Large-scale data analysis of uterine leiomyomas : from germline predisposition to somatic characterization

Uterine leiomyomas (ULs) are extremely common, benign smooth muscle tumors. Their incidence is 70% in the Caucasian population by the age of fifty and even higher in black women. They cause symptoms such as pain and abnormal menstrual bleeding in 25% of the affected women. At present, surgery is still the only widely used curative treatment option. Taken together, ULs cause both significant morbidity and a huge economic burden. Based on driver alterations, ULs have been divided into three distinct subtypes: 70-80% of ULs have a MED12 mutation, 10-15% a HMGA2 overexpression, and 1% a biallelic FH inactivation. The driver event for the remaining 10-15% of ULs remains unknown. The subtypes have different molecular and clinical characteristics, but the tumorigenic mechanism of the driver events is elusive. Based on family studies, population disparity, and previous linkage- and association analyses, ULs have a hereditary component. The aim of this thesis was to characterize both the germline and somatic landscape of ULs utilizing various genome-wide methods and both biobank material and a large collection of over two thousand prospectively collected tumor samples. Previous studies on the heritable component of ULs have been limited by small sample sizes and have discovered only few significant loci. Furthermore, the role of these loci in myomagenesis remains unclear. In Study I, we performed the largest UL genome-wide association study (GWAS) to date revealing 22 significant loci. Most of the candidate genes could be categorized as either genitourinary development genes or genetic stability genes. Among the candidate genes were ESR1, MED12, TP53, and TERT. In Study II we scrutinized a set of tumors with an unknown driver event and discovered mutations in six of the nine SRCAP complex genes. Overall, these mutations were detected in 2% of all ULs. SRCAP complex loads variant histone H2A.Z into chromatin, mostly to active and bivalent transcription start sites and enhancers. We showed that this loading is defective in the SRCAP complex mutated lesions. By integrating data from various sources, we were also able to highlight the importance of bivalent regulation in all UL subtypes and pinpoint genes regulating development and differentiation, such as CBX2, CBX4, and CBX8, as potential players in UL genesis. In Study III we examined SNP-array data from 1,946 tumors and showed an association between parity and the total length of allelic imbalance, complex chromosomal rearrangements, and whole chromosome losses. Mechanical forces have been shown to be able to cause DNA damage; in pregnancy and parturition, the uterus undergoes major changes in size and is affected by large mechanical forces. Furthermore, we showed in vitro that stretching can cause damage and detected both increased DNA damage and repair in stretched myoma and myometrial cells. Taken together, we established mechanical stretching as a potential new mechanism for tumorigenesis. The differential diagnosis of uterine tumors is sometimes complicated. In Study IV we detected nine tumors initially diagnosed as ULs expressing tyrosine kinase fusion genes. Such fusions have not been described in ULs but are typical for inflammatory myofibroblastic tumors (IMTs). IMT is a rare tumor type with intermediate malignant potential. These tumors can have a fascicular growth pattern that closely resembles ULs. We discovered that the protein expression and morphological pattern of the tyrosine kinase fusion-positive samples were leiomyoma-like. In gene expression level, some differences to UL subtypes were detected. Among the pathways enriched in the tyrosine kinase fusion-positive lesions was epithelial-to-mesenchymal transformation. Our results raise the question on whether these tumors are UL-like IMTs or tyrosine kinase fusion-positive ULs and highlight the heterogeneity of uterine lesions.Kohdun leiomyoomat, lyhyemmin myoomat, ovat hyvänlaatuisia sileälihaskudoskasvaimia. Niiden ilmaantuvuus on 70% valkoisessa väestössä viiteenkymmeneen ikävuoteen mennessä. Ne aiheuttavat oireita, esimerkiksi kipua ja vuotohäiriöitä, 25%:lla potilaita. Tällä hetkellä leikkaus on ainoa parantava hoito. Myoomat on jaettu kolmeen selväpiirteiseen alaryhmään: 70-80%:lla myoomista on MED12-geenin mutaatio, 10-15%:lla HMGA2-geenin yli-ilmentyminen ja 1%:lla bialleelinen FH-geenin inaktivaatio. Tämän väitöskirjatyön tarkoituksena oli kartoittaa myoomien erityispiirteitä huomioiden sekä ituradan että somaattiset muutokset. Tätä varten hyödynsimme genominlaajuisia menetelmiä ja yli kahdentuhannen kasvaimen näytesarjaa. Ensimmäisessä osatyössä suoritimme tähän asti suurimman myoomien genominlaajuisen assosiaatioanalyysin, joka paljasti 22 tilastollisesti merkitsevää lokusta. Suurin osa kandidaattigeeneistä liittyi kohdun kehitykseen tai geneettisen vakauden ylläpitoon. Toisessa osatyössä havaitsimme mutaatiota kuudessa yhdeksästä SRCAP kompleksin geenissä. Näitä mutaatioita havaittiin kaikkiaan kahdessa prosentissa kaikista myoomista. SRCAP kompleksin tehtävä on ladata varianttihistoni H2A.Z kromatiinille, useimmiten aktiiviselle ja bivalenteille transkription aloituskohdille ja tehostajaelementeille. Me näytimme tämän lataamisen olevan puutteellinen myoomissa, joilla on SRCAP kompleksin mutaatio. Kolmannessa osatyössä hyödynsimme SNP-siru dataa ja näytimme assosiaation synnyttäneisyyden ja alleelisten epätasapainoalueiden pituuden, monimutkaisten kromosomaalisten muutoksien ja koko kromosomin puutoksien välillä. Näytimme lisäksi in vitro kokeessa, että venytys aiheuttaa DNA vaurioita sekä myooma että myometrium soluissa. Kaiken kaikkiaan päättelimme mekaanisen stressin olevan uusi potentiaalinen mekanismi kasvainten synnylle. Neljännessä osatyössä havaitsimme yhdeksän alun perin myoomana diagnosoitua näytettä, jotka ilmensivät tyrosiinikinaasifuusiogeeniä. Tällaisia fuusiogeenejä ei ole kuvattu kohdun myoomissa, mutta ne ovat tyypillisiä tulehduksellisissa myofibroblastikasvaimissa. Tämä on harvinainen ja joissain tapauksissa pahanlaatuinen kasvaintyyppi, jolla voi olla leiomyoomaa muistuttava kasvutapa. Tuloksemme herättävät kysymyksen siitä, tulisiko nämä fuusiopositiiviset kasvaimet luokitella leiomyoomiksi vai tulehduksellisiksi myofibroblastikasvaimiksi

Why do infants need out-of-hospital emergency medical services? A retrospective, population-based study

BackgroundThe challenges encountered in emergency medical services (EMS) contacts with children are likely most pronounced in infants, but little is known about their out-of-hospital care. Our primary aim was to describe the characteristics of EMS contacts with infants. The secondary aims were to examine the symptom-based dispatch system for nonverbal infants, and to observe the association of unfavorable patient outcomes with patient and EMS mission characteristics.MethodsIn a population-based 5-year retrospective cohort of all 1712 EMS responses for infants (agePeer reviewe

Outcomes in children evaluated but not transported by ambulance personnel: Retrospective cohort study

Peer reviewe

Pediatric traumas and neighborhood socioeconomic characteristics: A population based study

Background: Identifying pediatric populations at risk for traumas would enable development of emergency medical services and emergency departments for children. Elucidation of the nature of socioeconomic differences in the incidence of pediatric out-of-hospital emergencies is needed to overcome inequities in child health. Methods: We retrieved all ambulance contacts during 17.12.2014-16.12.2018 involving children (0-15 years) in Helsinki, Finland and separated traumatic and nontraumatic emergencies. We compared the incidences of these emergencies in the pediatric population with socioeconomic markers of the scene of the emergency and of the residential area of the child. Results: Of 11,742 ambulance contacts involving children 4113 (35.0%) were traumatic. Traumatic emergencies occurred more often in neighborhoods with lower median income/household (P= 0.043) and were more common in children living in areas with lower median income/inhabitant (P = 0.001), higher unemployment (P < 0.001), and lower education (P < 0.001). The associations were weaker for traumatic than nontraumatic emergencies. Higher proportion of a pediatric population in a residential area (P= 0.005) had a protective effect. Exclusion of clinically unnecessary ambulance responses did not change the results. Conclusion: Traumatic emergencies in children are more common in areas with lower socioeconomic status. The possible protective effect of urban planning merits further studies. Type of study: Prognostic. Level of evidence: II. (c) 2020 Elsevier Inc. All rights reserved.Peer reviewe

Ambulance crew-initiated non-conveyance in the Helsinki EMS system-A retrospective cohort study

Background Ambulance patients are usually transported to the hospital in the emergency medical service (EMS) system. The aim of this study was to describe the non-conveyance practice in the Helsinki EMS system and to report mortality following non-conveyance decisions. Methods All prehospital patients >= 16 years attended by the EMS but not transported to a hospital during 2013-2017 were included in the study. EMS mission- and patient-related factors were collected and examined in relation to patient death within 30 days of the EMS non-conveyance decision. Results The EMS performed 324,207 missions with a patient during the study period. The patient was not transported in 95,909 (29.6%) missions; 72,233 missions met the study criteria. The patient mean age (standard deviation) was 59.5 (22.5) years; 55.5% of patients were female. The most common dispatch codes were malaise (15.0%), suspected decline in vital signs (14.0%), and falling over (12.9%). A total of 960 (1.3%) patients died within 30 days after the non-conveyance decision. Multivariate logistic regression analysis revealed that mortality was associated with the patient's inability to walk (odds ratio 3.19, 95% confidence interval 2.67-3.80), ambulance dispatch due to shortness of breath (2.73, 2.27-3.27), decreased level of consciousness (2.72, 1.75-4.10), decreased blood oxygen saturation (2.64, 2.27-3.06), and abnormal systolic blood pressure (2.48, 1.79-3.37). Conclusion One-third of EMS missions did not result in patient transport to the hospital. Thirty-day mortality was 1.3%. Abnormalities in multiple respiratory-related vital signs were associated with an increased likelihood of death within 30 days.Peer reviewe

Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.Peer reviewe

Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma

One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility(1), and are a common cause of hysterectomy(2). They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA2(3). Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex(4), and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice(5). Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.Peer reviewe

Kuurosokeiden kokemuksia tulkin käytöstä sairaalassa ja kommunikaatiosta hoitohenkilökunnan kanssa

Kuisma Heli & Mikkola Soile. Kuurosokeiden kokemuksia tulkin käytöstä sairaalassa ja kommunikaatiosta hoitohenkilökunnan kanssa. Kevät 2018, 54 s., 2 liitettä. Diakonia-ammattikorkeakoulu, Viittomakielen ja tulkkauksen koulutus, tulkki (AMK). Opinnäytetyön tavoitteena oli kartoittaa kuurosokeiden kokemuksia tulkin käytöstä sairaalassa ja kommunikaatiosta hoitohenkilökunnan kanssa. Opinnäytetyön aineiston keruu toteutettiin haastattelemalla yhtätoista kuurosokeaa henkilöä, jotka olivat olleet sairaalahoidossa vähintään yhden vuorokauden ajan. Haastattelut toteutettiin henkilökohtaisesti sekä sähköpostin ja puhelimen välityksellä. Haastatteluista selvisi, että sairaalan hoitohenkilökunta ei tiedä tarpeeksi kuurosokeudesta ja sen vaikutuksista kommunikaatioon. Selkeä ja rauhallinen puhe sekä katsekontakti keskustelukumppanin kanssa koettiin tärkeäksi kommunikaation sujumisessa. Tulkin käyttö helpotti kommunikaatiotilanteita, mutta tulkkia olisi tarvittu myös opastamiseen sairaalassa ja vuorovaikutustilanteisiin muidenkin ihmisten kuin hoitohenkilökunnan kanssa. Vastausten perusteella kuurosokeiden kommunikaatio ymmärretään laajempana kokonaisuutena. Fyysisen tilan ominaisuudet, kuten valaistus ja akustiikka, vaikuttavat kuurosokean itsenäiseen tiedon saamiseen. Fyysisen tilan tärkeys kommunikaatiossa korostuu, kun kuurosokea on sairaalahoidossa uudessa ympäristössä. Opinnäytetyön loppuun koottiin vastauksista viisi toivetta sairaalan hoitohenkilökunnalle kuurosokean asiakkaan kanssa toimimiseen. Hoitohenkilökunnan toivottiin hankkivan tietoa kuurosokeiden kommunikaatiosta ja opastamisesta, puhuvan kuurosokealle normaalisti, mutta selkeästi, kertovan kuka on ja kenelle puhuu, huomioivan, että kuurosokeus on yksilöllistä ja fyysinen ympäristö vaikuttaa kuurosokean tiedon saamiseen.Kuisma Heli & Mikkola Soile. Experiences of deafblind people using an interpreter in hospital and their experiences of communicating with the nursing staff in hospital 54 pp., 2 appendices. Language: Finnish. Spring 2018. Diaconia University of Applied Sciences. Degree Programme in Sign Language and Interpreting. Degree: Interpreter. The object of the thesis was to explore the experiences of deafblind people using an interpreter in hospital and their experiences of communicating with the nurses and the doctors in hospital. The material was collected by interviewing eleven deafblind persons who have been in a hospital at least for one night. The deafblind people were interviewed face-to-face and via e-mail and phone call. The results of the interview showed that the nursing staff do not have enough knowledge of deafblindness and how it affects communication. Calm and well articulated speech and eye contact are important while having a conversation with a deafblind person. Using an interpreter made the communication easier but the interviewees would have needed an interpreter also for guidance and interaction with other people. Based on the results of the interviews the communication of the deafblind also consists of the physical space, for example lightning and acoustics. The physical space affects the receiving of the information. If the environment is unfamiliar for the deafblind person the physical space needs to be free of distraction. The major results can be summarized as five wishes for the doctors and the nurses nursing deafblind people. The interviewees wished that the nursing staff would get more information about communication and guidance of deafblind people. The nursing staff should speak normally but well articulated and when they are talking to a deafblind person they should tell their name and who they are talking to. They should also take into consideration that every deafblind person is different and the physical space affects how deafblind people get information.Opinnäytetyön viittomakielinen tiivistelmä löytyy Diakonia-ammattikorkeakoulun Turun-kampukselta

"LAPSEN KASVOILTA PAISTAA ONNELLISUUS" Tyytyväisyyskysely Auta Lasta ry:n päiväkodeissa olevien lasten vanhemmille

TIIVISTELMÄ Kuisma, Heli. ”Lapsen kasvoilta paistaa onnellisuus” Tyytyväisyyskysely Auta Lasta ry:n päiväkodeissa olevien lasten vanhemmille. Oulu, syksy 2015. 43 sivua, 2 liitettä. Diakonia-ammattikorkeakoulu, Sosiaalialan koulutusohjelma, Sosionomi (AMK) + lastentarhanopettajan virkakelpoisuus. Opinnäytetyön tarkoituksena oli suunnitella ja toteuttaa asiakastyytyväisyyskysely Auta Lasta ry:n päiväkodeille. Tavoitteena oli saada päiväkodeille hyödyllistä tietoa, jota he voivat hyödyntää kehittäessään toimintaansa. Työssä käytettiin sekä laadullisen että määrällisen tutkimuksen menetelmiä. Aineistonkeruumenetelmänä oli verkkokysely. Aineisto analysoitiin määrälliselle tutkimukselle tyypillisesti erilaisten kuvioiden avulla ja kuvaamalla keskiarvoja. Avoimien kysymysten vastauksien analysointiin käytettiin aineistolähtöistä sisällönanalyysiä. Kyselyn perusteella vanhemmat olivat pääosin tyytyväisiä lastensa päivähoitoon. Erityistä kiitosta sai henkilökunta. Tiedon saamiseen lapsen päivän kulusta toivottiin parannusta. Asiasanat: asiakastyytyväisyyskysely, varhaiskasvatus, kasvatuskumppanuus, laadunarviointi.ABSTRACT Kuisma, Heli. ”Happiness is written on the child’s face”. Satisfaction survey for the parents whose children are in the kindergarten of Auta Lasta ry. 42 pages, 2 appendices. Language: Finnish. Oulu, autumn 2015. Diaconia University of Applied Sciences. Degree Programme in Social Services. Degree title: Bachelor of Social Services + Option of Kindergarten teacher. The purpose of the thesis was to plan and carry out a satisfaction survey on two kindergartens of Auta Lasta ry, Finland. The object was to get useful information for the kindergartens so that they can develop their activities. In this thesis both qualitative and quantitative research and analysing methods were employed. The data were collected via an Internet survey. The data were analysed by using diagrams and describing average figures. Verbal answers were analysed by using data-based content analysis. According to the answers, parents were mainly satisfied with the day care of their children. Especially the staff were praised. Parents hoped to get more information about the course of the day for the child. Key words: satisfaction survey, early childhood education, companionship of care and education, quality assessmen

Prehospital COVID-19 patients discharged at the scene – an observational study

Abstract Background Emergency medical services (EMS) were the first point of contact for many COVID-19 patients during the pandemic. The aim of this study was to investigate whether the non-conveyance decision of a COVID-19 patient was more frequently associated with a new EMS call than direct ambulance transport to the hospital. Methods All confirmed COVID-19 patients with an EMS call within 14 days of symptom onset were included in the study. Patients were compared based on their prehospital transport decision (transport vs. non-conveyance). The primary endpoint was a new EMS call within 10 days leading to ambulance transport. Results A total of 1 286 patients met the study criteria; of these, 605 (47.0%) were male with a mean (standard deviation [SD]) age of 50.5 (SD 19.3) years. The most common dispatch codes were dyspnea in 656 (51.0%) and malaise in 364 (28.3%) calls. High-priority dispatch was used in 220 (17.1%) cases. After prehospital evaluation, 586 (45.6%) patients were discharged at the scene. Oxygen was given to 159 (12.4%) patients, of whom all but one were transported. A new EMS call leading to ambulance transport was observed in 133 (10.3%) cases; of these, 40 (30.1%) were in the group primarily transported and 93 (69.9%) were among the patients who were primarily discharged at the scene (p<.001). There were no significant differences in past medical history, presence of abnormal vital signs, or total NEWS score. Supplemental oxygen was given to 33 (24.8%) patients; 3 (2.3%) patients received other medications. Conclusion Nearly half of all prehospital COVID-19 patients could be discharged at the scene. Approximately every sixth of these had a new EMS call and ambulance transport within the following 10 days. No significant deterioration was seen among patients primarily discharged at the scene. EMS was able to safely adjust its performance during the first pandemic wave to avoid ED overcrowding