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Intestinal epithelium is capable of rapid regeneration, which is associated with transient changes in cellular identity. Some of these changes involve an enrichment of fetal-like gene expression and simultaneous suppression of adult stem cell signature. Interestingly, the upregulation of fetal-like marker Stem cell antigen 1 (Sca1) is modulated by extracellular matrix (ECM) which is known to guide epithelial cells during regeneration. Our recently published decellularized small intestinal ECM (iECM) system retains the composition and topology of natural ECM. This makes it an attractive system for ex vivo studies addressing regeneration. This thesis aimed to gain insight into the fetal-like identity and its dynamics using an ex vivo iECM system. Intriguingly, Sca1 expressing cells on iECM displayed migratory features, such as a leading edge and changes in nuclear morphology. Curiously, these features are typical for epithelial cells during development. Furthermore, based on marker gene expression during iECM re-epithelization, fetal-like state was upregulated while adult stem cell state was downregulated, revealing a gradually emerging inverse correlation. Additionally, data suggests that circadian rhythms may have a role in modulating the fetal-like state. iECM from an active-state mice indicated a reduced capability to induce fetal-like identity and overall re-epithelization compared to the rest-state iECM. The results of this thesis suggest further potential of iECM system in studying emergence of fetal-like state during re-epithelization and circadian rhythm impact on it.

Playing video games is a popular way to spend time and mobile gaming is one of the most growing entertainment industries in the world. Gaming is often associated with high level of motivation from the user as well as many negative and positive outcomes. Commitment towards games has invited countless of researches to examine what makes them so intriguing and motivating. This growing understanding gives developers more tools to design even better games and allows game-like features to be used in other contexts as well. This master’s thesis examines automatically gathered early log-data (n=100 000) from two free-to-play mobile games in order to create a model for retention. A model created using early log-data (first three days of play) creates opportunities to recognize potential players in an early phase and to evaluate early iterations of games that are in development. Furthermore, individual features are analyzed to study, what are the factors that influence coming back to the game at a later point (30 days after the installation of the game). The research questions in this thesis are: 1) Can commitment towards mobile games be modeled using early log-data? 2) How accurate predictions the created model can do? 3) What are the most important in-game features that predict retention? The model is created using a decision tree analysis, which was selected as a method due to its transparency and because it has been used before in earlier studies with similar designs. In both games, the rate of coming back to the game after 30 days of installation was 7.6%. A working model for retention was formulated which was able to predict coming back to the game with 33% accuracy. The most important in-game features that affect retention were the number of victories, the number of starts and the number of in-app-purchases during the three-day period after the game’s installation. Surprisingly, in-game rewards and achievements were the most insignificant features when predicting retention although they are often specifically designed to elevate user motivation. These results can influence design decisions made in game development by setting the focus on the factors that influence player commitment and behavior. Achievements and in-game rewards might feel too artificial and superficial compared to winning in game. If the system gives direct feedback of the effect of time and monetary sacrifice to the player’s performance, one might be able to reduce the number of players that decide to leave the game. The results also can be used to examine how game-like features are used in non-game systems where the goal is to tie together the high-level of motivation seen in games and socially impactful endeavors. Further studies of in-game behavior might also give new insights on game addiction and its negative effects on player well-being and business.

Objectives: Bisphenol A (BPA) is commonly used plasticizer that has endocrine disrupting properties. Fetal exposure to BPA has been associated with offspring behavioural problems. These associations may be mediated through BPA-induced alterations in the offspring DNA methylation (DNAm). This study examined whether fetal BPA exposure associates with behavioural problems and whether DNAm biomarker score for early pregnancy BPA exposure is linked with behavioural problems in the offspring. Methods: Participants were 442 mother-child pairs of the Finnish PREDO-cohort. I measured BPA from the early pregnancy urine samples and assayed DNAm in the cord blood with Illumina 450k or EPIC array. Mothers reported behavioural problems of their offspring with the Child Behaviour Checklist/1.5-5 (CBCL/1.5-5) at the mean child age of 3.8 years (SD = 1.0 years). I used LASSO regression to create a DNAm score for early pregnancy BPA exposure and tested the associations between BPA exposure, the DNAm score, and CBCL/1.5-5 scores with linear and logistic regressions. Results: After adjustments, early pregnancy BPA exposure was associated with higher risk for clinically meaningful internalizing (p = .02) and externalizing (p = .04) behavioural problems in the offspring. The DNAm score included eight CpG sites, explained 4.8% of the BPA variation, and was borderline significantly associated with a risk for clinically meaningful internalizing (p = .05) and externalizing behavioural problems (p = .06). Conclusions: Early pregnancy BPA exposure associated and DNAm biomarker for BPA exposure borderline associated with offspring behavioural problems. DNAm biomarker score for fetal BPA exposure showed promise and should be studied further in subsequent studies.

Aortic stenosis is the most important type of valvular heart disease among elderly patients, that often lead to valve replacement interventions. As the age structure shifts towards older age and life expectancy continues to rise, the prevalence of aortic stenosis is presumed to rise, resulting in more patients and additional expenses. Echocardiography is the most important tool for assessing aortic stenosis among patients. An experienced clinician can determine the severity of the disease with echocardiography alone, although the complete picture of a patient’s health must be evaluated during examination. The choice of intervention and timing thereof should be done by a heart team consisting consists of cardiologists, cardiac surgeons, radiologists, interventional radiologists and anaesthesiologists. Intervention is done by replacing the stenotic aortic valve with a functional synthetic valve either by surgical aortic valve replacement (SAVR) or by transcatheter aortic valve implant (TAVI). Echocardiography is used for evaluating prognosis and selecting type of care for each patient, based on the ECHO findings. This overview presents the use of transthoracic echocardiography as a tool for assessment of disease severity among patients with aortic stenosis, as well as advantages and limitations. The overview incudes a study of the clinical outcome of 30 patients with aortic stenosis treated with surgical aortic valve replacement and transcatheter aortic valve implant within the AS-AMYL study at the Helsinki University Hospital.

Synnytyksen käynnistyksen yleisimmät syyt Suomessa ovat yliaikaisuus ja lapsivedenmeno, jotka ovat miltei tasavertaiset yleisyydessään. Vuonna 2017 Suomessa synnytyksistä käynnistettiin 28,9 % ja tällöin lapsivedenmeno oli toiseksi yleisin syy käynnistykseen HYKS:ssä. HYKS:ssä synnytys käynnistetään 12 tunnin kuluessa lapsivedenmenosta GBS-positiivisilla synnyttäjillä ja 24 tunnin kuluttua GBS-negatiivisilla. Tutkimuksen tavoitteena oli selvittää lapsivedenmenon vaikutusta synnytyksen kulkuun ja lopputuloksiin niillä synnyttäjillä, joiden synnytys on käynnistetty lapsivedenmenon takia. Tutkimus on retrospektiivinen ja aineisto koostuu HYKS synnytyssairaaloiden synnyttäjistä vuodelta 2017. Synnyttäjien esitiedot, tiedot synnytysten käynnistyksestä ja etenemisestä sekä synnytysten päätetapahtumat ja syntyneiden lasten tiedot on kerätty sairaskertomuksista Obstetrix- ja Miranda-potilastietojärjestelmistä. Tiedot on analysoitu SPSS-taulukkolaskentaohjelman avulla. Tutkimuksessa todettiin ensisynnyttäjyyden, synnyttäjän lyhyen pituuden, ylipainon, aiemman keisarileikkauksen ja epäkypsän kohdunkaulan käynnistyksen alussa liittyvän lisääntyneeseen keisarileikkauksen riskiin, kuten aiemmissakin tutkimuksissa. Infektioita todettiin enemmän ensisynnyttäjillä ja keisarileikkaukseen päätyneillä. Synnytyksissä, jotka olivat keskimääräiseltä kestoltaan pidempiä lapsivedenmenosta ja/tai synnytyksen käynnistyksen alusta syntymään, ilmeni enemmän synnytyksen aikaisia tai jälkeisiä infektioita. GBS-positiivisille synnyttäjille annetaan HYKS:n hoitokäytännön mukaisesti ennaltaehkäisevä antibioottihoito lapsiveden mentyä ja heidän lapsillaan oli vähemmän infektioita kuin GBS-negatiivisten synnyttäjien lapsilla. Lapsivedenmenon ajankohdalla ei ollut vaikutusta lasten infektioiden esiintymiseen. Lapsivedenmenon vuoksi käynnistetyissä synnytyksissä äitien ja lasten infektioiden esiintyvyys ei poikennut muista HYKS:ssä vuonna 2017 käynnistetyistä synnytyksistä.

The role of decompressive craniectomy as a cure in traumatic brain injuries has been widely been discussed. Therefore our aim was to assess the independent effect of decompressive craniectomy the outcome and mortality of the patient. We conducted an open-cohort retrospective study on adult blunt TBI patients. Patients were divided into three groups; conservative treatment, acute craniotomy and mass lesion evacuation (craniotomy) and decompressive craniectomy. Outcome was assessed using Glasgow Outcome Scale and overall mortality six months after the operation. The adjusted multivariate analysis did not show an independent association between decompressive craniectomy and mortality. Decompressive craniectomy prooved to be an independent risk factor for poor neurological outcome with an OR of 3.06. In conclusion, operating TBI patients with decompressive craniectomy was found to be a life-saving intervention for patients who in other cases were destined to die. For stronger evidence this subject needs more research of a prospective type.

Tutkimuksen tavoite: Hydroklooritiatsidi on usein käytetty verenpainelääke, jonka yleinen haittavaikutus on veren uraattipitoisuuden nousu. Veren korkea uraattipitoisuus lisää riskiä sairastua sydän- ja veri- suonitauteihin. Halusimme tutkia hydroklooritiatsidin aiheuttaman plasman uraattipitoisuu- den nousun geneettistä taustaa, jota on vielä vasta vähän tutkittu. Potilaat ja menetelmät: GENRES on satunnaistettu, kaksoissokkoutettu ja lumekontrolloitu tutkimus, jossa 35-60- vuotiaille verenpainetautia sairastaville suomalaisille miehille annettiin neljää eri verenpai- nelääkettä neljän viikon jaksoissa. Jokaista verenpainelääkejaksoa edelsi 4 viikon lumelääke- hoitojakso. LIFE on satunnaistettu ja kaksoissokkoutettu tutkimus, jossa verrattiin losartaanin ja atenololin tehoa verenpainetaudin hoidossa. Ellei losartaanilla tai atenololilla saavutettu riittävän hyvää verenpainevastetta, rinnalle liitettiin hydroklooritiatsidi. Tutkimme 214 suo- malaisella miehellä GENRES-aineistossa genetiikan vaikutusta hydroklooritiatsidin aiheut- tamaan plasman uraattipitoisuuden nousuun koko perimän kattavalla assosiaatioanalyysillä. Teimme toistoanalyysin GENRES-tutkimuksen parhaille tuloksille käyttäen 465 suomalaisen LIFE-tutkimuspotilaan näytteitä. Valitsimme toistoanalyysiin SNP:t, joiden P-arvo oli alle 5 x 10-5 GENRES:ssä. Tulokset: GENRES-tutkimuksessa keskimääräinen plasman uraattipitoisuuden nousu hydroklooritiatsi- dihoidon aikana oli 50 ± 39 μmol/l. GENRES-tutkimuksessa löysimme 31 lokusta, jotka liit- tyivät hydroklooritiatsidin aiheuttamaan plasman uraattipitoisuuden nousuun P-arvolla < 5 x 10-5. rs1002976 lähellä VEGFC-geeniä assosioitui hydroklooritiatsidin aiheuttamaan muutok- seen molemmissa aineistoissa merkitsevästi. rs950569 lähellä BRINP3-geeniä replikoitui LI- FE:ssa osittain merkitsevästi. Aikaisemmin hydroklooritiatsidin aiheuttamaan uraattipitoi- suuden nousuun liitettyjen SNP:iden ja geenien analyysi tuotti lisää tietoa PADI4- ja ABCC4- geenien vaikutuksista. Yhteenveto: Olemme löytäneet muutaman uuden SNP:n ja löytäneet lisää tietoa jo tunnettujen geenivaih- teluiden vaikutuksesta hydroklooritiatsidin aiheuttamaan seerumin uraattipitoisuuden nou- suun.

As life expectancy increases, the effectiveness of cervical cancer screening programs needs to be reassessed for the older population. We addressed the effect of test history in and outside organized screening at age 50–64 years on later cervical cancer risk. A case-control study was conducted by deriving 229 cases of 65–79-year-old women with invasive cervical cancer in 2010–2019 from the Finnish Cancer Registry. Ten controls were matched for each case by birth year and hospital district. The effect of test uptake and abnormal results in 50–64-year-olds on cancer risk was investigated using conditional logistic regression and adjusted for self-selection. Test uptake within the 50–64-year age-group showed 75% lower odds of cervical cancer (adjusted odds ratio [aOR] = 0.25; 95% confidence interval [95% CI], 0.18–0.35). Untested women had 4.9 times higher odds than those tested with normal results (aOR = 4.86; 95% CI, 3.42–6.92). Having at least one abnormal test result increased the odds by 2.5 when compared to only normal results but showed lower odds when compared to untested women. The importance of testing is exhibited by the result showing a reduction of odds of cancer to one-fourth for those tested compared to untested. Similarly, receiving abnormal results was protective of cancer compared to having no tests highlighting the importance of proper follow-up. Therefore, screening history should be considered when further developing cervical cancer screening programs with special interest in non-attenders and those receiving abnormal results at older ages.

In our research we studied if the overexpression of VEGF-A would save the impaired tumor growth in PROX1 silenced colorectal cancer xenografts. We conducted both small hairpin PROX1 and VEGF-A gene transfers to SW1222 colorectal cancer cells using lentiviral vectors. SW1222 cell lines were then injected to Nod scid gamma mice and grown for 14 days for analysis. We also established 3D cocultures of genetically modified SW1222 cell line together with lymphatic endothelial cells or blood endothelial cells to analyze lymphangiogenesis and angiogenesis in vitro. We found out that overexpression of VEGF-A rescues the growth of PROX1 silenced tumors. Large necrotic areas in the central of the PROX1 silenced tumors remain even though VEGF-A overexpression induces greater vascularity in these xenografts. In 3D cocultures silencing of PROX1 did not affect in vitro lymphangiogenesis or angiogenesis.

Aims of the study. It is well known that many adolescents do not get enough sleep. However, there is little research about the possible connection between adolescent sleep and family functioning. In addition, these studies vary greatly in, e.g., methodology and ages of the participants and only a few studies have used actigraphy. The aim of the present study is to examine the associations between family functioning and adolescent sleep, more specifically sleep duration, sleep quality and sleep timing. Methods. The present study was a part of SleepHelsinki!, a population-based research project based in the University of Helsinki. Sleep and family functioning of 308 adolescents (70.5% females), aged 15–18, were measured. Both subjective (PSQI) and objective (actigraphy) measures of sleep were used. Linear and logistic regressions were used to statistically analyze the associations between family functioning and sleep timing and subjective sleep quality. Results and conclusions. The association between family functioning and sleep duration was non-significant. When sex was adjusted for, the association between family functioning and sleep timing remained non- significant. However, the association between subjective sleep quality and general family functioning was statistically significant. Furthermore, problematic family functioning was related to a higher risk of poor sleep quality. Male sex was related to a higher risk of having a challenging circadian rhythm. Based on the results of the present study, family functioning is connected to subjective sleep quality and more problematic family functioning is a risk factor for lower quality sleep in adolescents.