Powers of the likelihood ratio test and the correlation test using empirical bayes estimates for various shrinkages in population pharmacokinetics.

International audienceWe compared the powers of the likelihood ratio test (LRT) and the Pearson correlation test (CT) from empirical Bayes estimates (EBEs) for various designs and shrinkages in the context of nonlinear mixed-effect modeling. Clinical trial simulation was performed with a simple pharmacokinetic model with various weight (WT) effects on volume (V). Data sets were analyzed with NONMEM 7.2 using first-order conditional estimation with interaction and stochastic approximation expectation maximization algorithms. The powers of LRT and CT in detecting the link between individual WT and V or clearance were computed to explore hidden or induced correlations, respectively. Although the different designs and variabilities could be related to the large shrinkage of the EBEs, type 1 errors and powers were similar in LRT and CT in all cases. Power was mostly influenced by covariate effect size and, to a lesser extent, by the informativeness of the design. Further studies with more models are needed

New bonded assembly configuration for dynamic mechanical analysis of adhesives

A new sample configuration has been developed in order to study molecular mobility of an adhesive in a bonded assembly configuration by dynamic mechanical analysis. The torsional rectangular mode is used to provide a shear solicitation all along the adherend/adhesive interface. The initial mechanical properties of each assembly's constituent are first investigated as reference. The modulus of aluminum foils used as substrates exhibits a classic elastic component and a slight viscous part due to microstructural changes or stress relaxation. Four relaxation modes are highlighted and identified for epoxy adhesive tested as a bulk material. Its viscoelastic behavior is compared to the one of adhesive tested in assembly configuration. The relaxation modes of the adhesive remain visible in spite of the sample stiffening by aluminum foils. Relaxation modes comparison shows that the temperature of loss modulus associated with the mechanical manifestation of glass transition slightly increases for the assembly configuration. Energy losses during this relaxation are much higher in the assembly configuration. Influence of rigid aluminum substrates is discussed in terms of the adhesively bonded joint solicitation mode

Goulphar: rapid access and expertise for standard two-color microarray normalization methods

BACKGROUND: Raw data normalization is a critical step in microarray data analysis because it directly affects data interpretation. Most of the normalization methods currently used are included in the R/BioConductor packages but it is often difficult to identify the most appropriate method. Furthermore, the use of R commands for functions and graphics can introduce mistakes that are difficult to trace. We present here a script written in R that provides a flexible means of access to and monitoring of data normalization for two-color microarrays. This script combines the power of BioConductor and R analysis functions and reduces the amount of R programming required. RESULTS: Goulphar was developed in and runs using the R language and environment. It combines and extends functions found in BioConductor packages (limma and marray) to correct for dye biases and spatial artifacts. Goulphar provides a wide range of optional and customizable filters for excluding incorrect signals during the pre-processing step. It displays informative output plots, enabling the user to monitor the normalization process, and helps adapt the normalization method appropriately to the data. All these analyses and graphical outputs are presented in a single PDF report. CONCLUSION: Goulphar provides simple, rapid access to the power of the R/BioConductor statistical analysis packages, with precise control and visualization of the results obtained. Complete documentation, examples and online forms for setting script parameters are available from

Extended Edge States in Finite Hall Systems

We study edge states of a random Schroedinger operator for an electron submitted to a magnetic field in a finite macroscopic two dimensional system of linear dimensions equal to L. The y direction is L-periodic and in the x direction the electron is confined by two smoothly increasing parallel boundary potentials. We prove that, with large probability, for an energy range in the first spectral gap of the bulk Hamiltonian, the spectrum of the full Hamiltonian consists only on two sets of eigenenergies whose eigenfuntions have average velocities which are strictly positive/negative, uniformly with respect to the size of the system. Our result gives a well defined meaning to the notion of edge states for a finite cylinder with two boundaries, and extends previous studies on systems with only one boundary.Comment: 24 pages, 1 figure; Submitte

Rivaroxabananddabigatraninpatientsundergoing catheter ablation of atrial fibrillation

Aims: The recent availability of the novel oral anticoagulants (NOACs) may have led to a change in the anticoagulation regimens of patients referred to catheter ablation of atrial fibrillation (AF). Preliminary data exist concerning dabigatran, but information regarding the safety and efficacy of rivaroxaban in this setting is currently scarce. Methods: and results Of the 556 consecutive eligible patients (age 61.0 ± 9.6; 74.6% men; 61.2% paroxysmal AF) undergoing AF catheter ablation in our centre (October 2012 to September 2013) and enroled in a systematic standardized 30-day follow-up period: 192 patients were under vitamin K antagonists (VKAs), 188 under rivaroxaban, and 176 under dabigatran. Peri-procedural mortality and significant systemic or pulmonary thromboembolism (efficacy outcome), as well as bleeding events (safety outcome) during the 30 days following the ablation were evaluated according to anticoagulation regimen. During a 12-month time interval, the use of the NOACs in this population rose from <10 to 70%. Overall, the rate of events was low with no significant differences regarding: thrombo-embolic events in 1.3% (VKA 2.1%; rivaroxaban 1.1%; dabigatran 0.6%; P = 0.410); major bleeding in 2.3% (VKA 4.2%; rivaroxaban 1.6%; dabigatran 1.1%; P = 0.112), and minor bleeding 1.4% (VKA 2.1%; rivaroxaban 1.6%; dabigatran 0.6%; P = 0.464). No fatal events were observed. Conclusion: The use of the NOAC in patients undergoing catheter ablation of AF has rapidly evolved (seven-fold) over 1 year. These preliminary data suggest that rivaroxaban and dabigatran in the setting of catheter ablation of AF are efficient and safe, compared with the traditional VKA

Enthalpy relaxation phenomena of epoxy adhesive in operational configuration: Thermal, mechanical and dielectric analyses

Thermal cycling in space environment can cause physical aging of polymers used in structural adhesive bonded joint. Later, they can initiate failure. A methodology to follow physical aging effects on their thermal, mechanical and dielectric properties is applied to a commercial epoxy adhesive. The analytic description, using Tool, Narayanaswamy and Moynihan model gives a good description of the enthalpy relaxation. It is completed by a phenomenological analysis of the evolution of the adhesive thermal transitions, mechanical properties and molecular mobility. Testedsamples with bondedassembly are representative ofin service configurations. The influence of physical aging on the adhesive and the associated bonded assemblies is analyzed

Structure of the calcium pyrophosphate monohydrate phase (Ca2P2O7·H2O): towards understanding the dehydration process in calcium pyrophosphate hydrates

Calcium pyrophosphate hydrate (CPP, Ca2P2O7·nH2O) and calcium orthophosphate compounds (including apatite, octa­calcium phosphate etc.) are among the most prevalent pathological calcifications in joints. Even though only two dihydrated forms of CPP (CPPD) have been detected in vivo (monoclinic and triclinic CPPD), investigations of other hydrated forms such as tetra­hydrated or amorphous CPP are relevant to a further understanding of the physicochemistry of those phases of biological inter­est. The synthesis of single crystals of calcium pyrophosphate monohydrate (CPPM; Ca2P2O7·H2O) by diffusion in silica gel at ambient temperature and the structural analysis of this phase are reported in this paper. Complementarily, data from synchrotron X-ray diffraction on a CPPM powder sample have been fitted to the crystal parameters. Finally, the relationship between the resolved structure for the CPPM phase and the structure of the tetra­hydrated calcium pyrophosphate [beta] phase (CPPT-[beta]) is discussed

Prediction of Shrinkage of Individual Parameters Using the Bayesian Information Matrix in Non-Linear Mixed Effect Models with Evaluation in Pharmacokinetics

ABSTRACT: Purpose: When information is sparse, individual parameters derived from a non-linear mixed effects model analysis can shrink to the mean. The objective of this work was to predict individual parameter shrinkage from the Bayesian information matrix (M BF ). We 1) Propose and evaluate an approximation of M BF by First-Order linearization (FO), 2) Explore by simulations the relationship between shrinkage and precision of estimates and 3) Evaluate prediction of shrinkage and individual parameter precision. Methods: We approximated M BF using FO. From the shrinkage formula in linear mixed effects models, we derived the predicted shrinkage from M BF . Shrinkage values were generated for parameters of two pharmacokinetic models by varying the structure and the magnitude of the random effect and residual error models as well as the design. We then evaluated the approximation of M BF FO and compared it to Monte-Carlo (MC) simulations. We finally compared expected and observed shrinkage as well as the predicted and estimated Standard Errors (SE) of individual parameters. Results: M BF FO was similar to M BF MC. Predicted and observed shrinkages were close . Predicted and estimated SE were similar. Conclusions: M BF FO enables prediction of shrinkage and SE of individual parameters. It can be used for design optimizatio

Stimulate feed intake before weaning and control intake after weaning to optimise health and growth performance

[EN] Post-weaning feed restriction is a common practice in rabbit farming to reduce mortality, but results in lower growth performance and slaughter weights. This study aimed to assess the influence of 2 diets both rich in fibre and low in starch, with high or low digestible energy (DE) and digestible protein (DP) contents for a constant DP/DE ratio offered from 18 to 70 d of age, on the growth performance and health parameters of rabbits. Eight hundred rabbit kits were divided in 2 experimental groups differing in the feed offered from 18 to 70 d: a high concentrate diet (HC group; 10.37 MJ DE/kg DM and 102 g DP/kg DM) or low concentrate diet (LC group; 9.63 MJ DE/kg DM and 95 g DP/kg DM). Feed was offered ad libitum before weaning (35 d) and from 63 to 70 d, while feed offered from 35 to 63 d was controlled to obtain similar DE intake in both groups. Feed intake, animal weights and health status were recorded weekly. Mortality was recorded daily. Feed intake was similar in both groups before weaning (P=0.204), and consequently the DE intake was higher in the HC group compared to the LC group before weaning (3.91 vs. 3.39 MJ, respectively; P=0.017). Feed intake from 63 to 70 d was lower in the HC than in the LC group (229 vs. 239 g/d/kit, respectively; P<0.001).Total DE ingested after weaning was similar in both groups (45.44 MJ; P=0.143). Kits were heavier in the HC group throughout the study (P<0.05). A higher average daily gain during the periods of 18-28, 35-42 and 56-63 d was seen in the HC group (+8.1%, +16.8% and +4.5%, respectively; P<0.05). Mortality and morbidity rates were similar between groups throughout the study (P=1.0 and P=0.104, respectively). Our results suggest that when the feed intake after weaning is controlled, i) the feeding strategy before weaning determines the weight at weaning and at slaughter age; and ii) rabbits fed a diet more highly concentrated but rich in fibre increase their growth performance without negative consequences on their digestive health.The authors gratefully acknowledge the technical help of C. Bannelier, B. Gabinaud and M. Segura (INRA, UMR 1388 GenPhySE), and the assistance of the staff at the rabbit experimental unit (PECTOUL, Toulouse, France).Read, T.; Combes, S.; Gidenne, T.; Destombes, N.; Grenet, L.; Fortun-Lamothe, L. (2015). Stimulate feed intake before weaning and control intake after weaning to optimise health and growth performance. World Rabbit Science. 23(3):145-153. doi:10.4995/wrs.2015.3977SWORD14515323