI: 29.7-37.6) in the 80:20 mixture, and 43.4% (CI: 40.5-46.3) in the 100:0 mixture. The mean area fraction of NMT was 60.5% (CI: 57.9-63.1) in the 50:50 mixture, 59.6% (CI: 56.4-62.7) in the 80:20 mixture, and 56.6% (CI: 53.7-59.5) in the 100:0 mixture. The mean area fraction of bone was 18.9% (CI: 16.9-20.9) in the 50:50 mixture and 6.8% (CI: 5-8.6) in the 80:20 mixture.

Conclusion: There is a great difference in the clinically estimated percentage and the histomorphometrically evaluated percentage of Bio-Oss((R)) at baseline, prior to grafting. The area fraction of different tissues presented in this study may be beneficial as guidance for histomorphometrical baseline calculations when different mixtures of Bio-Oss((R)) and autogenous bone are used as grafting materials.

Objective: To test the hypothesis of no difference in the long-term treatment outcome after osteotome-mediated sinus floor elevation with or without a grafting material. Materials and Methods: A MEDLINE/PubMed, Cochrane Library, and EMBASE search in combination with a hand-search of relevant journals was conducted, including human studies published in English from January 1, 1986 to December 1, 2017. Results: One comparative and 7 noncomparative studies fulfilled the inclusion criteria. Survival of suprastructures had never been compared within the same study. Meta-analysis demonstrated an overall estimated patient-based implant survival of 94%. Gain in vertical alveolar bone height was similar with the 2 treatment modalities. Noncomparative studies demonstrated high long-term survival rate of suprastructures and implants with the 2 treatment modalities, as well as limited periimplant marginal bone loss. Conclusion: High long-term implant survival was demonstrated after osteotome-mediated sinus floor elevation with or without a grafting material. However, long-term randomized controlled trials comparing the 2 treatment modalities are sparse. Hence, conclusions drawn from this systematic review should be interpreted with caution.

There is growing interest in assistive technology (AT) as a means of enabling participation in everyday activities for persons with dementia and their relatives. Health economic assessment of AT in dementia is of importance due to the consequences of the disease for both patients and relatives and to the high societal costs for dementia care. The aim of this article is to outline a model for assessment of AT interventions for persons with dementia. The model expands existing assessment models as it also includes evaluation of the intervention process. Methodological challenges and possibilities in making health economic assessments, including outcomes and costs, as well as process evaluation, are discussed in the article.

OBJECTIVE: To determine whether detection of invasive cervical cancer by screening results in better prognosis or merely increases the lead time until death.

DESIGN: Nationwide population based cohort study.

SETTING: Sweden.

PARTICIPANTS: All 1230 women with cervical cancer diagnosed during 1999-2001 in Sweden prospectively followed up for an average of 8.5 years.

MAIN OUTCOME MEASURES: Cure proportions and five year relative survival ratios, stratified by screening history, mode of detection, age, histopathological type, and FIGO (International Federation of Gynecology and Obstetrics) stage.

RESULTS: In the screening ages, the cure proportion for women with screen detected invasive cancer was 92% (95% confidence interval 75% to 98%) and for symptomatic women was 66% (62% to 70%), a statistically significant difference in cure of 26% (16% to 36%). Among symptomatic women, the cure proportion was significantly higher for those who had been screened according to recommendations (interval cancers) than among those overdue for screening: difference in cure 14% (95% confidence interval 6% to 23%). Cure proportions were similar for all histopathological types except small cell carcinomas and were closely related to FIGO stage. A significantly higher cure proportion for screen detected cancers remained after adjustment for stage at diagnosis (difference 15%, 7% to 22%).

CONCLUSIONS: Screening is associated with improved cure of cervical cancer. Confounding cannot be ruled out, but the effect was not attributable to lead time bias and was larger than what is reflected by down-staging. Evaluations of screening programmes should consider the assessment of cure proportions.

Background: The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program.

Methods: We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided.

Results: Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups (Phomogeneity = .96). The risk for nonsquamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer.

Conclusions: Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against nonsquamous cancers.