Prolonged fluconazole exposure leads to a shift to Candida species with decreased susceptibility in breakthrough candidemia: prospective survey of the Fungal Infection Network of Switzerland

Objectives: To compare the clinical characteristics, species distribution and antifungal susceptibility of Candida bloodstream isolates (BSI) in breakthrough (BTC) vs. non-breakthrough candidemia (NBTC) and to study the effect of prolonged vs. short fluconazole (F) exposure in BTC.Methods: Candida BSI were prospectively collected during 2004- 2006 from 27 hospitals (seven university, 20 affiliated) of the FUNGINOS network. Susceptibility to F, voriconazole (V) and caspofungin (C) was tested in the FUNGINOS mycology reference laboratory by microtitre broth dilution method with the Sensititre YeastOneTM test panel. Clinical data were collected using standardized CRFs. BTC was defined as occurring during antifungal treatment/prophylaxis of at least three days duration prior to the candidemia. Susceptibility of BSI was defined according to 2010/2011 CLSI clinical breakpoints.Results: Out of 567 candidemia episodes, 550 Candida BSI were available. Of these, 43 (7.6%) were from BTC (37/43, 86% were isolated after F exposure). 38 BTC (88.4%) and 315 NBTC (55.6%) occurred in university hospitals (P < 0.001). The majority of patients developing BTC were immunocompromised: higher proportions of haematological malignancies (62.8% in BTC vs. 47.1% in NBTC, P < 0.001), neutropenia (37.2% vs. 11.8%, P < 0.001), acute GvHD (14% vs. 0.2%, P < 0.001), immunosuppressive drugs (74.4% vs. 7.8%, P < 0.001), and mucositis (32.6% vs. 2.3%, P < 0.001) were observed. Other differences between BTC and NBTC were higher proportions of patients with central venous catheters in the 2 weeks preceding candidemia (95.3% vs. 83.4%, P = 0.047) and receiving total parenteral nutrition (62.8% vs. 35.9%, P < 0.001), but a lower proportion of patients treated with gastric proton pump inhibitors (23.3% vs. 72.1%, P < 0.001). Overall mortality of BTC and NBTC was not different (34.9% vs. 31.7%, P = 0.73), while a trend to higher attributable mortality in BTC was found (13.9% vs. 6.9%, P = 0.12). Species identification showed a majority of C. albicans in both groups (51.2% in BTC vs. 62.9% in NBTC, P = 0.26), followed by C. glabrata (18.6% vs. 18.5%), C. tropicalis (2.3% vs. 6.3%) and C. parapsilosis (7.0% vs. 4.7%). Significantly more C. krusei were detected in BTC versus NBTC (11.6% vs. 1.6%, P = 0.002). The geometric mean MIC for F, V and C between BTC and NBTC isolates was not significantly different. However, in BTC there was a significant association between duration of F exposure and the Candida spp.: >10 days of F was associated with a significant shift from susceptible Candida spp. (C. albicans, C. parapsilosis, C. tropicalis, C. famata) to non-susceptible species (C. glabrata, C. krusei, C. norvegensis). Among 21 BTC episodes occurring after £10 days of F, 19% of the isolates were non-susceptible, in contrast to 68.7% in 16 BTC episodes occurring after >10 days of F (P = 0.003).Conclusions: Breakthrough candidemia occurred more often in immunocompromised hosts. Fluconazole administered for >10 days was associated with a shift to non-susceptible Candida spp.. Length of fluconazole exposure should be taken into consideration for the choice of empirical antifungal treatment.

Trace element distribution among rock-forming minerals from metamorphosed to partially molten basic igneous rocks in a contact aureole (Fuerteventura, Canaries)

Low pressure partial melting of basanitic and ankaramitic dykes gave rise to unusual, zebra-like migmatites, in the contact aureole of a layered pyroxenite-gabbro intrusion, in the root zone of an ocean island (Basal Complex, Fuerteventura, Canary Islands). These migmatites are characterised by a dense network of closely spaced, millimetre-wide leucocratic segregations. Their mineralogy consists of plagioclase (An(32-36)), diopside, biotite, oxides (magnetite, ilmenite), +/-amphibole, dominated by plagioclase in the leucosome and diopside in the melanosome. The melanosome is almost completely recrystallised, with the preservation of large, relict igneous diopside phenocrysts in dyke centres. Comparison of whole-rock and mineral major- and trace-element data allowed us to assess the redistribution of elements between different mineral phases and generations during contact metamorphism and partial melting. Dykes within and outside the thermal aureole behaved like closed chemical systems. Nevertheless, Zr, Hf, Y and REEs were internally redistributed, as deduced by comparing the trace element contents of the various diopside generations. Neocrystallised diopside - in the melanosome, leucosome and as epitaxial phenocryst rims - from the migmatite zone, are all enriched in Zr, Hf, Y and REEs compared to relict phenocrysts. This has been assigned to the liberation of trace elements on the breakdown of enriched primary minerals, kaersutite and sphene, on entering the thermal aureole. Major and trace element compositions of minerals in migmatite melanosomes and leucosomes are almost identical, pointing to a syn- or post-solidus reequilibration on the cooling of the migmatite terrain i.e. mineral-melt equilibria were reset to mineral-mineral equilibria. (C) 2007 Elsevier B.V. All rights reserved.

Self-similar community structure in a network of human interactions

We propose a procedure for analyzing and characterizing complex networks. We apply this to the social network as constructed from email communications within a medium sized university with about 1700 employees. Email networks provide an accurate and nonintrusive description of the flow of information within human organizations. Our results reveal the self-organization of the network into a state where the distribution of community sizes is self-similar. This suggests that a universal mechanism, responsible for emergence of scaling in other self-organized complex systems, as, for instance, river networks, could also be the underlying driving force in the formation and evolution of social networks.

Identification of neuronal network properties from the spectral analysis of calcium imaging signals in neuronal cultures

Neuronal networks in vitro are prominent systems to study the development of connections in living neuronal networks and the interplay between connectivity, activity and function. These cultured networks show a rich spontaneous activity that evolves concurrently with the connectivity of the underlying network. In this work we monitor the development of neuronal cultures, and record their activity using calcium fluorescence imaging. We use spectral analysis to characterize global dynamical and structural traits of the neuronal cultures. We first observe that the power spectrum can be used as a signature of the state of the network, for instance when inhibition is active or silent, as well as a measure of the network's connectivity strength. Second, the power spectrum identifies prominent developmental changes in the network such as GABAA switch. And third, the analysis of the spatial distribution of the spectral density, in experiments with a controlled disintegration of the network through CNQX, an AMPA-glutamate receptor antagonist in excitatory neurons, reveals the existence of communities of strongly connected, highly active neurons that display synchronous oscillations. Our work illustrates the interest of spectral analysis for the study of in vitro networks, and its potential use as a network-state indicator, for instance to compare healthy and diseased neuronal networks.

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

Voltage fluctuations in IC power supply distribution

The supply voltage decrease and powerconsumption increase of modern ICs made the requirements for low voltage fluctuation caused by packaging and on-chip parasitic impedances more difficult to achieve. Most of the research works on the area assume that all the nodes of the chip are fed at thesame voltage, in such a way that the main cause of disturbance or fluctuation is the parasitic impedance of packaging. In the paper an approach to analyze the effect of high and fast current demands on the on-chip power supply network. First an approach to model the entire network by considering a homogeneous conductive foil is presented. The modification of the timing parameters of flipflops caused by spatial voltage drops through the IC surface are also investigated.

On the q=1/2 non-extensive maximum entropy distribution

A detailed mathematical analysis on the q = 1/2 non-extensive maximum entropydistribution of Tsallis' is undertaken. The analysis is based upon the splitting of such adistribution into two orthogonal components. One of the components corresponds to theminimum norm solution of the problem posed by the fulfillment of the a priori conditionson the given expectation values. The remaining component takes care of the normalizationconstraint and is the projection of a constant onto the Null space of the "expectation-values-transformation"

Performance Evaluation of Six-Sectored Configuration in Hexagonal WCDMA (UMTS) Cellular Network Layout

The objective of this master's thesis is to evaluate the optimum performance of sixsectored hexagonal layout of WCDMA (UMTS) network and analyze the performance at the optimum point. The maximum coverage and the maximum capacity are the main concern of service providers and it is always a challenging task for them to achieve economically. Because the optimum configuration of a network corresponds to a configuration which minimizes the number of sites required to provide a target service probability in the planning area which in turn reduces the deployment cost. The optimum performance means the maximum cell area and themaximum cell capacity the network can provide at the maximum antenna height satisfying the target service probability. Hexagon layout has been proven as the best layout for the cell deployment. In this thesis work, two different configurations using six-sectored sites have been considered for the performance comparison. In first configuration, each antenna is directed towards each corner of hexagon, whereas in second configurationeach antenna is directed towards each side of hexagon. The net difference in the configurations is the 30 degree rotation of antenna direction. The only indoor users in a flat and smooth semi-urban environment area have been considered for the simulation purpose where the traffic distribution is 100 Erl/km2 with 12.2 kbps speech service having maximum mobile speed of 3 km/hr. The simulation results indicate that a similar performance can be achieved in both the configurations, that is, a maximum of 947 m cellrange at antenna height of 49.5 m can be achieved when the antennas are directed towards the corner of hexagon, whereas 943.3 m cell range atantenna height of 54 m can be achieved when the antennas are directed towards the side of hexagon. However, from the interference point of view the first configuration provides better results. The simulation results also show that the network is coverage limited in both the uplink and downlink direction at the optimum point.

Different concentrations of Mg++ ions affect nuclear matrix protein distribution during thermal stabilization of isolated nuclei.

The nuclear matrix, a proteinaceous network believed to be a scaffolding structure determining higher-order organization of chromatin, is usually prepared from intact nuclei by a series of extraction steps. In most cell types investigated the nuclear matrix does not spontaneously resist these treatments but must be stabilized before the application of extracting agents. Incubation of isolated nuclei at 37C or 42C in buffers containing Mg++ has been widely employed as stabilizing agent. We have previously demonstrated that heat treatment induces changes in the distribution of three nuclear scaffold proteins in nuclei prepared in the absence of Mg++ ions. We studied whether different concentrations of Mg++ (2.0-5 mM) affect the spatial distribution of nuclear matrix proteins in nuclei isolated from K562 erythroleukemia cells and stabilized by heat at either 37C or 42C. Five proteins were studied, two of which were RNA metabolism-related proteins (a 105-kD component of splicing complexes and an RNP component), one a 126-kD constituent of a class of nuclear bodies, and two were components of the inner matrix network. The localization of proteins was determined by immunofluorescent staining and confocal scanning laser microscope. Mg++ induced significant changes of antigen distribution even at the lowest concentration employed, and these modifications were enhanced in parallel with increase in the concentration of the divalent cation. The different sensitivity to heat stabilization and Mg++ of these nuclear proteins might reflect a different degree of association with the nuclear scaffold and can be closely related to their functional or structural role.

Distribution systems of the food sector in Russia: the perspective of Finnish food industry

Finnish food producers' trade with Russia has experienced profound changes since the collapse of the Soviet Union. Simultaneously, the distribution systems of foodstuffs have changed remarkably. This study sheds some light into these changes and analyses the current situation in distribution systems of foodstuffs in Russia. In addition, the study discusses the possibilities of Finnish food producers to get more of their products to the shelves of Russian food retail stores. Before the 1998 financial crisis, the import of foreign foodstuffs was booming in Russia due to the overvalued rouble. As a result of the financial crisis, food import collapsed. The export of Finnish foodstuffs to Russia has been slowly recovering during the past few years, but in the most important product categories the pre-crisis levels have so far not been reached and maybe will not be reached. In certain product categories the growth has been only marginal. It seems that starting localproduction will become increasingly important in the future. This is further encouraged by the fact that Russian consumers favour domestic food products. Russian consumers are very price conscious and demand quality in food products. The perceived price-quality ratio is an important criterion in the purchase decision.The majority of foodstuff retail is still conducted via unorganised forms of trade (e.g. kiosks and marketplaces) but modern retail chains are developing at a fast pace in Russia. They are also expected to dominate the retail trade in foodstuffs over the unorganised forms of trade in the future. This will change the distribution systems as well. The retail chains are trying to shorten the distribution chain, similarly to what has been seen in the Western countries. This together with the strengthening of retail chains is likely to shrink the role of wholesalers, as the chains increasingly want to work directly with the producers. Many large retail chains are acquiring or have already acquired a distribution centre or centres in order to boost efficiency and control the flow of products. The strengthening of the retail chains also gives them power in negotiations, which the producers and distributors have to adjust to. For example store entry fees and retail chains' own private label products pose challenges to the food producers. In the food production sector the competition is fierce, as large Russianand foreign producers want to ensure their piece of the market. The largest producers utilise their size: they invest in big marketing campaigns and are willing to pay high entry fees to retail chains in order to secure a place on the store shelves and to build a strong brand in Russia. This complicates the situation from the viewpoint of small producers. Currently, the most popular type of distribution system among the interviewed Finnish food producers is based on a network of local distributors. There is, however, a strong consensus on the importanceof starting local production in order to be a serious actor in Russia in the future. Factors that hinder the starting of local production include the lack of local infrastructure and qualified staff, and the low risk tolerance of Finnish firms. Major barriers for entry in Russia are the actions of authorities, fierce competition, fragmented market and Finnish producers' heavy production costs. The suggested strategies for increasing the market share include focusing geographically or segment-wise, introducing new products, starting local production, andcooperation between Finnish producers. Smallness was one reason why Finnish producers had to cut down their operations in Russia due to the 1998 crisis. Smaller producers had fewer resources to tolerate losses during the period of crisis. Smallness is reflected also on trade negotiations with retail chains and distributors. It makes it harder to cope with the store entry fees and to differentiatefrom the mass of products propped up by expensive advertising. Finally, it makes it harder for Finnish producers to start or expand local production, as it is more difficult for a small producer to get financing and to tolerate the increased risks. Compensating for the smallness might become the crucial factor determining the future success of Finnish food producers in the Russian market.

Patents in the Information and Communications Technology Sector - Development Trends, Problem Areas and Pressures for Change

The patent system was created for the purpose of promoting innovation by granting the inventors a legally defined right to exclude others in return for public disclosure. Today, patents are being applied and granted in greater numbers than ever, particularly in new areas such as biotechnology and information andcommunications technology (ICT), in which research and development (R&D) investments are also high. At the same time, the patent system has been heavily criticized. It has been claimed that it discourages rather than encourages the introduction of new products and processes, particularly in areas that develop quickly, lack one-product-one-patent correlation, and in which theemergence of patent thickets is characteristic. A further concern, which is particularly acute in the U.S., is the granting of so-called 'bad patents', i.e. patents that do not factually fulfil the patentability criteria. From the perspective of technology-intensive companies, patents could,irrespective of the above, be described as the most significant intellectual property right (IPR), having the potential of being used to protect products and processes from imitation, to limit competitors' freedom-to-operate, to provide such freedom to the company in question, and to exchange ideas with others. In fact, patents define the boundaries of ownership in relation to certain technologies. They may be sold or licensed on their ownor they may be components of all sorts of technology acquisition and licensing arrangements. Moreover, with the possibility of patenting business-method inventions in the U.S., patents are becoming increasingly important for companies basing their businesses on services. The value of patents is dependent on the value of the invention it claims, and how it is commercialized. Thus, most of them are worth very little, and most inventions are not worth patenting: it may be possible to protect them in other ways, and the costs of protection may exceed the benefits. Moreover, instead of making all inventions proprietary and seeking to appropriate as highreturns on investments as possible through patent enforcement, it is sometimes better to allow some of them to be disseminated freely in order to maximize market penetration. In fact, the ideology of openness is well established in the software sector, which has been the breeding ground for the open-source movement, for instance. Furthermore, industries, such as ICT, that benefit from network effects do not shun the idea of setting open standards or opening up their proprietary interfaces to allow everyone todesign products and services that are interoperable with theirs. The problem is that even though patents do not, strictly speaking, prevent access to protected technologies, they have the potential of doing so, and conflicts of interest are not rare. The primary aim of this dissertation is to increase understanding of the dynamics and controversies of the U.S. and European patent systems, with the focus on the ICT sector. The study consists of three parts. The first part introduces the research topic and the overall results of the dissertation. The second part comprises a publication in which academic, political, legal and business developments that concern software and business-method patents are investigated, and contentiousareas are identified. The third part examines the problems with patents and open standards both of which carry significant economic weight inthe ICT sector. Here, the focus is on so-called submarine patents, i.e. patentsthat remain unnoticed during the standardization process and then emerge after the standard has been set. The factors that contribute to the problems are documented and the practical and juridical options for alleviating them are assessed. In total, the dissertation provides a good overview of the challenges and pressures for change the patent system is facing,and of how these challenges are reflected in standard setting.

The global carbon budget:a conflicting claims problem

Despite global environmental governance has traditionally couched global warming in terms of annual CO2 emissions (a flow), global mean temperature is actually determined by cumulative CO2 emissions in the atmosphere (a stock). Thanks to advances of scientific community, nowadays it is possible to quantify the \global carbon budget", that is, the amount of available cumulative CO2 emissions before crossing the 2oC threshold (Meinshausen et al., 2009). The current approach proposes to analyze the allocation of such global carbon budget among countries as a classical conflicting claims problem (O'Neill, 1982). Based on some appealing principles, it is proposed an efficient and sustainable allocation of the available carbon budget from 2000 to 2050 taking into account different environmental risk scenarios. Keywords: Carbon budget, Conflicting claims problem, Distribution, Climate change. JEL classification: C79, D71, D74, H41, H87, Q50, Q54, Q58.

Service Architecture in Mobile IP Telephony Network

Uudet palvelut ovat tarkeinta, mita asiakkaat odottavat uudelta teknologialta.Se on paaasiallinen syy siihen, etta asiakkaat ovat valmiita maksamaan uudesta teknologiasta ja kayttamaan sita. Sen vuoksi uuden verkon tuoma uusi palveluarkkitehtuuri on tarkea koko projektin onnistumiselle. Tama dokumentti keskittyy kolmannen sukupolven matkapuhelinverkkojen palveluarkkitehtuuriin, jonka viitemallista annetaan kuvaus. Verkon palvelut esitellaan ja kuvaillaan. Toteutukseen liittyvia asioita selostetaan. USA:n markkinoilla tarvittava WIN konsepti kuvataan ja sen toteutuksesta annetaan myos kuvaus. Lopussa kuvataan Pre-Paid tilaajien laskutustietojen kasittelya WIN konseptissa elvytystilanteessa.

IP Multicast in Future Mobile Networks

Erilaisten IP-pohjaisten palvelujen käyttö lisääntyy jatkuvasti samalla, kun käyttäjistä tulee yhä liikkuvaisempia. Tästä syystä IP- protokolla tulee väistämättä myös mobiiliverkkoihin. Tässä diplomityössä tutkitaan mobiliteetin IP multcastingiin tuomia ongelmia ja simuloidaan niitä Network Simulatoria käyttäen. Pääpaino on ongelmalla, joka aiheutuu multicast- ryhmänmuodostusviiveestä. Tätä ongelmaa simuloidaan, jotta viiveen, mobiilikäyttäjien palveluunsaapumistaajuuden ja Scalable Reliable Multicast (SRM) protokollan ajastinarvojen asetusten vaikutus repair request- pakettien määrään ja sitä kautta suoritettavien uudelleenlähetysten määrään selviäisi. Eri parametrien vaikutuksen tutkimiseksi esitetään simulaatiotuloksia varioiduilla parametreillä käyttäen CDF- käyriä. Tulosten perusteella merkittävin tekijä uudelleenlähetyspyyntöjen kannalta on protokollan ajastimien arvot ja haluttu palvelun taso, viiveen merkityksen jäädessä vähäiseksi. Työn lopuksi tutkitaan SRM- protokollan soveltuvuutta mobiiliverkkoihin ja pohditaan vaihtoehtoja toiminnan parantamiseksi.

Distribution and risk factors for Plasmodium and helminth co-infections: a cross-sectional survey among children in Bagamoyo district, coastal region of Tanzania.

BACKGROUND: Plasmodium and soil transmitted helminth infections (STH) are a major public health problem, particularly among children. There are conflicting findings on potential association between these two parasites. This study investigated the Plasmodium and helminth co-infections among children aged 2 months to 9 years living in Bagamoyo district, coastal region of Tanzania. METHODS: A community-based cross-sectional survey was conducted among 1033 children. Stool, urine and blood samples were examined using a broad set of quality controlled diagnostic methods for common STH (Ascaris lumbricoides, hookworm, Strongyloides stercoralis, Enterobius vermicularis, Trichuris trichura), schistosoma species and Wuchereria bancrofti. Blood slides and malaria rapid diagnostic tests (mRDTs) were utilized for Plasmodium diagnosis. RESULTS: Out of 992 children analyzed, the prevalence of Plasmodium infection was 13% (130/992), helminth 28.5% (283/992); 5% (50/992) had co-infection with Plasmodium and helminth. The prevalence rate of Plasmodium, specific STH and co-infections increased significantly with age (p < 0.001), with older children mostly affected except for S. stercoralis monoinfection and co-infections. Spatial variations of co-infection prevalence were observed between and within villages. There was a trend for STH infections to be associated with Plasmodium infection [OR adjusted for age group 1.4, 95% CI (1.0-2.1)], which was more marked for S. stercoralis (OR = 2.2, 95% CI (1.1-4.3). Age and not schooling were risk factors for Plasmodium and STH co-infection. CONCLUSION: The findings suggest that STH and Plasmodium infections tend to occur in the same children, with increasing prevalence of co-infection with age. This calls for an integrated approach such as using mass chemotherapy with dual effect (e.g., ivermectin) coupled with improved housing, sanitation and hygiene for the control of both parasitic infections.