A D-optimal designed population pharmacokinetic study of itraconazole capsules and solution in adults with cystic fibrosis

Background: Oral itraconazole (ITRA) is used for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis (CF) because of its antifungal activity against Aspergillus species. ITRA has an active hydroxy-metabolite (OH-ITRA) which has similar antifungal activity. ITRA is a highly lipophilic drug which is available in two different oral formulations, a capsule and an oral solution. It is reported that the oral solution has a 60% higher relative bioavailability. The influence of altered gastric physiology associated with CF on the pharmacokinetics (PK) of ITRA and its metabolite has not been previously evaluated. Objectives: 1) To estimate the population (pop) PK parameters for ITRA and its active metabolite OH-ITRA including relative bioavailability of the parent after administration of the parent by both capsule and solution and 2) to assess the performance of the optimal design. Methods: The study was a cross-over design in which 30 patients received the capsule on the first occasion and 3 days later the solution formulation. The design was constrained to have a maximum of 4 blood samples per occasion for estimation of the popPK of both ITRA and OH-ITRA. The sampling times for the population model were optimized previously using POPT v.2.0.[1] POPT is a series of applications that run under MATLAB and provide an evaluation of the information matrix for a nonlinear mixed effects model given a particular design. In addition it can be used to optimize the design based on evaluation of the determinant of the information matrix. The model details for the design were based on prior information obtained from the literature, which suggested that ITRA may have either linear or non-linear elimination. The optimal sampling times were evaluated to provide information for both competing models for the parent and metabolite and for both capsule and solution simultaneously. Blood samples were assayed by validated HPLC.[2] PopPK modelling was performed using FOCE with interaction under NONMEM, version 5 (level 1.1; GloboMax LLC, Hanover, MD, USA). The PK of ITRA and OH‑ITRA was modelled simultaneously using ADVAN 5. Subsequently three methods were assessed for modelling concentrations less than the LOD (limit of detection). These methods (corresponding to methods 5, 6 & 4 from Beal[3], respectively) were (a) where all values less than LOD were assigned to half of LOD, (b) where the closest missing value that is less than LOD was assigned to half the LOD and all previous (if during absorption) or subsequent (if during elimination) missing samples were deleted, and (c) where the contribution of the expectation of each missing concentration to the likelihood is estimated. The LOD was 0.04 mg/L. The final model evaluation was performed via bootstrap with re-sampling and a visual predictive check. The optimal design and the sampling windows of the study were evaluated for execution errors and for agreement between the observed and predicted standard errors. Dosing regimens were simulated for the capsules and the oral solution to assess their ability to achieve ITRA target trough concentration (Cmin,ss of 0.5-2 mg/L) or a combined Cmin,ss for ITRA and OH-ITRA above 1.5mg/L. Results and Discussion: A total of 241 blood samples were collected and analysed, 94% of them were taken within the defined optimal sampling windows, of which 31% where taken within 5 min of the exact optimal times. Forty six per cent of the ITRA values and 28% of the OH-ITRA values were below LOD. The entire profile after administration of the capsule for five patients was below LOD and therefore the data from this occasion was omitted from estimation. A 2-compartment model with 1st order absorption and elimination best described ITRA PK, with 1st order metabolism of the parent to OH-ITRA. For ITRA the clearance (ClItra/F) was 31.5 L/h; apparent volumes of central and peripheral compartments were 56.7 L and 2090 L, respectively. Absorption rate constants for capsule (kacap) and solution (kasol) were 0.0315 h-1 and 0.125 h-1, respectively. Comparative bioavailability of the capsule was 0.82. There was no evidence of nonlinearity in the popPK of ITRA. No screened covariate significantly improved the fit to the data. The results of the parameter estimates from the final model were comparable between the different methods for accounting for missing data, (M4,5,6)[3] and provided similar parameter estimates. The prospective application of an optimal design was found to be successful. Due to the sampling windows, most of the samples could be collected within the daily hospital routine, but still at times that were near optimal for estimating the popPK parameters. The final model was one of the potential competing models considered in the original design. The asymptotic standard errors provided by NONMEM for the final model and empirical values from bootstrap were similar in magnitude to those predicted from the Fisher Information matrix associated with the D-optimal design. Simulations from the final model showed that the current dosing regimen of 200 mg twice daily (bd) would provide a target Cmin,ss (0.5-2 mg/L) for only 35% of patients when administered as the solution and 31% when administered as capsules. The optimal dosing schedule was 500mg bd for both formulations. The target success for this dosing regimen was 87% for the solution with an NNT=4 compared to capsules. This means, for every 4 patients treated with the solution one additional patient will achieve a target success compared to capsule but at an additional cost of AUD $220 per day. The therapeutic target however is still doubtful and potential risks of these dosing schedules need to be assessed on an individual basis. Conclusion: A model was developed which described the popPK of ITRA and its main active metabolite OH-ITRA in adult CF after administration of both capsule and solution. The relative bioavailability of ITRA from the capsule was 82% that of the solution, but considerably more variable. To incorporate missing data, using the simple Beal method 5 (using half LOD for all samples below LOD) provided comparable results to the more complex but theoretically better Beal method 4 (integration method). The optimal sparse design performed well for estimation of model parameters and provided a good fit to the data.

Statnote 9: The one-way analysis of variance (random effects model)

There is an alternative model of the 1-way ANOVA called the 'random effects' model or ‘nested’ design in which the objective is not to test specific effects but to estimate the degree of variation of a particular measurement and to compare different sources of variation that influence the measurement in space and/or time. The most important statistics from a random effects model are the components of variance which estimate the variance associated with each of the sources of variation influencing a measurement. The nested design is particularly useful in preliminary experiments designed to estimate different sources of variation and in the planning of appropriate sampling strategies.

Theorems on the Convergence of Series in Generalized Lommel-Wright Functions

Mathematics Subject Classification: 30B10, 30B30; 33C10, 33C20

A look into diversity in the radio and music industry in Spain

UNESCO’s approval of the Convention on the Protection and Promotion of the Diversity of Cultural Expressions (UNESCO, 2005) has been an important element in catalyzing any attempt to measure the diversity of cultural industries (UIS, 2011). Within this framework, this article analyzes the relations between the music and radio industries in Spain from a critical perspective through the analysis of available data on recorded music offer and consumption (sales lists, radio-formula lists, the characteristics of the phonographic and radio markets) in different key moments due to the emergence of new formats and devices (CDS, Mp3, Internet).The main goal of this work is to study the evolution of the Spanish record market in terms of diversity from the end of the 1970s to the present, through the study of radio music hits lists and, the business structure of the phonographic and radio sectors, and phonograms top sales

SAMPLING BIAS IN EVALUATING THE PROBABILITY OF SEISMICALLY INDUCED SOIL LIQUEFACTION WITH SPT & CPT CASE HISTORIES

Several deterministic and probabilistic methods are used to evaluate the probability of seismically induced liquefaction of a soil. The probabilistic models usually possess some uncertainty in that model and uncertainties in the parameters used to develop that model. These model uncertainties vary from one statistical model to another. Most of the model uncertainties are epistemic, and can be addressed through appropriate knowledge of the statistical model. One such epistemic model uncertainty in evaluating liquefaction potential using a probabilistic model such as logistic regression is sampling bias. Sampling bias is the difference between the class distribution in the sample used for developing the statistical model and the true population distribution of liquefaction and non-liquefaction instances. Recent studies have shown that sampling bias can significantly affect the predicted probability using a statistical model. To address this epistemic uncertainty, a new approach was developed for evaluating the probability of seismically-induced soil liquefaction, in which a logistic regression model in combination with Hosmer-Lemeshow statistic was used. This approach was used to estimate the population (true) distribution of liquefaction to non-liquefaction instances of standard penetration test (SPT) and cone penetration test (CPT) based most updated case histories. Apart from this, other model uncertainties such as distribution of explanatory variables and significance of explanatory variables were also addressed using KS test and Wald statistic respectively. Moreover, based on estimated population distribution, logistic regression equations were proposed to calculate the probability of liquefaction for both SPT and CPT based case history. Additionally, the proposed probability curves were compared with existing probability curves based on SPT and CPT case histories.

Exact and heuristic algorithms for the integrated planning of multi-energy systems

The aim of this thesis is to present exact and heuristic algorithms for the integrated planning of multi-energy systems. The idea is to disaggregate the energy system, starting first with its core the Central Energy System, and then to proceed towards the Decentral part. Therefore, a mathematical model for the generation expansion operations to optimize the performance of a Central Energy System system is first proposed. To ensure that the proposed generation operations are compatible with the network, some extensions of the existing network are considered as well. All these decisions are evaluated both from an economic viewpoint and from an environmental perspective, as specific constraints related to greenhouse gases emissions are imposed in the formulation. Then, the thesis presents an optimization model for solar organic Rankine cycle in the context of transactive energy trading. In this study, the impact that this technology can have on the peer-to-peer trading application in renewable based community microgrids is inspected. Here the consumer becomes a prosumer and engages actively in virtual trading with other prosumers at the distribution system level. Moreover, there is an investigation of how different technological parameters of the solar Organic Rankine Cycle may affect the final solution. Finally, the thesis introduces a tactical optimization model for the maintenance operations’ scheduling phase of a Combined Heat and Power plant. Specifically, two types of cleaning operations are considered, i.e., online cleaning and offline cleaning. Furthermore, a piecewise linear representation of the electric efficiency variation curve is included. Given the challenge of solving the tactical management model, a heuristic algorithm is proposed. The heuristic works by solving the daily operational production scheduling problem, based on the final consumer’s demand and on the electricity prices. The aggregate information from the operational problem is used to derive maintenance decisions at a tactical level.

Biased Random-key Genetic Algorithms For The Winner Determination Problem In Combinatorial Auctions.

Abstract In this paper, we address the problem of picking a subset of bids in a general combinatorial auction so as to maximize the overall profit using the first-price model. This winner determination problem assumes that a single bidding round is held to determine both the winners and prices to be paid. We introduce six variants of biased random-key genetic algorithms for this problem. Three of them use a novel initialization technique that makes use of solutions of intermediate linear programming relaxations of an exact mixed integer-linear programming model as initial chromosomes of the population. An experimental evaluation compares the effectiveness of the proposed algorithms with the standard mixed linear integer programming formulation, a specialized exact algorithm, and the best-performing heuristics proposed for this problem. The proposed algorithms are competitive and offer strong results, mainly for large-scale auctions.

Urothelial Carcinogen Resistance Driven By Stronger Toll-like Receptor 2 (tlr2) And Uroplakin Iii (up Iii) Defense Mechanisms: A New Model.

The objective of the study was to illustrate the applicability and significance of the novel Lewis urothelial cancer model compared to the classic Fisher 344. Fischer 344 and Lewis females rats, 7 weeks old, were intravesical instilled N-methyl-N-nitrosourea 1.5 mg/kg every other week for a total of four doses. After 15 weeks, animals were sacrificed and bladders analyzed: histopathology (tumor grade and stage), immunohistochemistry (apoptotic and proliferative indices) and blotting (Toll-like receptor 2-TLR2, Uroplakin III-UP III and C-Myc). Control groups received placebo. There were macroscopic neoplastic lesions in 20 % of Lewis strain and 70 % of Fischer 344 strain. Lewis showed hyperplasia in 50 % of animals, normal bladders in 50 %. All Fischer 344 had lesions, 20 % papillary hyperplasia, 30 % dysplasia, 40 % neoplasia and 10 % squamous metaplasia. Proliferative and apoptotic indices were significantly lower in the Lewis strain (p < 0.01). The TLR2 and UP III protein levels were significantly higher in Lewis compared to Fischer 344 strain (70.8 and 46.5 % vs. 49.5 and 16.9 %, respectively). In contrast, C-Myc protein levels were significantly higher in Fischer 344 (22.5 %) compared to Lewis strain (13.7 %). The innovative Lewis carcinogen resistance urothelial model represents a new strategy for translational research. Preservation of TLR2 and UP III defense mechanisms might drive diverse urothelial phenotypes during carcinogenesis in differently susceptible individuals.

Validation of the Deardorff model for estimating energy balance components for a sugarcane crop

The quantification of the available energy in the environment is important because it determines photosynthesis, evapotranspiration and, therefore, the final yield of crops. Instruments for measuring the energy balance are costly and indirect estimation alternatives are desirable. This study assessed the Deardorff's model performance during a cycle of a sugarcane crop in Piracicaba, State of São Paulo, Brazil, in comparison to the aerodynamic method. This mechanistic model simulates the energy fluxes (sensible, latent heat and net radiation) at three levels (atmosphere, canopy and soil) using only air temperature, relative humidity and wind speed measured at a reference level above the canopy, crop leaf area index, and some pre-calibrated parameters (canopy albedo, soil emissivity, atmospheric transmissivity and hydrological characteristics of the soil). The analysis was made for different time scales, insolation conditions and seasons (spring, summer and autumn). Analyzing all data of 15 minute intervals, the model presented good performance for net radiation simulation in different insolations and seasons. The latent heat flux in the atmosphere and the sensible heat flux in the atmosphere did not present differences in comparison to data from the aerodynamic method during the autumn. The sensible heat flux in the soil was poorly simulated by the model due to the poor performance of the soil water balance method. The Deardorff's model improved in general the flux simulations in comparison to the aerodynamic method when more insolation was available in the environment.

Study of the equatorial Atlantic Ocean mixing layer using a one-dimensional turbulence model

The General Ocean Turbulence Model (GOTM) is applied to the diagnostic turbulence field of the mixing layer (ML) over the equatorial region of the Atlantic Ocean. Two situations were investigated: rainy and dry seasons, defined, respectively, by the presence of the intertropical convergence zone and by its northward displacement. Simulations were carried out using data from a PIRATA buoy located on the equator at 23º W to compute surface turbulent fluxes and from the NASA/GEWEX Surface Radiation Budget Project to close the surface radiation balance. A data assimilation scheme was used as a surrogate for the physical effects not present in the one-dimensional model. In the rainy season, results show that the ML is shallower due to the weaker surface stress and stronger stable stratification; the maximum ML depth reached during this season is around 15 m, with an averaged diurnal variation of 7 m depth. In the dry season, the stronger surface stress and the enhanced surface heat balance components enable higher mechanical production of turbulent kinetic energy and, at night, the buoyancy acts also enhancing turbulence in the first meters of depth, characterizing a deeper ML, reaching around 60 m and presenting an average diurnal variation of 30 m.

Stress distribution in the cervical region of an upper central incisor in a 3D finite element model

The aim of this study was to evaluate the stress distribution in the cervical region of a sound upper central incisor in two clinical situations, standard and maximum masticatory forces, by means of a 3D model with the highest possible level of fidelity to the anatomic dimensions. Two models with 331,887 linear tetrahedral elements that represent a sound upper central incisor with periodontal ligament, cortical and trabecular bones were loaded at 45º in relation to the tooth's long axis. All structures were considered to be homogeneous and isotropic, with the exception of the enamel (anisotropic). A standard masticatory force (100 N) was simulated on one of the models, while on the other one a maximum masticatory force was simulated (235.9 N). The software used were: PATRAN for pre- and post-processing and Nastran for processing. In the cementoenamel junction area, tensile forces reached 14.7 MPa in the 100 N model, and 40.2 MPa in the 235.9 N model, exceeding the enamel's tensile strength (16.7 MPa). The fact that the stress concentration in the amelodentinal junction exceeded the enamel's tensile strength under simulated conditions of maximum masticatory force suggests the possibility of the occurrence of non-carious cervical lesions such as abfractions.

Aging and fluctuation-dissipation ratio in a nonequilibrium q-state lattice model

A generalized version of the nonequilibrium linear Glauber model with q states in d dimensions is introduced and analyzed. The model is fully symmetric, its dynamics being invariant under all permutations of the q states. Exact expressions for the two-time autocorrelation and response functions on a d-dimensional lattice are obtained. In the stationary regime, the fluctuation-dissipation theorem holds, while in the transient the aging is observed with the fluctuation-dissipation ratio leading to the value predicted for the linear Glauber model.

The Coupled Aerosol and Tracer Transport model to the Brazilian developments on the Regional Atmospheric Modeling System (CATT-BRAMS) - Part 1: Model description and evaluation

We introduce the Coupled Aerosol and Tracer Transport model to the Brazilian developments on the Regional Atmospheric Modeling System (CATT-BRAMS). CATT-BRAMS is an on-line transport model fully consistent with the simulated atmospheric dynamics. Emission sources from biomass burning and urban-industrial-vehicular activities for trace gases and from biomass burning aerosol particles are obtained from several published datasets and remote sensing information. The tracer and aerosol mass concentration prognostics include the effects of sub-grid scale turbulence in the planetary boundary layer, convective transport by shallow and deep moist convection, wet and dry deposition, and plume rise associated with vegetation fires in addition to the grid scale transport. The radiation parameterization takes into account the interaction between the simulated biomass burning aerosol particles and short and long wave radiation. The atmospheric model BRAMS is based on the Regional Atmospheric Modeling System (RAMS), with several improvements associated with cumulus convection representation, soil moisture initialization and surface scheme tuned for the tropics, among others. In this paper the CATT-BRAMS model is used to simulate carbon monoxide and particulate material (PM(2.5)) surface fluxes and atmospheric transport during the 2002 LBA field campaigns, conducted during the transition from the dry to wet season in the southwest Amazon Basin. Model evaluation is addressed with comparisons between model results and near surface, radiosondes and airborne measurements performed during the field campaign, as well as remote sensing derived products. We show the matching of emissions strengths to observed carbon monoxide in the LBA campaign. A relatively good comparison to the MOPITT data, in spite of the fact that MOPITT a priori assumptions imply several difficulties, is also obtained.

Cosmic distance duality relation and the shape of galaxy clusters

Context. Observations in the cosmological domain are heavily dependent on the validity of the cosmic distance-duality (DD) relation, eta = D(L)(z)(1+ z)(2)/D(A)(z) = 1, an exact result required by the Etherington reciprocity theorem where D(L)(z) and D(A)(z) are, respectively, the luminosity and angular diameter distances. In the limit of very small redshifts D(A)(z) = D(L)(z) and this ratio is trivially satisfied. Measurements of Sunyaev-Zeldovich effect (SZE) and X-rays combined with the DD relation have been used to determine D(A)(z) from galaxy clusters. This combination offers the possibility of testing the validity of the DD relation, as well as determining which physical processes occur in galaxy clusters via their shapes. Aims. We use WMAP (7 years) results by fixing the conventional Lambda CDM model to verify the consistence between the validity of DD relation and different assumptions about galaxy cluster geometries usually adopted in the literature. Methods. We assume that. is a function of the redshift parametrized by two different relations: eta(z) = 1+eta(0)z, and eta(z) = 1+eta(0)z/(1+z), where eta(0) is a constant parameter quantifying the possible departure from the strict validity of the DD relation. In order to determine the probability density function (PDF) of eta(0), we consider the angular diameter distances from galaxy clusters recently studied by two different groups by assuming elliptical (isothermal) and spherical (non-isothermal) beta models. The strict validity of the DD relation will occur only if the maximum value of eta(0) PDF is centered on eta(0) = 0. Results. It was found that the elliptical beta model is in good agreement with the data, showing no violation of the DD relation (PDF peaked close to eta(0) = 0 at 1 sigma), while the spherical (non-isothermal) one is only marginally compatible at 3 sigma. Conclusions. The present results derived by combining the SZE and X-ray surface brightness data from galaxy clusters with the latest WMAP results (7-years) favors the elliptical geometry for galaxy clusters. It is remarkable that a local property like the geometry of galaxy clusters might be constrained by a global argument provided by the cosmic DD relation.

Cyclic variability of the circumstellar disk of the Be star zeta Tauri II. Testing the 2D global disk oscillation model

Context. About 2/3 of the Be stars present the so-called V/R variations, a phenomenon characterized by the quasi-cyclic variation in the ratio between the violet and red emission peaks of the HI emission lines. These variations are generally explained by global oscillations in the circumstellar disk forming a one-armed spiral density pattern that precesses around the star with a period of a few years. Aims. This paper presents self-consistent models of polarimetric, photometric, spectrophotometric, and interferometric observations of the classical Be star zeta Tauri. The primary goal is to conduct a critical quantitative test of the global oscillation scenario. Methods. Detailed three-dimensional, NLTE radiative transfer calculations were carried out using the radiative transfer code HDUST. The most up-to-date research on Be stars was used as input for the code in order to include a physically realistic description for the central star and the circumstellar disk. The model adopts a rotationally deformed, gravity darkened central star, surrounded by a disk whose unperturbed state is given by a steady-state viscous decretion disk model. It is further assumed that this disk is in vertical hydrostatic equilibrium. Results. By adopting a viscous decretion disk model for zeta Tauri and a rigorous solution of the radiative transfer, a very good fit of the time-average properties of the disk was obtained. This provides strong theoretical evidence that the viscous decretion disk model is the mechanism responsible for disk formation. The global oscillation model successfully fitted spatially resolved VLTI/AMBER observations and the temporal V/R variations in the H alpha and Br gamma lines. This result convincingly demonstrates that the oscillation pattern in the disk is a one-armed spiral. Possible model shortcomings, as well as suggestions for future improvements, are also discussed.