The Plight of the Metabolite: Oxidative Stress and Tear Film Destabilisation Evident in Ocular Allergy Sufferers across Seasons in Victoria, Australia.

Ocular allergy (OA) is characterised by ocular surface itchiness, redness, and inflammation in response to allergen exposure. The primary aim of this study was to assess differences in the human tear metabolome and lipidome between OA and healthy controls (HCs) across peak allergy (spring-summer) and off-peak (autumn-winter) seasons in Victoria, Australia. A total of 19 participants (14 OA, 5 HCs) aged 18-45 were recruited and grouped by allergy questionnaire score. Metabolites and lipids from tear samples were analysed using mass spectrometry. Data were analysed using TraceFinder and Metaboanalyst. Metabolomics analysis showed 12 differentially expressed (DE) metabolites between those with OA and the HCs during the peak allergy season, and 24 DE metabolites were found in the off-peak season. The expression of niacinamide was upregulated in OA sufferers vs. HCs across both seasons (p ≤ 0.05). A total of 6 DE lipids were DE between those with OA and the HCs during the peak season, and 24 were DE in the off-peak season. Dysregulated metabolites affected oxidative stress, inflammation, and homeostasis across seasons, suggesting a link between OA-associated itch and ocular surface damage via eye rubbing. Tear lipidome changes were minimal between but suggested tear film destabilisation and thinning. Such metabolipodome findings may pave new and exciting ways for effective diagnostics and therapeutics for OA sufferers in the future.

Anterior segment optical coherence tomography meibography compared with keratograph meibography.

PURPOSE: The aim of this study was to determine the feasibility of using readily accessible technology, anterior segment optical coherence tomography (AS-OCT), to detect and grade meibomian gland dropout and examine its interchangeability with the Oculus Keratograph 5M (K5M). METHODS: A total of 30 participants (30 eyes) with a median age of 21 (range = 19-28 years) were recruited. Meibography was performed using two commercially available imaging devices to look at the structure of the meibomian glands and grade them subjectively in real time, and image analysis was used to quantify meibomian gland loss objectively. Gland loss as imaged by the two techniques was graded using the meiboscore grading schema. Test-retest reliability was determined with intraclass correlation coefficients (ICCs). Weighted kappa was used to evaluate agreement between the two imaging devices and four methods of image analysis. Spearman and Pearson correlation coefficients were used to determine the association of structural measurements between each of the techniques. The agreement between the two imaging techniques was determined with the Bland-Altman analysis. RESULTS: Reliability of subjective grading was strong for AS-OCT (ICC: 0.92, 95% CI: 0.83-0.96, p < 0.001) and K5M (ICC: 0.96, 95% CI: 0.96-0.91, p = 0.001). Image analysis with ImageJ reliability was strong between the imaging devices (ICC: 0.84, 95% CI: 0.55-0.94, p < 0.001). Agreement between each subjective technique was fair, κ = 0.45 (95% CI: 0.17-0.73, p < 0.001) and a positive Spearman correlation was also observed (r = 0.52, p < 0.001). There was no significant difference between the mean meibomian gland loss measured with ImageJ between AS-OCT and K5M (0.92 ± 6.28, p = 0.26). The 95% limits of agreement were -12.45% to +14.04%. CONCLUSION: These findings suggest subjective real-time grading of meibomian gland loss could be performed using readily available AS-OCT technology and that this method was interchangeable with the K5M.

Virtual simulated international placements as an innovation for internationalisation in undergraduate programs: a mixed methods study.

BACKGROUND: Inherent features in virtual simulation could be utilised to deliver collaborative global education that is inclusive, accessible, and valued by students and facilitators. The aim of this study was to evaluate the impact of the International Eyecare Community (IEC) platform's virtual simulated international placements (VSIP) in optometric education. METHODS: An international, multi-center, cross-sectional mixed methods study with Deakin University, Australia, and the Elite School of Optometry, India, was used to evaluate the impact of VSIP in the IEC using pre-existing deidentified data collected from teaching and learning activities within the optometry course curriculum. Data on students and facilitators perceptions of the VSIP were collected through deidentified transcripts from focus group discussions. The data were interpreted using descriptive statistics and qualitative analysis using constant comparison for thematic analysis. RESULTS: A total of 64 out of 167 student participants completed survey responses (39%) and 46 out of 167 (28%) completed self-reflective inventories. Focus groups with 6 student participants and 6 facilitator participants were recorded and analysed. Student participants reported the IEC was relevant (98% agreement) and motivated them to apply theoretical knowledge to a clinical context (97% agreement). The themes identified through qualitative analysis were: factors inherent to the virtual simulation that enabled learning through VSIP, the VSIP supported cognitive apprenticeship, VSIP enabled clinical learning for optometric education, VSIP' role in cross-cultural professional identity development in optometry students. CONCLUSION: The study found that the VSIP platform helped to motivate students to learn and improve their clinical skills. The VSIP was considered a potential supplement to physical clinical placements and could revolutionize global optometric education by offering co-learning across cultures.

The Open Perimetry Initiative: A framework for cross-platform development for the new generation of portable perimeters.

The Open Perimetry Initiative was formed in 2010 with the aim of reducing barriers to clinical research with visual fields and perimetry. Our two principal tools are the Open Perimetry Interface (OPI) and the visualFields package with analytical tools. Both are fully open source. The OPI package contains a growing number of drivers for commercially available perimeters, head-mounted devices, and virtual reality headsets. The visualFields package contains tools for the analysis and visualization of visual field data, including methods to compute deviation values and probability maps. We introduce a new frontend, the opiApp, that provides tools for customization for visual field testing and can be used as a frontend to run the OPI. The app can be used on the Octopus 900 (Haag-Streit), the Compass (iCare), the AP 7000 (Kowa), and the IMO (CREWT) perimeters, with permission from the device manufacturers. The app can also be used on Android phones with virtual reality headsets via a new driver interface, the PhoneHMD, implemented on the OPI. The use of the tools provided by the OPI library is showcased with a custom static automated perimetry test for the full visual field (up to 50 degrees nasally and 80 degrees temporally) developed with the OPI driver for the Octopus 900 and using visualFields for statistical analysis. With more than 60 citations in clinical and translational science journals, this initiative has contributed significantly to expand research in perimetry. The continued support of researchers, clinicians, and industry are key in transforming perimetry research into an open science.

A Review of Emerging Tear Proteomics Research on the Ocular Surface in Ocular Allergy.

Ocular allergy is an immunoglobulin E-mediated Type I hypersensitivity reaction localised to the ocular surface and surrounding tissues. Primary signs and symptoms of ocular allergy include itching, redness, irritation and inflammation. Eye-rubbing caused by itching has been shown to alter ocular surface protein concentrations in conditions linked to ocular allergy such as keratoconus. In keratoconus, the cornea begins to thin and sag over time, leading to progressive vision loss and blindness in severe conditions. Due to the high incidence of ocular allergy sufferers rubbing their eyes in response to symptoms of itching, the protein landscape of the ocular surface may be significantly altered. Differential protein expression caused by long-term inflammation and eye-rubbing may lead to subsequent changes in ocular surface structure and function over time. This review aims to summarise and explore the findings of current ocular allergy proteome research conducted using techniques such as gel electrophoresis, mass spectrometry and lab-on-a-chip proteomics. Proteins of interest for this review include differentially expressed immunoglobulins, mucins, functional proteins, enzymes and proteins with previously uncharacterised roles in ocular allergy. Additionally, potential applications of this research are addressed in terms of diagnostics, drug development and future research prospects.

Entrapment of diagnostic catheter within Advisor HD grid mapping catheter.

The potential for catheter entanglement with the HD Grid mapping catheter is explicitly stated in the manufacturer's product manual. A case of an entrapped 6 French quadripolar diagnostic catheter within an HD Grid mapping catheter is presented. We discuss the diagnosis, management, and resolution of this complication in our patient. The patient's arrhythmia was successfully eliminated, and no vascular complication in the postprocedural setting nor arrhythmia recurrence at follow-up were observed. Strategies to prevent and safely manage this complication, while salvaging access, are also discussed.

Temporal Wedge Defects in Glaucoma: Structure/Function Correlation With Threshold Automated Perimetry of the Full Visual Field.

PRECIS: We used the Open Perimetry Interface (OPI) to design a static automated perimetry test of the full visual field. About half of our glaucoma cohort had defects in the far peripheral inferotemporal visual field that correlate well with related damage to the superior nasal optic disc. AIMS: To test the hypothesis that in glaucoma patients with mild visual loss, perimetric nerve fiber bundle defects present outside 30 degrees will correlate well with areas of Cirrus ocular coherence tomography (OCT) retinal nerve fiber layer thinning. METHODS: We tested 27 consecutive glaucoma subjects with mild vision loss (mean deviation better than -4 dB) with a SITA standard test, 2 size V custom OPI tests (OPI 30-2 and OPI Peripheral) and Cirrus OCT. Two observers assigned qualitative grades to each type of visual field test based on their level of correlation with OCT retinal nerve fiber layer and ganglion cell thickness. RESULTS: Discrete temporal wedge defects were found on the OPI peripheral V test in 26% of cases whereas more extensive inferior temporal loss (including inferior temporal wedge defect region) was present in 22% of other cases. OCT data correlated best with the OPI peripheral test for 8 glaucoma subjects. The OPI central 30-2 test correlated best for 9 glaucoma subjects; the remainder of subjects had equal central/peripheral correlations. CONCLUSIONS: About half of our glaucoma cohort have defects in the far peripheral inferotemporal visual field that correlate well with related damage to the superior nasal optic disc. Adding a threshold automated perimetry test of the far periphery improves structure/function correlations and adds useful clinical information.

Threshold Automated Perimetry of the Full Visual Field in Patients With Glaucoma With Mild Visual Loss.

PRECIS: The authors used the Open Perimetry Interface to design a static automated perimetry test of the full field. Abnormal test locations in the nasal midperiphery and temporal inferior sector area best separated glaucomas from normals. PURPOSE: The peripheral visual field in glaucoma outside 30 degrees is largely unexplored with static perimetry. Their goal was to use threshold static automated perimetry to characterize the visual loss in glaucoma of the central 30 degrees and the far periphery. PATIENTS AND METHODS: The authors administered the 30-2 perimetric test to 27 patients with early stage glaucoma (with mean deviation better than -4 dB) with the Goldmann III and V stimulus sizes and a custom test from 30 to up to 87 degrees with the size V stimulus twice within a month. The authors quantified (1) the retest variability, (2) the proportion of patients flagged as abnormal (at level 0.05) on the basis of pointwise probability distributions obtained from 63 ocular healthy observers, (3) the pointwise statistical distance using the Kullback-Leibler divergence between normal and glaucoma eyes, and (4) the effect of eccentricity on visual loss. RESULTS: Size V 30-2 testing identified significantly more abnormal test locations (36%) than size III 30-2 (30%; P=0.004). Kullback-Leibler divergence between healthy and glaucoma distributions was greatest for the nasal midperipheral test locations and the inferior temporal sector area. A more pronounced decrease was found in visual sensitivity with eccentricity in the patients with glaucoma compared with the ocular healthy participants across the full visual field (P<0.001). CONCLUSIONS: Patients with glaucoma demonstrate a systematic decrease in sensitivity with eccentricity across the full visual field. Goldmann size V stimuli better detected visual loss in patients with glaucoma with mild loss than size III.

Threshold Static Automated Perimetry of the Full Visual Field in Idiopathic Intracranial Hypertension.

Purpose: To characterize visual loss across the full visual field in idiopathic intracranial hypertension (IIH) patients with mild central visual loss. Methods: We tested the full visual field (50° nasal, 80° temporal, 30° superior, 45° inferior) of 1 eye of 39 IIH patients by using static perimetry (size V) with the Open Perimetry Interface. Participants met the Dandy criteria for IIH and had at least Frisén grade 1 papilledema with better than -5 dB mean deviation (MD) centrally. Two observers (MW and AS) evaluated the visual field defects, adjudicated any differences, and reviewed optical coherence tomography data. Results: We found a greater MD loss peripherally than centrally (central 26°). The median MD (and corresponding median absolute deviations) was -1.37 dB (1.61 dB) for the periphery and -0.77 dB (0.87 dB) for the central 26°, P < 0.001. There were about 30% more abnormal test locations identified in the periphery (P = 0.12), and the mean defect depth increased with eccentricity (P < 0.001). The most frequent defect found was a temporal wedge (23% of cases) in the periphery with another 23% that included this sector with inferior temporal loss. Although the presence of papilledema limited correlation, 55% of the temporal wedge defects had optical coherence tomography retinal nerve fiber layer deficits in the corresponding superonasal location. Other common visual field defects were inferonasal loss, superonasal loss, and superior and inferior arcuate defects. Seven patients (18%) had visual field defects in the periphery with normal central visual field testing. Conclusion: In IIH patients, we found substantial visual loss both outside 30° of the visual field and inside 30° with the depth of the defect increasing linearly with eccentricity. Temporal wedge defects were the most common visual field defect in the periphery. Static threshold perimetry of the full visual field appears to be clinically useful in IIH patients.

A New SITA Perimetric Threshold Testing Algorithm: Construction and a Multicenter Clinical Study.

PURPOSE: To describe a new time-saving threshold visual field-testing strategy-Swedish Interactive Thresholding Algorithm (SITA) Faster, which is intended to replace SITA Fast-and to report on a clinical evaluation of this new strategy. DESIGN: Description and validity analysis for modifications applied to SITA Fast. METHODS: Five centers tested 1 eye of each of 126 glaucoma and glaucoma suspect patients with SITA Faster, SITA Fast, and SITA Standard at each of 2 visits. Outcomes included test time, mean deviation, and the visual field index (VFI), significant test points in probability maps, and intertest threshold variability. RESULTS: Mean (standard deviation) test times were 171.9 (45.3) seconds for SITA Faster, 247.0 (56.7) for SITA Fast, and 369.5 (64.5) for SITA Standard (P < .001). SITA Faster test times averaged 30.4 % shorter than SITA Fast and 53.5 % shorter than SITA Standard. Mean deviation was similar among all 3 tests.VFI did not differ between SITA Fast and SITA Faster tests, mean difference 0%, but VFI values were 1.2% lower with SITA Standard compared to both SITA Fast (P = .007) and SITA Faster (P = .002). A similar trend was seen with a slightly higher number of significant test points with SITA Standard than with SITA Fast and SITA Faster. All 3 tests had similar test-retest variability over the entire range of threshold values. CONCLUSIONS: SITA Faster saved considerable test time. SITA Faster and SITA Fast gave almost identical results. There were small differences between SITA Faster and SITA Standard, of the same character as previously shown for SITA Fast vs SITA Standard.

Data obtained with an open-source static automated perimetry test of the full visual field in healthy adults.

The data were gathered from 98 eyes of 98 ocular healthy subjects. The subject ages ranged from 18 to 79 years with a mean (and standard deviation) of 47 (17) years. Each subject underwent two visual field tests, one of the central visual field (64 locations within 26° of fixation) and one of the peripheral visual field (64 locations with eccentricity from 26° to up to 81°). Luminance thresholds for the Goldmann size V stimulus (with a diameter of 1.72° of visual angle) were obtained with the ZEST Bayesian test procedure. Each test was conducted twice within 90 days.

Milrinone Dosing and a Culture of Caution in Clinical Practice.

Milrinone is an invaluable agent in the treatment of end-stage heart failure patients who are refractory to optimal medical therapy. In addition to its use in acute decompensated heart failure, milrinone can also be employed as a home infusion therapy or a bridge to cardiac transplant. Concerns about its adverse effects, such as an increased risk of arrhythmias and hypotension, often limit the doses of milrinone used in clinical practice. In addition, milrinone is infrequently used or avoided entirely in patients with acute renal failure or end-stage renal disease because the drug is primarily cleared by renal excretion. Despite these concerns, studies that comprehensively reconcile the dose-response relationship and adverse events are scarce, and no clear provisions exist to guide milrinone dosing. After a brief discussion of the pharmacokinetics of milrinone, this article examines milrinone dosing, observed hemodynamic benefits, and documented adverse events across different studies.

Assessing the GOANNA Visual Field Algorithm Using Artificial Scotoma Generation on Human Observers.

PURPOSE: To validate the performance of a new perimetric algorithm (Gradient-Oriented Automated Natural Neighbor Approach; GOANNA) in humans using a novel combination of computer simulation and human testing, which we call Artificial Scotoma Generation (ASG). METHODS: Fifteen healthy observers were recruited. Baseline conventional automated perimetry was performed on the Octopus 900. Visual field sensitivity was measured using two different procedures: GOANNA and Zippy Estimation by Sequential Testing (ZEST). Four different scotoma types were induced in each observer by implementing a novel technique that inserts a step between the algorithm and the perimeter, which in turn alters presentation levels to simulate scotomata in human observers. Accuracy, precision, and unique number of locations tested were measured, with the maximum difference between a location and its neighbors (Max_d) used to stratify results. RESULTS: GOANNA sampled significantly more locations than ZEST (paired t-test, P < 0.001), while maintaining comparable test times. Difference plots showed that GOANNA displayed greater accuracy than ZEST when Max_d was in the 10 to 30 dB range (with the exception of Max_d = 20 dB; Wilcoxon, P < 0.001). Similarly, GOANNA demonstrated greater precision than ZEST when Max_d was in the 20 to 30 dB range (Wilcoxon, P < 0.001). CONCLUSIONS: We have introduced a novel method for assessing accuracy of perimetric algorithms in human observers. Results observed in the current study agreed with the results seen in earlier simulation studies, and thus provide support for performing larger scale clinical trials with GOANNA in the future. TRANSLATIONAL RELEVANCE: The GOANNA perimetric testing algorithm offers a new paradigm for visual field testing where locations for testing are chosen that target scotoma borders. Further, the ASG methodology used in this paper to assess GOANNA shows promise as a hybrid between computer simulation and patient testing, which may allow more rapid development of new perimetric approaches.

Targeted spatial sampling using GOANNA improves detection of visual field progression.

PURPOSE: A new automated visual field testing approach that samples scotoma edges at a finer spatial resolution, GOANNA (Gradient-Oriented Automated Natural Neighbour Approach) was previously shown to improve accuracy and precision around those regions compared to current procedures in computer simulation. The purpose of this study was to observe if this improvement translated to more accurate classification of glaucomatous progression. METHODS: Computer simulations were undertaken on six procedures: three variants of GOANNA on 150 locations; two variants of ZEST on 52 locations; and the ideal case where true thresholds are perfectly measured. The median number of presentations of GOANNA was matched to ZEST. The procedures were run on 156 sequences of simulated progressing fields and 156 sequences of stable fields to determine sensitivity and specificity using point-wise linear regression. Reliable (0% FP, 0% FN) and typical false positive (15% FP, 3% FN) response error conditions were investigated. Area under ROC curves (AUC) were plotted against the number of visual fields acquired to evaluate the performance of these procedures. RESULTS: The GOANNA framework exhibited equal or greater AUC than ZEST at all visits when baseline fields were initially defective (under both response error conditions) and when baseline fields were initially healthy when no false responses were made. Retest implementations of GOANNA exhibited an improvement over the original GOANNA after the first seven visits when fields were initially healthy. CONCLUSION: The results suggest that the improvement in precision and accuracy around scotoma borders seen in the GOANNA framework translates to earlier and more accurate detection of progressing fields compared with ZEST, especially in the early stages of glaucomatous progression.

Customized, automated stimulus location choice for assessment of visual field defects.

PURPOSE: To introduce a perimetric algorithm (gradient-oriented automated natural neighbor approach [GOANNA]) that automatically chooses spatial test locations to improve characterization of visual field (VF) loss without increasing test times. METHODS: Computer simulations were undertaken to assess the performance of GOANNA. GOANNA was run on a 3° grid of 150 locations, and was compared with a zippy estimation by sequential testing (ZEST) thresholding strategy for locations in the 24-2 test pattern, with the remaining 98 locations being interpolated. Simulations were seeded using empirical data from 23 eyes with glaucoma that were measured at all 150 locations. The performance of the procedures was assessed by comparing the output thresholds to the input thresholds (accuracy and precision) and by evaluating the number of presentations required for the procedure to terminate (efficiency). RESULTS: When collated across whole-fields, there was no significant difference in accuracy, precision, or efficiency between GOANNA and ZEST. However, GOANNA targeted presentations on scotoma borders; hence it was more precise and accurate at locations where the sensitivity gradient within the VF was high. CONCLUSIONS: Compared with ZEST, GOANNA was marginally less precise in areas of the VF that had spatially uniform sensitivity, but improved accuracy and precision in regions surrounding scotoma edges. GOANNA provides a principled framework for automatic placement of additional test locations to provide spatially denser testing around the borders of VF loss.

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer.

Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34ßE12) and EGFR in 699 triple-negative invasive breast cancers in tissue microarrays using the streptavidin-biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34ßE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor-positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498-0.994; P=0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468-0.974; P=0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed.