Identifying the semantics of eligibility criteria of clinical trials based on relevant medical ontologies

An important objective of the INTEGRATE project1 is to build tools that support the efficient execution of post-genomic multi-centric clinical trials in breast cancer, which includes the automatic assessment of the eligibility of patients for available trials. The population suited to be enrolled in a trial is described by a set of free-text eligibility criteria that are both syntactically and semantically complex. At the same time, the assessment of the eligibility of a patient for a trial requires the (machineprocessable) understanding of the semantics of the eligibility criteria in order to further evaluate if the patient data available for example in the hospital EHR satisfies these criteria. This paper presents an analysis of the semantics of the clinical trial eligibility criteria based on relevant medical ontologies in the clinical research domain: SNOMED-CT, LOINC, MedDRA. We detect subsets of these widely-adopted ontologies that characterize the semantics of the eligibility criteria of trials in various clinical domains and compare these sets. Next, we evaluate the occurrence frequency of the concepts in the concrete case of breast cancer (which is our first application domain) in order to provide meaningful priorities for the task of binding/mapping these ontology concepts to the actual patient data. We further assess the effort required to extend our approach to new domains in terms of additional semantic mappings that need to be developed.

Explicit Expressions for Solar Panel Equivalent Circuit Parameters Based on Analytical Formulation and the Lambert W-Function

Due to the high dependence of photovoltaic energy efficiency on environmental conditions (temperature, irradiation...), it is quite important to perform some analysis focusing on the characteristics of photovoltaic devices in order to optimize energy production, even for small-scale users. The use of equivalent circuits is the preferred option to analyze solar cells/panels performance. However, the aforementioned small-scale users rarely have the equipment or expertise to perform large testing/calculation campaigns, the only information available for them being the manufacturer datasheet. The solution to this problem is the development of new and simple methods to define equivalent circuits able to reproduce the behavior of the panel for any working condition, from a very small amount of information. In the present work a direct and completely explicit method to extract solar cell parameters from the manufacturer datasheet is presented and tested. This method is based on analytical formulation which includes the use of the Lambert W-function to turn the series resistor equation explicit. The presented method is used to analyze commercial solar panel performance (i.e., the current-voltage–I-V–curve) at different levels of irradiation and temperature. The analysis performed is based only on the information included in the manufacturer’s datasheet.

Explicit expressions for solar panel equivalent circuit parameters based on analytical formulation and the Lambert W - Function

Due to the high dependence of photovoltaic energy efficiency on environmental conditions (temperature, irradiation...), it is quite important to perform some analysis focusing on the characteristics of photovoltaic devices in order to optimize energy production, even for small-scale users. The use of equivalent circuits is the preferred option to analyze solar cells/panels performance. However, the aforementioned small-scale users rarely have the equipment or expertise to perform large testing/calculation campaigns, the only information available for them being the manufacturer datasheet. The solution to this problem is the development of new and simple methods to define equivalent circuits able to reproduce the behavior of the panel for any working condition, from a very small amount of information. In the present work a direct and completely explicit method to extract solar cell parameters from the manufacturer datasheet is presented and tested. This method is based on analytical formulation which includes the use of the Lambert W-function to turn the series resistor equation explicit. The presented method is used to analyze the performance (i.e., the I - V curve) of a commercial solar panel at different levels of irradiation and temperature. The analysis performed is based only on the information included in the manufacturer's datasheet.

Multiscale modeling of the plastic behaviour in single crystal tungsten: from atomistic to crystal plasticity simulations

En una planta de fusión, los materiales en contacto con el plasma así como los materiales de primera pared experimentan condiciones particularmente hostiles al estar expuestos a altos flujos de partículas, neutrones y grandes cargas térmicas. Como consecuencia de estas diferentes y complejas condiciones de trabajo, el estudio, desarrollo y diseño de estos materiales es uno de los más importantes retos que ha surgido en los últimos años para la comunidad científica en el campo de los materiales y la energía. Debido a su baja tasa de erosión, alta resistencia al sputtering, alta conductividad térmica, muy alto punto de fusión y baja retención de tritio, el tungsteno (wolframio) es un importante candidato como material de primera pared y como posible material estructural avanzado en fusión por confinamiento magnético e inercial. Sin embargo, el tiempo de vida del tungsteno viene controlado por diversos factores como son su respuesta termo-mecánica en la superficie, la posibilidad de fusión y el fallo por acumulación de helio. Es por ello que el tiempo de vida limitado por la respuesta mecánica del tungsteno (W), y en particular su fragilidad, sean dos importantes aspectos que tienes que ser investigados. El comportamiento plástico en materiales refractarios con estructura cristalina cúbica centrada en las caras (bcc) como el tungsteno está gobernado por las dislocaciones de tipo tornillo a escala atómica y por conjuntos e interacciones de dislocaciones a escalas más grandes. El modelado de este complejo comportamiento requiere la aplicación de métodos capaces de resolver de forma rigurosa cada una de las escalas. El trabajo que se presenta en esta tesis propone un modelado multiescala que es capaz de dar respuestas ingenieriles a las solicitudes técnicas del tungsteno, y que a su vez está apoyado por la rigurosa física subyacente a extensas simulaciones atomísticas. En primer lugar, las propiedades estáticas y dinámicas de las dislocaciones de tipo tornillo en cinco potenciales interatómicos de tungsteno son comparadas, determinando cuáles de ellos garantizan una mayor fidelidad física y eficiencia computacional. Las grandes tasas de deformación asociadas a las técnicas de dinámica molecular hacen que las funciones de movilidad de las dislocaciones obtenidas no puedan ser utilizadas en los siguientes pasos del modelado multiescala. En este trabajo, proponemos dos métodos alternativos para obtener las funciones de movilidad de las dislocaciones: un modelo Monte Cario cinético y expresiones analíticas. El conjunto de parámetros necesarios para formular el modelo de Monte Cario cinético y la ley de movilidad analítica son calculados atomísticamente. Estos parámetros incluyen, pero no se limitan a: la determinación de las entalpias y energías de formación de las parejas de escalones que forman las dislocaciones, la parametrización de los efectos de no Schmid característicos en materiales bcc,etc. Conociendo la ley de movilidad de las dislocaciones en función del esfuerzo aplicado y la temperatura, se introduce esta relación como ecuación de flujo dentro de un modelo de plasticidad cristalina. La predicción del modelo sobre la dependencia del límite de fluencia con la temperatura es validada experimentalmente con ensayos uniaxiales en tungsteno monocristalino. A continuación, se calcula el límite de fluencia al aplicar ensayos uniaxiales de tensión para un conjunto de orientaciones cristalográticas dentro del triángulo estándar variando la tasa de deformación y la temperatura de los ensayos. Finalmente, y con el objetivo de ser capaces de predecir una respuesta más dúctil del tungsteno para una variedad de estados de carga, se realizan ensayos biaxiales de tensión sobre algunas de las orientaciones cristalográficas ya estudiadas en función de la temperatura.-------------------------------------------------------------------------ABSTRACT ----------------------------------------------------------Tungsten and tungsten alloys are being considered as leading candidates for structural and functional materials in future fusion energy devices. The most attractive properties of tungsten for the design of magnetic and inertial fusion energy reactors are its high melting point, high thermal conductivity, low sputtering yield and low longterm disposal radioactive footprint. However, tungsten also presents a very low fracture toughness, mostly associated with inter-granular failure and bulk plasticity, that limits its applications. As a result of these various and complex conditions of work, the study, development and design of these materials is one of the most important challenges that have emerged in recent years to the scientific community in the field of materials for energy applications. The plastic behavior of body-centered cubic (bcc) refractory metals like tungsten is governed by the kink-pair mediated thermally activated motion of h¿ (\1 11)i screw dislocations on the atomistic scale and by ensembles and interactions of dislocations at larger scales. Modeling this complex behavior requires the application of methods capable of resolving rigorously each relevant scale. The work presented in this thesis proposes a multiscale model approach that gives engineering-level responses to the technical specifications required for the use of tungsten in fusion energy reactors, and it is also supported by the rigorous underlying physics of extensive atomistic simulations. First, the static and dynamic properties of screw dislocations in five interatomic potentials for tungsten are compared, determining which of these ensure greater physical fidelity and computational efficiency. The large strain rates associated with molecular dynamics techniques make the dislocation mobility functions obtained not suitable to be used in the next steps of the multiscale model. Therefore, it is necessary to employ mobility laws obtained from a different method. In this work, we suggest two alternative methods to get the dislocation mobility functions: a kinetic Monte Carlo model and analytical expressions. The set of parameters needed to formulate the kinetic Monte Carlo model and the analytical mobility law are calculated atomistically. These parameters include, but are not limited to: enthalpy and energy barriers of kink-pairs as a function of the stress, width of the kink-pairs, non-Schmid effects ( both twinning-antitwinning asymmetry and non-glide stresses), etc. The function relating dislocation velocity with applied stress and temperature is used as the main source of constitutive information into a dislocation-based crystal plasticity framework. We validate the dependence of the yield strength with the temperature predicted by the model against existing experimental data of tensile tests in singlecrystal tungsten, with excellent agreement between the simulations and the measured data. We then extend the model to a number of crystallographic orientations uniformly distributed in the standard triangle and study the effects of temperature and strain rate. Finally, we perform biaxial tensile tests and provide the yield surface as a function of the temperature for some of the crystallographic orientations explored in the uniaxial tensile tests.

Train-induced pressure on pedestrians

A simple analytical model for the train-induced flow and its effects on pedestrians is presented in this paper. The expressions developed for the induced air velocity and pressure on the pedestrian surface, as well as their dependence with time, are obtained from unsteady potential theory. The relevant parameters and their effects are analysed, in particular the sensitivity of the pressure coefficient and its rate of change on the train and pedestrian transverse size, the distance to the tracks and the pressure measurement location on the pedestrian surface. In spite of the extreme simplicity of the model and the expressions obtained, good correlation is observed with previously existing experiments. With this work, an absence of published studies concerning analytical approaches to the problem of vehicle-induced pressure on pedestrians is intended to be covered, allowing for simplified testing procedures.

Spacecraft launch depressurization loads

The pressure variation inside the launch vehicle fairing during climb through the atmosphere induces structural loads on the walls of closed-type spacecrafts or equipment boxes. If the evacuation of the air is not fast enough, excessive pressure loading can result in damage of elements exposed to the rising pressure jump, which depends mainly on the geometry of venting holes, the effective volume of air to be evacuated, and the characteristic time of pressure variation under the fairing. A theoretical study of the reservoir discharge forced by the fairing time-dependent pressure variation is presented. The basic mathematical model developed can yield both a numerical solution for the pressure jump and an asymptotic solution for the most relevant case, the small-prcssurc-jump limit, showing the dependence on a single nondimensional parameter: the ratio of the reservoir discharge to the fairing pressure profile characteristic times. The asymptotic solution validity range upper limit, obtained by comparison with the numerical solution, is determined by the starting of choked operation. Very high sensitivity of the maximum pressure jump to the ratio of characteristic times has been observed. Another relevant finding is that the pressure profiles for different launchers can be considered similar when rewritten in appropriate form and only their characteristic times are required for the analysis. The simple expressions of the asymptotic solution are a useful tool for preliminarily sizing the reservoir discharge geometry and estimating depressurization loads

Are pharmacological randomised controlled clinical trials relevant to real-life asthma populations? : A protocol for an UNLOCK study from the IPCRG

Funding The IPCRG provided funding for this research project as an UNLOCK Group study for which the funding was obtained through an unrestricted grant by Novartis AG, Basel, Switzerland. Novartis has no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This study will include data from the Optimum Patient Care Research Database and is undertaken in collaboration with Optimum Patient Care and the Respiratory Effectiveness Group.

In situ investigation of rapid subsurface flow : Identification of relevant spatial structures beyond heterogeneity

Non peer reviewed

PET Tracers to Study Clinically Relevant Hepatic Transporters

Date of Acceptance: 02/06/2015

GPIIIa-(49–66) is a major pathophysiologically relevant antigenic determinant for anti-platelet GPIIIa of HIV-1-related immunologic thrombocytopenia

High-affinity (Kd = 1 × 10−9 M) anti-platelet GPIIIa has been isolated from serum immune complexes of immunologic thrombocytopenic HIV-1-infected patients (HIV-1-ITP). Affinity-purified anti-platelet antibody reacted with a recombinant GPIIIa-(1–200) and -(1–66) fusion peptide and with an 18-mer GPIIIa-(49–66) peptide but not with seven other GPIIIa peptides spanning the length of GPIIIa. Most of the anti-platelet antibody (≈85%) could be adsorbed to and eluted from a GPIIIa-(49–66) affinity column. Binding of antibody to platelets could be inhibited by GPIIIa-(49–66) or an equimolar peptide-albumin conjugate (IC50 = 2 μM). Sera from 7 control subjects and 10 classic autoimmune thrombocytopenic patients gave background reactivity with GPIIIa-(49–66). HIV-1-ITP sera from 16 patients reacted with a mean OD 6-fold greater than background (range, 4- to 9-fold). Serum anti-GPIIIa-(49–66) concentration correlated inversely with platelet count, R2 = 0.51, n = 31, P < 0.0001. Because mouse platelet GPIIIa-(49–66) has 83% homology with human GPIIIa and mouse monocytes contain Fc receptors for the human IgG1-κ/λ antibody, we determined the in vivo effect of human anti-GPIIIa on mouse platelets. Affinity-purified antibody, 25–50 μg given i.p., resulted in a precipitous drop in platelet count to 30% of baseline, with nadir at 4 hr and return to normal in 36 hr. No effect was noted with control IgG. Acute thrombocytopenia could be prevented or reversed by the injection of the GPIIIa-(49–66) albumin conjugate at zero time or 2 hr after antibody, respectively, but not with a scrambled peptide-albumin conjugate. Thus HIV-1-ITP patients have high-affinity anti-platelet GPIIIa against a major antigenic determinant, GPIIIa-(49–66), which correlates inversely with platelet count and induces thrombocytopenia in mice.

Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma

Neuroblastoma (NB) is a common pediatric tumor that exhibits a wide range of biological and clinical heterogeneity. EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases and ligand ephrins play pivotal roles in neural and cardiovascular development. High-level expression of transcripts encoding EPHB6 receptors (EPHB6) and its ligands ephrin-B2 and ephrin-B3 (EFNB2, EFNB3) is associated with low-stage NB (stages 1, 2, and 4S) and high TrkA expression. In this study, we showed that EFNB2 and TrkA expressions were associated with both tumor stage and age, whereas EPHB6 and EFNB3 expressions were solely associated with tumor stage, suggesting that these genes were expressed in distinct subsets of NB. Kaplan-Meier and Cox regression analyses revealed that high-level expression of EPHB6, EFNB2, and EFNB3 predicted favorable NB outcome (P < 0.005), and their expression combined with TrkA expression predicted the disease outcome more accurately than each variable alone (P < 0.00005). Interestingly, if any one of the four genes (EPHB6, EFNB2, EFNB3, or TrkA) was expressed at high levels in NB, the patient survival was excellent (>90%). To address whether a good disease outcome of NB was a consequence of high-level expression of a “favorable NB gene,” we examined the effect of EPHB6 on NB cell lines. Transfection of EPHB6 cDNA into IMR5 and SY5Y expressing little endogenous EPHB6 resulted in inhibition of their clonogenicity in culture. Furthermore, transfection of EPHB6 suppressed the tumorigenicity of SY5Y in a mouse xenograft model, demonstrating that high-level expressions of favorable NB genes, such as EPHB6, can in fact suppress malignant phenotype of unfavorable NB.

An in vitro study of the dynamic features of the major histocompatibility complex class I complex relevant to its role as a versatile peptide-receptive molecule

The major histocompatibility complex class I complex consists of a heavy chain and a light chain (β2-microglobulin, β2m), which assemble with a short endogenously derived peptide in the endoplasmic reticulum. The class I peptide can be directly exchanged, either at the cell surface or, as recently described, in vesicles of the endocytic compartments, thus allowing exogenous peptides to enter the class I presentation pathway. To probe the interactions between the components of the class I molecule, we analyzed the exchange of peptide and β2m by using purified, recombinant H2-Kb/peptide complexes in a cell-free in vitro system. The exchange of competitor peptide was primarily dependent on the off-rate of the original peptide in the class I binding groove. Peptide exchange was not enhanced by the presence of exogenous β2m, as exchange occurred to the same extent in its absence. Thus, the exchange of peptide and β2m are independent events. The exchange rate of β2m also was not affected by the dissociation rates of the original peptides. Furthermore, peptides could substantially exchange into class I molecules over a pH range of 5.5 to 7.5, conditions prevalent in certain endocytic compartments. We conclude that the dynamic properties of the components of class I molecules explain its function as a highly peptide-receptive molecule. The major histocompatibility complex class I can readily receive peptides independent of the presence of exogenous β2m, even at a low pH. Such properties are relevant to class I peptide acquisition, which can occur at the cell surface, as well as in specialized endosomes.

The InterPro database, an integrated documentation resource for protein families, domains and functional sites

Signature databases are vital tools for identifying distant relationships in novel sequences and hence for inferring protein function. InterPro is an integrated documentation resource for protein families, domains and functional sites, which amalgamates the efforts of the PROSITE, PRINTS, Pfam and ProDom database projects. Each InterPro entry includes a functional description, annotation, literature references and links back to the relevant member database(s). Release 2.0 of InterPro (October 2000) contains over 3000 entries, representing families, domains, repeats and sites of post-translational modification encoded by a total of 6804 different regular expressions, profiles, fingerprints and Hidden Markov Models. Each InterPro entry lists all the matches against SWISS-PROT and TrEMBL (more than 1 000 000 hits from 462 500 proteins in SWISS-PROT and TrEMBL). The database is accessible for text- and sequence-based searches at http://www.ebi.ac.uk/interpro/. Questions can be emailed to interhelp@ebi.ac.uk.

Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse

Heterozygous reeler mice (HRM) haploinsufficient for reelin express ≈50% of the brain reelin content of wild-type mice, but are phenotypically different from both wild-type mice and homozygous reeler mice. They exhibit, (i) a down-regulation of glutamic acid decarboxylase 67 (GAD67)-positive neurons in some but not every cortical layer of frontoparietal cortex (FPC), (ii) an increase of neuronal packing density and a decrease of cortical thickness because of neuropil hypoplasia, (iii) a decrease of dendritic spine expression density on basal and apical dendritic branches of motor FPC layer III pyramidal neurons, and (iv) a similar decrease in dendritic spines expressed on the basal dendrite branches of CA1 pyramidal neurons of the hippocampus. To establish whether the defect of GAD67 down-regulation observed in HRM is responsible for neuropil hypoplasia and decreased dendritic spine density, we studied heterozygous GAD67 knockout mice (HG67M). These mice exhibited a down-regulation of GAD67 mRNA expression in FPC (about 50%), but they expressed normal amounts of reelin and had no neuropil hypoplasia or down-regulation of dendritic spine expression. These findings, coupled with electron-microscopic observations that reelin colocalizes with integrin receptors on dendritic spines, suggest that reelin may be a factor in the dynamic expression of cortical dendritic spines perhaps by promoting integrin receptor clustering. These findings are interesting because the brain neurochemical and neuroanatomical phenotypic traits exhibited by the HRM are in several ways similar to those found in postmortem brains of psychotic patients.