Implementation of bayesian therapeutic drug monitoring in modern patient care

The variability observed in drug exposure has a direct impact on the overall response to drug. The largest part of variability between dose and drug response resides in the pharmacokinetic phase, i.e. in the dose-concentration relationship. Among possibilities offered to clinicians, Therapeutic Drug Monitoring (TDM; Monitoring of drug concentration measurements) is one of the useful tool to guide pharmacotherapy. TDM aims at optimizing treatments by individualizing dosage regimens based on blood drug concentration measurement. Bayesian calculations, relying on population pharmacokinetic approach, currently represent the gold standard TDM strategy. However, it requires expertise and computational assistance, thus limiting its large implementation in routine patient care. The overall objective of this thesis was to implement robust tools to provide Bayesian TDM to clinician in modern routine patient care. To that endeavour, aims were (i) to elaborate an efficient and ergonomic computer tool for Bayesian TDM: EzeCHieL (ii) to provide algorithms for drug concentration Bayesian forecasting and software validation, relying on population pharmacokinetics (iii) to address some relevant issues encountered in clinical practice with a focus on neonates and drug adherence. First, the current stage of the existing software was reviewed and allows establishing specifications for the development of EzeCHieL. Then, in close collaboration with software engineers a fully integrated software, EzeCHieL, has been elaborated. EzeCHieL provides population-based predictions and Bayesian forecasting and an easy-to-use interface. It enables to assess the expectedness of an observed concentration in a patient compared to the whole population (via percentiles), to assess the suitability of the predicted concentration relative to the targeted concentration and to provide dosing adjustment. It allows thus a priori and a posteriori Bayesian drug dosing individualization. Implementation of Bayesian methods requires drug disposition characterisation and variability quantification trough population approach. Population pharmacokinetic analyses have been performed and Bayesian estimators have been provided for candidate drugs in population of interest: anti-infectious drugs administered to neonates (gentamicin and imipenem). Developed models were implemented in EzeCHieL and also served as validation tool in comparing EzeCHieL concentration predictions against predictions from the reference software (NONMEM®). Models used need to be adequate and reliable. For instance, extrapolation is not possible from adults or children to neonates. Therefore, this work proposes models for neonates based on the developmental pharmacokinetics concept. Patients' adherence is also an important concern for drug models development and for a successful outcome of the pharmacotherapy. A last study attempts to assess impact of routine patient adherence measurement on models definition and TDM interpretation. In conclusion, our results offer solutions to assist clinicians in interpreting blood drug concentrations and to improve the appropriateness of drug dosing in routine clinical practice.

Description and implementation of cut calculation-method in a sawmill

Työn tavoitteena oli kuvata ja ottaa käyttöön sahauseräkohtaisen kannattavuuden laskentamenetelmä sahalle, sekä tehdä laskentamalli menetelmän tueksi. Sahauksen peruskäsitteiden jälkeen työssä on esitelty sahan tuotantoprosessi. Tuotantoprosessi on kuvattu kirjallisuuden ja asiantuntijoiden haastattelujen perusteella. Seuraavaksi kartoitettiin hyötyjä ja vaikutuksia, mitä laskentamenetelmältä odotetaan.. Kustannuslaskennan teoriaa selvitettiin kirjallisuuslähteitä käyttäen silmälläpitäen juuri tätä kehitettävää laskentamenetelmää. Lisäksi esiteltiin Uimaharjun sahalla käytettävät ja laskentaan liittyvät laskenta- ja tietojärjestelmät.Nykyisin sahalla ei ole minkäänlaista menetelmää sahauseräkohtaisen tuloksen laskemiseksi. Pienillä muutoksilla sahan tietojärjestelmään ja prosessikoneisiin voidaan sahauserä kuljettaa prosessin läpi niin, että jokaisessa prosessin vaiheessa sille saadaan kohdistettua tuotantotietoa. Eri vaiheista saatua tietoa käyttämällä saadaan tarkasti määritettyä tuotteet, joita sahauserä tuotti ja paljonko tuotantoresursseja tuottamiseen kului. Laskentamalliin syötetään tuotantotietoja ja kustannustietoa ja saadaan vastaukseksi sahauserän taloudellinen tulos.Toimenpide ehdotuksena esitetään lisätutkimusta tuotantotietojen automaattisesta keräämisestä manuaalisen työn ja virheiden poistamiseksi. Suhteellisen pienillä panoksilla voidaan jokaiselle sahauserälle kerätä tuotantotiedot täysin automaattisesti. Lisäksi kehittämäni laskentamallin tilalle tulisi hankkia sovellus, joka käyttäisi paremmin hyväksi nykyisiä tietojärjestelmiä ja poistaisi manuaalisen työvaiheen laskennassa.

Software testing design and implementation in a small software company

Monet ohjelmistoyritykset ovat alkaneet kiinnittää yhä enemmän huomiota ohjelmistotuotteidensa laatuun. Tämä on johtanut siihen, että useimmat niistä ovat valinneet ohjelmistotestauksen välineeksi, jolla tätä laatua voidaan parantaa. Testausta ei pidä rajoittaa ainoastaan ohjelmistotuotteeseen itseensä, vaan sen tulisi kattaa koko ohjelmiston kehitysprosessi. Validaatiotestauksessa keskitytään varmistamaan, että lopputuote täyttää sille asetetut vaatimukset, kun taas verifikaatiotestausta käytetään ennaltaehkäisevänä testauksena, jolla pyritään poistamaan virheitä jo ennenkuin ne pääsevät lähdekoodiin asti. Työ, johon tämä diplomityö perustuu, tehtiin alkukevään ja kesän aikana vuonna 2003 Necsom Oy:n toimeksiannosta. Necsom on pieni suomalainen ohjelmistoyritys, jonka tutkimus- ja kehitysyksikkö toimii Lappeenrannassa.Tässä diplomityössä tutustutaan aluksi ohjelmistotestaukseen sekä eri tapoihin sen organisoimiseksi. Tämän lisäksi annetaan yleisiä ohjeita testisuunnitelmien ja testaustapausten tekoon, joita onnistunut ja tehokas testaus edellyttää. Kun tämä teoria on käyty läpi, esitetään esimerkkinä kuinka sisäinen ohjelmistotestaus toteutettiin Necsomilla. Lopuksi esitetään johtopäätökset, joihin päädyttiin käytännön testausprosessin seuraamisen jälkeen ja annetaan jatkotoimenpide-ehdotuksia.

Software methods for HTML files protection in local / corporate networks: review and implementation

Tässä luomistyössä on esitetty tutkimus informaation suojaamisen menetelmien osalta paikallisissa ja ryhmäkuntaisissa verkoissa. Tutkimukseen kuuluu nykyaikaisten kryptagraafisten järjestelmien, Internetin/Intranetin ohjelmointikeinojen ja pääsyoikeuksien jakelumenetelmien analyysi. Tutkimusten perusteella on laadittu ohjelmiston prototyyppi HTML-tiedostojen suojaamista varten. Ohjelmiston laatimisprosessi on sisältänyt vaatimusten, järjestelmän ja suojelukomponenttien suunnittelun ja protytyypin testauksen. Ohjelmiston realisoinnin jälkeen kirjoitettiin käyttöohjeet. Ohjelmiston prototyyppi suojaa informaatiota HTML-tiedoston koko käytön aikana ja eri yrityksissä voidaan käyttää sitä pienien laajennuksien jälkeen.

Interface Implementation for GPRS/PCU Software Testing with Emulators

Jatkuvasti lisääntyvä matkapuhelinten käyttäjien määrä, internetin kehittyminen yleiseksi tiedon ja viihteen lähteeksi on luonut tarpeen palvelulle liikkuvan työaseman liittämiseksi tietokoneverkkoihin. GPRS on uusi teknologia, joka tarjoaa olemassa olevia matka- puhelinverkkoja (esim. NMT ja GSM) nopeamman, tehokkaamman ja taloudellisemman liitynnän pakettidataverkkoihin, kuten internettiin ja intranetteihin. Tämän työn tavoitteena oli toteuttaa GPRS:n paketinohjausyksikön (Packet Control Unit, PCU) testauksessa tarvittavat viestintäajurit työasemaympristöön. Aidot matkapuhelinverkot ovat liian kalliita, eikä niistä saa tarvittavasti lokitulostuksia, jotta niitä voisi käyttää GPRS:n testauksessa ohjelmiston kehityksen alkuvaihessa. Tämän takia PCU-ohjelmiston testaus suoritetaan joustavammassa ja helpommin hallittavassa ympäristössä, joka ei aseta kovia reaaliaikavaatimuksia. Uusi toimintaympäristö ja yhteysmedia vaativat PCU:n ja muiden GPRS-verkon yksiköiden välisistä yhteyksistä huolehtivien ohjelman osien, viestintäajurien uuden toteutuksen. Tämän työn tuloksena syntyivät tarvittavien viestintäajurien työasemaversiot. Työssä tarkastellaan eri tiedonsiirtotapoja ja -protokollia testattavan ohjelmiston vaateiden, toteutetun ajurin ja testauksen kannalta. Työssä esitellään kunkin ajurin toteuttama rajapinta ja toteutuksen aste, eli mitkä toiminnot on toteutettu ja mitä on jätetty pois. Ajureiden rakenne ja toiminta selvitetään siltä osin, kuin se on oleellista ohjelman toiminnan kannalta.

Critical Success Factors in the Implementation of the Balanced Scorecard

Tutkielman tavoitteena on tunnistaa kriittiset menestystekijät balanced scorecardin käyttöönotossa. Tutkimus on luonteeltaan selittävä tapaustutkimus. Tutkimuksen haastatteluaineisto on kerätty suomalaisyrityksistä, jotka ovat ottaneet onnistuneesti balanced scorecardin käyttöön organisaatiossa. Yksi tapauksista osoittautui kuitenkin epäonnistuneeksi. Balanced scorecardin onnistuneeseen käyttöönottoon vaikuttaa usea eri tekijä. Tutkielmassa käyttöönottoon vaikuttavat menestystekijät on jaettu neljään eri ryhmään, jotka ovat tekijät liittyen organisaatioon, resursseihin, käyttöönottoprosessiin ja itse balanced scorecardiin. Viitekehys havainnollistaa kriittisten menestystekijöiden keskinäisiä suhteita. Johdon sitoutuminen, ajankäyttö sekä avoin kommunikaatio ovat eräitä keskeisiä menestystekijöitä balanced scorecardin käyttöönottoprosessissa. Lisäksi balanced scorecardin onnistuneeseen käyttöönottoon on kaksi perusedellytystä: organisaation strategian selkeys sekä ympäristön tuki prosessille.

IAS 14 - Segment Reporting; The Requirements and Implementation

The principal aim of this study is to clarify the requirements of segment reporting and compare the requirements with the actual! implementation on different business lines. The empirical part was concluded by interviewing randomly selected companies that are publicly listed on the Helsinki Exchanges. The theoretical part of the study (chapters 2 and 3) will give basic information about shifting to IAS -standards and the requirements of IAS -standards. In order to meet the principal aim, a pre-empiric research was conducted by studying the annual accounts (year 2002) of randomly selected companies that already follow the IAS -standards of reporting. The companies in the pre-empiric research consist of both domestic and foreign companies. The aim of the pre-empiric study was to give a basis for the interview process on the empiric part of the study. The study indicates that implementing segment reporting has not brought any major concerns or problems. This is due to the fact that most companies that were examined - being publicly listed companies - have traditionally had a clear division between their geographical and commercial segments, and also been obliged to give reports according to these segments. In case of changes in corporate structure, shifting on new lines of businesses or downsizing of operations, the problems in reporting according to IAS -standards, may arise. Such changes will also require changes on information systems, providing the essential information for segment reporting. According to this study, most companies choose the commercial segment as their primary segment for reporting. The pre-empiric study indicates, that most of the companies already following the IAS -standards, still have a lot of improvement to do, in order to meet all the IAS requirements.

Implementation of counter testing in Nokia Automation System

In this study the performance measurement, a part of the research and development of the RNC, was improved by implementing counter testing to the Nokia Automation System. The automation of counter testing is a feature the customer ordered, because performing counter testing manually is rather complex. The objective was to implement an automated counter testing system, which once configured correctly, would manage to run the testing and perform the analysis. The requirements for the counter testing were first studied. It was investigated if the auto-mation of the feature was feasible in the meetings with the customer. The basic functionality required for the automation was also drawn. The technologies used in the architecture of the Nokia Automation System were studied. Based on the results of the study, a new technology, wxWidgets, was introduced. The new technology was necessary to facilitate the implementing of the required feature. Finally the implementation of the counter testing was defined and implemented. The result of this study was the automation of the counter testing method developed as a new feature for the Nokia Automation System. The feature meets the specifications and requirements set by the customer. The performing of the counter testing feature is totally automated. Only configuration of the test cases is done by the user. The customer has presented new requests to further develop the feature and there are plans by the Nokia Automation System developers to implement those in the near future. The study describes the implementation of the counter testing feature introduced. The results of the study give guidelines for further developing the feature.

The down-regulation of disgust by implementation intentions: experiential and physiological concomitants

Emotion regulation plays a key role in mental health and psychopathology. Therefore, it seems important to develop effective forms of emotion regulation. Implementation intentions are if-then plans that help people attain their self-regulatory goals. Perspective-taking and response-focused implementation intentions have been shown to reduce feelings of unpleasantness and arousal, respectively, in response to briefly presented disgusting pictures. The present study addressed the open research questions whether forming these types of implementation intentions is effective in regulating affect during prolonged presentation of disgusting pictures, and whether it is associated with changes in physiological arousal. Eighty-one participants viewed disgusting, neutral, and pleasant pictures of 6 s duration under four instructions: the goal intention to not get disgusted, this goal intention furnished with a perspective-taking or a response-focused implementation intention, and no emotion regulation instructions. The dependent variables were ratings of disgust, valence, arousal, and electrodermal activity. Only perspective-taking implementation intention participants significantly reduced their disgust and unpleasantness as compared to goal-intention and control participants. Arousal and skin conductance did not significantly differ between conditions. The effectiveness of response-focused but not perspective-taking implementation intentions seems to be substantially reduced during sustained exposure duration.

Diffusion of Administrative Innovation: TQM Implementation and Effectiveness in a Global

The main objective of this dissertation is to create new knowledge on an administrative innovation, its adoption, diffusion and finally its effectiveness. In this dissertation the administrative innovation is approached through a widely utilized management philosophy, namely the total quality management (TQM) strategy. TQM operationalizes a self-assessment procedure, which is based on continual improvement principles and measuring the improvements. This dissertation also captures the theme of change management as it analyzes the adoption and diffusion of the administrative innovation. It identifies innovation characteristics as well as organisational and individual factors explaining the adoption and implementation. As a special feature, this study also explores the effectiveness of the innovation based on objective data. For studying the administrative innovation (TQM model), a multinational Case Company provides a versatile ground for a deep, longitudinal analysis. The Case Company started the adoption systematically in the mid 1980s in some of its units. As part of their strategic planning today, the procedure is in use throughout the entire global company. The empirical story begins from the innovation adoption decision that was made in the Case Company over 22 years ago. In order to be able to capture the right atmosphere and backgrounds leading to the adoption decision, key informants from that time were interviewed, since the main target was to clarify the dynamics of how an administrative innovation develops. In addition, archival material was collected and studied, available memos and data relating to the innovation, innovation adoption and later to the implementation contained altogether 20500 pages of documents. A survey was furthermore conducted at the end of 2006 focusing on questions related to the innovation, organization and leadership characteristics and the response rate totalled up to 54%. For measuring the effectiveness of the innovation implementation, the needed longitudinal objective performance data was collected. This data included the profit unit level experience of TQM, the development of the self assessment scores per profit unit and performance data per profit unit measured with profitability, productivity and customer satisfaction. The data covered the years 1995-2006. As a result, the prerequisites for the successful adoption of an administrative innovation were defined, such as the top management involvement, support of the change agents and effective tools for implementation and measurement. The factors with the greatest effect on the depth of the implementation were the timing of the adoption and formalization. The results also indicated that the TQM model does have an effect on the company performance measured with profitability, productivity and customer satisfaction. Consequently this thesis contributes to the present literature (i) by taking into its scope an administrative innovation and focusing on the whole innovation implementation process, from the adoption, through diffusion until its consequences, (ii) because the studied factors with an effect on the innovation adoption and diffusion are multifaceted and grouped into individual, organizational and environmental factors, and a strong emphasis is put on the role of the individual change agents and (iii) by measuring the depth and consistency of the administrative innovation. This deep analysis was possible due to the availability of longitudinal data with triangulation possibilities.

Evaluation and implementation process for commercial elevator landing doors

Tason ovet voivat olla joko itsesuunniteltuja ja -tehtyjä, tai itse malli ja tuote voidaan ostaa myös yrityksen ulkoa. Tätä make-or-buy kysymystä pohdittaessa ilmenee monta tekijää, jotka vaikuttavat päätökseen. Jos yritys käsittää ostamisen parempana vaihtoehtona, tuote tarvitsee myösimplementointisuunnitelman. Tämän työn päätavoite oli luoda arviointi- ja implementointiprosessi kaupallisille hissin tason oville. Muut tavoitteet olivat: selvittää syyt tälle erikoiselle toiminnolle, löytää kaupallisten ovien käyttöön liittyvät edut ja haitat, sekä luoda kriteerit tason ovien arvioinnille. Lopputuloksena saatiin, että tämän prosessin suorittajan pitää sitoutua arviointi- ja implementointiprosessiin,ja että myös virtuaalitehdas tarvitaan täydentämään arviointivaihetta. Mutta tärkein havainto oli, että tulevaisuuden ovistrategia ei ole vielä täysin päätetty ja siitä syystä yrityksen omat ovimallit pitäisi testata ja verrata niitä kaupallisiin ovimalleihin käyttämällä tämän työn arviointiprosessia.

Biological variation of established and novel biomarkers for atherosclerosis: Results from a prospective, parallel-group cohort study.

BACKGROUND: Biomarkers are a promising tool for the management of patients with atherosclerosis, but their variation is largely unknown. We assessed within-subject and between-subject biological variation of biomarkers in peripheral artery disease (PAD) patients and healthy controls, and defined which biomarkers have a favorable variation profile for future studies. METHODS: Prospective, parallel-group cohort study, including 62 patients with stable PAD (79% men, 65±7years) and 18 healthy control subjects (44% men, 57±7years). Blood samples were taken at baseline, and after 3-, 6-, and 12-months. We calculated within-subject (CVI) and between-subject (CVG) coefficients of variation and intra-class correlation coefficient (ICC). RESULTS: Mean levels of D-dimer, hs-CRP, IL-6, IL-8, MMP-9, MMP-3, S100A8/A9, PAI-1, sICAM-1, and sP-selectin levels were higher in PAD patients than in healthy controls (P≤.05 for all). CVI and CVG of the different biomarkers varied considerably in both groups. An ICC≥0.5 (indicating moderate-to-good reliability) was found for hs-CRP, D-Dimer, E-selectin, IL-10, MCP-1, MMP-3, oxLDL, sICAM-1 and sP-selectin in both groups, for sVCAM in healthy controls and for MMP-9, PAI-1 and sCD40L in PAD patients. CONCLUSIONS: Single biomarker measurements are of limited utility due to large within-subject variation, both in PAD patients and healthy subjects. D-dimer, hs-CRP, MMP-9, MMP-3, PAI-1, sP-selectin and sICAM-1 are biomarkers with both higher mean levels in PAD patients and a favorable variation profile making them most suitable for future studies.

A Legislator under Surveillance: The Creation and Implementation of Swiss Banking Legislation 1910-1934

This paper analyses how banking regulation was introduced in Switzerland - one of the world's most prominent financial centres - which remained in place until the beginning of the twenty-first century. It shows that the law adopted on 8 November 1934 is a perfect example of capture of the regulator by the regulated. Essentially a political response in the context of the economic crisis of the 1930s, it largely reflected the interests of banking circles by limiting the intervention of the State as much as possible. The introduction of the new legislation was facilitated by the temporary weakness of Swiss banking circles, as they depended on the State to delay or prevent the collapse of many major credit institutions. They did not manage to derail the law as they had two decades earlier when they scuppered the federal bill on banks drawn up between 1914 and 1916. But this time they were better organized and more united, and intervened all the more effectively in the legislative process itself. The 1934 law is thus distinctive in that it made no structural changes to the architecture of the financial centre but merely codified its practices through flexible legislation meant to reassure the public. The law was aimed less at controlling banking activity than at keeping - thanks to skilfully calibrated political concessions - the State from having to intervene more directly in the internal management of banks or in the fixing of interest rates and the export of capital.