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Pharmacokinetic/pharmacodynamic (PK/PD) modelling is a discipline currently under the umbrella of pharmacometrics, and aims to describe, understand and predict the time course of in vivo drug action.
In general PK/PD comprises three major elements: (1) pharmacokinetics (PK), (2) pharmacodynamics (PD), and (3) disease progression. However, given the fact that anaesthesia procedures take place in short periods of time, where the general state of the patient remains unaltered, in this chapter we will limit the focus to the interrelationship between PK and PD.
Although both obesity and ageing are risk factors for cognitive impairment, there is no evidence in Chile on how obesity levels are associated with cognitive function. Therefore, the aim of the present study was to investigate the association between adiposity levels and cognitive impairment in older Chilean adults. This cross-sectional study includes 1384 participants, over 60 years of age, from the Chilean National Health Survey 2009–2010. Cognitive impairment was evaluated using the Mini-Mental State Examination. BMI and waist circumference (WC) were used as measures of adiposity. Compared with people with a normal BMI, the odds of cognitive impairment were higher in participants who were underweight (OR 4·44; 95 % CI 2·43, 6·45; P < 0·0001), overweight (OR 1·86; 95 % CI 1·06, 2·66; P = 0·031) and obese (OR 2·26; 95 % CI 1·31, 3·21; P = 0·003). The associations were robust after adjustment for confounding variables. Similar results were observed for WC. Low and high levels of adiposity are associated with an increased likelihood of cognitive impairment in older adults in Chile.
The mass loss process along the AGB phase is crucial for the formation of circumstellar envelopes (CSEs), which in the post-AGB phase will evolve into planetary nebulae (PNe). There are still important issues that need to be further explored in this field; in particular, the formation of axially symmetric PNe from spherical CSEs. To address the problem, we have conducted high S/N IRAM 30 m observations of 12COJ = 1−0 and J = 2−1, and 13COJ = 1−0 in a volume-limited unbiased sample of semi-regular variables (SRs). We also conducted Yebes 40 m SiO J = 1−0 observations in 1/2 of the sample in order to complement our 12CO observations. We report a moderate correlation between mass loss rate and the 12CO(1−0)−to−12CO(2−1) line intensity ratio, introducing a possible new method for determining mass loss rates of SRs with short analysis time. We also find that for several stars the SiO profiles are very similar to the 12CO profiles, a totally unexpected result unless these are non-standard envelopes.
A numerical study of the saturation process inside a rectangular open cavity is presented. Previous experiments and linear stability analysis of the problem completely described the flow in its onset, as well as in a saturated regime, characterized by three-dimensional centrifugal modes. The morphology of the modes found in the experiments matched the ones predicted by linear analysis, but with a shift in frequencies for the oscillating modes. A three-dimensional incompressible direct numerical simulation (DNS) is employed for a detailed investigation of the saturation process inside a cavity with dimensions similar to the one used in the experiments, to further explain the behaviour of these modes. In this work, periodic boundary conditions are first imposed to better understand the effect of the saturation process far from the walls. Then, the effects of spanwise solid wall boundary conditions are investigated with a DNS reproducing the full dynamics of the experiments. The main flow structures are identified using the dynamic mode decomposition technique and compared with previous experimental and linear stability analysis results. The main reason for the aforementioned shift in frequency is explained in this paper, as it is a function of the velocity of the main recirculating vortex.
A theoretical study of linear global instability of incompressible flow over a rectangular spanwise-periodic open cavity in an unconfined domain is presented. Comparisons with the limited number of results available in the literature are shown. Subsequently, the parameter space is scanned in a systematic manner, varying Reynolds number, incoming boundary-layer thickness and length-to-depth aspect ratio. This permits documenting the neutral curves and leading eigenmode characteristics of this flow. Correlations constructed using the results obtained collapse all available theoretical data on the three-dimensional instabilities.
Networks of protected areas are one of the main strategies used to address the biodiversity crisis. These should encompass as many species and ecosystems as possible, particularly in territories with high biological diversity, such as the Spanish arid zones. We produce a priority ranking of the arid zones of south-east Spain according to the rarity and richness of their characteristic flora and the level of endangerment. The resulting hierarchy shows that optimal zones for the preservation of the flora are located outside the network of protected areas. In particular, it is important to extend the network and encourage the creation of microreserves in the depression of the River Guadiana Menor (Granada), where there is least protection. This river valley is a particularly important arid site because of its unique flora and fauna, and palaeontological and archaeological findings.
Three-dimensional instabilities arising in open cavity flows are responsible for complex broad-banded dynamics. Existing studies either focus on theoretical properties of ideal simplified flows or observe the final state of experimental flows. This paper aims to establish a connection between the onset of the centrifugal instabilities and their final expression within the fully saturated flow. To that end, a linear three-dimensional modal instability analysis of steady two-dimensional states developing in an open cavity of aspect ratio
(length over depth) is conducted. This analysis is performed together with an experimental study in the same geometry adding spanwise endwalls. Two different Reynolds numbers are investigated through spectral analyses and modal decomposition. The physics of the flow is thoroughly described exploiting the strengths of each methodology. The main flow structures are identified and salient space and time scales are characterised. Results indicate that the structures obtained from linear analysis are mainly consistent with the fully saturated experimental flow. The analysis also brings to light the selection and alteration of certain wave properties, which could be caused by nonlinearities or the change of spanwise boundary conditions.
The information stored in animal feed databases is highly variable, in terms of both provenance and quality; therefore, data pre-processing is essential to ensure reliable results. Yet, pre-processing at best tends to be unsystematic; at worst, it may even be wholly ignored. This paper sought to develop a systematic approach to the various stages involved in pre-processing to improve feed database outputs. The database used contained analytical and nutritional data on roughly 20 000 alfalfa samples. A range of techniques were examined for integrating data from different sources, for detecting duplicates and, particularly, for detecting outliers. Special attention was paid to the comparison of univariate and multivariate solutions. Major issues relating to the heterogeneous nature of data contained in this database were explored, the observed outliers were characterized and ad hoc routines were designed for error control. Finally, a heuristic diagram was designed to systematize the various aspects involved in the detection and management of outliers and errors.
High-resolution monochromated electron energy loss spectroscopy (EELS) at subnanometric spatial resolution and <200 meV energy resolution has been used to assess the valence band properties of a distributed Bragg reflector multilayer heterostructure composed of InAlN lattice matched to GaN. This work thoroughly presents the collection of methods and computational tools put together for this task. Among these are zero-loss-peak subtraction and nonlinear fitting tools, and theoretical modeling of the electron scattering distribution. EELS analysis allows retrieval of a great amount of information: indium concentration in the InAlN layers is monitored through the local plasmon energy position and calculated using a bowing parameter version of Vegard Law. Also a dielectric characterization of the InAlN and GaN layers has been performed through Kramers-Kronig analysis of the Valence-EELS data, allowing band gap energy to be measured and an insight on the polytypism of the GaN layers.
We report first principles modeling of partially hydrogenated graphene, with a variety of hydrogen induced superstructures. The dependence of the optical gap on hydrogen content and coverage is examined, to assess the best configurations suitable for optoelectronic applications. Electron and optical DFT LDA gaps in the range between 0.2 and 1.5 eV were obtained for low hydrogen coverage. For such systems, hydrogen clustering (by saturating neighbouring C dangling bonds at the opposite sides of the graphene sheet) is energetically most favourable and generally produces larger gap. More homogeneous H distribution one-side bonded to C-host atoms is, in contrast, less energetically favourable or even structurally unstable and generally produces smaller gap. In addition, ordering of hydrogen was observed at 50% of H, that offers a possibility of transforming 2D graphene to an array of 1D nanowires Calculated linear optical anisotropy and nonlinear second harmonic generation (this will be discussed in a forthcoming paper) indicate these are not only gap sensitive, but can provide an access to microscopic details of the 2D nano-sheets such as symmetry, hydrogen induced structure, degree of hydrogenation, chemical bonding and many others, all promising for device application. The approach developed can be used for graphene/ graphane single layer or bilayer, formed on top of various substrates, where experimental geometries may not provide conditions for complete hydrogenation of the 2D nano-sheet(s).
Changes in the cardiac β-adrenergic system in early stages of Trypanosoma cruzi infection have been described. Here, we studied an early (135 days post-infection–p.i.) and a late stage (365 days p.i.) of the cardiac chronic form of the experimental infection (Tulahuen or SGO-Z12 strains), determining plasma epinephrine and norepinephrine levels, β-receptor density, affinity and function, cardiac cAMP concentration and phosphodiesterase activity, cardiac contractility, and the presence of β-receptor autoantibodies. Tulahuen-infected mice presented lower epinephrine and norepinephrine levels; lower β-receptor affinity and density; a diminished norepinephrine response and higher cAMP levels in the early stage, and a basal contractility similar to non-infected controls in the early and augmented in the late stage. The Tulahuen strain induced autoantibodies with weak β-receptor interaction. SGO-Z12-infected mice presented lower norepinephrine levels and epinephrine levels that diminished with the evolution of the infection; lower β-receptor affinity and an increased density; unchanged epinephrine and norepinephrine response in the early and a diminished response in the late stage; higher cAMP levels and unchanged basal contractility. The SGO-Z12 isolate induced β-receptor autoantibodies with strong interaction with the β-receptors. None of the antibodies, however, acted a as β-receptor agonist. The present results demonstrate that this system is seriously compromised in the cardiac chronic stage of T. cruzi infection.
Oxidative modification of LDL is thought to play an important role in the development of atherosclerosis. Susceptibility of LDL to peroxidation may partly depend on the compositional characteristics of the antioxidant and fatty acid content. The aim of this study was to examine the association between levels of antibodies to oxidized LDL and the various serum fatty acids in women. A total of 465 women aged 18–65 years were selected randomly from the adult population census of Pizarra, a town in southern Spain. Measurement of anti-oxidized-LDL was done by ELISA and the fatty acid composition of serum phospholipids was determined by GC. The levels of anti-oxidized-LDL antibodies were significantly related with age (r − 0·341, P < 0·001), BMI (r − 0·239, P < 0·001), waist:hip ratio (r − 0·285, P < 0·001), glucose (r − 0·208, P < 0·001), cholesterol (r − 0·243, P < 0·001), LDL-cholesterol (r − 0·185, P = 0·002), EPA (r − 0·159, P = 0·003), DHA (r − 0·121, P = 0·026), and the sum of the serum phospholipid n-3 PUFA (r − 0·141, P = 0·009). Multiple regression analysis showed that the variables that explained the behaviour of the levels of anti-oxidized-LDL antibodies were age (P < 0·001) and the serum phospholipid EPA (P < 0·001). This study showed that the fatty acid composition of serum phospholipids, and especially the percentage of EPA, was inversely related with the levels of anti-oxidized-LDL antibodies.
Hyperuricaemia is one of the components of metabolic syndrome. Both oxidative stress and hyperinsulinism are important variables in the genesis of this syndrome and have a close association with uric acid (UA). We evaluated the effect of an oral glucose challenge on UA concentrations. The study included 656 persons aged 18 to 65 years. Glycaemia, insulin, UA and plasma proteins were measured at baseline and 120 min after an oral glucose tolerance test (OGTT). The baseline sample also included measurements of total cholesterol, triacylglycerol (TAG) and HDL-cholesterol. Insulin resistance was calculated with the homeostasis model assessment. UA levels were significantly lower after the OGTT (281·93 (sd 92·19) v. 267·48 (sd 90·40) μmol/l; P < 0·0001). Subjects with a drop in UA concentrations >40·86 μmol/l (>75th percentile) had higher plasma TAG levels (P = 0·0001), baseline insulin (P = 0·02) and greater insulin resistance (P = 0·034). Women with a difference in plasma concentrations of UA above the 75th percentile had higher baseline insulin levels (P = 0·019), concentration of plasma TAG (P = 0·0001) and a greater insulin resistance index (P = 0·029), whereas the only significant difference in men was the level of TAG. Multiple regression analysis showed that the basal TAG levels, insulin at 120 min, glycaemia at 120 min and waist:hip ratio significantly predicted the variance in the UA difference (r2 0·077). Levels of UA were significantly lower after the OGTT and the individuals with the greatest decrease in UA levels are those who have greater insulin resistance and higher TAG levels.
Two patients with a history of epistaxis who were both found to have a nasolacrimal duct melanoma are presented. A literature review revealed that no previous cases of primary nasolacrimal duct melanoma have been reported. Current therapeutic modalities are discussed.
Pump and probe experiments have been performed on Er-doped rib-loaded waveguides containing Si nanoclusters grown by reactive magnetron sputtering. An Er3+ absorption cross-section of about 5×10−21 cm2 has been found at 1534 nm by insertion losses measurements. Transmission measurements at 1310 nm under optical pumping (488 nm) shows a decreasing of the signal because of confined carrier absorption of the Si nanoclusters. Amplification experiments at 1535 nm evidence two pump power regimes: losses due to confined carrier absorption in the Si nanoclusters at low pump powers and signal amplification at high pump powers. For strong optical pumping, signal enhancement of about 1.2 dB/cm was observed.
We study the optical and structural properties of rib-loaded waveguides working in the 600-900 nm spectral range. A Si nanocrystal-rich SiOx with Si excess nominally ranging from 10 to 20% forms the active region of the waveguide. Starting materials were fused silica wafers and 2 μm-thick SiO2 thermally grown onto Si substrate. Si nanocrystals were precipitated by annealing at 1100°C after quadruple Si ion implantation to high doses in a flat profile. The complete phase separation and formation of Si nanocrystals were monitored by means of optical tools, such as Raman, optical absorption and photoluminescence. Grain size distribution was obtained by electron microscopy. The actual Si excess content was obtained by X-ray photoelectron spectroscopy. The rib-loaded structure of the waveguide was fabricated by photolitographic and reactive ion etching processes, with patterned rib widths ranging from 1 to 8 μm. M-lines spectroscopy measurements provided a direct measurement of the refractive index and thickness of the active layers versus Si excess. When coupling a probe signal at 780 nm or 633 nm into the waveguide, an attenuation of at least 11 dB/cm was observed. These propagation losses have been attributed to Mie scattering, waveguide irregularities and direct absorption by the silicon nanocrystals.
Rib-loaded silica waveguides containing Si nanocrystals were grown by quadruple implantation of Si ions into a 2 μm-thick thermally-grown SiO2 layer. The thickness of the resulting flat-profile active region was about 300 nm, with a 9.5% Si excess (determined by X-ray photoelectron spectroscopy). Complete phase separation and nanocrystal formation was assured by annealing at 1100 °C, and studied by means of optical tools such as Raman and luminescence. The rib-loaded structure of the waveguides was fabricated by photolithographic and reactive ion etching processes, with patterned rib widths ranging from 1 to 8 μm. Efficient light propagation was observed when end-fire coupling a probe signal both at 633 nm and 780 nm into the waveguides, with attenuation losses as low as 11 dB/cm. Signal amplification experiments, with pulsed and continuous wave (CW) top pumping, have shown increased signal absorption when the pump power is raised. This couples with the lack of any fast component in the time decay of the amplified spontaneous emissions as measured by ns pulsed pumping Variable Stripe Length (VSL) experiments. These two phenomena are interpreted as due to the lack of stimulated emission in these nanocrystalline systems.
This paper presents a study of the damage production in yttria-stabilized cubic zirconia single crystals irradiated with medium-energy (from 30 to 450 keV) heavy ions (from He to Cs). The disorder created in the two sublattices (Zr4+ and O2−) of the crystals and the lattice sites of heavy ions were determined as a function of the irradiation fluence by in situ Rutherford backscattering and channeling experiments using a 3 MeV 4He ion beam. Damage is created at a depth close to the ion projected range at low fluences and growths towards greater depths with increasing fluences once the saturation has been reached. The kinetics of the damage accumulation process reveals three stages, which (excepted for He) essentially depend on the number of displacements per atom (dpa) induced by irradiating ions (ballistic contribution). Channeling results show that the lattice location of the heaviest atoms (Xe, Cs and I) varies with the nature of implanted species (chemical contribution). The experimental data can be represented in a diagram involving both the number of dpa and the implanted ion concentration, which could be used to predict the damage evolution in other ion-irradiated nuclear ceramics.