Theory and data for area summation of contrast with and without uncertainty:evidence for a noisy energy model

Contrast sensitivity improves with the area of a sine-wave grating, but why? Here we assess this phenomenon against contemporary models involving spatial summation, probability summation, uncertainty, and stochastic noise. Using a two-interval forced-choice procedure we measured contrast sensitivity for circular patches of sine-wave gratings with various diameters that were blocked or interleaved across trials to produce low and high extrinsic uncertainty, respectively. Summation curves were steep initially, becoming shallower thereafter. For the smaller stimuli, sensitivity was slightly worse for the interleaved design than for the blocked design. Neither area nor blocking affected the slope of the psychometric function. We derived model predictions for noisy mechanisms and extrinsic uncertainty that was either low or high. The contrast transducer was either linear (c1.0) or nonlinear (c2.0), and pooling was either linear or a MAX operation. There was either no intrinsic uncertainty, or it was fixed or proportional to stimulus size. Of these 10 canonical models, only the nonlinear transducer with linear pooling (the noisy energy model) described the main forms of the data for both experimental designs. We also show how a cross-correlator can be modified to fit our results and provide a contemporary presentation of the relation between summation and the slope of the psychometric function.

Visual field and structural alterations in age-related macular degeneration

The thesis investigated progression of the central 10° visual field with structural changes at the macula in a cross-section of patients with varying degrees of agerelated macular degeneration (AMD). The relationships between structure and function were investigated for both standard and short-wavelength automated perimetry (SWAP). Factors known to influence the measure of visual field progression were considered, including the accuracy of the refractive correction on SWAP thresholds and the learning effect. Techniques of assessing the structure to function relationships between fundus images and the visual field were developed with computer programming and evaluated for repeatability. Drusen quantification of fundus photographs and retro-mode scanning laser ophthalmoscopic images was performed. Visual field progression was related to structural changes derived from both manual and automated methods. Principal Findings: • Visual field sensitivity declined with advancing stage of AMD. SWAP showed greater sensitivity to progressive changes than standard perimetry. • Defects were confined to the central 5°. SWAP defects occurred at similar locations but were deeper and wider than corresponding standard perimetry defects. • The central field became less uniform as severity of AMD increased. SWAP visual field indices of focal loss were of more importance when detecting early change in AMD, than indices of diffuse loss. • The decline in visual field sensitivity over stage of severity of AMD was not uniform, whereas a linear relationship was found between the automated measure of drusen area and visual field parameters. • Perimetry exhibited a stronger relationship with drusen area than other measures of visual function. • Overcorrection of the refraction for the working distance in SWAP should be avoided in subjects with insufficient accommodative facility. • The perimetric learning effect in the 10° field did not differ significantly between normal subjects and AMD patients. • Subretinal deposits appeared more numerous in retro-mode imaging than in fundus photography.

Relationships between fundus image quantification and visual field status in age-related macular degeneration

Presentation Purpose:To relate structural change to functional change in age-related macular degeneration (AMD) in a cross-sectional population using fundus imaging and the visual field status. Methods:10 degree standard and SWAP visual fields and other standard functional clinical measures were acquired in 44 eyes of 27 patients at various stages of AMD, as well as fundus photographs. Retro-mode SLO images were captured in a subset of 29 eyes of 19 of the patients. Drusen area, measured by automated drusen segmentation software (Smith et al. 2005) was correlated with visual field data. Visual field defect position was compared to the position of the imaged drusen and deposits using custom software. Results:The effect of AMD stage on drusen area within the 6000µm was significant (One-way ANOVA: F = 17.231, p < 0.001), however the trend was not strong across all stages. There were significant linear relationships between visual field parameters and drusen area. The mean deviation (MD) declined by 3.00dB and 3.92dB for each log % drusen area for standard perimetry and SWAP, respectively. The visual field parameters of focal loss displayed the strongest correlations with drusen area. The number of pattern deviation (PD) defects increased by 9.30 and 9.68 defects per log % drusen area for standard perimetry and SWAP, respectively. Weaker correlations were found between drusen area and visual acuity, contrast sensitivity, colour vision and reading speed. 72.6% of standard PD defects and 65.2% of SWAP PD defects coincided with retinal signs of AMD on fundus photography. 67.5% of standard PD defects and 69.7% of SWAP PD defects coincided with deposits on retro-mode images. Conclusions:Perimetry exhibited a stronger relationship with drusen area than other measures of visual function. The structure-function relationship between visual field parameters and drusen area was linear. Overall the indices of focal loss had a stronger correlation with drusen area in SWAP than in standard perimetry. Visual field defects had a high coincidence proportion with retinal manifestations of AMD.Smith R.T. et al. (2005) Arch Ophthalmol 123:200-206.

Grid-texture mechanisms in human vision:contrast detection of regular sparse micro-patterns requires specialist templates

Previous work has shown that human vision performs spatial integration of luminance contrast energy, where signals are squared and summed (with internal noise) over area at detection threshold. We tested that model here in an experiment using arrays of micro-pattern textures that varied in overall stimulus area and sparseness of their target elements, where the contrast of each element was normalised for sensitivity across the visual field. We found a power-law improvement in performance with stimulus area, and a decrease in sensitivity with sparseness. While the contrast integrator model performed well when target elements constituted 50–100% of the target area (replicating previous results), observers outperformed the model when texture elements were sparser than this. This result required the inclusion of further templates in our model, selective for grids of various regular texture densities. By assuming a MAX operation across these noisy mechanisms the model also accounted for the increase in the slope of the psychometric function that occurred as texture density decreased. Thus, for the first time, mechanisms that are selective for texture density have been revealed at contrast detection threshold. We suggest that these mechanisms have a role to play in the perception of visual textures.

Prestressed concrete beams with stirrups subjected to torsion, bending and shear

Reported in this thesis are test results of 37 eccentrically prestressed beams with stirrups. Single variable parameters were investigated including the prestressing force, the prestressing steel area, the concrete strength, the aspect ratio h/b and the stirrups size and spacing. Interaction of bending, torsion and shear was also investigated by testing a series of beams subjected to varying bending/torsional moment ratios. For the torsional strength an empirical expression of linear format is proposed and can be rearranged in a non-dimensional interaction form: T/To+V/Vo+M/Mo+Ps/Po+Fs/Fo=Pc2/Fsp. This formula which is based on an average experimental steel stress lower than the yield point is compared with 243 prestressed beams containing ' stirrups, including the author's test beams, and good agreement is obtained. For the theoretical analysis of the problem of torsion combined with bending and shear in concrete beams with stirrups, the method of torque-friction is proposed and developed using an average steel stress. A general linear interaction equation for combined torsion with bending and/or shear is proposed in the following format: (fi) T/Tu=1 where (fi) is a combined loading factor to modify the pure ultimate strength for differing cases of torsion with bending and/or shear. From the analysis of 282 reinforced and prestressed concrete beams containing stirrups, including the present investigation, good agreement is obtained between the method and the test results. It is concluded that the proposed method provides a rational and simple basis for predicting the ultimate torisional strength and may also be developed for design purposes.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself. • Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDS • The first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed. • The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates. • The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS - To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS - Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS - The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS - The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.