Single nucleotide polymorphisms in the APCS gene influence geographic atrophy secondary to VEGF inhibition therapy in neovascular macular degeneration.

Introduction: Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly mostly due to the development of neovascular AMD (nAMD) or geographic atrophy (GA). Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are an effective therapeutic option for nAMD. Following anti-VEGF treatments, increased atrophy of the retinal pigment epithelium (RPE) and choriocapillaries that resembles GA has been reported. We sought to evaluate the underlying genetic influences that may contribute to this process. Methods: We selected 68 single nucleotide polymorphisms (SNPs) from genes previously identified as susceptibility factors in AMD, along with 43 SNPs from genes encoding the VEGF protein and its cognate receptors as this pathway is targeted by treatment. We enrolled 467 consecutive patients (Feb 2009 to October 2011) with nAMD who received anti-VEGF therapy. The acutely presenting eye was designated as the study eye and retinal tomograms graded for macular atrophy at study exit. Statistical analysis was performed using PLINK to identify SNPs with a P value < 0.01. Logistic regression models with macular atrophy as dependent variable were fitted with age, gender, smoking status, common genetic risk factors and the identified SNPs as explanatory variables. Results: Grading for macular atrophy was available in 304 study eyes and 70% (214) were classified as showing macular atrophy. In the unadjusted analysis we observed significant associations between macular atrophy and two independent SNPs in the APCS gene: rs6695377: odds ratio (OR) = 1.98; 95% confidence intervals (CI): 1.23, 3.19; P = 0.004; rs1446965: OR = 2.49, CI: 1.29, 4.82; P = 0.006 and these associations remained significant after adjustment for covariates. Conclusions: VEGF is a mitogen and growth factor for choroidal blood vessels and the RPE and its inhibition could lead to atrophy of these key tissues. Anti-VEGF treatment can interfere with ocular vascular maintenance and may be associated with RPE and choroidal atrophy. As such, these medications, which block the effects of VEGF, may influence the development of GA. The top associated SNPs are found in the APCS gene, a highly conserved glycoprotein that encodes Serum amyloid P (SAP) which opsonizes apoptotic cells. SAP can bind to and activate complement components via binding to C1q, a mechanism by which SAP may remove cellular debris, affecting regulation of the three complement pathways.

Continuity - based and discontinuity - based segmentation in transparent and spatially segregated global motion

The mechanisms underlying the parsing of a spatial distribution of velocity vectors into two adjacent (spatially segregated) or overlapping (transparent) motion surfaces were examined using random dot kinematograms. Parsing might occur using either of two principles. Surfaces might be defined on the basis of similarity of motion vectors and then sharp perceptual boundaries drawn between different surfaces (continuity-based segmentation). Alternatively, detection of a high gradient of direction or speed separating the motion surfaces might drive the process (discontinuity-based segmentation). To establish which method is used, we examined the effect of blurring the motion direction gradient. In the case of a sharp direction gradient, each dot had one of two directions differing by 135°. With a shallow gradient, most dots had one of two directions but the directions of the remainder spanned the range between one motion-defined surface and the other. In the spatial segregation case the gradient defined a central boundary separating two regions. In the transparent version the dots were randomly positioned. In both cases all dots moved with the same speed and existed for only two frames before being randomly replaced. The ability of observers to parse the motion distribution was measured in terms of their ability to discriminate the direction of one of the two surfaces. Performance was hardly affected by spreading the gradient over at least 25% of the dots (corresponding to a 1° strip in the segregation case). We conclude that detection of sharp velocity gradients is not necessary for distinguishing different motion surfaces.

Relationship between biomedical catheter surface properties and lubricity as determined using textural analysis and multiple regression analysis

In this study, the surface properties of and work required to remove 12 commercially available and developmental catheters from a model biological medium (agar), a measure of catheter lubricity, were characterised and the relationships between these properties were examined using multiple regression and correlation analysis. The work required for removal of catheter sections (7 cm) from a model biological medium (1% w/w agar) were examined using tensile analysis. The water wettability of the catheters were characterised using dynamic contact angle analysis, whereas surface roughness was determined using atomic force microscopy. Significant differences in the ease of removal were observed between the various catheters, with the silicone-based materials generally exhibiting the greatest ease of removal. Similarly, the catheters exhibited a range of advancing and receding contact angles that were dependent on the chemical nature of each catheter. Finally, whilst the microrugosities of the various catheters differed, no specific relationship to the chemical nature of the biomaterial was apparent. Using multiple regression analysis, the relationship between ease of removal, receding contact angle and surface roughness was defined as: Work done (N mm) 17.18 + 0.055 Rugosity (nm)-0.52 Receding contact angle (degrees) (r = 0.49). Interestingly, whilst the relationship between ease of removal and surface roughness was significant (r = 0.48, p = 0.0005), in which catheter lubricity increased as the surface roughness decreased, this was not the case with the relationship between ease of removal and receding contact angle (r = -0.18, p > 0.05). This study has therefore uniquely defined the contributions of each of these surface properties to catheter lubricity. Accordingly, in the design of urethral catheters. it is recommended that due consideration should be directed towards biomaterial surface roughness to ensure maximal ease of catheter removal. Furthermore, using the method described in this study, differences in the lubricity of the various catheters were observed that may be apparent in their clinical use. (C) 2003 Elsevier Ltd. All rights reserved.

Cartographic veracity in medieval mapping: analyzing geographical variation in the Gough Map of Great Britain

This article explores statistical approaches for assessing the relative accuracy of medieval mapping. It focuses on one particular map, the Gough Map of Great Britain. This is an early and remarkable example of a medieval “national” map covering Plantagenet Britain. Conventionally dated to c. 1360, the map shows the position of places in and coastal outline of Great Britain to a considerable degree of spatial accuracy. In this article, aspects of the map's content are subjected to a systematic analysis to identify geographical variations in the map's veracity, or truthfulness. It thus contributes to debates among historical geographers and cartographic historians on the nature of medieval maps and mapping and, in particular, questions of their distortion of geographic space. Based on a newly developed digital version of the Gough Map, several regression-based approaches are used here to explore the degree and nature of spatial distortion in the Gough Map. This demonstrates that not only are there marked variations in the positional accuracy of places shown on the map between regions (i.e., England, Scotland, and Wales), but there are also fine-scale geographical variations in the spatial accuracy of the map within these regions. The article concludes by suggesting that the map was constructed using a range of sources, and that the Gough Map is a composite of multiscale representations of places in Great Britain. The article details a set of approaches that could be transferred to other contexts and add value to historic maps by enhancing understanding of their contents.

Improved fault diagnosis in multivariate systems using regression-based reconstruction

Subspace monitoring has recently been proposed as a condition monitoring tool that requires considerably fewer variables to be analysed compared to dynamic principal component analysis (PCA). This paper analyses subspace monitoring in identifying and isolating fault conditions, which reveals that the existing work suffers from inherent limitations if complex fault senarios arise. Based on the assumption that the fault signature is deterministic while the monitored variables are stochastic, the paper introduces a regression-based reconstruction technique to overcome these limitations. The utility of the proposed fault identification and isolation method is shown using a simulation example and the analysis of experimental data from an industrial reactive distillation unit.