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.

Antibacterial activity of low amperage and low voltage electric current (DC)

Infection is a major clinical problem associated with the use of intravenous catheters.The efficacy of a direct electric current (10µA, 9V) via electrode-conducting carbon impregnated catheters to prevent colonisation of catheters by micro-organisms was investigated. The range of organisms susceptible to 10µA was determined by a zone of inhibition test. The catheters acting as the anode and the cathode were inserted into a nutrient agar plate inoculated with a lawn of bacteria. There was no zone of inhibition observed around the anode. Organisms susceptible to 10µA at the cathode were Staphylococcus aureus (2 strains), Staphylococcus epidermidis (5 strains), Escherichia coli and Klebsiella pneumoniae (2 strains each), and one strain of the following micro-organisms: Staphylococcus hominis, Proteus mirabilis, Pseudomonas aeruginosa and Candida albicans. The zones ranged from 6 to 16 mm in diameter according to the organisms under test. The zone size was proportional to the amperage (10 - 100 µA) and the number of organisms on the plate. Ten µA did not prevent adhesion of staphylococci to the cathode nor did it affect their growth in nutrient broth. However, it was bactericidal to adherent bacteria on the cathodal catheter and significantly reduced the number of bacteria on the catheter after 4 to 24 h application of electricity. The antimicrobial activity of low amperage electric current under anaerobic conditions and in the absence of chloride ions against bacteria attached to the surface of a current carrying electrode was also investigated.The mechanisms of the bactericidal activity associated with the cathode were investigated with S. epidermidis and S. aureus. The inhibition zone was greatly reduced in the presence of catalase. There was no zone around the cathode when the test was carried out under anaerobic conditions. Hydrogen peroxide was produced at the cathode surface under aerobic conditions, but not in the absence of oxygen. A salt-bridge apparatus was used to demonstrate further that hydrogen peroxide was produced at the cathode, and chlorine at the anode. The antimicrobial activity of low amperage electric current under anaerobic conditions and in the absence of chloride ions against bacteria attached to the surface of a current carrying electrode was also investigated. Antibacterial activity was reduced under anaerobic conditions, which is compatible with the role of hydrogen peroxide as a primary bactericidal agent of electricity associated with the cathode. A reduction in chloride ions did not significantly reduce the antibacterial activity suggesting chlorine plays only a minor role in the bactericidal activity against organisms attached to anodal electrode surfaces. The bactericidal activity of electric current associated with the cathode and H202 was greatly reduced in the presence of 50 μM to 0.5 mM magnesium ions in the test menstrum. Ten μA applied via the catheters did not prevent the initial biofilm growth by the adherent bacteria but reduced the number of bacteria in the biofilm by 2 log order aiter 24 h. The results suggested that 10 μA may prevent the colonisation of catheters by both the extra~ and intra-luminal routes. The localised production of hydrogen peroxide and chlorine and the intrinsic activity due to electric current may offer a useful method for the eradication of bacteria from catheter surfaces.

Aid allocation of the emerging Central and Eastern European donors

This paper examines the main characteristics of the (re-)emerging foreign aid policies of the Visegrád countries (the Czech Republic, Hungary, Poland, Slovakia), concentrating on the allocation of their aid resources. I adopt an econometric approach, similar to the ones used in the literature, for analysing the aid allocation of the OECD DAC donors. Using this approach, I examine the various factors that influence aid allocation of the Visegrád countries, using data for the years between 2001 and 2008. The most important conclusion is that the amount of aid a partner country gets from the four emerging donors is not influenced by the level of poverty or the previous performance of the recipients (measured by the level of economic growth or the quality of institutions). The main determining factor seems to be geographic proximity, as countries in the Western Balkans and the Post-Soviet region receive much more aid from the Visegrád countries than other recipients. Historical ties (pre-1989 development relations) and international obligations in the cases of Afghanistan and Iraq are also found to be significant explanatory factors. This allocation is in line with the foreign political and economic interests of these new donors. Although there are clear similarities between the four donors, this paper also identifies some individual country characteristics.

Optimal design of the renewable energy map of Greece using weighted goal-programming and data envelopment analysis

Renewable energy forms have been widely used in the past decades highlighting a "green" shift in energy production. An actual reason behind this turn to renewable energy production is EU directives which set the Union's targets for energy production from renewable sources, greenhouse gas emissions and increase in energy efficiency. All member countries are obligated to apply harmonized legislation and practices and restructure their energy production networks in order to meet EU targets. Towards the fulfillment of 20-20-20 EU targets, in Greece a specific strategy which promotes the construction of large scale Renewable Energy Source plants is promoted. In this paper, we present an optimal design of the Greek renewable energy production network applying a 0-1 Weighted Goal Programming model, considering social, environmental and economic criteria. In the absence of a panel of experts Data Envelopment Analysis (DEA) approach is used in order to filter the best out of the possible network structures, seeking for the maximum technical efficiency. Super-Efficiency DEA model is also used in order to reduce the solutions and find the best out of all the possible. The results showed that in order to achieve maximum efficiency, the social and environmental criteria must be weighted more than the economic ones.

Aid Allocation of the Emerging Central and Eastern European Donors

The paper examines the main characteristics of the (re)emerging foreign aid policies of the Visegrád countries (the Czech Republic, Hungary, Poland, Slovakia), concentrating on the allocation of their aid resources. We adopt an econometric approach, similar to the ones used in the literature for analyzing the aid allocation of the OECD DAC donors. Using this approach, we examine the various factors that influence aid allocation of the Visegrád countries, using data for the years between 2001 and 2008. Our most important conclusion is that the amount of aid a partner county gets from the four emerging donors is not influenced by the level of poverty or the previous performance (measured by the level of economic growth or the quality of institutions) of the recipients. The main determining factor seems to be geographic proximity, as countries in the Western-Balkans and the Post-Soviet region receive much more aid from the Visegrád countries than other recipients. Historical ties (pre-1989 development relations) and international obligations in the case of Afghanistan and Iraq are also found to be significant explanatory factors. This allocation is in line with the foreign political and economic interests of these new donors. While there are clear similarities between the four donors, the paper also identifies some individual country characteristics.

Aid Allocation of the Emerging Central and Eastern European Donors

The paper examines the main characteristics of the (re)emerging foreign aid policies of the Visegrád countries (the Czech Republic, Hungary, Poland, Slovakia), concentrating on the allocation of their aid resources. We adopt an econometric approach, similar to the ones used in the literature for analyzing the aid allocation of the OECD DAC donors. Using this approach, we examine the various factors that influence aid allocation of the Visegrád countries, using data for the years between 2001 and 2008. Our most important conclusion is that the amount of aid a partner county gets from the four emerging donors is not influenced by the level of poverty or the previous performance (measured by the level of economic growth or the quality of institutions) of the recipients. The main determining factor seems to be geographic proximity, as countries in the Western-Balkans and the Post-Soviet region receive much more aid from the Visegrád countries than other recipients. Historical ties (pre-1989 development relations) and international obligations in the case of Afghanistan and Iraq are also found to be significant explanatory factors. This allocation is in line with the foreign political and economic interests of these new donors. While there are clear similarities between the four donors, the paper also identifies some individual country characteristics.

Statistical analysis and optimal classification of blood cell populations using Gaussian distributions

This dissertation develops a new figure of merit to measure the similarity (or dissimilarity) of Gaussian distributions through a novel concept that relates the Fisher distance to the percentage of data overlap. The derivations are expanded to provide a generalized mathematical platform for determining an optimal separating boundary of Gaussian distributions in multiple dimensions. Real-world data used for implementation and in carrying out feasibility studies were provided by Beckman-Coulter. It is noted that although the data used is flow cytometric in nature, the mathematics are general in their derivation to include other types of data as long as their statistical behavior approximate Gaussian distributions. ^ Because this new figure of merit is heavily based on the statistical nature of the data, a new filtering technique is introduced to accommodate for the accumulation process involved with histogram data. When data is accumulated into a frequency histogram, the data is inherently smoothed in a linear fashion, since an averaging effect is taking place as the histogram is generated. This new filtering scheme addresses data that is accumulated in the uneven resolution of the channels of the frequency histogram. ^ The qualitative interpretation of flow cytometric data is currently a time consuming and imprecise method for evaluating histogram data. This method offers a broader spectrum of capabilities in the analysis of histograms, since the figure of merit derived in this dissertation integrates within its mathematics both a measure of similarity and the percentage of overlap between the distributions under analysis. ^

Essays on intergenerational and regional aspects of water management

This dissertation consists of three essays on different aspects of water management. The first essay focuses on the sustainability of freshwater use by introducing the notion that altruistic parents do bequeath economic assets for their offspring. Constructing a two-period, over-lapping generational model, an optimal ratio of consumption and pollution for old and young generations in each period is determined. Optimal levels of water consumption and pollution change according to different parameters, such as, altruistic degree, natural recharge rate, and population growth. The second essay concerns water sharing between countries in the case of trans-boundary river basins. The paper recognizes that side payments fail to forge water-sharing agreement among the international community and that downstream countries have weak bargaining power. An interconnected game approach is developed by linking the water allocation issue with other non-water issues such as trade or border security problems, creating symmetry between countries in bargaining power. An interconnected game forces two countries to at least partially cooperate under some circumstances. The third essay introduces the concept of virtual water (VW) into a traditional international trade model in order to estimate water savings for a water scarce country. A two country, two products and two factors trade model is developed, which includes not only consumers and producer's surplus, but also environmental externality of water use. The model shows that VW trade saves water and increases global and local welfare. This study should help policy makers to design appropriate subsidy or tax policy to promote water savings especially in water scarce countries.^

A branch and efficiency algorithm for the optimal design of supply chain networks

Supply chain operations directly affect service levels. Decision on amendment of facilities is generally decided based on overall cost, leaving out the efficiency of each unit. Decomposing the supply chain superstructure, efficiency analysis of the facilities (warehouses or distribution centers) that serve customers can be easily implemented. With the proposed algorithm, the selection of a facility is based on service level maximization and not just cost minimization as this analysis filters all the feasible solutions utilizing Data Envelopment Analysis (DEA) technique. Through multiple iterations, solutions are filtered via DEA and only the efficient ones are selected leading to cost minimization. In this work, the problem of optimal supply chain networks design is addressed based on a DEA based algorithm. A Branch and Efficiency (B&E) algorithm is deployed for the solution of this problem. Based on this DEA approach, each solution (potentially installed warehouse, plant etc) is treated as a Decision Making Unit, thus is characterized by inputs and outputs. The algorithm through additional constraints named “efficiency cuts”, selects only efficient solutions providing better objective function values. The applicability of the proposed algorithm is demonstrated through illustrative examples.

Effects of alternating current voltage amplitude and oxide capacitance on mid-gap interface state defect density extractions in In0.53Ga 0.47As capacitors

This work looks at the effect on mid-gap interface state defect density estimates for In0.53Ga0.47As semiconductor capacitors when different AC voltage amplitudes are selected for a fixed voltage bias step size (100 mV) during room temperature only electrical characterization. Results are presented for Au/Ni/Al2O3/In0.53Ga0.47As/InP metal–oxide–semiconductor capacitors with (1) n-type and p-type semiconductors, (2) different Al2O3 thicknesses, (3) different In0.53Ga0.47As surface passivation concentrations of ammonium sulphide, and (4) different transfer times to the atomic layer deposition chamber after passivation treatment on the semiconductor surface—thereby demonstrating a cross-section of device characteristics. The authors set out to determine the importance of the AC voltage amplitude selection on the interface state defect density extractions and whether this selection has a combined effect with the oxide capacitance. These capacitors are prototypical of the type of gate oxide material stacks that could form equivalent metal–oxide–semiconductor field-effect transistors beyond the 32 nm technology node. The authors do not attempt to achieve the best scaled equivalent oxide thickness in this work, as our focus is on accurately extracting device properties that will allow the investigation and reduction of interface state defect densities at the high-k/III–V semiconductor interface. The operating voltage for future devices will be reduced, potentially leading to an associated reduction in the AC voltage amplitude, which will force a decrease in the signal-to-noise ratio of electrical responses and could therefore result in less accurate impedance measurements. A concern thus arises regarding the accuracy of the electrical property extractions using such impedance measurements for future devices, particularly in relation to the mid-gap interface state defect density estimated from the conductance method and from the combined high–low frequency capacitance–voltage method. The authors apply a fixed voltage step of 100 mV for all voltage sweep measurements at each AC frequency. Each of these measurements is repeated 15 times for the equidistant AC voltage amplitudes between 10 mV and 150 mV. This provides the desired AC voltage amplitude to step size ratios from 1:10 to 3:2. Our results indicate that, although the selection of the oxide capacitance is important both to the success and accuracy of the extraction method, the mid-gap interface state defect density extractions are not overly sensitive to the AC voltage amplitude employed regardless of what oxide capacitance is used in the extractions, particularly in the range from 50% below the voltage sweep step size to 50% above it. Therefore, the use of larger AC voltage amplitudes in this range to achieve a better signal-to-noise ratio during impedance measurements for future low operating voltage devices will not distort the extracted interface state defect density.

Essays on Intergenerational and Regional Aspects of Water Management

This dissertation consists of three essays on different aspects of water management. The first essay focuses on the sustainability of freshwater use by introducing the notion that altruistic parents do bequeath economic assets for their offspring. Constructing a two-period, over-lapping generational model, an optimal ratio of consumption and pollution for old and young generations in each period is determined. Optimal levels of water consumption and pollution change according to different parameters, such as, altruistic degree, natural recharge rate, and population growth. The second essay concerns water sharing between countries in the case of trans-boundary river basins. The paper recognizes that side payments fail to forge water-sharing agreement among the international community and that downstream countries have weak bargaining power. An interconnected game approach is developed by linking the water allocation issue with other non-water issues such as trade or border security problems, creating symmetry between countries in bargaining power. An interconnected game forces two countries to at least partially cooperate under some circumstances. The third essay introduces the concept of virtual water (VW) into a traditional international trade model in order to estimate water savings for a water scarce country. A two country, two products and two factors trade model is developed, which includes not only consumers and producer’s surplus, but also environmental externality of water use. The model shows that VW trade saves water and increases global and local welfare. This study should help policy makers to design appropriate subsidy or tax policy to promote water savings especially in water scarce countries.

Wireless Networks with Energy Harvesting and Power Transfer: Joint Power and Time Allocation

In this letter, we consider wireless powered communication networks which could operate perpetually, as the base station (BS) broadcasts energy to the multiple energy harvesting (EH) information transmitters. These employ “harvest then transmit” mechanism, as they spend all of their energy harvested during the previous BS energy broadcast to transmit the information towards the BS. Assuming time division multiple access (TDMA), we propose a novel transmission scheme for jointly optimal allocation of the BS broadcasting power and time sharing among the wireless nodes, which maximizes the overall network throughput, under the constraint of average transmit power and maximum transmit power at the BS. The proposed scheme significantly outperforms “state of the art” schemes that employ only the optimal time allocation. If a single EH transmitter is considered, we generalize the optimal solutions for the case of fixed circuit power consumption, which refers to a much more practical scenario.