Microbial diagnosis of bloodstream infection: towards molecular diagnosis directly from blood.

When a bloodstream infection (BSI) is suspected, most of the laboratory results-biochemical and haematologic-are available within the first hours after hospital admission of the patient. This is not the case for diagnostic microbiology, which generally takes a longer time because blood culture, which is to date the reference standard for the documentation of the BSI microbial agents, relies on bacterial or fungal growth. The microbial diagnosis of BSI directly from blood has been proposed to speed the determination of the etiological agent but was limited by the very low number of circulating microbes during these paucibacterial infections. Thanks to recent advances in molecular biology, including the improvement of nucleic acid extraction and amplification, several PCR-based methods for the diagnosis of BSI directly from whole blood have emerged. In the present review, we discuss the advantages and limitations of these new molecular approaches, which at best complement the culture-based diagnosis of BSI.

Emerging single-cell technologies in immunology.

During evolution, the immune system has diversified to protect the host from the extremely wide array of possible pathogens. Until recently, immune responses were dissected by use of global approaches and bulk tools, averaging responses across samples and potentially missing particular contributions of individual cells. This is a strongly limiting factor, considering that initial immune responses are likely to be triggered by a restricted number of cells at the vanguard of host defenses. The development of novel, single-cell technologies is a major innovation offering great promise for basic and translational immunology with the potential to overcome some of the limitations of traditional research tools, such as polychromatic flow cytometry or microscopy-based methods. At the transcriptional level, much progress has been made in the fields of microfluidics and single-cell RNA sequencing. At the protein level, mass cytometry already allows the analysis of twice as many parameters as flow cytometry. In this review, we explore the basis and outcome of immune-cell diversity, how genetically identical cells become functionally different, and the consequences for the exploration of host-immune defense responses. We will highlight the advantages, trade-offs, and potential pitfalls of emerging, single-cell-based technologies and how they provide unprecedented detail of immune responses.

Benchmarked Quality Measurement Process in a Software Validation Process

Jatkuva laadunmittaus osana ohjelmistoprosessia on yleistynyt ohjelmistoyritysten keskuudessa viime vuosien aikana. ISO 9001:2000 -laatustandardi vaatii yrityksiltä tuotteiden ja prosessien laadun mittaamista ja seuraamista. Laadun mittareiden valinta on haastava tehtävä. Yritykset luulevat usein mittaavansa laatua, vaikka ne todellisuudessa mittaavatkin ohjelmistojen eri ominaisuuksia kuten kokoa tai monimutkaisuutta. Tässä diplomityössä kehitetään ohjelmistojen validointiprosessiin vertailuun perustuva laadunmittausprosessi ohjelmistotuotteiden laadun arviointiin, mittaamiseen ja seurantaan. Laatumittarit valitaan ennalta määriteltyjen kriteereiden mukaisesti, ja niille asetetaan tavoitearvot vertailuanalyysistä saatujen tulosten perusteella. Laadunmittausprosessin lisäksi työssä annetaan suositus prosessin käyttöönotosta ja käytöstä osana yrityksen toimintaa, mikä mahdollistaa jatkuvan seurannan sekä kehityksen tulevaisuudessa.

Paperitehtaan avaintehtävissä tarvittava talousosaaminen

Tutkielman päätavoitteena oli määritellä, mitä on paperitehtaan avaintehtävissä tarvittava, tulos- ja kustannustietoista toimintaa edistävä talousosaaminen. Kirjallisuusanalyysin perusteella muodostettiin malli talousosaamisen rakentumisesta. Mallia testattiin haastattelemalla erään paperitehtaan avaintehtävissä toimivia henkilöitä. Tulosten perusteella muodostettiin lopullinen käsitys paperitehtaassa tarvittavasta talousosaamisesta ja sen kehittämiseksi soveltuvista menetelmistä. Tutkimus osoitti, että talousosaaminen rakentuu sekä työntekijän sisäisten ominaisuuksien että hänen tiedollisen ja taidollisen talousosaamisen yhdistelmästä. Tietotaitotaso näyttäisi jakautuvan useaan eri kerrokseen sen mukaan, miten laajalti tiedot ja taidot ovat organisaatiossa sovellettavissa. Tärkeimmiksi sisäisiksi ominaisuuksiksi muodostuivat vuorovaikutusosaaminen, vastuuntuntoisuus ja ongelmanratkaisukyky. Talousosaamisen vahvistamisessa avainasemaan nousivat vuorovaikutukselliset, erityisesti viestintään liittyvät keinot ja osaamisen hyödyntämistä tukevan työympäristön luominen.

Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies.

PURPOSE: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. METHODS: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. RESULTS: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. CONCLUSION: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.

Adsorption energy and spin state of first-row transition metals adsorbed on MgO(100)

Slab and cluster model spin-polarized calculations have been carried out to study various properties of isolated first-row transition metal atoms adsorbed on the anionic sites of the regular MgO(100) surface. The calculated adsorption energies follow the trend of the metal cohesive energies, indicating that the changes in the metal-support and metal-metal interactions along the series are dominated by atomic properties. In all cases, except for Ni at the generalized gradient approximation level, the number of unpaired electron is maintained as in the isolated metal atom. The energy required to change the atomic state from high to low spin has been computed using the PW91 and B3LYP density-functional-theory-based methods. PW91 fails to predict the proper ground state of V and Ni, but the results for the isolated and adsorbed atom are consistent within the method. B3LYP properly predicts the ground state of all first-row transition atom the high- to low-spin transition considered is comparable to experiment. In all cases, the interaction with the surface results in a reduced high- to low-spin transition energy.

Coev-web: a web platform designed to simulate and evaluate coevolving positions along a phylogenetic tree.

BACKGROUND: Available methods to simulate nucleotide or amino acid data typically use Markov models to simulate each position independently. These approaches are not appropriate to assess the performance of combinatorial and probabilistic methods that look for coevolving positions in nucleotide or amino acid sequences. RESULTS: We have developed a web-based platform that gives a user-friendly access to two phylogenetic-based methods implementing the Coev model: the evaluation of coevolving scores and the simulation of coevolving positions. We have also extended the capabilities of the Coev model to allow for the generalization of the alphabet used in the Markov model, which can now analyse both nucleotide and amino acid data sets. The simulation of coevolving positions is novel and builds upon the developments of the Coev model. It allows user to simulate pairs of dependent nucleotide or amino acid positions. CONCLUSIONS: The main focus of our paper is the new simulation method we present for coevolving positions. The implementation of this method is embedded within the web platform Coev-web that is freely accessible at http://coev.vital-it.ch/, and was tested in most modern web browsers.

Wavelets in real-time paper web analysis

Online paper web analysis relies on traversing scanners that criss-cross on top of a rapidly moving paper web. The sensors embedded in the scanners measure many important quality variables of paper, such as basis weight, caliper and porosity. Most of these quantities are varying a lot and the measurements are noisy at many different scales. The zigzagging nature of scanning makes it difficult to separate machine direction (MD) and cross direction (CD) variability from one another. For improving the 2D resolution of the quality variables above, the paper quality control team at the Department of Mathematics and Physics at LUT has implemented efficient Kalman filtering based methods that currently use 2D Fourier series. Fourier series are global and therefore resolve local spatial detail on the paper web rather poorly. The target of the current thesis is to study alternative wavelet based representations as candidates to replace the Fourier basis for a higher resolution spatial reconstruction of these quality variables. The accuracy of wavelet compressed 2D web fields will be compared with corresponding truncated Fourier series based fields.

Characterisation of anatomical properties of the human basal ganglia using magnetic resonance imaging

The detailed in-vivo characterization of subcortical brain structures is essential not only to understand the basic organizational principles of the healthy brain but also for the study of the involvement of the basal ganglia in brain disorders. The particular tissue properties of basal ganglia - most importantly their high iron content, strongly affect the contrast of magnetic resonance imaging (MRI) images, hampering the accurate automated assessment of these regions. This technical challenge explains the substantial controversy in the literature about the magnitude, directionality and neurobiological interpretation of basal ganglia structural changes estimated from MRI and computational anatomy techniques. My scientific project addresses the pertinent need for accurate automated delineation of basal ganglia using two complementary strategies: ? Empirical testing of the utility of novel imaging protocols to provide superior contrast in the basal ganglia and to quantify brain tissue properties; ? Improvement of the algorithms for the reliable automated detection of basal ganglia and thalamus Previous research demonstrated that MRI protocols based on magnetization transfer (MT) saturation maps provide optimal grey-white matter contrast in subcortical structures compared with the widely used Tl-weighted (Tlw) images (Helms et al., 2009). Under the assumption of a direct impact of brain tissue properties on MR contrast my first study addressed the question of the mechanisms underlying the regional specificities effect of the basal ganglia. I used established whole-brain voxel-based methods to test for grey matter volume differences between MT and Tlw imaging protocols with an emphasis on subcortical structures. I applied a regression model to explain the observed grey matter differences from the regionally specific impact of brain tissue properties on the MR contrast. The results of my first project prompted further methodological developments to create adequate priors for the basal ganglia and thalamus allowing optimal automated delineation of these structures in a probabilistic tissue classification framework. I established a standardized workflow for manual labelling of the basal ganglia, thalamus and cerebellar dentate to create new tissue probability maps from quantitative MR maps featuring optimal grey-white matter contrast in subcortical areas. The validation step of the new tissue priors included a comparison of the classification performance with the existing probability maps. In my third project I continued investigating the factors impacting automated brain tissue classification that result in interpretational shortcomings when using Tlw MRI data in the framework of computational anatomy. While the intensity in Tlw images is predominantly

Factors Affecting Consumer’s Illicit Purchase of Copyrighted Digital Work

Peer-to-Peer (P2P) technology has revolutionized file exchange activities besides enhancing processing power distribution. As such, this technology which is nowadays made freely available to all internet users also imposes a threat as it enables the illegal distribution of copyrighted digital work. P2P technology continuously evolves in a greater pace than copyright legislation, leading to compatibility gaps between the applicability of copyright law and the illicit file sharing and downloading. Such issues give high incentives to consumers to practise piracy using P2P systems with a low perception of risk towards prosecution, leading to substantial losses for copyright owners. This study focuses on developing insights for content owners on consumer behaviour towards piracy in Finland, where quantitative analyses are assessed using a data set based on a survey conducted by the Helsinki Institute for IT. The research approach investigates the significance of three fundamental areas in relation to evaluate consumer behaviour as: environmental-related factors, innovation-related factors and consumer-related. each of these are integrates concepts derived in previous theoretical models such as the technology acceptance model, theory of reasoned action, theory of planned behaviour, the issue-risk-judgement model and the Hunt & Vitell’s model.

Polímeros com capacidade de reconhecimento molecular no controlo da libertação de fármacos. Parte 1: síntese e caracterização

Molecularly imprinted polymers (MIPs) consist of synthetic macromolecular matrix, obtained through molecular imprinting-based methods that show ability to selectively recognize important biological molecules and its application in the drug delivery field is under development. In the present review the main aspects related to the synthesis and characterization of MIPs are studied. The fundamental variables participating in the synthesis process, such as template molecule, functional monomers, cross-linking agents, solvents and imprinting approaches are discussed. Moreover, the main available methods for MIPs chemical and morphological characterization are presented and the importance of the obtained information is discussed.

Idea- ja innovaatioporfolion hallinta

Tässä kandidaatintyössä tarkastellaan idea- ja innovaatioportfolion hallintaa, portfoliojohtamista sekä näihin soveltuvia erilaisia menetelmiä yrityksen näkökulmasta. Tavoitteena on luoda yleiskatsaus yleisimpiin käytettyihin menetelmiin ja viitekehyksiin. Lähteinä työssä on käytetty sähköisiä tietokantoja ja alan kirjallisuutta. Käytetyimmät portfolion hallintamenetelmät voidaan jakaa neljään ryhmään: taloudelliset ja rahamääräiset mittarit, liiketoimintastrategiat, portfoliokartat tai kupla-diagrammit, scorecard:it eli pisteytystaulukot sekä tarkistuslistat. Idea- ja innovaatioportfolion hallinnan tavoitteena on luoda yrityksen kannalta mahdollisimman tehokas ja tuottava portfolio, joka on kuitenkin linjassa yrityksen strategian kanssa. Portfolion projekteille jaettavissa olevat resurssit ovat niukat, joten resurssien jakoon ja tehokkaaseen hyödyntämiseen tulee kiinnittää huomiota. Portfolion tasapainottamiseksi on hyvä tarkastella kehitys- ja tutkimusprojektien määrää, kokoa ja riskiä. Teknologiatiekartta on yrityksen strateginen työkalu, jolla se voi suunnata toimintaansa kohti sen visiota. Teknologiatiekartta koostuu yrityksen valitsemista markkinoista, niille suunnatuista tuotteista tai palveluista, sekä näiden vaatimista tuotekehitysprojekteista ja teknologioista. Projektien etenemistä voidaan tarkastella stage-gate -mallin avulla. Stage-gate jakaa projektin porteilla eri vaiheisiin. Jokaisen portin läpäistäkseen projektin tulee täyttää sille asetetut vaatimukset. Menetelmät eivät takaa menestystä, vaan yrityksen on valittava itselleen sopivat menetelmät siten, että ne tukevat portfoliojohtamista ja sopivat yhteen yrityskulttuurin kanssa. Pelkkä mittareihin tuijottaminen ei riitä, vaan niiden taakse on myös osattava katsoa ja huomioida yrityksen strategia.

Alumiinipainevalujen purseen- ja jäysteenpoiston kehitysmahdollisuudet

Valupurseiden ja jäysteiden poistaminen on osa alumiinipainevalujen tuotantoprosessia. Työssä on tutkittu käytössä olevien ja uusien menetelmien mahdollisuuksia taloudellisempaan tuotantoon. Purseiden ja jäysteiden poistamiseen käytettävien menetelmien lisäksi tutkimuskohteita ja ideoita on haettu muista metallien työstömenetelmistä. Valupurseiden ja jäysteiden määritelmiä, muodostumista ja luokittelua on esitelty laajasti. Menetelmien tutkimus on painottunut valupurseiden poistamiseen ja valun jälkeistä leikkaamista on tutkittu erityisesti sisäpuolisten muotojen työstämiseen käytettyjen pistintyökalujen kautta. Muotin ulostyöntötapin purseen poistaminen on ollut tärkeä asia menetelmien tutkimuksissa. Valupurseiden, leikkaus- ja koneistusjäysteiden poistamiseksi lastuavista työstömenetelmistä tutkittuja ovat koneistaminen koneistuskeskuksella, aventaminen, hiertopuhallus, suihkuhiertäminen, vesisuihkuleikkaus, ultraäänityöstö, harjaus, painehiertäminen, hiominen kohdistetuilla ja kohdistamattomilla menetelmillä. Myös terminen jäysteenpoistomenetelmä (TEM), kemiallinen työstö (ECM) ja laserleikkaus on otettu esiin tutkimuksessa. Työn tuloksena on näkemys tutkittujen menetelmien jatkokehitystarpeesta ja mahdollisuudesta soveltaa niitä sarjatuotantoon.

Experiences in using a structured method in finding and defining new innovations: the strategic options approach

Investment decision-making on far-reaching innovation ideas is one of the key challenges practitioners and academics face in the field of innovation management. However, the management practices and theories strongly rely on evaluation systems that do not fit in well with this setting. These systems and practices normally cannot capture the value of future opportunities under high uncertainty because they ignore the firm’s potential for growth and flexibility. Real options theory and options-based methods have been offered as a solution to facilitate decision-making on highly uncertain investment objects. Much of the uncertainty inherent in these investment objects is attributable to unknown future events. In this setting, real options theory and methods have faced some challenges. First, the theory and its applications have largely been limited to market-priced real assets. Second, the options perspective has not proved as useful as anticipated because the tools it offers are perceived to be too complicated for managerial use. Third, there are challenges related to the type of uncertainty existing real options methods can handle: they are primarily limited to parametric uncertainty. Nevertheless, the theory is considered promising in the context of far-reaching and strategically important innovation ideas. The objective of this dissertation is to clarify the potential of options-based methodology in the identification of innovation opportunities. The constructive research approach gives new insights into the development potential of real options theory under non-parametric and closeto- radical uncertainty. The distinction between real options and strategic options is presented as an explanans for the discovered limitations of the theory. The findings offer managers a new means of assessing future innovation ideas based on the frameworks constructed during the course of the study.

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