605 research outputs found

    Combining supervised and unsupervised named entity recognition to detect psychosocial risk factors in occupational health checks

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    Introduction: In occupational health checks the information about psychosocial risk factors, which influence work ability, is documented in free text. Early detection of psychosocial risk factors helps occupational health care to choose the right and targeted interventions to maintain work capacity. In this study the aim was to evaluate if we can automate the recognition of these psychosocial risk factors in occupational health check electronic records with natural language processing (NLP). Materials and methods: We compared supervised and unsupervised named entity recognition (NER) to detect psychosocial risk factors from health checks’ documentation. Occupational health nurses have done these records. Results: Both methods found over 60% of psychosocial risk factors from the records. However, the combination of BERT-NER (supervised NER) and QExp (query expansion/paraphrasing) seems to be more suitable. In both methods the most (correct) risk factors were found in the work environment and equipment category. Conclusion: This study showed that it was possible to detect risk factors automatically from free-text documentation of health checks. It is possible to develop a text mining tool to automate the detection of psychosocial risk factors at an early stage</p

    Heart failure – risk factors and the validity of diagnoses

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    Heart failure (HF) is a global health problem. HF risk factors remain understudied. The roles that diabetes and sodium consumption play in HF remain unknown. Furthermore, the validity of HF diagnoses in the Finnish Hospital Discharge Register (FHDR) has not been thoroughly evaluated. This thesis aims to discover sodiumand diabetes-related HF risk factors, validate FHDR-based HF diagnoses, and investigate if the subtyping of register-based HF diagnoses could be improved through electronic health record (EHR) data mining. A 24-hour urinary sodium excretion (mean 183 mmol/d) was measured from 4,630 individuals to assess the relationship between salt intake and incident HF (Study I). We used data from 3,834 diabetic and 90,177 nondiabetic individuals to evaluate the diabetes status-related differences in risk factors and mediators of HF (Study II). Medical records of 120 HF cases and 120 controls were examined to study the validity of HF diagnoses (Study III). We drew data from 33,983 patients to assess if HF diagnoses could be subtyped more accurately through EHR data mining (Study IV) and validated the mining-based versus clinical subtyping in 100 randomly selected patients. In Study I, we observed that high sodium intake was associated with incident coronary artery disease (CAD) and diabetes, but not HF. In Study II, the risk of HF was 2.7-fold in individuals with diabetes compared to nondiabetic participants. Conventional cardiovascular disease risk factors and biomarkers for cardiac strain, myocardial injury, and inflammation were associated with incident HF in both groups. The strongest mediators of HF in diabetes were the direct effect of diabetes and the indirect effects mediated by obesity, cardiac strain/volume overload, and hyperglycemia. In studies III and IV, HF diagnoses of the FHDR had good predictive values (NPV 0.83, PPV 0.85), even when patients with preexisting heart conditions were used as controls. With additional EHR-mined data, the accuracy of our algorithm to correctly classify individuals into HF subtypes versus clinical assessment was 86 %. The findings in this thesis show that register-based HF is an accurate endpoint and that EHR data mining can improve this accuracy. Our results also elucidate the role of sodium and diabetes as HF risk factors.Sydämen vajaatoiminta: riskitekijät ja diagnoosien validiteetti Sydämen vajaatoiminta on maailmanlaajuinen terveysongelma, jonka riskitekijät ovat osin epäselviä. Suolan käytön yhteyttä ja diabeteksen aiheuttamaa korkeaa riskiä vajaatoimintaan ei ole riittävästi tutkittu. Vajaatoimintadiagnoosien validiteettia Hoitoilmoitusjärjestelmä (HILMO)-sairaalarekisterissä ei tiedetä. Tässä väitöskirjatyössä tutkittiin suolaan ja diabetekseen liittyviä sydämen vajaatoiminnan riskitekijöitä, validoitiin HILMO-pohjaiset vajaatoimintadiagnoosit ja selvitettiin, voidaanko vajaatoimintaa alatyypittää tekstinlouhintaa käyttämällä. Suolan saannin ja vajaatoiminnan välisen suhteen arvioimiseksi (tutkimus I) tutkittiin 4 630 henkilön vuorokausivirtsan natrium (keskimäärin 183 mmol/d). Diabetekseen liittyvien sydämen vajaatoiminnan riskitekijöiden selvittämiseksi (tutkimus II) käytiin läpi 3 834 diabeetikon ja 90 177 verrokin tiedot. Vajaatoimintadiagnoosien validiteettia (tutkimus III) varten tutkimme 120 vajaatoimintatapauksen ja 120 verrokin (joilla oli muu sydänsairaus) potilastiedot ja tarkempaa alatyypitystä (tutkimus IV) varten keräsimme tietoja 33 983 potilaasta ja validoimme tiedonlouhintaan perustuvan alatyypityksen 100 satunnaisella potilaalla. Tutkimuksessa I suolan saanti oli yhteydessä sepelvaltimotaudin ja diabeteksen kehittymiseen, mutta tulokset eivät olleet merkitseviä vajaatoiminnan osalta. Tutkimuksessa II diabeetikoiden vajaatoimintariski oli 2,7-kertainen verrokkeihin verrattuna. Molemmilla tavanomaiset riskitekijät ja sydämen venyvyyden, sydänvaurion ja tulehduksen merkkiaineet olivat yhteydessä vajaatoimintaan. Merkittävimmät diabeteksen vajaatoimintaa välittävät muuttujat olivat diabeteksen suora vaikutus sekä epäsuorat ylipainon, sydämen venymisen ja hyperglykemian vaikutukset. Tutkimuksissa III ja IV HILMO-rekisterin vajaatoimintadiagnoosin prediktiiviset arvot olivat hyviä (NPV 0,83, PPV 0,85) verrattuna muihin sydänsairaisiin potilaihin ja tiedonlouhinnan alatyypityksen tarkkuus verrattuna kliiniseen oli 86 %. Tämä väitöskirja osoittaa, että HILMO-pohjaiset vajaatoimintadiagnoosit toimivat tieteellisenä päätetapahtumana ja että vajaatoiminnan alatyyppiä voidaan tarkentaa tekstilouhinnalla, sekä tuo uutta tietoa suolasta ja diabeteksesta vajaatoiminnan riskitekijöinä

    Record of the meeting of the Advisory Committee on Immunization Practices : June 18-19, 2003

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    Competence assessment in anaesthesia nursing care

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    In order to provide high-quality anaesthesia nursing care, competence assessment of nurses is essential. However, in anaesthesia nursing care there has been a lack of psychometrically tested competence assessment scales. Therefore, the purpose of this study was i) to develop an Anaesthesia Nursing Competence Scale (AnestComp) and ii) to assess the anaesthesia nursing competence of nurses using the scale, with the goal of promoting anaesthesia nursing competence of nurses and providing high-quality anaesthesia care. The study was carried out in two phases: Phase I focused on describing the concept of anaesthesia nursing competence based on a literature review and experts’ descriptions which then became the foundation for the AnestComp; this was followed by testing the psychometric properties of the scale. In Phase II, the anaesthesia nursing competence of anaesthesia nurses (n=222) was self-assessed by using the AnestComp. The psychometric properties of the AnestComp were tested: reliability (Cronbach’s α), face validity, content validity, and construct validity. In this study, the data of nursing students (n=205) were also collected and analysed for the purpose of the construct validity testing of the AnestComp. Anaesthesia nursing competence is a multi-dimensional conception comprising of seven competence areas: (1) ethics of anaesthesia care, (2) patient risk care, (3) patient engagement with technology, (4) collaboration within anaesthesia care, (5) anaesthesia patient care with medication, (6) anaesthesia nursing intervention, and (7) knowledge of anaesthesia care. The AnestComp developed based on these competence areas consists of 39 items and uses a Visual Analogue Scale (0-100mm). The AnestComp is considered a promising scale for assessing the anaesthesia nursing competence of nurses based on the testing of psychometric properties. Nurses’ self-assessed competence (VAS 88) exceeded the expected level; in this study, the expected level was set as a mean of VAS 80. Collaboration within anaesthesia care was the highest competence area, whereas patient risk care and knowledge of anaesthesia care were the lowest, and thus identified as fields requiring educational needs. Work experience and specialised anaesthesia nursing education were significant factors related to the higher anaesthesia nursing competence of nurses. The competence of nurses (particularly novices) in patient risk care and knowledge of anaesthesia care should be ensured through regular competence assessments. More opportunity for specialised anaesthesia nursing education might be one way to improve the anaesthesia nursing competence of nurses.Ammattipätevyyden arviointi anestesiahoitotyössä Ammattipätevyyden arviointi on välttämätöntä korkealaatuisen anestesiahoitotyön toteuttamiseksi. Anestesiahoitotyössä ei ole aikaisemmin ollut validia psykometrisesti testattua ammattipätevyyden arviointimittaria. Tämän tutkimuksen tarkoituksena oli i) kehittää validi ammattipätevyyden arviointimittari anestesiahoitotyötä varten (AnestComp) ja ii) arvioida anestesiahoitajien anestesiahoitotyön ammattipätevyyttä hyödyntämällä kehitettyä arviointimittaria. Tavoitteena oli anestesiahoitotyön pätevyyden ja korkealaatuisen anestesiahoidon edistäminen. Tutkimus toteutettiin kahdessa vaiheessa. Vaihe I painottui anestesiahoitotyön ammattipätevyyden käsitteen kuvaamiseen kirjallisuuskatsauksen ja asiantuntijoiden kuvausten perusteella. Sen jälkeen kehitettiin anestesiahoitotyön ammattipätevyysmittari (AnestComp) ja testattiin sen psykometriset ominaisuudet. Vaiheessa II anestesiahoitajat (n=222) itsearvioivat ammattipätevyyttään AnestComp mittarilla. Tilastollisten aineistojen analyysissä AnestComp-mittarin luotettavuus (Cronbachin α) ja rakennevaliditeetti testattiin sairaanhoitajien aineistolla. Tässä tutkimuksessa myös sairaanhoitajaopiskelijoiden (n = 205) aineistot kerättiin ja analysoitiin AnestComp-mittarin rakennevaliditeettitestausta varten. Anestesiahoitotyön pätevyyttä kuvataan moniulotteisena käsitteenä, joka käsittää seitsemän pätevyysaluetta: (1) anestesiahoidon etiikka, (2) anestesiapotilaan riskien hoito, (3) teknologiavälitteinen potilashoito, (4) yhteistyö anestesiahoidossa, (5) anestesiapotilaan lääkehoito, (6) anestesiahoitotyön interventio sekä (7) tietämys anestesiahoidosta. Näiden ammattipätevyysalueiden pohjalta kehitettiin AnestComp-mittari (39 väittämää, VAS 0-100). Sitä pidettiin psykometristen ominaisuuksien testauksen perusteella lupaavana mittarina anestesiahoitotyön ammattipätevyyden arvioimiseksi. Sairaanhoitajien itsearvioitu pätevyys (VAS 88) ylitti odotetun tason, joka tässä tutkimuksessa oli asetettu VAS 80:ksi. Korkein pätevyysalue oli yhteistyö anestesiahoidossa, mutta anestesiapotilaan riskien hoito ja tietämys anestesiahoidosta tunnistettiin matalimmiksi ammattipätevyysalueiksi. Työkokemus ja erikoistunut anestesiahoitajakoulutus olivat merkittäviä tekijöitä, jotka liittyivät sairaanhoitajien ammattiosaamisen korkeampaan pätevyyteen. Sairaanhoitajien osaaminen (erityisesti uusien hoitajien) kahdella heikoimmalla ammattipätevyyden osa-alueilla tulisi varmistaa säännöllisten ammattipätevyysarviointien avulla. Mahdollisuus erikoistua anestesiahoitotyöhön voisi olla keino edistää anestesiahoitotyön ammattipätevyyttä

    Preface

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    Knowledge base integration in biomedical natural language processing applications

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    With the progress of natural language processing in the biomedical field, the lack of annotated data due to regulations and expensive labor remains an issue. In this work, we study the potential of knowledge bases for biomedical language processing to compensate for the shortage of annotated data. Accordingly, we experiment with the integration of a rigorous biomedical knowledge base, the Unified Medical Language System, in three different biomedical natural language processing applications: text simplification, conversational agents for medication adherence, and automatic evaluation of medical students' chart notes. In the first task, we take as a use case simplifying medication instructions to enhance medication adherence among patients. Given the lack of an appropriate parallel corpus, the Unified Medical Language System provided simpler synonyms for an unsupervised system we devise, and we show a positive impact on comprehension through a human subjects study. As for the second task, we devise an unsupervised system to automatically evaluate chart notes written by medical students. The purpose of the system is to speed up the feedback process and enhance the educational experience. With the lack of training corpora, utilizing the Unified Medical Language System proved to enhance the accuracy of evaluation after integration into the baseline system. For the final task, the Unified Medical Language System was used to augment the training data of a conversational agent that educates patients on their medications. As part of the educational procedure, the agent needed to assess the comprehension of the patients by evaluating their answers to predefined questions. Starting with a small seed set of paraphrases of acceptable answers, the Unified Medical Language System was used to artificially augment the original small seed set via synonymy. Results did not show an increase in quality of system output after knowledge base integration due to the majority of errors resulting from mishandling of counts and negations. We later demonstrate the importance of a (lacking) entity linking system to perform optimal integration of biomedical knowledge bases, and we offer a first stride towards solving that problem, along with conclusions on proper training setup and processes for automatic collection of an annotated dataset for biomedical word sense disambiguation

    Front-Line Physicians' Satisfaction with Information Systems in Hospitals

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    Day-to-day operations management in hospital units is difficult due to continuously varying situations, several actors involved and a vast number of information systems in use. The aim of this study was to describe front-line physicians' satisfaction with existing information systems needed to support the day-to-day operations management in hospitals. A cross-sectional survey was used and data chosen with stratified random sampling were collected in nine hospitals. Data were analyzed with descriptive and inferential statistical methods. The response rate was 65 % (n = 111). The physicians reported that information systems support their decision making to some extent, but they do not improve access to information nor are they tailored for physicians. The respondents also reported that they need to use several information systems to support decision making and that they would prefer one information system to access important information. Improved information access would better support physicians' decision making and has the potential to improve the quality of decisions and speed up the decision making process.Peer reviewe

    Optimizing text mining methods for improving biomedical natural language processing

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    The overwhelming amount and the increasing rate of publication in the biomedical domain make it difficult for life sciences researchers to acquire and maintain all information that is necessary for their research. Pubmed (the primary citation database for the biomedical literature) currently contains over 21 million article abstracts and more than one million of them were published in 2020 alone. Even though existing article databases provide capable keyword search services, typical everyday-life queries usually return thousands of relevant articles. For instance, a cancer research scientist may need to acquire a complete list of genes that interact with BRCA1 (breast cancer 1) gene. The PubMed keyword search for BRCA1 returns over 16,500 article abstracts, making manual inspection of the retrieved documents impractical. Missing even one of the interacting gene partners in this scenario may jeopardize successful development of a potential new drug or vaccine. Although manually curated databases of biomolecular interactions exist, they are usually not up-to-date and they require notable human effort to maintain. To summarize, new discoveries are constantly being shared within the community via scientific publishing, but unfortunately the probability of missing vital information for research in life sciences is increasing. In response to this problem, the biomedical natural language processing (BioNLP) community of researchers has emerged and strives to assist life sciences researchers by building modern language processing and text mining tools that can be applied at large-scale and scan the whole publicly available literature and extract, classify, and aggregate the information found within, thus keeping life sciences researchers always up-to-date with the recent relevant discoveries and facilitating their research in numerous fields such as molecular biology, biomedical engineering, bioinformatics, genetics engineering and biochemistry. My research has almost exclusively focused on biomedical relation and event extraction tasks. These foundational information extraction tasks deal with automatic detection of biological processes, interactions and relations described in the biomedical literature. Precisely speaking, biomedical relation and event extraction systems can scan through a vast amount of biomedical texts and automatically detect and extract the semantic relations of biomedical named entities (e.g. genes, proteins, chemical compounds, and diseases). The structured outputs of such systems (i.e., the extracted relations or events) can be stored as relational databases or molecular interaction networks which can easily be queried, filtered, analyzed, visualized and integrated with other structured data sources. Extracting biomolecular interactions has always been the primary interest of BioNLP researcher because having knowledge about such interactions is crucially important in various research areas including precision medicine, drug discovery, drug repurposing, hypothesis generation, construction and curation of signaling pathways, and protein function and structure prediction. State-of-the-art relation and event extraction methods are based on supervised machine learning, requiring manually annotated data for training. Manual annotation for the biomedical domain requires domain expertise and it is time-consuming. Hence, having minimal training data for building information extraction systems is a common case in the biomedical domain. This demands development of methods that can make the most out of available training data and this thesis gathers all my research efforts and contributions in that direction. It is worth mentioning that biomedical natural language processing has undergone a revolution since I started my research in this field almost ten years ago. As a member of the BioNLP community, I have witnessed the emergence, improvement– and in some cases, the disappearance–of many methods, each pushing the performance of the best previous method one step further. I can broadly divide the last ten years into three periods. Once I started my research, feature-based methods that relied on heavy feature engineering were dominant and popular. Then, significant advancements in the hardware technology, as well as several breakthroughs in the algorithms and methods enabled machine learning practitioners to seriously utilize artificial neural networks for real-world applications. In this period, convolutional, recurrent, and attention-based neural network models became dominant and superior. Finally, the introduction of transformer-based language representation models such as BERT and GPT impacted the field and resulted in unprecedented performance improvements on many data sets. When reading this thesis, I demand the reader to take into account the course of history and judge the methods and results based on what could have been done in that particular period of the history

    Is it Psychosomatic? - An Inquiry into the Nature and Role of Medical Concepts

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    Medical diagnoses define the possible modes of being ill from the medical point of view. Medical diagnoses are theoretical concepts that gain their meaning as a part of the prevailing medical theory. As medical theories change over time, also medical concepts change, as can be seen in the long history of medical thinking. The purpose of this essay is to illustrate medical thinking through examining the formation and use of one example of a particular medical concept “psychosomatic” in medical theory and practice. The approach taken in this essay reflects the writings of Lev Vygotsky, who argued that scientific concepts are tools for scientific thinking. Since all conceptual tools have their own developmental history, to understand the content of any scientific concept to the full we need to understand the processes leading to adoption of that particular concept for scientific inquiry at that particular moment in history. Vygotsky’s approach for analysing the development of science through analysing its concepts is reflected to the writings of Kuhn and Fleck on the development of science. It is argued, that Kuhn’s theory does not apply to the development of medicine. While Fleck’s approach seems to fit better to analysing the theoretical development in medicine, it remains somewhat superficial in analysing the nature and role of concepts in medical thinking. The use of medical concepts in medical practice is discussed in the light of Mikael Leiman’s ideas on the therapeutic encounter as a dialogical process. While Leiman also draws from Vygotsky he takes the issue further toward semiotic understanding of clinical dialogue by using Bakhtin’s and Voloshinov’s ideas of the semiotic nature of human communication

    New insights in Autoimmune Polyendocrine Syndromes 1 and 2

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    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene located on chromosome 21 (21q22.3). AIRE deficiency causes a loss in central immune tolerance, leading to the failure to eliminate autoreactive T cells in the thymus and allowing their escape to the periphery. Because of a founder effect, APECED is particularly prevalent in Finland (1/25,000) but is observed worldwide with variable prevalence. APECED patients are susceptible to mucocutaneous candidiasis and multiple endocrine autoimmune diseases such as primary hypoparathyroidism, adrenal insufficiency, primary hypogonadism, type 1 diabetes, hypothyroidism, and hypophysitis. They may also develop additional nonendocrine autoimmune diseases, such as alopecia areata/totalis, vitiligo, gastro-intestinal (GI) diseases, keratitis or tubulointerstitial nephritis (TIN). In addition, the patients typically develop a variety of serum tissue-specific autoantibodies, which are predictive of the development of autoimmune disease and anticytokine antibodies such as those against type I interferons and Th17-related interleukin IL-17 and IL-22. The aim of this thesis was to study such manifestations of APECED that have not been well characterized before and also, to study health-related quality of life among Finnish APECED and Addison s disease/APS2 patients. We evaluated the clinical GI features and searched for novel markers of GI dysfunction in a Finnish cohort of 31 APECED patients. The main upper GI symptoms were dysphagia and retrosternal pain (45%) and the lower GI symptoms were constipation (48%), diarrhoea (45%) and malabsorption (16%). Previously, L-amino-acid decarboxylase (AADC) and tryptophan hydroxylase type 1 (TPH-1) antibodies have been demonstrated in APECED. AADC antibodies were found in 51% and TPH-1 antibodies in 39% of all patients. Also, a T cell response to AADC was detected in 43%. One third of the patients had autoimmune enteropathy (AIE)-related 75 kDa antigen (AIE-75, 33%) and villin (29%) autoantibodies, and antibodies against brush borders and Paneth cells (PCs) were detected in 29% and 20%, respectively. Mucosal intestinal IL-17 expression was decreased or negative in 77% of the intestinal samples. Duodenal chromogranin A and serotonin expression was absent or decreased in 50% and 66% of the patients, respectively. Of the clinical symptoms, constipation correlated with negative serotonin staining (p less than 0.05) and with AADC antibodies (p = 0.019). Importantly, we found a correlation between autoantibodies against AADC, which are critical for serotonin and DOPA synthesis, and constipation. Constipation was also associated with a lack of serotonin expression in the enteroendocrine cells (EECs). Paneth cells (PCs) were lacking in the duodenum in 20% of our intestinal samples, even though this was not associated with GI symptoms. In this Finnish APECED patient cohort, 17% (5/30) had moderate-to-severe renal failure, including 10% (3/30) with TIN requiring transplantation, haemodialysis or immunosuppressive treatment. However, the latter did not seem to be efficient in controlling disease progression. All 3 patients with TIN had circulating antibodies against the distal part of the nephron, as did 30% of all cohort cases. The pathogenic relevance of such circulating antibodies is still unclear. The immunological basis of hypoparathyroidism in APECED was explored by studying circulating calcium-sensing receptor (CaSR) and NALP5 antibodies. Although they were detected in 16 of 44 (36%) and 13 of 44 (30%) patients, respectively, we failed to find any clinically relevant statistical association. These APECED patients did not present circulating antibodies for other autoimmune diseases such as rheumatoid arthritis, celiac disease, bullous pemphigoid or pemphigus vulgaris. Some patients had antinuclear antibodies at a low-titre without clinical significance. Secondly, we evaluated the health-related quality of life among Finnish APECED and Addison s disease/APS2 patients and sought to determine which factors may predict a possible impairment. Using health-related quality of life (HRQoL) questionnaires for APECED (SF-36) and Addison s disease/APS2 patients (SF-36, 15D), we indeed observed impaired HRQoL. For the APECED patients, general health, emotional well-being and energy/vitality were the most diminished aspects of HRQoL. Among the patients with Addison s disease/APS2, compared to a large control population, physical or emotional role functioning, energy/vitality and general health were most affected. Discomfort and symptoms, vitality, and sexual activity were the most affected dimensions of the 15D scores. Affiliation with a patients association, female gender, the presence of non-APS2 inflammatory comorbidities, lower educational level and a longer disease duration were independent predictors of impaired HRQoL in these patients. Taken together, the results of this thesis show that APECED patients are genetically prone to develop autoantibodies to a multitude of tissue antigens but are still tolerant to some common autoantigens. The true clinical and biological relevance of these circulating autoantibodies has not yet been elucidated, and it is possible that they are only a reflection of T cell-mediated immunity. They may, however, have a cumulative effect and clinical disease may arise only in patients with a combination of circulating antibodies, as seen in diabetes type 1. This may explain why we failed to find any association between any single type of antibody and a given symptom. For the lower GI track manifestations, we hypothesise a cumulative effect of the autoimmunity directed against both the enteroendocrine cells and the Paneth cells, leading to a dysfunction in both the secretion of serotonin in the gut and the secretion of antimicrobiobial defensins. Such a disturbance would have an effect on the gut microbiota. The question of whether the neutralising antibodies against cytokines may have a paradoxical protective effect is open to debate. Lastly, despite having a high number of manifestations, patients with APECED seem to cope with their disease. Patients with Addison s disease have significantly impaired HRQoL compared to the general population.Autoimmuunipolyendokrinopatia-kandidiaasi-ektodermidystrofia (APECED, OMIM 240300) on harvinainen, autosomissa peittyvästi periytyvä sairaus, joka aiheutuu mutaatioista kromosomissa 21 (21q22.3) sijaitsevassa autoimmune regulator (AIRE) geenissä. AIRE:n toiminnallinen puutos johtaa n.s keskusimmuunitoleranssin menetykseen siten että autoreaktiiviset T-solut eivät tuhoudu kateenkorvassa vaan pääsevät karkaamaan perifeeriseen verenkiertoon. APECED:in esiintyvyys Suomessa on erityisen korkea (1/25,000) johtuen ns. perustaja-mutaatiosta AIRE-geenissä, mutta tautia tavataan myös muualla maailmassa vaihtelevalla esiintyvyydellä. APECED-potilaat ovat alttiita ihon ja limakalvojen krooniselle hiivatulehdukselle ja heillä voi esiintyä useita autoimmuunitauteja, kuten lisäkilpirauhasen, lisämunuaisen kuoren, kilpirauhasen sekä sukuelinten vajaatoimintaa, tyypin 1 diabetesta ja aivolisäkkeen tulehdusta. Näiden lisäksi APECED-potilaat kärsivät usein myös muista ei-endokriinisistä autoimmuunitaudeista kuten pälvikaljusta (alopesia), valkopälvestä (vitiligo), silmän sarveiskalvon tulehduksesta, munuaisputkien tulehduksesta (tubulointerstitiaalinen nefriitti, TIN),) sekä suoliston sairauksista. Potilailla havaitaan tyypillisesti seerumissa erilaisia kudos- ja elinspesifejä autovasta-aineita sekä vasta-aineita useita tulehdusvälittäjäaineita eli sytokiineja kohtaan. Viime mainitut kohdistuvat tavallisimmin tyypin I interferonia sekä Th17-immuunivasteeseen liittyviä interleukiineja IL-17 ja IL-22 kohtaan ja ennakoivat autoimmuunitaudin puhkeamista. Tässä väitöskirjassa on tutkittu tarkemmin kahta aiemmin huonosti tunnettua APECED:iin liittyvää oireistoa: ruoansuolatuskanavan sekä munuaisten ja virtsateiden oireita. Kyselytutkimuksen avulla kartoitimme potilaiden kokemat ruuansulatuskanavaperäiset oireet ja tutkimme suoliston toimintahäiriöiden tautimekanismia 31 suomalaista APECED-potilasta käsittävässä aineistossa. Tyypillisiä ylemmän ruoansulatuskanavan oireita olivat nielemishäiriöt ja rintalastan takainen kipu (45%) ja alemman ruoansulatuskanavan osalta ummetus (48%), ripuli (45%) ja imeytymishäiriöt (16%). Jo aiemmin on tiedetty APECED-potilailla esiintyvän vasta-aineita suoliston toiminnan kannalta keskeisten enteroendokriinisten (EE) solujen erittämiä entsyymejä tryptofaanihydroksylaasia (TPH-1) ja aromaattista L-aminohappodekarboksylaasia (AADC) kohtaan. Potilasaineistossamme AADC-vasta-aineita esiintyi 51%:lla sekä TPH-1 vasta-aineita 39%:lla potilaista. Uutena löydöksenä osoitimme T-soluperäisen immuunivasteen AADC:tä kohtaan 43%:llä. Kolmasosalla potilaista oli osoitettavissa autovasta-aineita myös autoimmuuni enteropatiaan liittyvää antigeenia (AIE-75) sekä ravinnon imeytymisestä vastaavien enterosyyttien mikrovilluksissa esiintyvää villiiniä vastaan. Lisäksi löysimme vasta-aineita suolen sukasaumaa (29% potilaista) ja suolirauhasten Panethin soluja (20% potilaista) vastaan. Suolen limakalvon IL-17:ää tuottavien solujen määrä oli alentunut tai puuttui 77%:ssa tapauksista. Pohjukkaissuolen kromograniini-A-proteiinia tuottavien EE- solujen määrä oli vähentynyt tai puuttui 50%:ssa ja vastaavasti serotoniinia tuottavien solujen määrä 66%:ssa suolistonäytteistä. Potilaiden oireista ummetus korreloi negatiivisesti EE- solujen serotoniini-ilmentymisen (p alle 0.05) sekä AADC-vasta-aineiden kanssa (p alle 0.05). Huomionarvoista on, että havaitsimme merkittävän yhteyden ummetuksen ja serotoniini- ja dopamiinisynteesille keskeistä AADC-entsyymiä vastaan muodostuneiden vasta-aineiden välillä. Uusi havainto oli myös se, että suolistoon antimikrobisia defensiinejä tuottavat Panethin solut puuttuivat 20%:ssa potilaiden duodenum-näytteistä, joskaan tämä ei suoraan korreloinut kliinisten oireiden kanssa. Tutkimistamme APECED- potilaista 17% (5/30) kärsi keskivaikeasta tai vaikeasta munuaisen vajaatoiminnasta, ja 10%:lla (3/30) potilaista oli TIN, joka vaati elinsiirteen, hemodialyysiä tai immunosuppressiivistä hoitoa. Näistä viime mainittu ei kuitenkaan osoittautunut riittäväksi taudinkulun hallinnoimisessa. Kaikilla kolmella TIN:istä kärsivällä potilaalla todettin verenkierrossa vasta-aineita nefronin distaalista osaa, munuaistiehyettä kohtaan. Samoja vasta-aineita löytyi kaikkiaan 30%:lta aineistomme potilaista, mutta niiden merkitys TIN:in patogeneesissä on vielä tuntematon. Tutkimme myös APECED:issä esiintyvään lisäkilpirauhasen vajaatoimintaan liittyviä immunologisia taustamekanismeja määrittämällä verenkierrossa olevia kalsiumia tunnistavaa reseptoria (CaSR) ja NALP5-valkuaista kohtaan muodostuneiden vasta-aineiden määrän. Huolimatta siitä, että osoitimme vasta-aineita CaSR:ia vastaan 16/44 (36%) potilaalla ja NALP5:ttä vastaan 13/44 (30%) potilaalla, emme löytäneet kliinisesti relevanttia korrelaatiota. APECED-potilaillamme ei ollut veressään muussa väestössä tavallisten autoimmuunitautien kuten nivelreuman, keliakian, ihon autoimmuuni rakkulatautien (pemfigoidi ja pemfigus) vasta-aineita, mutta joillakin heistä oli matala-tiitterisiä tumavasta-aineita ilman niihin liittyviä kliinisiä muutoksia. Väitöskirjaan sisältyvät myös alkuperäistutkimukset potilaiden elämänlaadun kannalta keskeisistä tekijöistä ja terveyteen liittyvästä elämänlaadusta suomalaisilla APECED- ja Addisonin tauti/APS2 potilailla. Käyttäessämme terveyteen liittyviä kyselytutkimuksia (SF-36) APECED-potilailla sekä (SF-36 sekä 15D) Addisonin tauti/APS2-potilailla, kävi ilmi, että molempien potilasryhmien elämänlaatu oli alentunut. APECED-ryhmässä elämänlaatuun vaikuttivat negatiivisimmin heikentyneet yleinen terveydentila, henkinen hyvinvointi sekä energisyys/elinvoima. Addisonin tauti/APS2-potilailla elämänlaatuun negatiivisimmin vaikuttivat alentunut yleinen fyysinen ja emotionaalinen toiminta, terveydentila sekä energisyys/elinvoima. 15D-kyselyn merkittävimmin muuttuneita tekijöitä olivat vaivat ja oireet, elinvoima sekä seksuaalinen aktiivisuus. Näiden potilaiden heikentyneeseen elämänlaatuun vaikuttivat eniten seuraavat erilliset tekijät: potilasyhdistykseen kuuluminen, naissukupuoli, muut kuin APS-2:een kuuluvat tulehdustaudit, alempi koulutustaso sekä pitkittynyt sairauden kesto. Tässä väitöskirjassa esitetyt tulokset osoittavat, että APECED-potilailla on runsaasti autovasta-aineita monia kudosantigeeneja vastaan mutta samalla potilaat ovat tolerantteja tietyille yleisille autoantigeeneille. Näiden kiertävien autovasta-aineiden lopullinen kliininen sekä biologinen merkitys on vielä tuntematon mutta on mahdollista, että ne ovat vain yksi T-soluvälitteisen immuniteetin osa-alue. On mahdollista, että näillä kiertävillä vasta-aineilla on kumulatiivinen vaikutus ja oireiden puhkeamiseen vaaditaan vasta-aineiden yhdistelmä, kuten on esimerkiksi tyypin 1 diabeteksessä. Tämä voisi selittää myös miksi yksittäisten vasta-aineiden ja kliinisten oireiden välillä ei tässä työssä aina voitu osoittaa merkitsevää assosiaatiota
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