NÄIN MEILLÄ PÄÄTETÄÄN : Vammaisten itsemääräämisoikeus palveluohjauksessa Varsinais-Suomessa

Luhtanen, Paula & Savola, Marina. Näin meillä päätetään. Vammaisten itsemääräämisoikeus palveluohjauksessa Varsinais-Suomessa. Diak, Pori. Kevät 2015, 55 s., 2 liitettä. Diakonia-ammattikorkeakoulu, Sosiaalialan koulutusohjelma, sosionomi (AMK). Näin meillä päätetään, on Diakonia-ammattikorkeakoulun sosiaalialan koulutusohjelman opinnäytetyö, joka tehtiin kvalitatiivisen tutkimuksen menetelmin Varsinais-Suomen alueella. Opinnäyteyön tutkimuskysymykset olivat: miten palveluohjauksessa tulee näkyväksi asiakkaan etu, ja miten palveluohjauksessa todentuu kehitysvammaisen asiakkaan itsemääräämisoikeus sekä miten vahvistetaan ja tuetaan kehitysvammaisen omien tavoitteiden toteutumista. Aineiston keruu toteutettiin Webropol-kyselyn avulla. Kysely lähetettiin kaikille Varsinais-Suomen kuntien vammaispalveluista vastaaville työntekijöille ja niitä lähetettiin 24 kappaletta. Saatu laadullinen aineisto analysoitiin sisällönanalyysiä hyödyntäen. Tulosten mukaan vammaisten itsemääräämisoikeus palveluohjauksessa voitiin jakaa ns. estäviin ja mahdollistaviin tekijöihin. Ammattihenkilöstöä ohjaavat ammatilliset taidot sekä eettisyys, mutta samaan aikaan myös tarveharkintaa ohjaavat lainalaisuudet. Niissä vastauksissa, joissa vammaisten itsemääräämisoikeutta tuettiin vahvimmin, nousi esiin myös vahva palveluohjaksellinen työote. Johtopäätöksenä voitiin todeta, että tämä opinnäytetyö sekä aikaisempi tutkimustieto tukevat ajatusta siitä, että vammaisten itsemääräämisoikeus on edelleen monista poliittisista muutoksista huolimatta heikosti toteutuvaa. Tutkimuksen tulosten mukaan tulkittiin, että muutoksen tulisi lähteä ammattihenkilöstön asenteesta ja palveluohjauk-sellisen työotteen lisäämisestä.ABSTRACT “This is how the decisions are made”, is a Diaconia university of applied sciences social service education program thesis that has been done with qualitative research methods in the area of Varsinais-Suomi. The research questions were: How does the advantage of a customer become visible in case management, how is it possible to realize the self-determination of a customer and how is it possible to reinforce and support the disables own goals. The collecting of material was executed by a Webropol-questionnaire. The questionnaire was sent to all employees in charge of disability services in Varsinais-Suomi municipalities and 24 questionnaires were sent. The qualitative material gathered was analyzed using content analysis. According to the findings the self-determination of the disabled in case management can be divided into preventing and allowing factors. The professional personnel need their expertise and an ethical approach to work, as well as they need to work in accordance with the specific laws. In those answers where the self-determination of the disabled was supported the strongest, also a strong case management was practiced. As a conclusion it is notable that this thesis and the previous researches support the idea that the self determination of the disabled is despite several political changes weakly performed. According to our research findings we interpret that the change should start from the attitudes of the professional personnel and adding more case management

Somatic mutations in autoimmunity

Autoimmune diseases are caused by a dysregulated immune response against self-antigens. They affect more than 5% of the population in the Western countries, but curative therapies do not exist. However, the molecular mechanisms that cause autoimmune diseases are mostly unknown. In this thesis, we focused on T cells with the aim of characterizing the landscape of somatic mutations in immune-associated genes. We used rheumatoid arthritis (RA) patients and patients suffering from immunodeficiency and autoimmunity as disease models. In study I, we collected a cohort of 82 newly diagnosed RA patients. We performed deep T-cell receptor (TCR) profiling from 65 RA patients’ CD8+ cells. To discover somatic mutations, we sequenced CD4+ and CD8+ cells of 25 RA patients and 20 healthy controls with a targeted deep sequencing panel and complemented the results with exome sequencing in 3 cases. We discovered 30 novel somatic mutations in the CD8+ cells of 5 RA patients and one mutation in one of the healthy controls. Of the discovered mutations in RA, 30% affected cell proliferation and 20% were related to immune functions. Mutations were restricted to specific, expanded CD8+ memory T-cell populations. Felty’s syndrome (a rare form of RA) and large granular lymphocyte (LGL) leukemia often present with a similar patient phenotype. In study II, we showed that the diseases are unified by somatic, activating STAT3 mutations in CD8+ cells. Felty’s syndrome patients harbor similar STAT3 mutations, with a prevalence (43%) comparable to previously described LGL leukemia cohorts. In addition, these 2 diseases shared similar cytokine profiles. Since both diseases are treated similarly, we suggest that these entities could be considered parts of the same disease continuum. Study III investigated the prevalence of somatic mutations in hematopoietic stem cells (clonal hematopoiesis) in RA patients. Targeted deep sequencing from 59 RA patients’ whole blood samples revealed clonal hematopoiesis in 17% of cases. However, clonal hematopoiesis did not associate with clinical parameters in our study setting. Study IV aimed to investigate whether somatic mutations associate with autoimmunity and lymphoproliferation in the context of immunodeficiency. We sequenced 2533 genes from CD4+ and CD8+ cells of 17 immunodeficiency patients. Immunodeficiency patients harbored 45 somatic mutations in 65% of cases. Mutations in tumor suppressor and oncogenes occurred in 35%, but mutations in genes affecting lymphocyte functions, inflammation, and cell proliferation were also common. Clonal hematopoiesis variants also existed in 24% of patients. In summary, we have shown that somatic mutations in T cells and clonal hematopoiesis variants are common in RA and immunodeficiency patients. Our work provides a molecular link between autoimmune disease and cancerous processes, introducing a novel concept in the field of immunology.Somaattisia mutaatioita eli elämän aikana syntyneitä mutaatioita kertyy elimistön eri kudoksiin elämän aikana. Somaattiset mutaatiot ovat keskeinen tekijä syöpäkasvainten kehityksessä, mutta niiden merkitystä ja kirjoa muissa kuin syöpätaudeissa tunnetaan huonommin. Autoimmuunisairauksissa immuunijärjestelmä hyökkää omia kudoksia vastaan. Yli 5%:lla länsimaiden väestöstä onkin jokin autoimmuunisairaus. Tästä huolimatta autoimmuunisairauksien mekanismit ovat huonosti tunnettuja. Selvitimme tässä väitöskirjatyössä somaattisten mutaatioiden kirjoa nivelreuma- sekä immuunipuutospotilaiden valkosoluissa. On mahdollista, että jotkin somaattiset mutaatiot voivat vaikuttaa immuunisolujen toimintaa tulehdusta edistäväksi syövänkehityksen sijaan. Ensimmäisessä osatyössä kuvasimme ensimmäistä kertaa somaattisia mutaatiota kypsissä T-soluissa nivelreumapotilailla. Tällaisia geneettisiä muutoksia esiintyy noin viidesosalla nivelreumapotilaista. Neljännessä osatyössä osoitimme, että immuunipuutospotilaiden aineistossamme 65%:lla oli myös somaattisia mutaatioita kypsissä T-soluissa. Myös terveiltä yksilöiltä löytyi mutaatioita. Somaattiset mutaatiot T-soluissa ovat siis hyvin yleinen ilmiö, ja osa niistä sijaitsi tunnetuissa kasvunrajoite- tai syöpägeeneissä tai tulehdusvasteita säätelevissä geeneissä. Myös veren kantasoluista peräisin ovat, verisyöpään liittyvien geenien mutaatiot ovat yleisiä. Kolmannessa osatyössä löysimme tällaisia mutaatioita 17%:lta (10/59) nivelreumapotilaalta. Väitöskirjan toisessa osatyössä osoitimme, että tietyt somaattiset mutaatiot liittävät harvinaisen nivelreuman alatyypin (Feltyn oireyhtymä) ja suurten granulaaristen lymfosyyttien (LGL) leukemian yhden sairauden jatkumoksi. Molemmissa sairauksissa esiintyy nimittäin somaattisia STAT3-mutaatioita samantasoisella esiintyvyydellä (Feltyn oireyhtymässä 43%:lla potilaista) Tämä väitöskirjatyö tuo esiin, että somaattiset mutaatiot immuunisoluissa ovat siis yleisiä löydöksiä nivelreuma- ja immuunipuutospotilailla. Immuunivälitteisissä sairauksissa ja syövässä on siten samankaltaisia molekyylitason löydöksiä, mikä tuo esiin uuden mahdollisen säätelymekanismin immuunisolujen toiminnoille. Jatkotutkimukset mutaatioiden kirjosta, yleisyydestä, ja käytännön merkityksistä sairauksien säätelijöinä ovat kuitenkin tarpeen

LGL-leukemia ja autoimmuniteetti : autoimmuunisairauden ja syövän rajapinta hämärtyy

English summaryPeer reviewe

Novel Ex Vivo DOAC Removal Methods Reduce Interference in Lupus Anticoagulant Testing

Direct oral anticoagulants (DOAC) interfere in laboratory coagulation testing. The aim here was to study how commercial DOAC removal methods, DOAC Filter® and DOAC-Stop™, perform to eliminate DOAC concentrations and false positive results in lupus anticoagulant (LAC) testing. We acquired 50 patient samples with high concentrations of DOACs: apixaban (n = 18, range 68–572 ng/mL), dabigatran (n = 8, range 47–154 ng/mL), edoxaban (n = 8, range 35–580 ng/mL) and rivaroxaban (n = 16, range 69–285 ng/mL). DOACs were removed ex vivo with either DOAC Filter® (n = 28) or DOAC-Stop™ (n = 22). Additionally, commercial control and calibrator samples were studied (n = 13 for DOAC Filter®, n = 14 for DOAC-Stop™). LAC screening was performed before and after DOAC removal. Both DOAC Filter® and DOAC-Stop™ were effective in removing DOAC concentrations in samples: DOAC concentrations decreased to median of 0 ng/mL (range 0–48 ng/mL). Only one sample had more than residual 25 ng/mL of DOAC (apixaban). Before DOAC removal, 96% (48/50) of patient samples and over 90% (12/13 DOAC Filter®, 13/14 DOAC-Stop™) of control/calibrator samples were positive in the LAC screening. In patient samples, LAC screening turned negative in 61% (17/28) after DOAC Filter® and 45% (10/22) after DOAC-Stop™ treatment. All control samples became negative after DOAC removal. In conclusion, DOAC removal ex vivo reduces false positives in LAC screening. DOAC removal halved the need for confirmation or mixing tests- Although a subset of patients would require further testing, DOAC removal reduces unnecessary repeated LAC testing

Somaattiset mutaatiot terveyden ja sairauden rajapinnalla

English summaryPeer reviewe

Clonal hematopoiesis in patients with rheumatoid arthritis

Peer reviewe

A robust pipeline with high replication rate for detection of somatic variants in the adaptive immune system as a source of common genetic variation in autoimmune disease

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of > 55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.Peer reviewe

Somatic STAT3 mutations in Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia

Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3, which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8(+) T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that ten of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.Peer reviewe

Somatic mutations and T-cell clonality in patients with immunodeficiency

Common variable immunodeficiency (CVID) and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is, however, implicated. To study whether somatic mutations in CD4(+) and CD8(+) T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset CVID and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2,533 immune-associated genes from CD4(+) and CD8(+) cells. Deep T-cell receptor b-sequencing was used to characterize CD4(+) and CD8(+) T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in CVID, and 48% in controls. Clonal hematopoiesis-associated variants in both CD4(+)and CD8(+) cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immuneand proliferative functions, such as STAT5B (2 patients), C5AR1 (2 patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, CVID patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4(+) and CD8(+) cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.Peer reviewe