Human disease and drug pharmacology, complex as real life

In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-torefuse argument that is spurring the development of multitarget therapies.

Maintenance of Traffic for Innovative Geometric Design Work Zones, 2015

Currently there are no guidelines within the Manual on Uniform Traffic Control Devices (MUTCD) on construction phasing and maintenance of traffic (MOT) for retrofit construction and maintenance projects involving innovative geometric designs. The research presented in this report addressed this gap in existing knowledge by investigating the state of the practice of construction phasing and MOT for several types of innovative geometric designs including the roundabout, single point urban interchange (SPUI), diverging diamond interchange (DDI), restricted-crossing left turn (RCUT), median U-turn (MUT), and displaced left turn (DLT). This report provides guidelines for transportation practitioners in developing construction phasing and MOT plans for innovative geometric designs. This report includes MOT Phasing Diagrams to assist in the development of MOT strategies for innovative designs. The MOT Phasing Diagrams were developed through a review of literature, survey, interviews with practitioners, and review of plans from innovative geometric design projects. These diagrams are provided as a tool to assist in improving work zone safety and mobility through construction of projects with innovative geometric designs. The aforementioned synthesis of existing knowledge documented existing practices for these types of designs.

Use of social networks for academic purposes: a case study

Purpose This paper aims to analyse various aspects of an academic social network: the profile of users, the reasons for its use, its perceived benefits and the use of other social media for scholarly purposes. Design/methodology/approach The authors examined the profiles of the users of an academic social network. The users were affiliated with 12 universities. The following were recorded for each user: sex, the number of documents uploaded, the number of followers, and the number of people being followed. In addition, a survey was sent to the individuals who had an email address in their profile. Findings Half of the users of the social network were academics and a third were PhD students. Social sciences scholars accounted for nearly half of all users. Academics used the service to get in touch with other scholars, disseminate research results and follow other scholars. Other widely employed social media included citation indexes, document creation, edition and sharing tools and communication tools. Users complained about the lack of support for the utilisation of these tools. Research limitations/implications The results are based on a single case study. Originality/value This study provides new insights on the impact of social media in academic contexts by analysing the user profiles and benefits of a social network service that is specifically targeted at the academic community.

Case-based learning in VTLE: An effective strategy for improving learning design

This article presents preliminary research from an instructional design perspective on the design of the case method as an integral part of pedagogy and technology. Key features and benefitsusing this teaching and learning strategy in a Virtual Teaching and Learning Environment(VTLE) are identified, taking into account the requirements of the European Higher Education Area (EHEA) for a competence-based curricula design. The implications of these findings for alearning object approach exploring the possibilities of learning personalization, reusability and interoperability trough IMS LD, are also analyzed.

Joint physical-MAC layer design of the broadcast channel protocol in adhoc networks

Broadcast transmission mode in ad hoc networks is critical to manage multihop routing or providing medium accesscontrol (MAC)-layer fairness. In this paper, it is shown that ahigher capacity to exchange information among neighbors may beobtained through a physical-MAC cross-layer design of the broadcastprotocol exploiting signal separation principles. Coherentdetection and separation of contending nodes is possible throughtraining sequences which are selected at random from a reducedset. Guidelines for the design of this set are derived for a lowimpact on the network performance and the receiver complexity.

Identification of Research Portfolio for the Development of Filtration Equipment

This piece of work which is Identification of Research Portfolio for Development of Filtration Equipment aims at presenting a novel approach to identify promising research topics in the field of design and development of filtration equipment and processes. The projected approach consists of identifying technological problems often encountered in filtration processes. The sources of information for the problem retrieval were patent documents and scientific papers that discussed filtration equipments and processes. The problem identification method adopted in this work focussed on the semantic nature of a sentence in order to generate series of subject-action-object structures. This was achieved with software called Knowledgist. List of problems often encountered in filtration processes that have been mentioned in patent documents and scientific papers were generated. These problems were carefully studied and categorized. Suggestions were made on the various classes of these problems that need further investigation in order to propose a research portfolio. The uses and importance of other methods of information retrieval were also highlighted in this work.

Joint array combining and MLSE for single-user receivers in multipath Gaussian multiuser channels

The well-known structure of an array combiner along with a maximum likelihood sequence estimator (MLSE) receiveris the basis for the derivation of a space-time processor presentinggood properties in terms of co-channel and intersymbol interferencerejection. The use of spatial diversity at the receiver front-endtogether with a scalar MLSE implies a joint design of the spatialcombiner and the impulse response for the sequence detector. Thisis faced using the MMSE criterion under the constraint that thedesired user signal power is not cancelled, yielding an impulse responsefor the sequence detector that is matched to the channel andcombiner response. The procedure maximizes the signal-to-noiseratio at the input of the detector and exhibits excellent performancein realistic multipath channels.

Linear transceiver design in nonregenerative relays with channel state information

This paper deals with the design of nonregenerativerelaying transceivers in cooperative systems where channel stateinformation (CSI) is available at the relay station. The conventionalnonregenerative approach is the amplify and forward(A&F) approach, where the signal received at the relay is simplyamplified and retransmitted. In this paper, we propose an alternativelinear transceiver design for nonregenerative relaying(including pure relaying and the cooperative transmission cases),making proper use of CSI at the relay station. Specifically, wedesign the optimum linear filtering performed on the data to beforwarded at the relay. As optimization criteria, we have consideredthe maximization of mutual information (that provides aninformation rate for which reliable communication is possible) fora given available transmission power at the relay station. Threedifferent levels of CSI can be considered at the relay station: onlyfirst hop channel information (between the source and relay);first hop channel and second hop channel (between relay anddestination) information, or a third situation where the relaymay have complete cooperative channel information includingall the links: first and second hop channels and also the directchannel between source and destination. Despite the latter beinga more unrealistic situation, since it requires the destination toinform the relay station about the direct channel, it is useful as anupper benchmark. In this paper, we consider the last two casesrelating to CSI.We compare the performance so obtained with theperformance for the conventional A&F approach, and also withthe performance of regenerative relays and direct noncooperativetransmission for two particular cases: narrowband multiple-inputmultiple-output transceivers and wideband single input singleoutput orthogonal frequency division multiplex transmissions.

Hybrid turbo FEC/ARQ systems and distributed space-time coding for cooperative transmission

Cooperative transmission can be seen as a "virtual" MIMO system, where themultiple transmit antennas are in fact implemented distributed by the antennas both at the source and the relay terminal. Depending on the system design, diversity/multiplexing gainsare achievable. This design involves the definition of the type of retransmission (incrementalredundancy, repetition coding), the design of the distributed space-time codes, the errorcorrecting scheme, the operation of the relay (decode&forward or amplify&forward) and thenumber of antennas at each terminal. Proposed schemes are evaluated in different conditionsin combination with forward error correcting codes (FEC), both for linear and near-optimum(sphere decoder) receivers, for its possible implementation in downlink high speed packetservices of cellular networks. Results show the benefits of coded cooperation over directtransmission in terms of increased throughput. It is shown that multiplexing gains areobserved even if the mobile station features a single antenna, provided that cell wide reuse of the relay radio resource is possible.

Developing of supplier network in shipbuilding industry

Työn tarkoituksena on selvittää minkälaisen verkoston Aker Yards Oy, kokonaistoimittajat ja kokonaistoimittajien alihankkijat muodostavat. Lisäksi arvioidaan verkostoriskit, joita Aker Yards Oy kohtaa toimiessaan verkostossa. Tutkimus suoritettiin tekemällä kysely verkostossa oleville kokonaistoimittajille sekä haastattelemalla kuutta henkilöä Aker Yards Oy:stä. Suhteita ja verkostoa analysoitiin tutkimalla verkoston yksittäisiä toimijoita sekä näiden välisiä suhteita. Riskejä analysoitiin tarkastelemalla niiden tunnistettuja syitä. Työn tuloksena on verkostokuva, joka piirrettiin kyselytulosten perusteella. Suhteiden ja verkoston analyysillä päädyttiin tehtäviin, joita Aker Yards Oy:n johdon tulisi toteuttaa, jotta verkostosta ja yksittäisistä toimittajista saataisiin irti mahdollisimman paljon. Lisäksi suhteita ja verkostoa käsiteltiin niiden tuloksellisen johtamisen näkökulmasta. Riskianalyysista saatiin tuloksena uhkaavimpien riskien arviointi.

Trials using a crossover design and ambulatory blood pressure recordings to determine the efficacy of antihypertensive agents in individual patients.

The antihypertensive effects of the beta-blocking agent betaxolol and the calcium entry blocker verapamil were compared in a crossover single-blind trial. Seventeen patients with uncomplicated essential hypertension took either betaxolol or a slow-release formulation of verapamil for two consecutive 6-week periods. The sequence of treatment phases was randomly allocated and a 2-week washout period preceded each treatment. The antihypertensive effect of the test drugs was assessed both at the physician's office and during everyday activities using a portable blood pressure recorder. The crossover design of the trial made it possible to evaluate the antihypertensive efficacy of betaxolol and verapamil both in the group as a whole and in the individual patient. The individual patient response to one of these agents was not a reliable indicator of the same patient's response to the alternative agent. Betaxolol brought both office and ambulatory recorded blood pressures under control in a larger fraction of patients than verapamil, although the magnitude of the blood pressure fall in the responders was equal for each drug. These observations stress the need for an individualized approach to the evaluation of antihypertensive therapy. The present results also demonstrate that optimal antihypertensive therapy is still a matter of trial and error. The precise methodology that ought to characterize crossover trials may make it possible to improve the therapeutic approach to hypertensive patients.

Safety of intramuscular influenza vaccine in patients receiving oral anticoagulation therapy: a single blinded multi-centre randomized controlled clinical trial

Influenza vaccines are recommended for administration by the intramuscular route. However, many physicians use the subcutaneous route for patients receiving an oral anticoagulant because this route is thought to induce fewer hemorrhagic side effects. Our aim is to assess the safety of intramuscular administration of influenza vaccine in patients on oral anticoagulation therapy. Methods: Design: Randomised, controlled, single blinded, multi-centre clinical trial. Setting: 4 primary care practices in Barcelona, Spain. Participants: 229 patients on oral anticoagulation therapy eligible for influenza vaccine during the 20032004 season. Interventions: intramuscular administration of influença vaccine in the experimental group (129 patients) compared to subcutaneous administration in the control group (100 patients). Primary outcome: change in the circumference of the arm at the site of injection at 24 hours. Secondary outcomes: appearance of local reactions and pain at 24 hours and at 10 days; change in INR (International Normalized Ratio) at 24 hours and at 10 days. Analysis was by intention to treat using the 95% confidence intervals of the proportions or mean differences. Results: Baseline variables in the two groups were similar. No major side effects or major haemorrhage during the follow-up period were reported. No significant differences were observed in the primary outcome between the two groups. The appearance of local adverse reactions was more frequent in the subcutaneous administration group (37,4% vs. 17,4%, 95% confidence interval of the difference 8,2% to 31,8%). Conclusion: This study shows that the intramuscular administration route of influenza vaccine in patients on anticoagulant therapy does not have more side effects than the subcutaneous administration route

The role of auditory cortices in the retrieval of single-trial auditory-visual object memories.

Single-trial encounters with multisensory stimuli affect both memory performance and early-latency brain responses to visual stimuli. Whether and how auditory cortices support memory processes based on single-trial multisensory learning is unknown and may differ qualitatively and quantitatively from comparable processes within visual cortices due to purported differences in memory capacities across the senses. We recorded event-related potentials (ERPs) as healthy adults (n = 18) performed a continuous recognition task in the auditory modality, discriminating initial (new) from repeated (old) sounds of environmental objects. Initial presentations were either unisensory or multisensory; the latter entailed synchronous presentation of a semantically congruent or a meaningless image. Repeated presentations were exclusively auditory, thus differing only according to the context in which the sound was initially encountered. Discrimination abilities (indexed by d') were increased for repeated sounds that were initially encountered with a semantically congruent image versus sounds initially encountered with either a meaningless or no image. Analyses of ERPs within an electrical neuroimaging framework revealed that early stages of auditory processing of repeated sounds were affected by prior single-trial multisensory contexts. These effects followed from significantly reduced activity within a distributed network, including the right superior temporal cortex, suggesting an inverse relationship between brain activity and behavioural outcome on this task. The present findings demonstrate how auditory cortices contribute to long-term effects of multisensory experiences on auditory object discrimination. We propose a new framework for the efficacy of multisensory processes to impact both current multisensory stimulus processing and unisensory discrimination abilities later in time.

From the Resource-Base to Firm Boundaries in the Electricity Network Business - Case Lappeenrannan Energia Oy

Tutkielman tavoitteena oli selvittääcase -yrityksen resurssi- ja kyvykkyyspohjaa resurssiperustaisen näkemyksen mukaan, sekä yrityksen rajoja transaktiokustannusteorian mukaan. Tutkimusongelmia lähestyttiin kirjallisuuskatsauksella, puoli-strukturoiduilla teemahaastatteluilla, sekä kyselylomakkeilla. Tutkielman päätuloksiksi voidaan Tukea löydetty resurssikuilu, resurssien ja kyvykkyyksien tutkinta, sekä kyselylomakkeiden rakentaminen ja käyttö. Tutkielman paljastamasta kuilusta voidaan erottaa kolme päähaastetta; ikääntyvät sähköverkot, ikääntyvä henkilökunta ja liiketoimintaosaamisen puute. Lisäksi resurssien ja kyvykkyyksien tutkinta nosti esille organisaation rutiineja ja prosesseja, ja kyselylomakkeet osoittautuivat varsin toimiviksi tutkimuksen kontekstissa. Yhteenvetona voidaan todeta, että sähköverkkoliiketoiminta ja case yritys ovat suuren rakennemuutoksen alla, joka tuo mukanaan suuria haasteita myös lähitulevaisuudessa.

Finding the Fit Between Engineering Design and Cost Information

This paper analyzes the possibilities of integrating cost information and engineering design. Special emphasis is put on finding the potential of using the activity-based costing (ABC) method. Today, the problem of cost estimation in engineering design is that there are two separate extremes of knowledge. On the one extreme, the engineers model the technical parametres behindcosts in great detail but do not get appropriate cost information to their elegant models. On the other extreme, the accounting professionals are stuck with traditional cost accounting methods driven by the procedures and cycles of financial accounting. Therefore, in many cases, the cost information needs of various decision making groups, for example design engineers, are not served satisfactorily. This paper studies if the activity-based costing (ABC) method could offer a compromise between the two extremes. Recognizing activities and activity chains as well as activity and cost drivers could be specially beneficial for design engineers. Also, recognizing the accurate and reliable product costs of existing products helps when doing variant design. However, ABC is not at its best if the cost system becomes too complicated. This is why a comprehensive ABC-cost information system with detailed cost information for the use of design engineers should be examined critically. ABC is at its best when considering such issues as which activities drive costs, the cost of product complexity, allocating indirect costs on the products, the relationships between processes and costs, and the cost of excess capacity.