Glaucoma: the retina and beyond

Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of recent developments in techniques for monitoring RGC health is provided, including recent progress towards the development of RGC specific contrast agents. The review concludes by discussing techniques to assess glaucomatous changes in the brain using MRI and the clinical relevance of glaucomatous-associated changes in the visual centres of the brain

Automatic quantitative analysis of experimental primary and secondary retinal neurodegeneration: implications for optic neuropathies.

Secondary neurodegeneration is thought to play an important role in the pathology of neurodegenerative disease, which potential therapies may target. However, the quantitative assessment of the degree of secondary neurodegeneration is difficult. The present study describes a novel algorithm from which estimates of primary and secondary degeneration are computed using well-established rodent models of partial optic nerve transection (pONT) and ocular hypertension (OHT). Brn3-labelled retinal ganglion cells (RGCs) were identified in whole-retinal mounts from which RGC density, nearest neighbour distances and regularity indices were determined. The spatial distribution and rate of RGC loss were assessed and the percentage of primary and secondary degeneration in each non-overlapping segment was calculated. Mean RGC number (82 592±681) and RGC density (1695±23.3 RGC/mm(2)) in naïve eyes were comparable with previous studies, with an average decline in RGC density of 71±17 and 23±5% over the time course of pONT and OHT models, respectively. Spatial analysis revealed greatest RGC loss in the superior and central retina in pONT, but significant RGC loss in the inferior retina from 3 days post model induction. In comparison, there was no significant difference between superior and inferior retina after OHT induction, and RGC loss occurred mainly along the superior/inferior axis (~30%) versus the nasal-temporal axis (~15%). Intriguingly, a significant loss of RGCs was also observed in contralateral eyes in experimental OHT. In conclusion, a novel algorithm to automatically segment Brn3a-labelled retinal whole-mounts into non-overlapping segments is described, which enables automated spatial and temporal segmentation of RGCs, revealing heterogeneity in the spatial distribution of primary and secondary degenerative processes. This method provides an attractive means to rapidly determine the efficacy of neuroprotective therapies with implications for any neurodegenerative disorder affecting the retina

Conditional Sampling for Max-Stable Processes with a Mixed Moving Maxima Representation

This paper deals with the question of conditional sampling and prediction for the class of stationary max-stable processes which allow for a mixed moving maxima representation. We develop an exact procedure for conditional sampling using the Poisson point process structure of such processes. For explicit calculations we restrict ourselves to the one-dimensional case and use a finite number of shape functions satisfying some regularity conditions. For more general shape functions approximation techniques are presented. Our algorithm is applied to the Smith process and the Brown-Resnick process. Finally, we compare our computational results to other approaches. Here, the algorithm for Gaussian processes with transformed marginals turns out to be surprisingly competitive.Comment: 35 pages; version accepted for publication in Extremes. The final publication is available at http://link.springer.co

Improving the quality of orthopaedic elective and trauma operative notes: A completed audit loop study

Introduction: Good medical practice dictates that comprehensive documentation of all surgical procedures is paramount in maintaining a high standard of patient care. This study audited the quality of operative note keeping for elective and trauma procedures against the standards set by the British Orthopaedic Association (BOA) and The Royal College of Surgeons of England (RCSE) guidelines. Patients and methods: A retrospective assessment of the operative notes of every patient undergoing a total knee and hip replacement (elective cases) was carried out over a period of 2 months. Data recorded were compared against BOA guidelines. Within this time a randomised selection of trauma operative notes were also assessed, and the recorded data were compared against RCSE guidelines. Change in practice was implemented and the audit cycle completed. A total of 173 operative notes were evaluated. Results: There was a significant improvement (p-value < 0.05) in the quality of total knee replacement notes, with an increase in the percentage of data points from 68.6% to 93%. Similarly the quality of total hip replacement notes showed significant improvement (p-value < 0.01) with an increase in the percentage of data points from 67.5% to 86%. However trauma operative notes showed minimal improvement. Discussion: This study showed that the quality of elective operative notes was improved through surgeon education and the circulation of a guideline based electronic operative note. We have further plans to implement procedure specific notes for the most common types of trauma cases to help improve the quality of trauma operative notes

Dog10K: an international sequencing effort to advance studies of canine domestication, phenotypes and health

Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health

Assessing anesthetic activity through modulation of the membrane dipole potential

There is great individual variation in response to general anaesthetics leading to difficulties in optimal dosing and sometimes even accidental awareness during general anaesthesia (AAGA). AAGA is a rare but potentially devastating complication affecting between 0.1% and 2% of patients undergoing surgery. The development of novel, personalised screening techniques to accurately predict a patient's response to GA and the risk of AAGA remains an unmet clinical need. In the present study we demonstrate the principle of using a fluorescent reporter of the membrane dipole potential, di-8-ANEPPs, as a novel method to monitor anaesthetic activity using a well-described inducer/non-inducer pair. The membrane dipole potential has previously been suggested to contribute a novel mechanism of anaesthetic action (Qin et al 1995). We show the fluorescence ratio of di-8-ANEPPs changed in response to physiological concentrations of the anaesthetic 1-chloro-1,2,2-trifluorocyclobutane (F3) but not the structurally similar non-inducer 1,2-dichlorohexafluorocyclobutane (F6) to artificial membranes and in vitro retinal cell systems. Modulation of the membrane dipole provides an explanation to overcome limitations associated with alternative membrane-mediated mechanisms of GA action. Furthermore, by combining this technique with non-invasive retinal imaging technologies, we propose this technique could provide a novel and non-invasive technique to monitor GA susceptibility and identify patients at risk of AAGA

Glaucoma Rose Plot Analysis: detecting early structural progression using angular histograms

Purpose To evaluate the novel Rose Plot Analysis (RPA) in the analysis and presentation of glaucoma structural progression data. Design Case-control image analysis study using retrospective retinal imaging series. Subjects Subjects with open-angle glaucoma with at least 5 registered spectral-domain OCT scans. Methods Glaucoma RPA was developed, combining a novel application of angular histograms and dynamic cluster analysis of circumpapillary retinal nerve fiber layer (cRNFL) OCT data. Rose Plot Analysis plots were created for each eye and each visit. Significant clusters of progression were indicated in red. Three masked clinicians categorized all RPA plots (progressing, not progressing), in addition to measuring the significant RPA area. A masked OCT series assessment with linear regression of averaged global and sectoral cRNFL thicknesses was conducted as the clinical imaging standard. Main Outcome Measures Interobserver agreement was compared between RPA and the clinical imaging standard. Discriminative ability was assessed using receiver-operating characteristic curves. The time to detection of progression was compared using a Kaplan–Meier survival analysis, and the agreement of RPA with the clinical imaging standard was calculated. Results Seven hundred fourty-three scans from 98 eyes were included. Interobserver agreement was significantly greater when categorizing RPA (κ, 0.86; 95% confidence interval [CI], 0.81–0.91) compared with OCT image series (κ, 0.66; 95% CI, 0.54–0.77). The discriminative power of RPA to differentiate between eyes that were progressing and not progressing (area under the curve [AUC], 0.97; 95% CI, 0.92–1.00) was greater than that of global cRNFL thickness (AUC, 0.71; 95% CI, 0.59–0.82; P < 0.0001) and equivalent to that of sectoral cRNFL regression (AUC, 0.97; 95% CI, 0.92–1.00). A Kaplan–Meier survival analysis showed that progression was detected 8.7 months sooner by RPA than by global cRNFL linear regression (P < 0.0001) in progressing eyes but was not sooner than with sectoral cRNFL (P = 0.06). Rose Plot Analysis showed substantial agreement with the presence of significant thinning on sectoral cRNFL linear regression (κ, 0.715; 95% CI, 0.578–0.853). Conclusions Rose Plot Analysis has been shown to provide accurate and intuitive, at-a-glance data analysis and presentation that improve interobserver agreement and may aid early diagnosis of glaucomatous disease progression