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Although lung transplantation has become a routine procedure and is optimal therapy for patients with end-stage pulmonary diseases, the lifespan of lung allografts is still shorter than that of other organ transplants. As acute allograft rejection is one of the main risk factors for the development of chronic lung allograft dysfunction (CLAD) which threatens the long-term survival rate of the recipients, it is crucial to predict and diagnose acute lung allograft rejection. However, there are no specific methods established so far to predict acute rejection (AR). Even though the histopathological evaluation of transbronchial biopsies (TBBs) is used as the gold standard to ensure the diagnosis of AR, it is essential to discover novel biomarkers for AR to overcome the limitations of the TBB-based invasive diagnostics. Recently extracellular vesicles (EVs) got noticed as potential biomarkers in various fields of medicine based on the findings that they exist in high concentration in body fluids and deliver functional genetic molecules which can modulate gene expression in target cells. In that regard, this preliminary study was designed with two different approaches; a time-point analysis and a case analysis of rejection and non-rejection episodes to validate their potentials as diagnostic and predictive biomarkers for acute lung allograft rejection. To discover biomarkers, EV RNA was isolated from the plasma of four patients that was collected at different time points, and whole EV mRNA transcriptome sequencing was performed on the Illumina platform to obtain at least 15 million reads. The time-point analysis showed that the mRNA contents of EVs changed according to the time points and clinical presentations of the patients. At the same time, gene expression profiles showed that mRNA molecules inside the EVs change from innate immunity to adaptive immunity related signatures with the time after transplantation. Furthermore, the case analysis identified that EVs contain RNA molecules that are closely related to the migration of leukocytes and adaptive immune system during acute rejection episodes. In conclusion, the profiles of EV RNA may reflect the immune responses that are taking place in the recipient’s body. Therefore, it is speculated that EVs may play an essential role in the development of AR by transferring functional mRNA molecules to the allograft, immune cells, and endothelial cells. On that account, EV transcriptome profiling could be used as a diagnostic tool for AR in the future, as well as a therapeutic tool by engineering EVs to target specific genes that may be involved in the development of AR. Keywords: extracellular vesicles, lung transplantation, transplantation immunology, RNA sequencing, acute lung allograft rejection, biomarkers

Objective: Cardiovascular disease is one of the leading causes of death in the world and elevated blood pressure is one of the major risk factors for cardiovascular disease. Health behavior such as alcohol use, smoking and physical activity as well as obesity are known to affect the risk for cardiovascular disease. Also temperament has been shown to be associated with the risk for cardiovascular disease in numerous studies. The exact pathway through which the association between temperament and the risk for cardiovascular disease is mediated is so far unknown. Temperament has been shown to be associated with elevated blood pressure but not much research on the subject has yet been conducted. The aim of this study was to examine if temperament is associated with elevated blood pressure, which factors mediate the association and how they mediate it. Methods: The participants of the study were from The Cardiovascular Risk in Young Finns Study (CRYFS) and the data from the follow-up carried out in 2007. The subjects were divided into groups of elevated blood pressure and normal blood pressure according to their blood pressure levels. Temperament was assessed using a self-report form of the Temperament and Character Inventory (TCI-9) which measures the temperament traits of Cloninger's psychobiological theory - novelty seeking, harm avoidance, reward dependence and persistence. Concerning mediating variables the subjects were asked to answer questions about their alcohol use, smoking and physical activity. Body mass index was calculated from measures of weight and height. Logistic regression and correlation analyses were used for the analyses. Results and conclusions: A high level of reward dependence was related to a lower risk for elevated blood pressure. Two health behavior variables, higher level of alcohol use and greater body mass index were related to an increased risk. A weak association between a higher level of persistence and a lower level of blood pressure was also found. The association between reward dependence and elevated blood pressure showed evidence for being independent of the health behavior variables. Behavioral styles based on temperament are suggested as the mediating mechanism behind the association. For example behavioral styles could affect a person's tendency to seek medical help and health care. The concept of personalized health care expanded with temperament related information should be considered as a valuable potential asset for preventive health care in the future.

CNGB1-geenin virheet aiheuttavat verkkokalvon perinnöllistä pigmenttirappeumaa, retinitis pigmentosaa, joka periytyy autosomaalisesti ja peittyvästi. CNGB1-geenin poikkeamaan kytkeytyvä verkkokalvorappeuma alkaa useimmiten lapsuusiässä hämäräsokeutena. Näkökenttäpuutokset kehittyvät myöhemmin ja kaikkien potilaiden näöntarkkuus säilyy normaalina aikuisikään saakka. Tyypillisiä silmänpohjan muutoksia ovat ohentuneet verkkokalvon päävaltimot, verkkokalvon pigmenttiepiteelin ohentuma, vahamainen näköhermon pää sekä verkkokalvon pigmenttimuutokset. Tässä kuvattavaan tutkimukseen osallistui yksitoista potilasta, joilla kaikilla on todettu sama CNGB1-geenin tautia aiheuttava variantti c.2957A>T. Kaikille potilaille on suoritettu laaja silmätautiopillinen kliininen tutkimus. Tutkimusta varten potilastietojärjestelmästä kerättiin potilaiden oireiden alkamisikä sekä laatu niiden alkaessa, lasein korjattu näöntarkkuus, näkökenttien ja silmäpohjakuvien kehitys seurannan aikana, verkkokalvon muutokset valokerroskuvissa sekä autofluoresenssikuvien löydökset. Kaikkien potilaiden ensioire oli hämäräsokeus, joka kymmenellä potilaalla ilmeni jo lapsuudessa. Näöntarkkuuden, näkökentän laajuuden ja iän välillä todettiin olevan yhteys, siten, että sekä näöntarkkuus että näkökentän laajuus pienenivät potilaan vanhetessa. Mediaani-ikä sille, että näkö oli huonompi kuin normaalinäkö, oli 50,8 vuotta (keskihajonta 11,7 vuotta). Mediaani-ikä, jolloin potilaiden näkökenttä supistui oireisesti oli 52,0 vuotta (keskihajonta 13,9 vuotta). Silmänpohjakuvissa todettiin retinitis pigmentosalle tyypillisiä muutoksia, kuten retinopatiaa, atrofiaa, luusoluja, pääsuonikaarten ohenemista sekä kalpeat ja vahamaiset näköhermon päät. Myös näitä muutoksia oli sitä enemmän, mitä vanhemmasta potilaasta oli kyse. CNGB1-geenin variantin c.2957A>T aiheuttamaa verkkokalvon pigmenttirappeumaa sairastavilla potilailla tarkka näkö sekä näkökentän laajuus säilyvät pitkälle aikuisuuteen siitä huolimatta, että ensioireet alkavat jo lapsuudessa. Tauti etenee hitaasti, mahdollistaen laajan aikaikkunan taudin hoidolle.

Objective: Accumulating research has shown that severe illness and ICU care seem to affect the cognitive functioning of ICU survivors in many different patient populations. So far, there seems to be little research focusing on the cognitive functioning of circulatory shock patients. The purpose of this thesis was to investigate the cognitive functioning of circulatory shock patients during the first three months after ICU care. The study aimed to compare the level of cognitive functioning of circulatory shock patients with control subjects at the time of ICU discharge and three months thereafter. Further, a temporal viewpoint was added to explore the recovery of cognitive functioning within the first three months following ICU care. Methods: This study is part of the ASSESS-SHOCK 2 project. The sample (N = 99) included 51 circulatory shock patients and 48 control subjects. The cognitive functioning of circulatory shock patients was assessed at ICU discharge and 3 months thereafter with the MoCA test. The assessment 3 months after ICU discharge also included a comprehensive domain-specific neuropsychological evaluation including 23 tests. The control subjects were assessed once with the same methods. Both the performance means, and frequency of cognitive impairment were considered in the analyses. Group differences were studied with general linear models and analysis of covariance, with age and level of education as factors and covariates. The temporal change was studied with a general linear mixed model, with age, level of education, delirium, and severity of illness as factors and covariates. Results and conclusions: This study was one of the first to focus on the post-ICU cognitive functioning of all types of circulatory shock patients. As hypothesised, circulatory shock patients had a lower level of overall cognitive functioning at ICU discharge than the control subjects. The prevalence of cognitive impairment was 77% for the patients at ICU discharge and 43% three months thereafter, compared to 33% for the control subjects. The significant cognitive differences between the two groups disappeared during the first three months after ICU discharge, as the patients’ cognitive functioning seemed to recover during that period. A closer look at the performance on different cognitive domains revealed, however, that circulatory shock patients still seemed to perform worse than the control subjects in the domains of executive functions and attention, and visuomotor and visual functions at the 3-month follow-up. Based on the results, circulatory shock patients seem to be particularly vulnerable to experiencing cognitive difficulties after ICU care. The findings of this study highlight the importance of screening for post-ICU cognitive difficulties in patients treated for circulatory shock. Identifying the cognitive difficulties already at the hospital could help to set up rehabilitation programs, ensuring that the patients would receive the support needed for the best possible recovery.

Objective: Both stress-related exhaustion and depression have previously been associated with a decline in cognitive performance, but there is a lack of evidence on whether these conditions have different associations with different cognitive domains and whether they have additive effects on cognitive performance. Furthermore, very little is known about the cognitive effects of chronic stress-related exhaustion. Consequently, the aims of this study were to 1) examine the associations between current stress-related exhaustion and cognitive performance, 2) investigate whether different developmental trajectories of stress-related exhaustion are differently associated with cognitive performance, 3) compare the association between stress-related exhaustion and cognitive performance to the relationship between depressive symptoms and cognitive performance, 4) examine if individuals with comorbid stress-related exhaustion and depression have lower cognitive performance than individuals with at most one of these conditions (i.e., whether clinical stress-related exhaustion and clinical depression might have additive effects on cognitive performance). Methods: The data used in the study was a Finnish population-based sample of six cohorts born between 1962 and 1977 from the Cardiovascular Risk in Young Finns Study. Stress-related exhaustion was assessed using the Maastricht Questionnaire, depressive symptoms with the Beck Depression Inventory, and cognitive performance with four subtests of the Cambridge Neuropsychological Test Automated Battery, measuring visuospatial associative learning, reaction time, sustained attention, and executive functions. Cognitive performance and depressive symptoms were assessed in 2012, and stress-related exhaustion in 2001, 2007, and 2012. Participants were 35 to 50 years old in 2012. Linear associations between stress-related exhaustion and cognitive performance (N = 905) and depressive symptoms and cognitive performance (N = 904) were examined by conducting multivariate regression analyses. Age, sex, socioeconomic status, and parents’ socioeconomic status were controlled in the regression models. Additionally, multivariate analyses of variance were performed to investigate the different developmental trajectories of stress-related exhaustion and their relation to cognitive performance (N = 541) and the associations of comorbid stress-related exhaustion and depression with cognitive performance (N = 1273). Results and conclusion: The main finding was that high stress-related exhaustion is associated with slower reaction times, but not with performance in spatial working memory, visuospatial associative learning, or executive functions. Ongoing, chronic stress-related exhaustion was more strongly associated with slower reaction times than short-term exhaustion experienced years ago. Compared to depressive symptoms, high stress-related exhaustion was associated with slower reaction times also when subclinical cases were included, whereas only clinical levels of depressive symptoms had an association with slower reaction times. There were no differences in cognitive performance between individuals with only stress-related exhaustion or depression and those with comorbid stress-related exhaustion and depression, which supports the notion that these conditions do not have additive effects on cognitive performance. These findings add to the existing evidence of the cognitive effects of stress-related exhaustion in the general population and have several practical implications. Further research is needed on the topic, preferably with longitudinal designs, more comprehensive cognitive measures, and clinical assessment of the psychiatric symptoms.

In our study, we examined the effects of early-life stress on sleep, depressive behaviour and neurophysiological factors common for depression and sleep disturbances. As a model for early-life stress we used cross-fostered (CF) adolescent and adult, male and female rats. In spontaneous sleep, we found an increase in NREM and REM time in light period and an increased number of REM onsets in light and dark period in CF group. Baseline adenosine expression and BDNF levels in basal forebrain were decreased in CF animals. In the behavioural tests there were no detectable differences, nor in recovery sleep. This thesis will concentrate on the scientific background of the project, further discuss the findings in our study and demonstrate the writer’s personal role in the project.

Abstract Objectives. Despite the convincing evidence of efficacy of psychotherapy, its mechanisms of change in therapy are still unclear raising questions on what constitutes psychotherapy. In this work, the common and specific factors of cognitive behavioral therapy and psychodynamic psychotherapy were inspected by exploring psychotherapy manuals, which has not been previously studied in therapy research, using machine learning methods. The aim of this work was to gain understanding of the theoretical frames of different psychotherapy approaches and explore their distinguishability as well as semantic features. Methods. Textual psychotherapy manuals representing psychodynamic psychotherapy (n=4) and cognitive behavioral therapy (n=4) were analyzed using latent Dirichlet allocation topic modeling. The number of topics was pre-defined as 2, based on the number of therapy approaches. Additionally, a Bayesian method was used, defining the best fitting number of topics for the data. Logistic regression was performed for both solutions regarding the selection of the number of topics to observe the associations of textual topics with the therapy approaches. Two models were compared in their ability to correctly discriminate between the therapy approaches. Results and conclusions. The models consisting of 2 and 24 topics proved excellent in distinguishing the therapy approaches thus pointing towards the differentiable nature of these two approaches. The discriminative power of the model with 24 topics was based on few perfectly discriminative topics yet the model also included topics common for both therapy approaches. Based on this work, the approaches differed regarding relational and agency emphasis whereas shared expectations appeared as common factor.

In diagnosis of many viral and some other microbial infections, measurement of IgG avidity is a globally emerging approach for identifying primary infections and estimating the time of clinical onset. While many calculation methods have been introduced for conversion of the raw data into a numerical avidity value, little information exists on their comparison and whether the complex and laborious ones show superior performance. We here compare diverse approaches for avidity calculation, and introduce for clinical use a new, highly sensitive and specific one. Enzyme immune assay (EIA) absorbance data from 135 parvovirus B19 IgG-positive sera were analyzed in parallel with the new and two reference methods (Avidity1.2 software representing gold standard methodology; avidity index (AI) widely used due to its simplicity). When sample dilutions were selected on the basis of optimal EIA absorbances, all three approaches performed equally (receiver operating characteristic area-under-curve, AUC, discriminating primary infection from past immunity 0.969-0.971). When the samples were reanalyzed at either lower or higher absorbance levels, avidity status (low, borderline or high) was altered, on the average, in 3.7 % of the samples with the new method, in 5.6 % with Avidity1.2 and in 28 % with AI. The new approach was further validated with extensive serum panels for cytomegalovirus, Toxoplasma gondii, rubella and Epstein–Barr virus (AUC 0.990-1.000). It allows for accurate measurement of antimicrobial IgG avidity even from samples with low IgG level, while the globally popular AI approach provides an alternative for samples with sufficiently high IgG level.

The purpose of this study was to assess the best way to measure carpal alignment. The study compared computer-based measurements and manual measurements of the carpal alignment. The subjects of comparison were the methods of measuring the radioscaphoid, radiolunate, radiocapitate and radiometacarpal angles. 30 cone beam CT scans of healthy, uninjured, wrists were analyzed by automated software (Disior ltd) and by hand surgeons using lateral radiographs reconstructed from the CT scans. Six hand surgeons were given instructions on how to take the measurements. They analyzed both reconstructed radiographs in which the wrist bones were partially overlapping due to summation, and reconstructed radiographs, where overlapping of the wrist bones had been digitally removed. In addition, seven different hand surgeons were not given instructions on the measurement methods. They analyzed only the reconstructed radiographs with wrist bones overlapping. In manual measurements, the inter- and intra-observer reliability of the results varied from good to excellent (ICC: 0.77–0.99), both in the instructed and in the uninstructed group. Inter-observer reliability was better in the group instructed in the methods of measurement. Reliability was further improved in reconstructed radiographs where the overlapping of the carpal bones had been digitally removed. Intra-observer reliability was very similar in both the instructed and uninstructed groups, and improved when bony overlapping was removed. The software provided excellent intra-observer reliability (ICC 0.94-1.00) and result, that were highly comparable the instructed manual measurements from radiographs with no bony overlapping (mean difference range 1°-7°). Although statistically significant differences were seen between manual measurements and software measurements, the differences are too small to be clinically significant. The research shows that accurate and repeatable computer-aided measurements of the carpal alignment can be made from CT scans, thereby minimizing observational errors. Key words: Carpal alignment, measurement, reliability, computer-aided, digitally reconstructed radiographs

Background Since the ground-breaking phase III MPACT trial showed clear benefit of gemcitabine-nab-paclitaxel, this regimen has emerged as the standard of care for advanced pancreatic adenocarcinoma (PAC). Prior to this study, few studies have shown how results from randomized controlled trial translate to the real world. This study investigated how patients fared in the real world. Methods This single-centre, retrospective study was conducted in the Vaasa Central Hospital, Finland. 148 patients with PAC (ICD-10 C25) between 1/2011-12/2016 were identified with resectable, locally advanced or metastatic disease. Information about the basic characteristics, treatment regimens and adverse effects (AEs) were extracted from patient files and analysed. Results The median overall survival (OS) was 10.4 months for treated and 2.8 months for untreated patients. For metastatic disease OS was 4.9 months, for locally advanced 9.1 months. Patients who received 3 or more treatment lines had OS 19.1 months, while those who received 2 or 1 line had 11.3 and 6.2 months, respectively. The following grade 2-4 haematologic toxicities occurred: anaemia (n=19), leukopenia (n=49), neutropenia (n=55) and thrombocytopenia (n=9). Febrile neutropenia occurred 7 times. A total of 12 grade 5 AEs were recorded in 7 patients, and 3 other patients died of unknown complications. Conclusion This study shows that active treatment is worth pursuing in most PAC patients and study results from this real-world data study differ from randomized controlled trials. Special caution should be applied when continuing chemotherapy in patients with ECOG 2 and who are older than 70 years.