A novel blood-sparing agent in cardiac surgery? First in-patient experience with the synthetic serine protease inhibitor MDCO-2010: a phase II, randomized, double-blind, placebo-controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass

BACKGROUND Antifibrinolytics have been used for 2 decades to reduce bleeding in cardiac surgery. MDCO-2010 is a novel, synthetic, serine protease inhibitor. We describe the first experience with this drug in patients. METHODS In this phase II, double-blind, placebo-controlled study, 32 patients undergoing isolated primary coronary artery bypass grafting with cardiopulmonary bypass were randomly assigned to 1 of 5 increasing dosage groups of MDCO-2010. The primary aim was to evaluate pharmacokinetics (PK) with assessment of plasmatic concentrations of the drug, short-term safety, and tolerance of MDCO-2010. Secondary end points were influence on coagulation, chest tube drainage, and transfusion requirements. RESULTS PK analysis showed linear dosage-proportional correlation between MDCO-2010 infusion rate and PK parameters. Blood loss was significantly reduced in the 3 highest dosage groups compared with control (P = 0.002, 0.004 and 0.011, respectively). The incidence of allogeneic blood product transfusions was lower with MDCO-2010 4/24 (17%) vs 4/8 (50%) in the control group. MDCO-2010 exhibited dosage-dependent antifibrinolytic effects through suppression of D-dimer generation and inhibition of tissue plasminogen activator-induced lysis in ROTEM analysis as well as anticoagulant effects demonstrated by prolongation of activated clotting time and activated partial thromboplastin time. No systematic differences in markers of end organ function were observed among treatment groups. Three patients in the MDCO-2010 groups experienced serious adverse events. One patient experienced intraoperative thrombosis of venous grafts considered possibly related to the study drug. No reexploration for mediastinal bleeding was required, and there were no deaths. CONCLUSIONS This first-in-patient study demonstrated dosage-proportional PK for MDCO-2010 and reduction of chest tube drainage and transfusions in patients undergoing primary coronary artery bypass grafting. Antifibrinolytic and anticoagulant effects were demonstrated using various markers of coagulation. MDCO-2010 was well tolerated and showed an acceptable initial safety profile. Larger multi-institutional studies are warranted to further investigate the safety and efficacy of this compound.

Benchmark problems for reactive transport modeling of the generation and attenuation of acid rock drainage

Acid rock drainage (ARD) is a problem of international relevance with substantial environmental and economic implications. Reactive transport modeling has proven a powerful tool for the process-based assessment of metal release and attenuation at ARD sites. Although a variety of models has been used to investigate ARD, a systematic model intercomparison has not been conducted to date. This contribution presents such a model intercomparison involving three synthetic benchmark problems designed to evaluate model results for the most relevant processes at ARD sites. The first benchmark (ARD-B1) focuses on the oxidation of sulfide minerals in an unsaturated tailing impoundment, affected by the ingress of atmospheric oxygen. ARD-B2 extends the first problem to include pH buffering by primary mineral dissolution and secondary mineral precipitation. The third problem (ARD-B3) in addition considers the kinetic and pH-dependent dissolution of silicate minerals under low pH conditions. The set of benchmarks was solved by four reactive transport codes, namely CrunchFlow, Flotran, HP1, and MIN3P. The results comparison focused on spatial profiles of dissolved concentrations, pH and pE, pore gas composition, and mineral assemblages. In addition, results of transient profiles for selected elements and cumulative mass loadings were considered in the intercomparison. Despite substantial differences in model formulations, very good agreement was obtained between the various codes. Residual deviations between the results are analyzed and discussed in terms of their implications for capturing system evolution and long-term mass loading predictions.

Generation of long, fully modified, and serum-resistant oligonucleotides by rolling circle amplification

Rolling Circle Amplification (RCA) is an isothermal enzymatic method generating single-stranded DNA products consisting of concatemers containing multiple copies of the reverse complement of the circular template precursor. Little is known on the compatibility of modified nucleoside triphosphates (dN*TPs) with RCA, which would enable the synthesis of long, fully modified ssDNA sequences. Here, dNTPs modified at any position of the scaffold were shown to be compatible with rolling circle amplification, yielding long (>1 kb), and fully modified single-stranded DNA products. This methodology was applied for the generation of long, cytosine-rich synthetic mimics of telomeric DNA. The resulting modified oligo-nucleotides displayed an improved resistance to fetal bovine serum.

(Table 2) Actual and synthetic mass accumulation rate data and their absolute differences for ODP Site 115-707

Synthetic mass accumulation rates have been calculated for ODP Site 707 using depth-density and depth-porosity functions to estimate values for these parameters with increasing sediment thickness, at 1 Ma time intervals determined on the basis of published microfossil datums. These datums were the basis of the age model used by Peterson and Backman (1990, doi:10.2973/odp.proc.sr.115.163.1990) to calculate actual mass accumulation rate data using density and porosity measurements. A comparison is made between the synthetic and actual mass accumulation rate values for the time interval 37 Ma to the Recent for 1 Myr time intervals. There is a correlation coefficient of 0.993 between the two data sets, with an absolute difference generally less than 0.1 g/cm**2/kyr. We have used the method to extend the mass accumulation rate analysis back to the Late Paleocene (60 Ma) for Site 707. Providing age datums (e.g. fossil or magnetic anomaly data) are available the generation of synthetic mass accumulation rates can be calculated for any sediment sequence.

Column Generation Algorithms for Nonlinear Optimization II: Numerical Investigations

García et al. present a class of column generation (CG) algorithms for nonlinear programs. Its main motivation from a theoretical viewpoint is that under some circumstances, finite convergence can be achieved, in much the same way as for the classic simplicial decomposition method; the main practical motivation is that within the class there are certain nonlinear column generation problems that can accelerate the convergence of a solution approach which generates a sequence of feasible points. This algorithm can, for example, accelerate simplicial decomposition schemes by making the subproblems nonlinear. This paper complements the theoretical study on the asymptotic and finite convergence of these methods given in [1] with an experimental study focused on their computational efficiency. Three types of numerical experiments are conducted. The first group of test problems has been designed to study the parameters involved in these methods. The second group has been designed to investigate the role and the computation of the prolongation of the generated columns to the relative boundary. The last one has been designed to carry out a more complete investigation of the difference in computational efficiency between linear and nonlinear column generation approaches. In order to carry out this investigation, we consider two types of test problems: the first one is the nonlinear, capacitated single-commodity network flow problem of which several large-scale instances with varied degrees of nonlinearity and total capacity are constructed and investigated, and the second one is a combined traffic assignment model

How much energy will your NGN consume? A model for energy consumption in next generation access networks: The case of Spain

The contribution to global energy consumption of the information and communications technology (ICT) sector has increased considerably in the last decade, along with its growing relevance to the overall economy. This trend will continue due to the seemingly ever greater use of these technologies, with broadband data traffic generated by the usage of telecommunication networks as a primary component. In fact, in response to user demand, the telecommunications industry is initiating the deployment of next generation networks (NGNs). However, energy consumption is mostly absent from the debate on these deployments, in spite of the potential impact on both expenses and sustainability. In addition, consumers are unaware of the energy impact of their choices in ultra-broadband services. This paper focuses on forecasting energy consumption in the access part of NGNs by modelling the combined effect of the deployment of two different ultra-broadband technologies (FTTH-GPON and LTE), the evolution of traffic per user, and the energy consumption in each of the networks and user devices. Conclusions are presented on the levels of energy consumption, their cost and the impact of different network design parameters. The effect of technological developments, techno-economic and policy decisions on energy consumption is highlighted. On the consumer side, practical figures and comparisons across technologies are provided. Although the paper focuses on Spain, the analysis can be extended to similar countries.

Synthetic strategy of porous ZnO and CdS nanostructures doped ferroelectric liquid crystal and its optical behavior

A simple and scalable chemical approach has been proposed for the generation of 1-dimensional nanostructures of two most important inorganic materials such as zinc oxide and cadmium sulfide. By controlling the growth habit of the nanostructures with manipulated reaction conditions, the diameter and uniformity of the nanowires/nanorods were tailored. We studied extensively optical behavior and structural growth of CdS NWs and ZnO NRs doped ferroelectric liquid crystal Felix-017/100. Due to doping band gap has been changed and several blue shifts occurred in photoluminescence spectra because of nanoconfinement effect and mobility of charges.

Efficient hybrid monocular-stereo approach to on-board, video-based traffic sign detection and tracking

In this paper we propose an innovative method for the automatic detection and tracking of road traffic signs using an onboard stereo camera. It involves a combination of monocular and stereo analysis strategies to increase the reliability of the detections such that it can boost the performance of any traffic sign recognition scheme. Firstly, an adaptive color and appearance based detection is applied at single camera level to generate a set of traffic sign hypotheses. In turn, stereo information allows for sparse 3D reconstruction of potential traffic signs through a SURF-based matching strategy. Namely, the plane that best fits the cloud of 3D points traced back from feature matches is estimated using a RANSAC based approach to improve robustness to outliers. Temporal consistency of the 3D information is ensured through a Kalman-based tracking stage. This also allows for the generation of a predicted 3D traffic sign model, which is in turn used to enhance the previously mentioned color-based detector through a feedback loop, thus improving detection accuracy. The proposed solution has been tested with real sequences under several illumination conditions and in both urban areas and highways, achieving very high detection rates in challenging environments, including rapid motion and significant perspective distortion

Methods and Techniques for the Generation and Eficient Exploitation of RDB2RDF Mappings

RDB to RDF Mapping Language (R2RML) es una recomendación del W3C que permite especificar reglas para transformar bases de datos relacionales a RDF. Estos datos en RDF se pueden materializar y almacenar en un sistema gestor de tripletas RDF (normalmente conocidos con el nombre triple store), en el cual se pueden evaluar consultas SPARQL. Sin embargo, hay casos en los cuales la materialización no es adecuada o posible, por ejemplo, cuando la base de datos se actualiza frecuentemente. En estos casos, lo mejor es considerar los datos en RDF como datos virtuales, de tal manera que las consultas SPARQL anteriormente mencionadas se traduzcan a consultas SQL que se pueden evaluar sobre los sistemas gestores de bases de datos relacionales (SGBD) originales. Para esta traducción se tienen en cuenta los mapeos R2RML. La primera parte de esta tesis se centra en la traducción de consultas. Se propone una formalización de la traducción de SPARQL a SQL utilizando mapeos R2RML. Además se proponen varias técnicas de optimización para generar consultas SQL que son más eficientes cuando son evaluadas en sistemas gestores de bases de datos relacionales. Este enfoque se evalúa mediante un benchmark sintético y varios casos reales. Otra recomendación relacionada con R2RML es la conocida como Direct Mapping (DM), que establece reglas fijas para la transformación de datos relacionales a RDF. A pesar de que ambas recomendaciones se publicaron al mismo tiempo, en septiembre de 2012, todavía no se ha realizado un estudio formal sobre la relación entre ellas. Por tanto, la segunda parte de esta tesis se centra en el estudio de la relación entre R2RML y DM. Se divide este estudio en dos partes: de R2RML a DM, y de DM a R2RML. En el primer caso, se estudia un fragmento de R2RML que tiene la misma expresividad que DM. En el segundo caso, se representan las reglas de DM como mapeos R2RML, y también se añade la semántica implícita (relaciones de subclase, 1-N y M-N) que se puede encontrar codificada en la base de datos. Esta tesis muestra que es posible usar R2RML en casos reales, sin necesidad de realizar materializaciones de los datos, puesto que las consultas SQL generadas son suficientemente eficientes cuando son evaluadas en el sistema gestor de base de datos relacional. Asimismo, esta tesis profundiza en el entendimiento de la relación existente entre las dos recomendaciones del W3C, algo que no había sido estudiado con anterioridad. ABSTRACT. RDB to RDF Mapping Language (R2RML) is a W3C recommendation that allows specifying rules for transforming relational databases into RDF. This RDF data can be materialized and stored in a triple store, so that SPARQL queries can be evaluated by the triple store. However, there are several cases where materialization is not adequate or possible, for example, if the underlying relational database is updated frequently. In those cases, RDF data is better kept virtual, and hence SPARQL queries over it have to be translated into SQL queries to the underlying relational database system considering that the translation process has to take into account the specified R2RML mappings. The first part of this thesis focuses on query translation. We discuss the formalization of the translation from SPARQL to SQL queries that takes into account R2RML mappings. Furthermore, we propose several optimization techniques so that the translation procedure generates SQL queries that can be evaluated more efficiently over the underlying databases. We evaluate our approach using a synthetic benchmark and several real cases, and show positive results that we obtained. Direct Mapping (DM) is another W3C recommendation for the generation of RDF data from relational databases. While R2RML allows users to specify their own transformation rules, DM establishes fixed transformation rules. Although both recommendations were published at the same time, September 2012, there has not been any study regarding the relationship between them. The second part of this thesis focuses on the study of the relationship between R2RML and DM. We divide this study into two directions: from R2RML to DM, and from DM to R2RML. From R2RML to DM, we study a fragment of R2RML having the same expressive power than DM. From DM to R2RML, we represent DM transformation rules as R2RML mappings, and also add the implicit semantics encoded in databases, such as subclass, 1-N and N-N relationships. This thesis shows that by formalizing and optimizing R2RML-based SPARQL to SQL query translation, it is possible to use R2RML engines in real cases as the resulting SQL is efficient enough to be evaluated by the underlying relational databases. In addition to that, this thesis facilitates the understanding of bidirectional relationship between the two W3C recommendations, something that had not been studied before.

Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: A phase I trial

The carbohydrate antigen globo H commonly found on breast cancer cells is a potential target for vaccine therapy. The objectives of this trial were to determine the toxicity and immunogenicity of three synthetic globo H-keyhole limpet hemocyanin conjugates plus the immunologic adjuvant QS-21. Twenty-seven metastatic breast cancer patients received five vaccinations each. The vaccine was well tolerated, and no definite differences were observed among the three formulations. Serologic analyses demonstrated the generation of IgM antibody titers in most patients, with minimal IgG antibody stimulation. There was significant binding of IgM antibodies to MCF-7 tumor cells in 16 patients, whereas IgG antibody reactivity was observed in a few patients. There was evidence of complement-dependent cytotoxicity in several patients. Affinity column purification supported the specificity of IgM antibodies for globo H. On the basis of these data, globo H will constitute one component of a polyvalent vaccine for evaluation in high-risk breast cancer patients.

Synthetic transcripts of double-stranded Birnavirus genome are infectious.

We have developed a system for generation of infectious bursal disease virus (IBDV), a segmented double-stranded RNA virus of the Birnaviridae family, with the use of synthetic transcripts derived from cloned cDNA. Independent full-length cDNA clones were constructed that contained the entire coding and noncoding regions of RNA segments A and B of two distinguishable IBDV strains of serotype I. Segment A encodes all of the structural (VP2, VP4, and VP3) and nonstructural (VP5) proteins, whereas segment B encodes the RNA-dependent RNA polymerase (VP1). Synthetic RNAs of both segments were produced by in vitro transcription of linearized plasmids with T7 RNA polymerase. Transfection of Vero cells with combined plus-sense transcripts of both segments generated infectious virus as early as 36 hr after transfection. The infectivity and specificity of the recovered chimeric virus was ascertained by the appearance of cytopathic effect in chicken embryo cells, by immunofluorescence staining of infected Vero cells with rabbit anti-IBDV serum, and by nucleotide sequence analysis of the recovered virus, respectively. In addition, transfectant viruses containing genetically tagged sequences in either segment A or segment B of IBDV were generated to confirm the feasibility of this system. The development of a reverse genetics system for double-stranded RNA viruses will greatly facilitate studies of the regulation of viral gene expression, pathogenesis, and design of a new generation of live vaccines.

Rapid genome change in synthetic polyploids of Brassica and its implications for polyploid evolution.

Although the evolutionary success of polyploidy in higher plants has been widely recognized, there is virtually no information on how polyploid genomes have evolved after their formation. In this report, we used synthetic polyploids of Brassica as a model system to study genome evolution in the early generations after polyploidization. The initial polyploids we developed were completely homozygous, and thus, no nuclear genome changes were expected in self-fertilized progenies. However, extensive genome change was detected by 89 nuclear DNA clones used as probes. Most genome changes involved loss and/or gain of parental restriction fragments and appearance of novel fragments. Genome changes occurred in each generation from F2 to F5, and the frequency of change was associated with divergence of the diploid parental genomes. Genetic divergence among the derivatives of synthetic polyploids was evident from variation in genome composition and phenotypes. Directional genome changes, possibly influenced by cytoplasmic-nuclear interactions, were observed in one pair of reciprocal synthetics. Our results demonstrate that polyploid species can generate extensive genetic diversity in a short period of time. The occurrence and impact of this process in the evolution of natural polyploids is unknown, but it may have contributed to the success and diversification of many polyploid lineages in both plants and animals.

Library of libraries: approach to synthetic combinatorial library design and screening of "pharmacophore" motifs.

Construction of synthetic combinatorial libraries is described that allows for the generation of a library of motifs rather than a library of compounds. Peptide libraries based on this strategy were synthesized and screened with model targets streptavidin and anti-beta-endorphin antibody. The screens resulted in observation of expected motifs providing evidence of the effectiveness of the suggested approach.

Pharmaceutical industry : hazardous waste generation, treatment, and disposal.

Final report (SW-508) describing work performed for the Federal Solid waste management program under Contract no. 68-01-2684.

Human factors design of automated highway systems: first generation scenarios. Final report.

Federal Highway Administration, Office of Safety and Traffic Operations Research and Development, McLean, Va.