Effects of slit lamp-delivered retinal laser photobiomodulation in a rat model of choroidal neovascularization.

Neovascular age-related macular degeneration, also known as exudative or wet age-related macular degeneration, is the leading cause of blindness in the developed world. Photobiomodulation has the potential to target the up-stream hypoxic and pro-inflammatory drivers of choroidal neovascularization. This study investigated whether photobiomodulation attenuates characteristic pathological features of choroidal neovascularization in a rodent model. Experimental choroidal neovascularization was induced in Brown Norway rats with laser photocoagulation. A custom-designed, slit-lamp-mounted, 670 nm laser was used to administer retinal photobiomodulation every 3 days, beginning 6 days prior to choroidal neovascularization induction and continuing until the animals were killed 14 days later. The effect of photobiomodulation on the size of choroidal neovascular membranes was determined using isolectin-B4 immunohistochemistry and spectral domain-optical coherence tomography. Vascular leakage was determined with fluorescein angiography. The effect of treatment on levels of vascular endothelial growth factor expression was quantified with enzyme-linked immunosorbent assay. Treatment with photobiomodulation was associated with choroidal neovascular membranes that were smaller, had less fluorescein leakage, and a diminished presence of inflammatory cells as compared to sham eyes. These effects were not associated with a statistically significant difference in the level of vascular endothelial growth factor when compared to sham eyes. The data shown herein indicate that photobiomodulation attenuates pathological features of choroidal neovascularization in a rodent model by mechanisms that may be independent of vascular endothelial growth factor.

A 12-year follow up survey of childhood blindness at schools for the blind in Cambodia.

BACKGROUND: Cambodia is a low-income country in South East Asia with a population of 15.5 million people of whom 4.9 million (38%) are under the age of 16. The causes of childhood blindness in Cambodia have not been investigated since the first survey of schools for the blind done in 2009 by our group. Given the large demographic and economic shifts in Cambodia since 2009 it is important to determine if these causes have changed in order to ensure intervention programmes are appropriately targeted. The purpose of the present study is to investigate the prevalence of causes of childhood blindness at schools for the blind in Cambodia. METHODS: Students between the ages of 5 and 16 years who were attending schools for the blind in Cambodia were examined by a consultant paediatric ophthalmologist and had clinical photographs taken. Distance visual acuity was measured using a logMAR tumbling E chart and the WHO definitions of blindness and severe visual impairment were used. The examining ophthalmologist recorded the anatomical site and aetiology of vision loss using the WHO Prevention of Blindness eye examination record for children. Collected data were compared to a previous survey from 2009. RESULTS: Data from 73 students were included for analysis. The most common anatomical location of abnormality causing vision loss was the cornea (n = 20, 33.9%) followed by the lens and retina (n = 11, 18.64% each). Hereditary factors (n = 29, 49.15%) and childhood diseases (n = 27, 45.76%) were the most common aetiological causes of childhood blindness. The majority (71.19%) of childhood blindness was avoidable. The present study did not demonstrate 0a significant difference in the causes of childhood blindness compared to 2009. CONCLUSIONS: Corneal pathologies continue to represent the most common cause of vision loss amongst the surveyed population and the majority of causes of childhood blindness continue to be avoidable. These findings will facilitate the development of evidence-based targeted interventional programmes in Cambodia.

Building the workforce of tomorrow: The weighting of rural exposure in standardised curriculum vitae scoring criteria for entrance into Australian specialty training programs.

OBJECTIVE: To determine the weighting of rural exposure within publicly available standardised curriculum vitae (CV) scoring criteria for trainee medical officer's applying into medical and surgical specialty training programs in Australia and New Zealand. METHODS/DESIGN: An observational analysis of rural exposure point allocations within publicly available standardised CV scoring criteria for entrance into specialty training programs. SETTING: All Australian and New Zealand medical and surgical specialties training programs outlined by the Australian Health Practitioner Regulation Agency (AHPRA) who publish publicly available standardised CV scoring criteria for entrance into specialty training were included. RESULTS: Of the 14 specialty training programs that publish publicly available standardised CV scoring criteria, 8/14 allocate points towards rural exposure. While the allocation of points within this scoring domain varies between the eight training programs, the mean weighting of rural exposure is 13.7%. CONCLUSIONS: The relative weighting of rural exposure varies between the eight specialty training programs who include rural exposure as a CV scoring criteria. The deliberate and strategic construction of CV scoring criteria and inclusion of rural exposure points is important to continue developing the Australian rural specialist workforce. Future development of standardised CV scoring criteria should continue to consider point allocation towards rural exposure and related activities to ensure that the requirements of rural Australian healthcare needs are met across medical and surgical specialties.

High Polygenic Risk Is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open-Angle Glaucoma.

PURPOSE: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. METHODS: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment. MAIN OUTCOME MEASURES: Commencement or escalation of IOP-lowering therapy. RESULTS: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001). CONCLUSIONS: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A case study in applying artificial intelligence-based named entity recognition to develop an automated ophthalmic disease registry.

PURPOSE: Advances in artificial intelligence (AI)-based named entity extraction (NER) have improved the ability to extract diagnostic entities from unstructured, narrative, free-text data in electronic health records. However, there is a lack of ready-to-use tools and workflows to encourage the use among clinicians who often lack experience and training in AI. We sought to demonstrate a case study for developing an automated registry of ophthalmic diseases accompanied by a ready-to-use low-code tool for clinicians. METHODS: We extracted deidentified electronic clinical records from a single centre's adult outpatient ophthalmology clinic from November 2019 to May 2022. We used a low-code annotation software tool (Prodigy) to annotate diagnoses and train a bespoke spaCy NER model to extract diagnoses and create an ophthalmic disease registry. RESULTS: A total of 123,194 diagnostic entities were extracted from 33,455 clinical records. After decapitalisation and removal of non-alphanumeric characters, there were 5070 distinct extracted diagnostic entities. The NER model achieved a precision of 0.8157, recall of 0.8099, and F score of 0.8128. CONCLUSION: We presented a case study using low-code artificial intelligence-based NLP tools to produce an automated ophthalmic disease registry. The workflow created a NER model with a moderate overall ability to extract diagnoses from free-text electronic clinical records. We have produced a ready-to-use tool for clinicians to implement this low-code workflow in their institutions and encourage the uptake of artificial intelligence methods for case finding in electronic health records.

Ophthalmology Operation Note Encoding with Open-Source Machine Learning and Natural Language Processing.

INTRODUCTION: Accurate assignment of procedural codes has important medico-legal, academic, and economic purposes for healthcare providers. Procedural coding requires accurate documentation and exhaustive manual labour to interpret complex operation notes. Ophthalmology operation notes are highly specialised making the process time-consuming and challenging to implement. This study aimed to develop natural language processing (NLP) models trained by medical professionals to assign procedural codes based on the surgical report. The automation and accuracy of these models can reduce burden on healthcare providers and generate reimbursements that reflect the operation performed. METHODS: A retrospective analysis of ophthalmological operation notes from two metropolitan hospitals over a 12-month period was conducted. Procedural codes according to the Medicare Benefits Schedule (MBS) were applied. XGBoost, decision tree, Bidirectional Encoder Representations from Transformers (BERT) and logistic regression models were developed for classification experiments. Experiments involved both multi-label and binary classification, and the best performing model was used on the holdout test dataset. RESULTS: There were 1,000 operation notes included in the study. Following manual review, the five most common procedures were cataract surgery (374 cases), vitrectomy (298 cases), laser therapy (149 cases), trabeculectomy (56 cases), and intravitreal injections (49 cases). Across the entire dataset, current coding was correct in 53.9% of cases. The BERT model had the highest classification accuracy (88.0%) in the multi-label classification on these five procedures. The total reimbursement achieved by the machine learning algorithm was $184,689.45 ($923.45 per case) compared with the gold standard of $214,527.50 ($1,072.64 per case). CONCLUSION: Our study demonstrates accurate classification of ophthalmic operation notes into MBS coding categories with NLP technology. Combining human and machine-led approaches involves using NLP to screen operation notes to code procedures, with human review for further scrutiny. This technology can allow the assignment of correct MBS codes with greater accuracy. Further research and application in this area can facilitate accurate logging of unit activity, leading to reimbursements for healthcare providers. Increased accuracy of procedural coding can play an important role in training and education, study of disease epidemiology and improve research ways to optimise patient outcomes.

Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin.

Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.

Optimising vitrectomy operation note coding with machine learning.

BACKGROUND: The accurate encoding of operation notes is essential for activity-based funding and workforce planning. The aim of this project was to evaluate the procedural coding accuracy of vitrectomy and to develop machine learning, natural language processing (NLP) models that may assist with this task. METHODS: This retrospective cohort study involved vitrectomy operation notes between a 21-month period at the Royal Adelaide Hospital. Coding of procedures were based on the Medicare Benefits Schedule (MBS)-the Australian equivalent to the Current Procedural Terminology (CPT®) codes used in the United States. Manual encoding was conducted for all procedures and reviewed by two vitreoretinal consultants. XGBoost, random forest and logistic regression models were developed for classification experiments. A cost-based analysis was subsequently conducted. RESULTS: There were a total of 1724 procedures with individual codes performed within 617 vitrectomy operation notes totalling $1 528 086.60 after manual review. A total of 1147 (66.5%) codes were missed in the original coding that amounted to $736 539.20 (48.2%). Our XGBoost model had the highest classification accuracy (94.6%) in the multi-label classification for the five most common procedures. The XGBoost model was the most successful model in identifying operation notes with two or more missing codes with an AUC of 0.87 (95% CI 0.80-0.92). CONCLUSIONS: Machine learning has been successful in the classification of vitrectomy operation note encoding. We recommend a combined human and machine learning approach to clinical coding as automation may facilitate more accurate reimbursement and enable surgeons to prioritise higher quality clinical care.

Evaluating the Ability of Open-Source Artificial Intelligence to Predict Accepting-Journal Impact Factor and Eigenfactor Score Using Academic Article Abstracts: Cross-sectional Machine Learning Analysis.

BACKGROUND: Strategies to improve the selection of appropriate target journals may reduce delays in disseminating research results. Machine learning is increasingly used in content-based recommender algorithms to guide journal submissions for academic articles. OBJECTIVE: We sought to evaluate the performance of open-source artificial intelligence to predict the impact factor or Eigenfactor score tertile using academic article abstracts. METHODS: PubMed-indexed articles published between 2016 and 2021 were identified with the Medical Subject Headings (MeSH) terms "ophthalmology," "radiology," and "neurology." Journals, titles, abstracts, author lists, and MeSH terms were collected. Journal impact factor and Eigenfactor scores were sourced from the 2020 Clarivate Journal Citation Report. The journals included in the study were allocated percentile ranks based on impact factor and Eigenfactor scores, compared with other journals that released publications in the same year. All abstracts were preprocessed, which included the removal of the abstract structure, and combined with titles, authors, and MeSH terms as a single input. The input data underwent preprocessing with the inbuilt ktrain Bidirectional Encoder Representations from Transformers (BERT) preprocessing library before analysis with BERT. Before use for logistic regression and XGBoost models, the input data underwent punctuation removal, negation detection, stemming, and conversion into a term frequency-inverse document frequency array. Following this preprocessing, data were randomly split into training and testing data sets with a 3:1 train:test ratio. Models were developed to predict whether a given article would be published in a first, second, or third tertile journal (0-33rd centile, 34th-66th centile, or 67th-100th centile), as ranked either by impact factor or Eigenfactor score. BERT, XGBoost, and logistic regression models were developed on the training data set before evaluation on the hold-out test data set. The primary outcome was overall classification accuracy for the best-performing model in the prediction of accepting journal impact factor tertile. RESULTS: There were 10,813 articles from 382 unique journals. The median impact factor and Eigenfactor score were 2.117 (IQR 1.102-2.622) and 0.00247 (IQR 0.00105-0.03), respectively. The BERT model achieved the highest impact factor tertile classification accuracy of 75.0%, followed by an accuracy of 71.6% for XGBoost and 65.4% for logistic regression. Similarly, BERT achieved the highest Eigenfactor score tertile classification accuracy of 73.6%, followed by an accuracy of 71.8% for XGBoost and 65.3% for logistic regression. CONCLUSIONS: Open-source artificial intelligence can predict the impact factor and Eigenfactor score of accepting peer-reviewed journals. Further studies are required to examine the effect on publication success and the time-to-publication of such recommender systems.

Does Twitter improve the dissemination of ophthalmology scientific publications?

PURPOSE: To determine whether Twitter improves dissemination of ophthalmology scientific publications METHODS: Data were collected on articles published on PubMed between the years 2016 and 2021 (inclusive) and identified with the word "ophthalmology". Twitter performance metrics, including the number of tweets, number of likes, and number of retweets were collected from Twitter using the publicly available scientific API. Machine learning and descriptive statistics were used to outline Twitter performance metrics. RESULTS: The number of included articles was 433710. The percentage of articles that were in the top quartile for citation count, which had ≥1 tweet was 34.4% (number 437/1270). Conversely, the percentage of articles that were in the top quartile for citation count, which had 0 tweets was 27.8% (number 12023/43244). When machine learning was used to predict Twitter performance metrics an AUROC of 0.78 was returned. This was associated with an accuracy of 0.97 CONCLUSION: This study has shown preliminary evidence to support that Twitter may improve the dissemination of scientific ophthalmology publications.

Assessing the subjective quality of smartphone anterior segment photography: a non-inferiority study.

PURPOSE: To assess the subjective quality of anterior segment photos taken from a smartphone camera adapted to the slit lamp compared to a commercial inbuilt slit-lamp camera. METHODS: Non-inferiority study. Five paired images of the anterior segment of normal eyes were taken using an iPhone 11 (Apple, Inc., Calif., USA) camera attached to a universal slit-lamp adaptor and a commercial inbuilt slit-lamp camera (Haag-Streit Diagnostics, Bern, Switzerland). Images were collated into a survey in which ophthalmology students, residents, registrars, and consultants participated to select the image taken from the inbuilt slit-lamp camera. If the image quality was subjectively indistinguishable, we expected a 50:50 split for each photograph that was presented. We selected a 10% non-inferiority margin, with the hypothesis that no less than 40% of images believed to be from the conventional camera were in fact from the smartphone camera. RESULTS: There were 27 respondents in the survey: ophthalmology consultants (n = 7), registrars (n = 10), residents (n = 7), intern (n = 1) and students (n = 2). The mean correct identification across the respondents was 11.3 out of 25 (45.2%) images. Overall, the smartphone camera was non-inferior to the inbuilt slit-lamp camera (p < 0.001). The non-inferiority of the smartphone camera was significant for consultants (47.4%, p < 0.01), registrars (47.6%, p < 0.001) and residents (37.7%, p < 0.0001). CONCLUSIONS: Anterior segment images obtained with a smartphone camera were non-inferior to the commercial inbuilt slit-lamp camera. Smartphone cameras may be a non-inferior tool for communication of anterior segment images having implications for the ease of access to quality telehealth consultations.

Overcoming the impact of physiologic tremors in ophthalmology.

PURPOSE: Ophthalmic surgery involves the manipulation of micron-level sized structures such as the internal limiting membrane where tactile sensation is practically absent. All humans have physiologic tremors that are of low amplitude and not discernible to the naked eye; they do not adversely affect the majority of the population's daily functioning. However, during microsurgery, such tremors can be problematic. In this review, we focus on the impact of physiological tremors on ophthalmic microsurgery and offer a comparative discussion on the impact of such tremors on other surgical specialties. METHODS: A single investigator used the MEDLINE database (via PubMed) to search for and identify articles for inclusion in this systematic review. Ten key factors were identified as potentially having an impact on tremor amplitude: beta-blockers, muscle fatigue, robotic systems, handheld tools/micromanipulators, armrests/wrist supports, caffeine, diet, sleep deprivation, consuming alcohol, and workouts (exercise). These key terms were then searched using the advanced Boolean search tool and operators (i.e., AND, OR) available on PubMed: (*keyword*) AND (surgeon tremor OR microsurgery tremor OR hand steadiness OR simulator score). RESULTS: Ten studies attempted to quantify the baseline severity of operator physiologic tremor. Approximately 89% of studies accessing the impact of tremors on performance in regards to surgical metrics reported an improvement in performance compared to 57% of studies concluding that tremor elimination was of benefit when considering procedural outcomes. CONCLUSIONS: Robotic technology, new instruments, exoskeletons, technique modifications, and lifestyle factors have all demonstrated the potential to assist in overcoming tremors in ophthalmology.

Medical therapy for glaucoma: A review.

A number of pharmacological targets are exploited to modify the parameters in the Goldmann equation and reduce the intraocular pressure (IOP). This strategy constitutes the foundation for the medical management of glaucoma, the evolution of which, until only recently, has been in relative stagnation. A burst of innovation has produced new ocular hypotensive drugs and long-acting delivery methods, including intracameral delivery, which are expanding the clinician's medical armamentarium. A number of IOP-independent neuroprotection strategies have shown strong potential in animal models of glaucoma, but translational attempts have been surprisingly limited. However, while pharmacological options are expanding, the traditional role of topical medical therapy is being challenged by selective laser trabeculoplasty, micro-invasive glaucoma surgery, and sustained delivery methods. A scientifically rigorous assessment of new treatments will be critical to empower clinicians with evidence-based information to optimise vision preservation and quality of life outcomes for their patients.

Corneal Stiffness Parameters Are Predictive of Structural and Functional Progression in Glaucoma Suspect Eyes.

PURPOSE: To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results. METHODS: Baseline corneal SPs were measured using Corvis ST (Oculus Optikgeräte GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures. MAIN OUTCOME MEASURES: Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing. RESULTS: Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P < 0.001), synergistic with thinner CCT (P = 0.004) over a mean follow-up of 4.2 years. Eyes with higher SP-A1 and thinner CCT (thin and stiff corneas) showed accelerated RNFL thinning by 0.72 µm/year relative to eyes with lower SP-A1 and thicker CCT (95% confidence interval [CI], 0.17-1.28; P = 0.011) and were at 2.9-fold higher likelihood of fast RNFL progression of more than 1 µm/year (95% CI, 1.4-6.1; P = 0.006). Consistent results also were observed with GCIPL thinning. Furthermore, a higher SP-A1 was associated with a greater risk of visual field progression (P = 0.002), synergistic with thinner CCT (P = 0.010). Eyes with higher SP-A1 and thinner CCT were at 3.7-fold greater risk of visual field progression relative to eyes with thicker CCT and lower SP-A1 (95% CI, 1.3-10.5; P = 0.014). CONCLUSIONS: Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.

Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma.

PURPOSE: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma. DESIGN: Prospective, longitudinal study of preperimetric and perimetric glaucoma. PARTICIPANTS: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment. METHODS: Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients. MAIN OUTCOME MEASURES: OCT and HVF baseline status and longitudinal progression. RESULTS: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039). CONCLUSIONS: Cardiovascular disease is an important risk factor for glaucoma progression.

Physiological response of the retinal pigmented epithelium to 3-ns pulse laser application, in vitro and in vivo.

BACKGROUND: To treat healthy retinal pigmented epithelium (RPE) with the 3-ns retinal rejuvenation therapy (2RT) laser and to investigate the subsequent wound-healing response of these cells. METHODS: Primary rat RPE cells were treated with the 2RT laser at a range of energy settings. Treated cells were fixed up to 7 days post-irradiation and assessed for expression of proteins associated with wound-healing. For in vivo treatments, eyes of Dark Agouti rats were exposed to laser and tissues collected up to 7 days post-irradiation. Isolated wholemount RPE preparations were examined for structural and protein expression changes. RESULTS: Cultured RPE cells were ablated by 2RT laser in an energy-dependent manner. In all cases, the RPE cell layer repopulated completely within 7 days. Replenishment of RPE cells was associated with expression of the heat shock protein, Hsp27, the intermediate filament proteins, vimentin and nestin, and the cell cycle-associated protein, cyclin D1. Cellular tight junctions were lost in lased regions but re-expressed when cell replenishment was complete. In vivo, 2RT treatment gave rise to both an energy-dependent localised denudation of the RPE and the subsequent repopulation of lesion sites. Cell replenishment was associated with the increased expression of cyclin D1, vimentin and the heat shock proteins Hsp27 and αB-crystallin. CONCLUSIONS: The 2RT laser was able to target the RPE both in vitro and in vivo, causing debridement of the cells and the consequent stimulation of a wound-healing response leading to layer reformation.

Impact of cardiometabolic factors on retinal vasculature: A 3 × 3, 6 × 6 and 8 × 8-mm ocular coherence tomography angiography study.

BACKGROUND: Ocular coherence tomography angiography (OCTA) is available in varying size and resolution. We sought to characterise associations of cardiometabolic factors with retinal microvascular changes using 3 × 3, 6 × 6 and 8 × 8-mm OCTA scans to determine differences in detection with varying scan size. METHODS: Cross-sectional study of 247 cardiovascular patients from a single-centre tertiary-care hospital. Demographic, comorbidity and medication data were obtained. Patients underwent 3 × 3, 6 × 6 and 8 × 8-mm macula OCTA scanning using Carl Zeiss CIRRUS HD-OCT Model 5000. Angioplex and AngioTool software was used to quantify vascular parameters in the superficial capillary plexus. RESULTS: Increasing age, hypertension, dyslipidaemia, diabetes, chronic kidney disease, coronary artery disease and peripheral vascular disease were associated with reductions in vessel density, vessel perfusion, average vessel length and/or junction density in 3 × 3-mm OCTA (P < .05 for all). Conversely, smoking was associated with increased vessel density, vessel length and junction density in 3 × 3-mm OCTA (P < .05 for all). Associations of vessel abnormalities with cardiometabolic factors were progressively weakened and statistically attenuated in 6 × 6 and 8 × 8-mm OCTA scans. In multivariate analyses, dyslipidaemia remained an independent predictor of reduced vessel density, average vessel length and junction density (P < .05). CONCLUSIONS: Cardiometabolic factors are associated with multiple retinal microvascular changes in 3 × 3-mm OCTA scans. These associations were weakened and progressively attenuated in OCTA scans of larger 6 × 6 and 8 × 8-mm size. These findings advance our understanding of microcirculatory dysfunction and may have future implications for the screening and management of patients with cardiometabolic risk factors. Additional studies are required to further investigate these important associations.

Preclinical and clinical studies of photobiomodulation therapy for macular oedema.

AIMS/HYPOTHESIS: Diabetic macular oedema (DME) is the leading cause of visual impairment in people with diabetes. Intravitreal injections of vascular endothelial growth factor inhibitors or corticosteroids prevent loss of vision by reducing DME, but the injections must be given frequently and usually for years. Here we report laboratory and clinical studies on the safety and efficacy of 670 nm photobiomodulation (PBM) for treatment of centre-involving DME. METHODS: The therapeutic effect of PBM delivered via a light-emitting diode (LED) device was tested in transgenic mice in which induced Müller cell disruption led to photoreceptor degeneration and retinal vascular leakage. We also developed a purpose-built 670 nm retinal laser for PBM to treat DME in humans. The effect of laser-delivered PBM on improving mitochondrial function and protecting against oxidative stress was studied in cultured rat Müller cells and its safety was studied in pigmented and non-pigmented rat eyes. We then used the retinal laser to perform PBM in an open-label, dose-escalation Phase IIa clinical trial involving 21 patients with centre-involving DME. Patients received 12 sessions of PBM over 5 weeks for 90 s per treatment at a setting of 25, 100 or 200 mW/cm2 for the three sequential cohorts of 6-8 patients each. Patients were recruited from the Sydney Eye Hospital, over the age of 18 and had centre-involving DME with central macular thickness (CMT) of >300 µm with visual acuity of 75-35 Log minimum angle of resolution (logMAR) letters (Snellen visual acuity equivalent of 20/30-20/200). The objective of this trial was to assess the safety and efficacy of laser-delivered PBM at 2 and 6 months. The primary efficacy outcome was change in CMT at 2 and 6 months. RESULTS: LED-delivered PBM enhanced photoreceptor mitochondrial membrane potential, protected Müller cells and photoreceptors from damage and reduced retinal vascular leakage resulting from induced Müller cell disruption in transgenic mice. PBM delivered via the retinal laser enhanced mitochondrial function and protected against oxidative stress in cultured Müller cells. Laser-delivered PBM did not damage the retina in pigmented rat eyes at 100 mW/cm2. The completed clinical trial found a significant reduction in CMT at 2 months by 59 ± 46 µm (p = 0.03 at 200 mW/cm2) and significant reduction at all three settings at 6 months (25 mW/cm2: 53 ± 24 µm, p = 0.04; 100 mW/cm2: 129 ± 51 µm, p < 0.01; 200 mW/cm2: 114 ± 60 µm, p < 0.01). Laser-delivered PBM was well tolerated in humans at settings up to 200 mW/cm2 with no significant side effects. CONCLUSIONS/INTERPRETATION: PBM results in anatomical improvement of DME over 6 months and may represent a safe and non-invasive treatment. Further testing is warranted in randomised clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02181400 Graphical abstract.

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort.

Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.