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Purpose: To compare 1-year outcomes of eyes with diabetic macular edema (DME) treated in routine clinical practice based on the proportion of visits where intravitreal VEGF inhibitor injections were delivered., Design: Cohort study., Participants: There were 2288 treatment-naive eyes with DME starting intravitreal VEGF inhibitor therapy from October 31, 2015 to October 31, 2021 from the Fight Retinal Blindness! international outcomes registry., Methods: Eyes were grouped according to the proportion of visits at which an injection was received, Group A with less than the median of 67% (n = 1172) versus Group B with greater than the median (n = 1116)., Main Outcome Measures: Mean visual acuity (VA) change after 12 months of treatment., Results: The mean (95% confidence interval [CI]) VA change after 12 months of treatment was 3.6 (2.8-4.4) letters for eyes in Group A versus 5.2 (4.4-5.9) letters for eyes in Group B (P = 0.005). The mean (95% CI) central subfield thickness (CST) change was -69 (-76 to -61) μm and -85 (-92 to -78) μm for eyes in Group A versus Group B, respectively (P = 0.002). A moderate positive correlation was observed between the number of injections received over 12 months of treatment and the change in VA (P < 0.001). Additionally, eyes that received more injections had a moderately greater CST reduction., Conclusions: This registry analysis found that overall VA and anatomic outcomes tended to be better in DME eyes treated at a greater proportion of visits in the first year of intravitreal VEGF inhibitor therapy., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. All rights reserved.)

The aim of this study is to correlate small dot hyper-reflective foci (HRF) observed in spectral domain optical coherence tomography (SD-OCT) scans of an animal model of hyperglycaemia with focal electroretinography (fERG) response and immunolabelling of retinal markers. The eyes of an animal model of hyperglycaemia showing signs of diabetic retinopathy (DR) were imaged using SD-OCT. Areas showing dot HRF were further evaluated using fERG. Retinal areas enclosing the HRF were dissected and serially sectioned, stained and labelled for glial fibrillary acidic protein (GFAP) and a microglial marker (Iba-1). Small dot HRF were frequently seen in OCT scans in all retinal quadrants in the inner nuclear layer or outer nuclear layer in the DR rat model. Retinal function in the HRF and adjacent areas was reduced compared with normal control rats. Microglial activation was detected by Iba-1 labelling and retinal stress identified by GFAP expression in Müller cells observed in discrete areas around small dot HRF. Small dot HRF seen in OCT images of the retina are associated with a local microglial response. This study provides the first evidence of dot HRF correlating with microglial activation, which may allow clinicians to better evaluate the microglia-mediated inflammatory component of progressive diseases showing HRF., (© 2023 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Purpose: To validate the potential application of THEIA™ as clinical decision making assistant in a national screening program., Methods: A total of 900 patients were recruited from either an urban large eye hospital, or a semi-rural optometrist led screening provider, as they were attending their appointment as part of New Zealand Diabetic Eye Screening Programme. The de-identified images were independently graded by three senior specialists, and final results were aggregated using New Zealand grading scheme, which was then converted to referable/non-referable and Healthy/mild/more than mild/sight threatening categories., Results: THEIA™ managed to grade all images obtained during the study. Comparing the adjudicated images from the specialist grading team, "ground truth", with the grading by the AI platform in detecting "sight threatening" disease, at the patient level THEIA™ achieved 100% imageability, 100% [98.49-100.00%] sensitivity and [97.02-99.16%] specificity, and negative predictive value of 100%. In other words, THEIA™ did not miss any patients with "more than mild" or "sight threatening" disease. The level of agreement between the clinicians and the aggregated results was (k value: 0.9881, 0.9557, and 0.9175), and the level of agreement between THEIA™ and the aggregated labels was (k value: 0.9515)., Conclusion: This multi-centre prospective trial showed that THEIA™ did not miss referable disease when screening for diabetic retinopathy and maculopathy. It also had a very high level of granularity in reporting the disease level. As THEIA™ has been tested on a variety of cameras, operating in a range of clinics (rural/urban, ophthalmologist-led\optometrist-led), we believe that it will be a suitable addition to a public diabetic screening program., (© 2022. The Author(s).)

Objectives: To identify whether the outcomes of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in routine clinical practice have changed over time., Methods: We analysed 12-month outcomes in treatment-naïve eyes that started aflibercept or ranibizumab for nAMD (3802 eyes), DMO (975 eyes), Branch RVO (BRVO, 357 eyes), Central RVO (CRVO, 371 eyes) and Hemi-RVO (HRVO, 54 eyes) from 2015 and 2019 tracked in the prospectively designed observational Fight Retinal Blindness! Registry., Results: The mean VA change at 12-month for each year between 2015 and 2019 remained stable or otherwise showed no discernible trends over time in eyes with nAMD (+3.3 to +6 letters), DMO (+3.6 to +6.7 letters) and RVO (+10.3 to +11.7 letters for BRVO, +5.9 to +17.7 letters for CRVO and 10.2 to 20.7 letters for HRVO). The median number of VEGF-inhibitor injections in eyes that completed 12-month follow-up also remained stable at 8-9 for nAMD, 6-7 for DMO, 7-9 for RVO. Fewer eyes (

Purpose: Compare the 3-year outcomes of ranibizumab versus aflibercept in eyes with diabetic macular edema in daily practice., Methods: This was a retrospective analysis of naive diabetic macular edema eyes starting intravitreal injections of ranibizumab (0.5 mg) or aflibercept (2 mg) from January 1, 2013 to December 31, 2017 that were collected in the Fight Retinal Blindness! Registry., Results: We identified 534 eyes (ranibizumab-267 and aflibercept-267) of 402 patients. The adjusted mean (95% confidence interval) visual acuity change of +1.3 (-0.1 to 4.2) letters in the ranibizumab group and +2.4 (-0.2 to 5.1) letters (P = 0.001) in the aflibercept group at 3 years was not clinically different. However, the adjusted mean CST change seemed to remain significantly different throughout the 3-year period with higher reductions in favor of aflibercept (-87.8 [-108.3 to -67.4] µm for ranibizumab vs. -114.4 [-134.4 to -94.3] for aflibercept; P < 0.01). When baseline visual impairment was moderate (visual acuity ≤68 Early Treatment Diabetic Retinopathy Study letters), we found a faster improvement in visual acuity in eyes treated with aflibercept up until 18 months of treatment than eyes treated with ranibizumab, which then stayed similar until 36 months of treatment, whereas there was no apparent difference when baseline visual impairment was mild (visual acuity ≥69 Early Treatment Diabetic Retinopathy Study letters). The rate of serious adverse events was low., Conclusion: Aflibercept and ranibizumab were both effective and safe for diabetic macular edema over 3 years., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: Artificial intelligence (AI) technology is poised to revolutionize modern delivery of health care services. We set to evaluate the patient perspective of AI use in diabetic retinal screening., Design: Survey., Methods: Four hundred thirty-eight patients undergoing diabetic retinal screening across New Zealand participated in a survey about their opinion of AI technology in retinal screening. The survey consisted of 13 questions covering topics of awareness, trust, and receptivity toward AI systems., Results: The mean age was 59 years. The majority of participants identified as New Zealand European (50%), followed by Asian (31%), Pacific Islander (10%), and Maori (5%). Whilst 73% of participants were aware of AI, only 58% have heard of it being implemented in health care. Overall, 78% of respondents were comfortable with AI use in their care, with 53% saying they would trust an AI-assisted screening program as much as a health professional. Despite having a higher awareness of AI, younger participants had lower trust in AI systems. A higher proportion of Maori and Pacific participants indicated a preference toward human-led screening. The main perceived benefits of AI included faster diagnostic speeds and greater accuracy., Conclusions: There is low awareness of clinical AI applications among our participants. Despite this, most are receptive toward the implementation of AI in diabetic eye screening. Overall, there was a strong preference toward continual involvement of clinicians in the screening process. There are key recommendations to enhance the receptivity of the public toward incorporation of AI into retinal screening programs., Competing Interests: The authors have no other or conflicts of interest to declare., (Copyright © 2022 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Objectives: This study evaluated the 1-year treatment outcomes of bevacizumab for diabetic macular oedema (DMO) in routine clinical practice., Methods: A retrospective analysis was performed on 298 eyes of 220 patients with DMO that received intra-vitreal bevacizumab between 1 September 2013 and 31 August 2018 that were tracked by a prospectively designed, web-based observational registry-the Fight Retinal Blindness! Registry., Results: The mean visual acuity (95% confidence interval [CI]) at 1-year was 3 (2, 5) letters better than a mean (SD) of 68 (15) letters at study entry. Nearly a quarter of eyes achieved ≥20/40. Eyes presenting with better vision (≥20/40) tended to maintain that vision during the period of observation, whereas those presenting with worse vision (<20/40) gained a mean (95% CI) of 9 (5, 13) letters. A mean reduction in the macular thickness was observed over the study period with the central subfield improving by 29 µm (95% CI 17, 40) from a mean (SD) of 402 (109) µm at study entry. Eyes that completed 1 year of follow-up received a median (Q1, Q3) of 7 (4, 9) bevacizumab injections. Sixty-two eyes, ~20%, that started with bevacizumab changed to either another VEGF inhibitor or steroid (triamcinolone) during the period of observation. This did not lead to functional improvement for eyes changed to either ranibizumab or aflibercept despite a further reduction in macular thickness. An improvement in vision and reduction in macular thickness was noted in the 13 eyes that subsequently received triamcinolone. Approximately 10% of eyes dropped out over 12 months, even though their mean visual acuity had improved by seven letters from the initial visit., Conclusions: Bevacizumab is an effective treatment for DMO in unselected populations., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Objectives: To evaluate the prevalence of incidental non-diabetic ocular comorbidities detected at first screen in a large diabetic retinopathy (DR) screening programme., Design: Cross-sectional cohort study., Setting: Single large metropolitan diabetic eye screening programme in Auckland, New Zealand., Participants: Twenty-two thousand seven hundred and seventy-one participants who attended screening from September 2008 to August 2018., Results: Hypertensive retinopathy (HTR) was observed in 14.2% (3236/22 771) participants. Drusen were present in 14.0% participants under the age of 55 years, increasing to 20.5% in those 55 years and older. The prevalence of neovascular age-related macular degeneration (AMD) was 0.5% in participants aged<55 years, 2.4% in participants aged 55-75 years and 16% in participants aged>75 years. Retinal vein occlusion and retinal arterial embolus were prevalent in 0.7% and 0.02%, respectively, in participants aged<55 years, increasing to 2.2% and 0.4%, respectively, in those >75 years. Cataracts were common being present in 37.1% of participants over the age of 75 years. Only 386 individuals (1.7%) were labelled as glaucoma suspects. Geographic atrophy, epiretinal membrane, choroidal nevi and posterior capsular opacification had an increased prevalence in older individuals., Conclusions: Our data suggest that AMD, HTR and cataracts are routinely detected during DR screening. The incorporation of the detection of these ocular comorbidities during DR screening provide opportunities for patients to modify risk factors (smoking cessation and diet for AMD, blood pressure for HTR) and allow access to cataract surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate the prevalence and risk factors for the development of any and referable diabetic eye disease in a multi-ethnic New Zealand population with diabetes mellitus attending a regional retinal screening service., Methods: Retrospective observational cohort study of people living with diabetes who attended the Auckland Regional Diabetic Retinal Screening Programme 2006-2018 inclusive (n = 41,786)., Results: Any retinopathy/maculopathy was present at first screening for 48.2% [95% confidence interval (CI): 45.8%-50.6%] / 37.8% (95% CI: 35.5%- 40.1%) of people with Type 1 and 25% (95% CI: 24.6%-25.4%) / 21.9% (95% CI: 21.5%-22.3%) with Type 2 diabetes. Referable retinopathy at baseline screening was 4.4% (95% CI: 3.6%-5.3%) and 1.6% (95% CI: 1.5%-1.7%) among people with Type 1 and Type 2 diabetes mellitus, respectively. After 4 years, cumulative incidence for referable retinopathy /referable maculopathy was 12/36 per 1000 people with Type 1 and 2.4/16 per 1000 people with Type 2 diabetes. Independent hazards for disease progression varied for the diabetes cohort types but baseline grade, duration of diabetes, and HbA1c were common to all., Conclusions: Referable diabetic eye disease at the first screening and after 4 years of follow-up is uncommon. Lengthening of the screening intervals for people with no or mild diabetic eye disease at first screening assessment could be considered., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Importance: There are limited data on real-world outcomes of cataract surgery in eyes receiving intravitreal treatments for diabetic macular oedema (DMO)., Background: Cataract surgery may exacerbate oedema in some eyes with DMO resulting in inferior outcomes., Design: Matched, case-controlled retrospective study of observational data in routine clinical practice., Participants: Eyes receiving intravitreal treatments for DMO tracked in the Fight Retinal Blindness! Registry., Methods: Eyes that underwent cataract surgery were identified and matched 1:1 with phakic controls also receiving intravitreal injections for DMO. We also assessed potential factors that were associated with better visual acuity (VA) outcomes., Main Outcome Measures: Change in VA 6 months after cataract surgery., Results: Cataract surgery was identified in 208 eyes of 156 patients of which 147 eyes had 6 months of observations before and after surgery. The mean VA 6 months after surgery improved by 10.6 letters and was similar to their matched phakic controls (68.8 vs 69.2 letters; P = 0.8). Mean CST both 6 months before (341 μm) and after (360 μm) surgery were similar (P = 0.08). However, these eyes had thicker maculae and they received more injections than their matched phakic controls both before and after surgery. Eyes with worse VA before surgery and those that had received intravitreal treatment in the 4 weeks preceding surgery were more likely to gain vision., Conclusions and Relevance: Visual outcomes of cataract surgery in eyes receiving intravitreal therapy for DMO were reasonably better. Their maculae were thicker and required more injections in the 6 months before and after surgery than their phakic controls., (© 2019 Royal Australian and New Zealand College of Ophthalmologists.)

Convolutional Neural Networks (CNNs) have become a prominent method of AI implementation in medical classification tasks. Grading Diabetic Retinopathy (DR) has been at the forefront of the development of AI for ophthalmology. However, major obstacles remain in the generalization of these CNNs onto real-world DR screening programs. We believe these difficulties are due to use of 1) small training datasets (<5,000 images), 2) private and 'curated' repositories, 3) locally implemented CNN implementation methods, while 4) relying on measured Area Under the Curve (AUC) as the sole measure of CNN performance. To address these issues, the public EyePACS Kaggle Diabetic Retinopathy dataset was uploaded onto Microsoft Azure™ cloud platform. Two CNNs were trained; 1 a "Quality Assurance", and 2. a "Classifier". The Diabetic Retinopathy classifier CNN (DRCNN) performance was then tested both on 'un-curated' as well as the 'curated' test set created by the "Quality Assessment" CNN model. Finally, the sensitivity of the DRCNNs was boosted using two post-training techniques. Our DRCNN proved to be robust, as its performance was similar on 'curated' and 'un-curated' test sets. The implementation of 'cascading thresholds' and 'max margin' techniques led to significant improvements in the DRCNN's sensitivity, while also enhancing the specificity of other grades., Competing Interests: The authors have declared that no competing interests exist.

Diabetic retinopathy (DR) is a vascular disease of the neuroretina characterised by hyperglycaemia and inflammation. Current DR therapies target late-stage vascular defects and there is evidence to suggest that they contribute to geographic atrophy and retinal ganglion cell death long term. Therefore, alternative treatments that target common upstream disease mechanisms are needed. Recent studies have shown that connexin43 hemichannel blockers can reduce inflammation and prevent vessel leak in brain and spinal cord lesions. The aim of this study was to evaluate the effectiveness of a connexin43 hemichannel blocker (Peptide5) in a mouse model of DR in which pro-inflammatory cytokines, IL-1β and TNF-α, were intravitreally injected into non-obese diabetic (NOD, hyperglycaemic) mice. Fundus and optical coherence tomography images were taken to evaluate vessel dilation and beading as well as retinal and vitreous hyper-reflective foci (HRF). Immunohistochemistry was performed to assess levels of astrogliosis, microgliosis and inflammasome activation. Results showed that Peptide5 injection lowered the incidence of vessel dilation and beading, decreased the severity of vitreous and retinal HRF, and reduced sub-retinal fluid accumulation compared to the vehicle group. Furthermore, Peptide5 led to reduced connexin43 and GFAP upregulation, inhibited microglial infiltration into the outer nuclear layer and prevented upregulation of inflammasome markers compared to vehicle. The present study provides evidence in support of Peptide5, and connexin43 hemichannel block in general, as a potential upstream approach for the treatment of DR. KEY MESSAGES: Connexin43 is upregulated in a novel mouse model of diabetic retinopathy (DR). Connexin43 hemichannel block inhibits inflammation and inflammasome activation. Connexin43 hemichannel block prevents the development of clinical DR signs. Connexin43 hemichannel block is a potential upstream approach for DR treatment.

Diabetic retinopathy is a vascular disease of the retina characterised by hyperglycaemic and inflammatory processes. Most animal models of diabetic retinopathy are hyperglycaemia-only models that do not account for the significant role that inflammation plays in the development of the disease. In the present study, we present data on the establishment of a new animal model of diabetic retinopathy that incorporates both hyperglycaemia and inflammation. We hypothesized that inflammation may trigger and worsen the development of diabetic retinopathy in a hyperglycaemic environment. Pro-inflammatory cytokines, IL-1β and TNF-α, were therefore injected into the vitreous of non-obese diabetic (NOD) mice. CD1 mice were used as same genetic background controls. Fundus and optical coherence tomography images were obtained before (day 0) as well as on days 2 and 7 after intravitreal cytokine injection to assess vessel dilation and beading, retinal and vitreous hyper-reflective foci and retinal thickness. Astrogliosis and microgliosis were assessed using immunohistochemistry. Results showed that intravitreal cytokines induced vessel dilation, beading, severe vitreous hyper-reflective foci, retinal oedema, increased astrogliosis and microglia upregulation in diabetic NOD mice. Intravitreal injection of inflammatory cytokines into the eyes of diabetic mice therefore appears to provide a new model of diabetic retinopathy that could be used for the study of disease progression and treatment strategies., Competing Interests: We, the authors declare that no competing interests exist.

Purpose: To evaluate the efficacy of a large-spot subthreshold infrared laser protocol to treat diabetic maculopathy., Methods: In a prospective, fellow eye, controlled case series, all patients had clinically significant diabetic macular edema (DME) treated with a single application of subthreshold infrared (810 nm) laser. If bilateral disease was present, the fellow eye was treated with conventional macular laser. The study was to include 20 patients. Visual acuity and central macular thickness (CMT) measured by optical coherence tomography (OCT) were assessed in the study and fellow eyes at baseline and 6 months, and any changes were compared., Results: The 11th patient developed a choroidal infarct with subsequent profound loss of vision immediately after treatment. The study was terminated prematurely at this point. For the remaining 10 patients, there was a trend toward improvement in visual acuity in the study eye compared with the fellow eye at the 6-month follow-up (median change: +1.5 letters for study eye vs -6.5 letters for fellow eye; P = 0.08). There was also significant improvement in OCT-measured CMT in the study eye (mean decrease, 117 microm) compared with deterioration in OCT-measured CMT in the fellow eye (mean increase, 24 microm; P = 0.02)., Conclusion: This subthreshold infrared laser protocol led to improvement in OCT-measured CMT and stabilization of vision in most subjects. The current protocol is however unpredictable and should not be used in the treatment of DME without further modification.

This systematic review was performed to identify the specifics of an optimal diabetic retinopathy deep learning algorithm, by identifying the best exemplar research studies of the field, whilst highlighting potential barriers to clinical implementation of such an algorithm. Searching five electronic databases (Embase, MEDLINE, Scopus, PubMed, and the Cochrane Library) returned 747 unique records on 20 December 2019. Predetermined inclusion and exclusion criteria were applied to the search results, resulting in 15 highest-quality publications. A manual search through the reference lists of relevant review articles found from the database search was conducted, yielding no additional records. A validation dataset of the trained deep learning algorithms was used for creating a set of optimal properties for an ideal diabetic retinopathy classification algorithm. Potential limitations to the clinical implementation of such systems were identified as lack of generalizability, limited screening scope, and data sovereignty issues. It is concluded that deep learning algorithms in the context of diabetic retinopathy screening have reported impressive results. Despite this, the potential sources of limitations in such systems must be evaluated carefully. An ideal deep learning algorithm should be clinic-, clinician-, and camera-agnostic; complying with the local regulation for data sovereignty, storage, privacy, and reporting; whilst requiring minimum human input. [ABSTRACT FROM AUTHOR]