Shape Of Response Curve Research Articles

Effect of adult aging on pupillary response to auditory stimuli of varying levels of complexity

Pupil dilation as a measure of listening effort has been well documented (Kuchinsky et al., 2013), as has the association between adult aging and increased effort in listening tasks (Wingfield et al., 2015). However, age-related differences in the dynamics of pupillary response over time while attending to auditory stimuli have received less study; nor has the nature of the pupillary response to simple stimuli (tones) versus more complex speech stimuli (words, sentences) been systematically explored. In this study we examined multiple parameters of young adult and older adult listeners’ changes in pupil size, including peak amplitude and latency to peak, elicited while making decisions in response to auditory stimuli that varied in acoustic or linguistic complexity. Results showed that the latency to peak pupil size was slower for older adults and for increasingly complex stimuli. The shape of pupillary response curve also changed dramatically with the nature of the stimuli: attending to briefer stimuli (tones, words) resulted in a more peaked pupillary response curve than for sentence-length stimuli, which took a more complex form. These results suggest that both adult aging and stimulus complexity influence the dynamics of the pupillary response as an index of processing effort for acoustic stimuli.

Niche asymmetry of vascular plants increases with elevation

AbstractAimSpecies distributions along an environmental gradient are often not symmetric but skewed towards one end of the gradient. Various explanations for this skewness have been proposed but the patterns of niche asymmetry along extensive environmental gradients have been rarely explored. In this study, we tested three predictions of asymmetric abiotic stress limitation (AASL) hypothesis that predicts a steeper decrease in the probability of occurrence towards the more stressful end of a plant distributional range.LocationLadakh, arid Himalayas, where drought stress dominates in the lower elevation, whilst the cold stress dominates in the upper elevations.MethodsUsing data from 4062 plots (2640–6150 m a.s.l.), we explored the shapes of response curves of 395 vascular plant species through Huisman‐Olff‐Fresco models. We compared the observed patterns of niche asymmetry along the elevational gradient with null models.ResultsSpecies with symmetric response curves (61.5%) prevailed at lower elevations, whilst species with left‐skewed responses (36.2%) were significantly underrepresented up to 3750 m a.s.l. and occurred significantly more frequently at 5150–5450 m a.s.l. Right‐skewed responses were rare (2.3%) along the whole gradient. The steepness of the response increased with elevation. Response types were found in similar proportions across different habitats and functional groups.Main conclusionsOur results support the predictions of AASL hypothesis for cold limits, but not for dry limits. The low proportion of right‐skewed responses over the entire gradient suggests an effective adaptation of the local flora to arid conditions, or sufficient opportunity to avoid drought stress through the presence of favourable habitat patches. The accumulation of skewed responses at high elevations likely reflects shared physiological limits of many steppe species, whose distribution abruptly ends at the transition between steppe and alpine zones. Cold, therefore, represents a stronger barrier to species distribution than drought.

Thermally assisted OSL (TA-OSL) from various luminescence phosphors; an overview

The current status of the results on the thermally assisted optically stimulated luminescence (TA-OSL) signal performed on various naturally occurring as well as artificial luminescent phosphors is described. TA-OSL of anion deficient alumina doped with carbon and quartz has been reported to be effectively used towards dosimetry purposes, especially for large accumulated doses. Basic TA-OSL features, such as the stability, dose response, thermal assistance and TA-OSL curve shapes, along with the prevalence and the ubiquity of these features are discussed.

The shape of the plasma glucose curve during an oral glucose tolerance test as an indicator of Beta cell function and insulin sensitivity in end-pubertal obese girls.

It is hypothesized that the shape of the glucose curve during an oral glucose tolerance test is an early indicator of the risk for developing type 2 diabetes mellitus. In this study, we aimed to examine the shape of plasma glucose response curves and study their relationship with insulin sensitivity, insulin secretion and components of the metabolic syndrome in end-pubertal obese girls. Eighty-one end-pubertal obese girls [median (range) age: 14.4 (11.2-18.0) years; BMI: 34.6 (25.4-50.8) kg/m(²)] who underwent a 2-h oral glucose tolerance test were classified according to the shape of the glucose curve. Four shape types of the plasma glucose response curve were observed: 28 (34.6%) monophasic, 30 (37.0%) biphasic, 14 (17.3%) triphasic, and 9 (11.1%) unclassified. Patients with a monophasic shape had a higher area under the curve for glucose (p = 0.008), a lower early-phase insulin secretion (p = 0.005), and a poorer beta cell function relative to insulin sensitivity as reflected by the oral disposition index (p = 0.022) compared to the bi- and triphasic shape types. In addition, the triglyceride level and TG/HDL-C ratio was higher in patients with a monophasic shape compared to those with a biphasic shape (p = 0.040 and p = 0.048, respectively). In conclusion, end-pubertal obese girls with a monophasic plasma glucose curve are at increased risk for insulin resistance, which can contribute to the development of type 2 diabetes mellitus and cardiovascular diseases.

Numerical modeling of borehole-surface electromagnetic responses with 3-D finite difference method and comparison with physical simulations

Borehole-surface electromagnetic method (BSEM) is a high-accuracy electromagnetic prospecting method that uses AC-powered vertical finite line source as the excitation source. The observed surface electromagnetic field is inverted for the subsurface conductivity structure. In this paper, the total field is separated into a primary part, due to a horizontally layered host medium, and a secondary part due to 3-D heterogeneities. After solving for the primary field with an analytical method, the frequency-domain second-order differential equation for the secondary field is discretized by finite differences. A sparse matrix storage scheme is employed and a BiCGSSTAB(m) method with a diagonal matrix preconditioner is used to obtain the secondary field as well as the 3-D BSEM response of the model. We compare the result of anomalous responses of three-layered medium derived by 3-D forward modeling with the result of semi-analytical solution. We also perform physical simulation and 3-D numerical forward modeling based on similarity criterion. As a result, the shape of both anomalous response curves are the same, which validates the 3-D numerical simulation method. The anomalous fields of 3-D numerical forward and physical simulation share similar anomalous feature of symmetric bimodal structure that is consistent with its harmonic response curve. It demonstrates that borehole-surface electromagnetic method can be used not only for prospection by employing a multi-frequency response, but also can provide multi-angle information about subsurface anomaly by varying relative depths of vertical finite line source in the borehole.

Daily mean temperature and clinical kidney stone presentation in five U.S. metropolitan areas: a time-series analysis.

Background: High ambient temperatures are a risk factor for nephrolithiasis, but the precise relationship between temperature and kidney stone presentation is unknown.Objectives: Our objective was to estimate associations between mean daily temperature and kidney stone presentation according to lag time and temperatures.Methods: Using a time-series design and distributed lag nonlinear models, we estimated the relative risk (RR) of kidney stone presentation associated with mean daily temperatures, including cumulative RR for a 20-day period, and RR for individual daily lags through 20 days. Our analysis used data from the MarketScan Commercial Claims database for 60,433 patients who sought medical evaluation or treatment of kidney stones from 2005–2011 in the U.S. cities of Atlanta, Georgia; Chicago, Illinois; Dallas, Texas; Los Angeles, California; and Philadelphia, Pennsylvania.Results: Associations between mean daily temperature and kidney stone presentation were not monotonic, and there was variation in the exposure–response curve shapes and the strength of associations at different temperatures. However, in most cases RRs increased for temperatures above the reference value of 10°C. The cumulative RR for a daily mean temperature of 30°C versus 10°C was 1.38 in Atlanta (95% CI: 1.07, 1.79), 1.37 in Chicago (95% CI: 1.07, 1.76), 1.36 in Dallas (95% CI: 1.10, 1.69), 1.11 in Los Angeles (95% CI: 0.73, 1.68), and 1.47 in Philadelphia (95% CI: 1.00, 2.17). Kidney stone presentations also were positively associated with temperatures < 2°C in Atlanta, and < 10°C in Chicago and Philadelphia. In four cities, the strongest association between kidney stone presentation and a daily mean temperature of 30°C versus 10°C was estimated for lags of ≤ 3 days.Conclusions: In general, kidney stone presentations increased with higher daily mean temperatures, with the strongest associations estimated for lags of only a few days. These findings further support an adverse effect of high temperatures on nephrolithiasis.Citation: Tasian GE, Pulido JE, Gasparrini A, Saigal CS, Horton BP, Landis JR, Madison R, Keren R, for the Urologic Diseases in America Project. 2014. Daily mean temperature and clinical kidney stone presentation in five U.S. metropolitan areas: a time-series analysis. Environ Health Perspect 122:1081–1087; http://dx.doi.org/10.1289/ehp.1307703

Study on the spectral response curve shape variation of the reflection-mode GaN NEA photocathodes

The spectral response curves of the reflection-mode NEA GaN photocathodes are measured during the activation process and the degradation process by using the spectral response testing instrument, the results show the shapes of the spectral curves in the two procedures vary continuously. With the formation of the dipoles during the procedure of the activation of the photocathode, the effective electron affinity value on the surface decrease continuously, thus the spectrum response will increase continuously, especially the spectrum response increase more quickly in long wave-length band. When the activation process is over, because of the desorption of the Cs element, the double-dipole layer in the surface of the photocathode will be damaged, so the effective electron affinity value on the surface increases continuously, thus the spectrum response will decrease continuously, especially decrease more quickly in long wave-length band. This phenomenon cannot be explained with the regular quantum efficiency formula, the photon excited electron with high energy may result in this. With the energy increasing of the incident photon, the energy distribution of the electrons will shift toward the higher energy area, meanwhile the surface potential barrier influence the electron with low energy more severely to escape into the vacuum than those with high energy. These two reasons mentioned above will cause the shape variation of the spectral response curves.

Flux Calibration for LAMOST Spectroscopic Survey of the Galactic Anti-center

AbstractUnknown extinction of Galactic disk stars makes it difficult to select flux standards based on colors alone for the LAMOST Spectroscopic Survey of the Galactic Anti-center (LSS-GAC; Liu et al., this volume). To solve this problem, for each spectrograph of an LSS-GAC plate, 5 – 10 F-type stars are selected from spectroscopy-based stellar parameters (Teff, log g, [Fe/H]) and adopted as flux standards, and an iterative approach is adopted to calibrate spectra. From spectra processed with nominal response curves, stellar parameters are derived with the PKU stellar parameter pipeline, LSP3 (Liu et al., this volume). More realistic response curves are then derived by comparing the observed spectra with synthetic spectra (Munari et al. 2005). The later is reddened assuming a R=3.1 Fitzpatrick (1999) reddening law using E(B-V) obtained by comparing photometric and synthetic colors. New stellar parameters are derived from spectra reprocessed using the new response curves, iteratively. Comparison of LSS-GAC spectral colors with photometric ones yields differences on average 0.01±0.06 and −0.06±0.04 mag in g-r and r-i, respectively. The relatively large difference in r-i is caused by the fact that the current pipeline has opted to not to correct for the telluric absorption, most notably in the i-band. Comparison of multi-epoch LSS-GAC spectra indicates &lt; 8% uncertainties in the spectral shape from 4000 to 9000 Å. The LSS-GAC seems to yields spectra of more realistic SEDs than the SDSS (DR7) at low Galactic latitudes (Fig. 1). The shape of LAMOST response curves may vary by up to 20% in a given night, and even larger for different nights, indicating that flux calibration plate by plate is essential.

Which environmental variables should I use in my biodiversity model?

Appropriate selection of environmental variables is critical to the performance of biodiversity models, but has received less attention than the choice of modelling method. Online aggregators of biological and environmental data, such as the Global Biodiversity Information Facility and the Atlas of Living Australia, necessitate a rational approach to variable selection. We outline a set of general principles for systematically identifying, compiling, evaluating and selecting environmental variables for a biodiversity model. Our approach aims to maximise the information obtained from the analysis of biological records linked to a potentially large suite of spatial environmental variables. We demonstrate the utility of this structured framework through case studies with Australian vascular plants: regional modelling of a species distribution, continent-wide modelling of species compositional turnover and environmental classification. The approach is informed by three components of a biodiversity model: (1) an ecological framework or conceptual model, (2) a data model concerning availability, resolution and variable selection and (3) a method for analysing data. We expand the data model in structuring the problem of choosing environmental variables. The case studies demonstrate a structured approach for the: (1) cost-effective compilation of variables in the context of an explicit ecological framework for the study, attribute accuracy and resolution; (2) evaluation of non-linear relationships between variables using knowledge of their derivation, scatter plots and dissimilarity matrices; (3) selection and grouping of variables based on hypotheses of relative ecological importance and perceived predictor effectiveness; (4) systematic testing of variables as predictors through the process of model building and refinement and (5) model critique, inference and synthesis using direct gradient analysis to evaluate the shape of response curves in the context of ecological theory by presenting predictions in both geographic and environmental space.

DNA Reactivity as a Mode of Action and Its Relevance to Cancer Risk Assessment

The ability of a chemical to induce mutations has long been a driver in the cancer risk assessment process. The default strategy has been that mutagenic chemicals demonstrate linear cancer dose responses, especially at low exposure levels. In the absence of additional confounding information, this is a reasonable approach, because risk assessment is appropriately considered as being protective of human health. The concept of mode of action has allowed for an opportunity to move off this default position; mutagenicity is now not considered as the driver but rather the mode of action is. In a more precise way, it is the set of key events that define a mode of action that is fundamental in defining the shape of a cancer dose response. A key event is an informative bioindicator of the cancer response and as such should be predictive of the tumor response, at least in a qualitative way. A clear example of the use of key events in cancer risk assessment is for DNA reactive chemicals. A series of such key events is initiated by the production of DNA damage in target cells from direct interaction of the chemical with DNA leading to the production of mutations by misreplication that results in enhanced cell replication. This enhanced cell replication eventually leads to the development of preneoplastic cells and ultimately overt neoplasms. The response of each of these key events to dose of the chemical can inform the cancer dose-response curve shape. Thus, the dose-response curve for any DNA-reactive chemical can be predicted from knowledge of its mode of action and the behavior of the induced key events.

Distinct Phase Relationships between Suprachiasmatic Molecular Rhythms, Cerebral Cortex Molecular Rhythms, and Behavioral Rhythms in Early Runner (CAST/EiJ) and Nocturnal (C57BL/6J) Mice

We have previously established that CAST/EiJ (CAST) mice differ from normal mice, such as C57BL/6J (B6), in the timing of wheel-running onset relative to light/dark cycles. These mice provide an animal model for studies of the genetic and neurobiological basis for circadian phase misalignment in humans. Neither differences in endogenous circadian period nor the shape of the photic phase response curve explain the difference in the timing of activity onset between CAST and B6 mice, suggesting a mechanism downstream of the circadian clock. Here, we further test the hypothesis that the two strains differ with respect to circadian oscillations at the molecular level. Sleep/wake cycles were examined and rhythms of Period1 (Per1) and Period2 (Per2) expression were measured in the cerebral cortex, suprachiasmatic nucleus (SCN), and other hypothalamic regions. Basic sleep and molecular research laboratory. Male mice of the B6 and CAST inbred strains. None. Sleep/wake cycles were advanced by approximately 4 h in CAST mice relative to B6 mice. This was paralleled by phase-advanced rhythms of Per1 and Per2 expression, as measured byin situ hybridization, in the cerebral cortex of CAST relative to B6. By contrast, the timing of circadian oscillations and the photic induction ofPer1 and Per2 expression in the SCN were unaffected by strain. The advanced phase of wheel running and sleep/wake cycles in CAST mice relative to B6 mice is apparently not associated with differences in molecular oscillations in the SCN clock itself, but most likely in mechanisms downstream of the SCN clock. CAST mice may therefore provide a model system to investigate circadian downstream mechanisms underlying unusual patterns of entrainment to the ambient photoperiod. Jiang P; Franklin KM; Duncan MJ; O'Hara BF; Wisor JP. Distinct phase relationships between suprachiasmatic molecular rhythms, cerebral cortex molecular rhythms, and behavioral rhythms in early runner (CAST/EiJ) and nocturnal (C57BL/6J) mice. SLEEP 2012;35(10):1385-1394.

Inverse opal pH sensors with various protic monomers copolymerized with polyhydroxyethylmethacrylate hydrogel

pH sensitive inverse opal sensors were synthesized using various vinyl monomers containing acidic or basic substituents. Acrylic acid (AA), vinylphosphonic acid (VPA), vinylimidazole (VI), and dimethylaminoethylmethacrylic acid (DMAEMA) were respectively copolymerized with hydroxyethylmethacrylate (HEMA), the building block monomer of the hydrogel via UV-initiated photopolymerization. Opal templating and subsequent template removal enabled the fabrication of four inverse opal (IO) hydrogel colorimetric sensors, which responded to pH in different fashions. pH-dependent swelling of the IO hydrogel induced the red-shift of the diffracted color. The sensors containing AA or VPA, the proton donating monomers showed the color shifts from green to red with pH increase due to the increased concentration of carboxylate anions bound to the hydrogel. Diprotic VPA sensor exhibited two-step increases of diffracted wavelengths at its pKa1 and pKa2 respectively. The sensors containing proton acceptors, VI and DMAEMA showed the pH-dependent color changes in an opposite way to the AA sensor and the VPA sensor since their ionizations take place by lowering pH due to the protonation at the amino groups. The shapes of pH response curves of VI and DMAEMA sensors were similar but pKbs were different from each other. Optical diffraction responses of four sensors were compared with the calculated concentration ratios of the ionized species to the total monomer with pH variation, and a deswelling effect in the vicinities of pKas of phosphate buffer on the swelling response could be explained by shrinkage of PHEMA hydrogel under high ionic environment. In addition, copolymerization of AA, VPA and HEMA was carried out which resulted in a pH sensor exhibiting a wider range of pH for color change.

Intercomparing hillslope hydrological dynamics: Spatio‐temporal variability and vegetation cover effects

Generalizable process knowledge on hillslope hydrological dynamics is still very poor, yet indispensable for numerous theoretical and practical applications. To gain insight into the organization of hillslope hydrological dynamics we intercompared 90 observations of shallow water table dynamics at three neighboring large‐scale (33 × 75 m) hillslopes with similar slope, aspect, curvature, geologic, and pedologic properties but differences in vegetation cover (grassland, coniferous forest, and mixed forest) over a time period of 9 months. High‐resolution measurements of water table fluctuations, rainfall, and discharge in the creek at the foot of all hillslopes allowed a good system characterization. The aim of this study was to explore the spatio‐temporal variability of water table fluctuations within and between hillslopes, the effect of event and antecedent characteristics on the observed dynamics, and how the hillslope subsurface flow (SSF) response is reflected in the runoff response. To intercompare the SSF behavior we conducted an event‐based analysis of the percentage of well activation, several metrics characterizing the shape and timing of the water table response curves, rainfall characteristics, antecedent wetness conditions, and several runoff response metrics. The analysis reveals that there are distinct differences in SSF response between the grassland hillslope and the forested hillslopes, with a lower frequency of well activation and absolute water table rise at the grassland hillslope. Second, spatial patterns of water table dynamics differ between wet fall/winter/spring (predominantly saturation of the lower part of the hillslope, weaker water table response, and slower response times) and dry summer conditions (whole‐hillslope activation but higher spatial variability, generally stronger water table dynamics, and quicker response times). The observed seasonally changing water table dynamics suggest the development of a preferential flow network during high‐intensity rainstorms under dry summer conditions. Third, catchment runoff is strongly driven by hillslope dynamics, yet contrasting hydrographs during events with similar hillslope dynamics indicate the influence of additional processes. Overall, the observed high spatio‐temporal variability of seemingly homogeneous hillslopes calls for rethinking of current monitoring strategies and developing and testing new conceptual models of hillslope hydrologic processes.

Detection limit of chemical gases in ambient air with co-linear photo-thermal deflection spectroscopy

The frequency response of photo-thermal deflection spectroscopy, caused by infrared resonant absorption in analyte gases in open air using a common collinear pump-probe beam configuration, is studied using experiment and theory. The heat diffusion simulation and the experiment showed a roll-off of 50 to 60 Hz. This is in agreement with work performed by other authors. It was found, that the frequency response curve shapes for the numerical simulations of the deflection angle and the experimental deflection voltage signal disagreed by less than 20 percent over the range of 10 Hz to 1 kHz. A frequency dependent turbulence model is used to determine a noise floor as a function of modulation frequency, between 5 and 5000 Hz, for a probe beam at several different standoff distances from the analyte using parameter scaling. From both experiments, the turbulence equivalent concentration is extracted from the extrapolated curves. The best extrapolations give absorbances of 2·10−5 and 3.2·10−5 for 50°C and 75°C thermal sources, respectively. The most sensitive parameters, which the equivalent concentration depends on, are pump power, pump radius, standoff distance, and absorption length of the gas sample. Lens focusing at the detector allows a smaller detector to be used for probe beams which diverge from the source.

UNDERFLIGHT CALIBRATION OF SOHO /CDS AND HINODE /EIS WITH EUNIS-07

Flights of Goddard Space Flight Center's Extreme-Ultraviolet Normal-Incidence Spectrograph (EUNIS) sounding rocket in 2006 and 2007 provided updated radiometric calibrations for SOHO/CDS and Hinode/EIS. EUNIS carried two independent imaging spectrographs covering wavebands of 300-370 A in first order and 170-205 A in second order. After each flight, end-to-end radiometric calibrations of the rocket payload were carried out in the same facility used for pre-launch calibrations of CDS and EIS. During the 2007 flight, EUNIS, SOHO CDS and Hinode EIS observed the same solar locations, allowing the EUNIS calibrations to be directly applied to both CDS and EIS. The measured CDS NIS 1 line intensities calibrated with the standard (version 4) responsivities with the standard long-term corrections are found to be too low by a factor of 1.5 due to the decrease in responsivity. The EIS calibration update is performed in two ways. One is using the direct calibration transfer of the calibrated EUNIS-07 short wavelength (SW) channel. The other is using the insensitive line pairs, in which one member was observed by EUNIS-07 long wavelength (LW) channel and the other by EIS in either LW or SW waveband. Measurements from both methods are in good agreement, and confirm (within the measurement uncertainties) the EIS responsivity measured directly before the instrument's launch. The measurements also suggest that the EIS responsivity decreased by a factor of about 1.2 after the first year of operation. The shape of the EIS SW response curve obtained by EUNIS-07 is consistent with the one measured in laboratory prior to launch. The absolute value of the quiet-Sun He II 304 A intensity measured by EUNIS-07 is consistent with the radiance measured by CDS NIS in quiet regions near the disk center and the solar minimum irradiance obtained by CDS NIS and SDO/EVE recently.

Nonproportionality of Scintillator Detectors: Theory and Experiment. II

We report measurements of electron response of scintillators, including data on 29 halides, oxides, organics, and fluorides. We model the data based on combining the theories of: Onsager, to account for formation of excitons and excited activators; Birks, to allow for exciton-exciton annihilation; Bethe-Bloch, to relate electron stopping to its energy; and Landau, to describe how fluctuations in the linear energy deposited (dE/dx) lead to nonproportionality's contribution to resolution. In general there is satisfactory agreement with experiment, in terms of fitting the electron response data and reproducing the literature values of resolution. We find that the electron response curve shapes are more affected by the host lattice than by the activator or its concentration.

Optimal promotional time for maximum sales response with an initial market share in internet marketing

Most products usually have an initial market share at the beginning in marketing. In order to increase and maximize sales response, sellers can set an optimal promotional time limit. This paper aims to explain how an existing initial market share with vital parameters affects the range and shape of sales response curve to reach optimal promotional time. We use two opposite negative exponential growth functions to build a mathematical model, apply decision calculus to determine parameters, and optimize promotional time limits for maximum sales response. We demonstrate real numerical examples of e-mail marketing by using functions with or without an initial response. Furthermore, we also conduct sensitivity analyses to compare different optimal time limits by various response rates. This paper contributes to the field by providing a sales response model with an initial market share and can be applied to the general one force or two forces cases with vital capacity parameter and exponential growth coefficient to get more elastic, adequate, and complete results. Key words: Sales response, initial market share, diffusion function, decision calculus, optimal promotional time limits, negative exponential growth.

414 固定支持された複数のはりを有する弾性構造物の非線形連成振動

Nonlinear vibrations of the multiple beams which are fixed at their both ends to elastic structures under harmonic excitation are investigated. Van der Pol's method is used to determine the frequency resonance curves. The shape of response curves are hard spring types. Although there exist stable branches near the right hand side in the response curves for the system with a single beam, the corresponding branches become unstable for the system with multiple beams. In addition, additional branches appear, because the multiple beams are coupled with the structure. As the number of the beams increases, the number of these additional branches also increases. The beams vibrate at different amplitudes at the excitation frequency range where a sort of the autoparametric resonance occurs. The system may encounter fold bifurcations, pitchfork bifurcations and Hopf bifurcations depending on the values of the system parameters. Amplitude modulated motions, including chaotic vibrations, are observed in the numerical simulation. Corresponding to the unstable branches, each beam vibrates at different amplitudes; this means "localization phenomena."

Mysteries of LiF TLD response following high ionisation density irradiation: nanodosimetry and track structure theory, dose response and glow curve shapes

Three outstanding effects of ionisation density on the thermoluminescence (TL) mechanisms giving rise to the glow peaks of LiF:Mg,Ti (TLD-100) are currently under investigation: (1) the dependence of the heavy charged particle (HCP) relative efficiency with increasing ionisation density and the effectiveness of its modelling by track structure theory (TST), (2) the behaviour of the TL efficiency, f(D), as a function of photon energy and dose. These studies are intended to promote the development of a firm theoretical basis for the evaluation of relative TL efficiencies to assist in their application in mixed radiation fields. And (3) the shape of composite peak 5 in the glow curve for various HCP types and energies and following high-dose electron irradiation, i.e. the ratio of the intensity of peak 5a to peak 5. Peak 5a is a low-temperature satellite of peak 5 arising from electron-hole capture in a spatially correlated trapping centre/luminescent centre (TC/LC) complex that has been suggested to possess a potential as a solid-state nanodosemeter due to the preferential electron/hole population of the TC/LC at high ionisation density. It is concluded that (1) the predictions of TST are very strongly dependent on the choice of photon energy used in the determination of f(D); (2) modified TST employing calculated values of f(D) at 2 keV is in agreement with 5-MeV alpha particle experimental results for composite peak 5 but underestimates the 1.5-MeV proton relative efficiencies. Both the proton and alpha particle relative TL efficiencies of the high-temperature TL (HTTL) peaks 7 and 8 are underestimated by an order of magnitude suggesting that the HTTL efficiencies are affected by other factors in addition to radial electron dose; (3) the dose-response supralinearity of peaks 7 and 8 change rapidly with photon energy: this behaviour is explained in the framework of the unified interaction model as due to a very strong dependence on photon energy of the relative intensity of localised recombination and (4) the increased width and decrease in T(max) of composite peak 5 as a function of ionisation density is due to the greater relative intensity of peak 5a (a low-temperature component of peak 5 arising from two-energy transfer events, which leads to localised recombination).

Achieving a Quantitative Understanding of Antiretroviral Drug Efficacy

We are writing to expand upon some issues raised in a recent article by Henrich et al. [1] regarding the Instantaneous Inhibitory Potential (IIP), a novel index of antiviral activity developed by Shen et al. [2, 3]. IIP is the log reduction in single round infection events produced by a drug at clinically relevant concentrations. Because IIP takes into account the shape (slope) of the dose response curve, we have argued that it is a more accurate representation of intrinsic antiviral activity than conventional pharmacodynamic measures such as IC50 or inhibitory quotient (IQ, the ratio of clinical drug concentration to IC50). Importantly, the slope parameter is included in all of the fundamental equations of pharmacology including the Hill equation [3], the sigmoidal Emax model [4], and the Chou Talalay median effect equation [5]. Thus a true understanding of the dose effect relationship cannot be obtained achieved without inclusion of this parameter. It had been largely ignored in studies of antiretroviral drugs until our study showed that the slope parameter varies dramatically and in a class specific way for antiretroviral drugs[2, 3]. Indeed, we showed that differences in the slope parameter explain the higher antiviral activity of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) relative to the nucleoside analogue reverse transcriptase inhibitors (NRTIs). The superior activity of the NNRTIs and PIs, a well accepted concept that is incorporated into HIV treatment guidelines [6], is not explained by standard measures like IC50 or IQ. In this regard, the integrase strand transfer inhibitors (ISTIs) represent a special case discussed below. Henrich et al. [1] examined the relationship between the pharmacologic measures IIP and IQ and the outcomes of clinical trials of antiretroviral drugs. Not surprisingly, neither parameter showed a particularly strong correlation with outcome as measured by the fraction of patients who had undetectable HIV RNA after 48 weeks of treatment. It is important to note that IIP was developed to predict antiviral activity at a given drug concentration, not clinical outcome. As we pointed out in our original article [2, 3], clinical outcome is determined by many factors in addition to antiviral activity including pharmacokinetics, distribution, toxicity, adherence, drug interactions, and barriers to resistance. Henrich et al. suggest that these factors dominate the slope in determining drug efficacy and cite the superior clinical performance of efavirenz over indinavir as an example. Interestingly, this comparison provides a perfect illustration of how slope influences antiviral activity. Indinavir has a high slope which means that small increases in drug concentration give large increases in antiviral activity. Missing from the analysis by Henrich et al. is an appreciation of the fact that a high slope is can also have negative consequences for drug action because for drugs with a high slope, small decreases in drug concentration cause large decreases in activity. For drugs with a high slope and a short half life, the IIP falls dramatically during the dosing interval. As we pointed out [2, 3], when this effect is taken into account, efavirenz shows superior activity over the dosing interval, consistent with the clinical data. Thus we feel that it is important to avoid viewing the role of the slope parameter in an overly simplistic way. We believe that a true understanding of the efficacy of antiviral drugs requires consideration of five factors: (1) the intrinsic antiviral activity of a drug at a given concentration, which, according to fundamental laws of pharmacology, is a function of both IC50 and slope, (2) the change in the concentration of the drug over time, i.e pharmacokinetic, (3) factors such as convenience and toxicity that determine whether the patient will actually take the drug, (4) interactions with other drugs in the regimen, and (5) genetic barriers to resistance in the setting of suboptimal suppression. The superior performance of PIs like darunavir is largely a result of the first factor [2, 3] whereas for the ISTIs, the fourth factor is of particular importance (B. Jilek et al, manuscript in preparation). Our hope is that a quantitative analysis of all five factors will eventually allow a more rational choice of treatment regimens, particularly in patients with resistance.