PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects.

The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5'-splice site (5'SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5'SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches.

Comparison of the use of internal limiting membrane flaps versus conventional ILM peeling on post-operative anatomical and visual outcomes in large macular holes.

BACKGROUND: Idiopathic full-thickness macular hole (iFTMH) closure rates following conventional vitrectomy, gas tamponade and internal limiting membrane (ILM) peeling decrease when the minimum linear diameter (MLD) ≥ 500 microns. ILM flap creation has been proposed to improve closure in larger holes. This study evaluated the anatomical and functional impact of ILM flap introduction to routine practice in iFTMH ≥500 microns. METHODS: Retrospective, interventional analysis of prospectively collected data of 191 eyes from consecutive surgeries for primary iFTMH ≥500 microns performed by two surgeons between June 2018 and June 2022, during which both surgeons replaced ILM peeling with ILM flap creation. Post-operative best-corrected visual acuity (BCVA) and anatomical closure were compared between Group 1 (ILM peel) and Group 2 (ILM flap) in an intention-to-treat analysis. RESULTS: Rates of iFTMH closure were greater in the ILM flap group (77/80; 96.3%) than the ILM peel group (94/110; 85.5%) (OR = 4.37, 95% CI = 1.23-15.55, p = 0.023). A non-significant increase in post-operative BCVA improvement was observed in the ILM flap group (p = 0.084). There was no statistically significant difference in final BCVA (p = 0.83). Multivariate logistic regression found only MLD (OR = 0.993, 95% CI = 0.989-0.997, p = 0.001) and ILM flap group (OR = 5.795, 95% CI = 1.313-25.570, p = 0.020) predicted primary closure. CONCLUSION: ILM flap creation improves closure rates in larger holes and should be considered routinely in iFTMH ≥500 microns. Whether ILM flaps affect post-operative visual function remains uncertain.

Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Pluripotent stem cell-derived models of retinal disease: Elucidating pathogenesis, evaluating novel treatments, and estimating toxicity.

Blindness poses a growing global challenge, with approximately 26% of cases attributed to degenerative retinal diseases. While gene therapy, optogenetic tools, photosensitive switches, and retinal prostheses offer hope for vision restoration, these high-cost therapies will benefit few patients. Understanding retinal diseases is therefore key to advance effective treatments, requiring in vitro models replicating pathology and allowing quantitative assessments for drug discovery. Pluripotent stem cells (PSCs) provide a unique solution given their limitless supply and ability to differentiate into light-responsive retinal tissues encompassing all cell types. This review focuses on the history and current state of photoreceptor and retinal pigment epithelium (RPE) cell generation from PSCs. We explore the applications of this technology in disease modelling, experimental therapy testing, biomarker identification, and toxicity studies. We consider challenges in scalability, standardisation, and reproducibility, and stress the importance of incorporating vasculature and immune cells into retinal organoids. We advocate for high-throughput automation in data acquisition and analyses and underscore the value of advanced micro-physiological systems that fully capture the interactions between the neural retina, RPE, and choriocapillaris.

Outcomes of Treatment-Resistant Neovascular Age-Related Macular Degeneration Switched from Aflibercept to Faricimab.

PURPOSE: Although previous studies have demonstrated the efficacy of faricimab in treatment-naive patients with neovascular age-related macular degeneration (nAMD), its outcomes in patients switched from aflibercept are less understood. This study aimed to assess clinical anatomical and functional outcomes of switching to faricimab in patients undergoing aflibercept intravitreal injections (IVIs) for nAMD with suboptimal response. DESIGN: Retrospective case series. SUBJECTS: Patients with nAMD at a single tertiary care center who were switched from aflibercept to faricimab due to persistent suboptimal response. METHODS: Patients had received a minimum of 6 consecutive IVIs of aflibercept and showed persistent presence of intraretinal (IRF) or subretinal fluid (SRF) on OCT despite receiving aflibercept at 4 or 6-weekly intervals at the time of the switch. Patients receiving 4-weekly aflibercept were switched with either 2 or 3 loading doses of 4-weekly faricimab injections. Regression models were used to identify predictors of clinical outcomes. MAIN OUTCOME MEASURES: Visual acuity, central macular thickness (CMT), and OCT parameters were assessed preswitch and postswitch. RESULTS: Eighty-one eyes of 68 patients were included. The mean age was 79.1 years (standard deviation: 8.9), and females constituted 53% of cases. A statistically significant reduction in CMT was observed postswitch (P < 0.0001). The proportion of cases with IRF (P = 0.0219) and SRF (P < 0.000) decreased significantly. Overall clinical improvement on OCT was noted in 80% of patients. No significant improvement in ETDRS vision was observed. There was no evidence that switching regimen (2 vs. 3 loading doses) had an independent effect on clinical outcomes. CONCLUSION: Among patients with treatment-resistant nAMD, switching from aflibercept to faricimab may serve as a safe and effective option. Significant anatomical improvements were observed, with a trend toward visual stability. The loading regimen with 2 faricimab injections appeared to be sufficient for nonnaive patients. However, a longer follow-up and larger studies are warranted to confirm these findings. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Twenty-seven-gauge vitrectomy: a consecutive, single-centre case series with exclusive use over a 4-year period.

BACKGROUND: To assess the safety and effectiveness of the exclusive use of 27-gauge instruments for all vitreoretinal diseases requiring vitrectomy. METHODS: In this retrospective study, 1020 consecutive surgeries were performed on 958 eyes of 848 patients using 27-gauge instruments from March 2017 to June 2021. Patients with a minimum follow-up of 3 months were included. Surgical case-mix, best-corrected visual acuity (BCVA), intraocular pressure (IOP), intra- and post-operative complications, and surgery times were recorded. RESULTS: The study patients were followed up for averagely 11 months. Of the 1020 vitrectomies, 958 were primary procedures. Of the 148 retinal detachment (RD) cases, 138 (93%) required a single vitrectomy. Primary macular hole closure was achieved in 143 of 145 (99%) cases. The average surgical times were 55 and 38 min for RD surgeries and for all other indications, respectively. BCVA improved significantly at the final visit (20/49) compared with the pre-operative visit (20/78) (p < 0.01). IOP was similar at the pre-operative (14.8mmHg) and final (14.3mmHg) visits. Complications recorded include transient hypotony in 39 eyes, iatrogenic retinal breaks in 2 eyes, and a vitreous bleed in 1 other eye. CONCLUSION: This study revealed that 27-gauge vitrectomy instruments can be used for a wide range of indications, with exclusive use in certain settings. The outcomes were similar to other gauges, including for rhegmatogenous retinal detachment, with minimal complications.

Improved Outcomes with Heavy Silicone Oil in Complex Primary Retinal Detachment: A Large Multicenter Matched Cohort Study.

PURPOSE: To establish whether Densiron 68, a heavier-than-water endotamponade agent, is an effective alternative to conventional light silicone oil in primary rhegmatogenous retinal detachment (RD) surgery for eyes with inferior breaks in the detached retina and severe proliferative vitreoretinopathy (PVR). DESIGN: Cohort study of routinely collected data from the European Society of Retina Specialists and British and Eire Association of Vitreoretinal Surgeons vitreoretinal database between 2015 and 2022. PARTICIPANTS: All consecutive eyes that underwent primary rhegmatogenous RD surgery using Densiron 68 or light silicone oil as an internal tamponade agent. METHODS: To minimize confounding bias, we undertook 2:1 nearest-neighbor matching on inferior breaks, large inferior rhegmatogenous RDs, PVR, and, for visual analyses, baseline visual acuity (VA) between treatment groups. We fit regression models including prognostically relevant covariates, treatment-covariate interactions, and matching weights. We used g-computation with cluster-robust methods to estimate marginal effects. For nonlinear models, we calculated confidence intervals (CIs) using bias-corrected cluster bootstrapping with 9999 replications. MAIN OUTCOME MEASURES: Presence of a fully attached retina and VA at least 2 months after oil removal. RESULTS: Of 1061 eyes enrolled, 426 and 239 were included in our matched samples for anatomic and visual outcome analyses, respectively. The primary success rate was higher in the Densiron 68 group (113 of 142; 80%) compared with the light silicone oil group (180 of 284; 63%), with an adjusted odds ratio of 1.90 (95% CI, 1.63-2.23, P < 0.001). We also observed a significant improvement favoring Densiron 68 of -0.26 logarithm of the minimum angle of resolution (logMAR) in postoperative VA between the 2 groups (95% CI, -0.43 to -0.10, P = 0.002). The anatomic benefit of using Densiron 68 in eyes with inferior retinal breaks and large detachments was more pronounced among eyes with PVR grade C. We found no evidence of visual effect moderation by anatomic outcome or foveal attachment. CONCLUSIONS: Densiron achieved higher anatomic success rates and improved visual outcomes compared with conventional light silicone oil in eyes with inferior retinal pathology and severe PVR. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Tangential Retinal Displacement Increases After Macular Pucker Surgery: An Apparent Nonsense.

PURPOSE: To measure the tangential retinal displacement and vision before and after macular pucker surgery and study if Pars Plana Vitrectomy (PPV) with EpiRetinal Membrane (ERM) peeling allows the reconstitution of previous anatomy or else it results in a different configuration. METHODS: Retrospective series of patients undergoing PPV for ERM, with greater than 6-month follow-up before and after surgery, complete with best-corrected visual acuity (BCVA), Optical Coherence Tomography (OCT), M-charts, and InfraRed (IR) retinography. Tangential retinal displacement between Earliest visit (TE), time of surgery (T0) and latest available visit (TL) of the examined retina, concentric circles at 0.5, 1.5 and 4.5mm radii and the central horizontal and vertical meridian were measured. Tangential displacement was calculated as the optical flow of consecutive IR photos. RESULTS: The study comprised 32 patients: 15 males and 17 females. Average pre- and post-operative follow-up were 23.4±27.9 months and 19.2±11.8 months. BCVA reduced before surgery (0.69 ± 0.16 Snellen to 0.46 ± 0.17; p<0.001) and increased after (0.866 ± 0.16 Snellen; p<0.001). Horizontal and vertical metamorphopsia increased between before surgery but only horizontal metamorphopsia significantly reduced after. Average tangential displacement before surgery was 35.6±29.9 µm versus 56.6±41.3 µm after (p=0.023). Pre- and post-operative displacement within the fovea was less than over the entire area (p<0.001). CONCLUSION: Retinal tangential displacement between diagnosis and surgery (TE-T0) is less than the displacement occurring after surgery (T0-TL). Post-operative displacement does not represent the restoration of the anatomy existing before the disease ensued, but rather the resulting equilibrium of newly deployed forces.

Subthreshold Compared with Threshold Macular Photocoagulation for Diabetic Macular Edema: A Systematic Review and Meta-Analysis.

TOPIC: To compare the efficacy and safety of subthreshold macular laser to conventional focal laser photocoagulation for the treatment of vision loss secondary to diabetic macular edema (DME). CLINICAL RELEVANCE: Macular laser remains an important and cost effective treatment option for vision loss secondary to DME. Although anti-VEGF therapy is often first-line, macular laser is of utility in low-resource or remote settings, for patients at risk of loss to follow-up, and for DME not meeting country-specific reimbursement criteria for anti-VEGF therapy. Subthreshold laser is a modality that does not produce clinical or histologic evidence of thermal damage, thereby potentially limiting the common complications of conventional laser. METHODS: Ovid MEDLINE, EMBASE, and CENTRAL databases were searched for randomized controlled trials (RCTs) from inception to September 28, 2022. Meta-analyses were performed using random-effects modeling. Data were collected at 12 and 24 months for best-corrected visual acuity (BCVA), central retinal thickness, diabetic retinopathy severity scale, rate of adverse events, rate of enrolled patients not completing treatment, rate of patients receiving retreatment, and quality-of-life measures. The risk of bias and certainty of evidence were assessed using Cochrane's Risk-of-Bias version 2 and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) frameworks, respectively. Subgroup analysis was performed between subthreshold laser modalities and evaluated with Instrument to assess the Credibility of Effect Modification Analyses tool. RESULTS: Fourteen RCTs comprising 514 eyes receiving conventional laser and 574 eyes receiving subthreshold laser were included. Subthreshold laser likely results in no difference to BCVA (moderate GRADE certainty) compared with conventional laser. Conventional laser demonstrated a small, statistically significant improvement in central retinal thickness (low GRADE certainty); however, the magnitude of this improvement is unlikely to be clinically important. There may not be a difference in the rate of adverse events (low GRADE certainty) at 12 months when comparing subthreshold laser to conventional laser for DME. CONCLUSION: Randomized controlled trial literature to date suggests subthreshold laser to be as effective as conventional laser in the treatment of DME. Increased follow-up duration is needed to observe any long-term safety benefit from reduced retinal damage. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Natural History and Surgical Outcomes of Lamellar Macular Holes.

PURPOSE: To assess the natural history and surgical outcomes of lamellar macular holes (LMHs). DESIGN: Retrospective and consecutive case series. SUBJECTS: Patients with LMHs from multiple tertiary care centers. METHODS: Clinical charts and OCT scans were reviewed. MAIN OUTCOME MEASURES: The visual acuity (VA) changes and the occurrence rate of full-thickness macular hole (FTMH) were studied in both groups. Within the operated group, factors associated with 6-month VA and development of FTMH were explored. RESULTS: One hundred seventy-eight eyes were included, of which 89 were monitored and 89 underwent surgery. In the observation group, the mean VA decreased from 0.25 ± 0.18 to 0.28 ± 0.18 logarithm of the minimum angle of resolution (logMAR; P = 0.13), with 14 eyes (15.7%) that lost ≥ 0.2 logMAR VA, after 45.7 ± 33.3 months. Nine eyes (10.1%) spontaneously developed an FTMH. In the operated group, the mean VA increased from 0.47 ± 0.23 to 0.35 ± 0.25 logMAR at 6 months (P < 0.001) and 0.36 ± 0.28 logMAR (P = 0.001) after 24.1 ± 30.1 months. By multivariate analysis, better baseline VA (P < 0.001), the presence of an epiretinal membrane (P = 0.03), and the peeling of the internal limiting membrane (ILM; P = 0.02), with a greater effect of ILM perihole sparing, were associated with a greater 6-month VA. Perihole epiretinal proliferation sparing was associated with a better postoperative VA by univariate analysis (P = 0.03), but this was not significant by multivariate analysis. Eight eyes (9.0%) developed a postoperative FTMH. Using Cox proportional hazard ratios [HRs], pseudophakia at baseline (HR, 0.06; 95% confidence interval [CI], 0.00-0.75; P = 0.03) and peeling of the ILM (HR, 0.05; 95% CI, 0.01-0.39; P = 0.004) were protective factors, while ellipsoid zone disruption (HR, 10.5; 95% CI, 1.04-105; P = 0.05) was associated with an increased risk of FTMH. CONCLUSION: Observed eyes with LMH experienced, on average, progressive VA loss. Patients with LMH and altered vision may benefit from surgery. Internal limiting membrane peeling, with perihole ILM sparing, represents a crucial step of the surgery associated with a greater VA and a lower risk of postoperative FTMH. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Biomedical Data Annotation: An OCT Imaging Case Study.

In ophthalmology, optical coherence tomography (OCT) is a widely used imaging modality, allowing visualisation of the structures of the eye with objective and quantitative cross-sectional three-dimensional (3D) volumetric scans. Due to the quantity of data generated from OCT scans and the time taken for an ophthalmologist to inspect for various disease pathology features, automated image analysis in the form of deep neural networks has seen success for the classification and segmentation of OCT layers and quantification of features. However, existing high-performance deep learning approaches rely on huge training datasets with high-quality annotations, which are challenging to obtain in many clinical applications. The collection of annotations from less experienced clinicians has the potential to alleviate time constraints from more senior clinicians, allowing faster data collection of medical image annotations; however, with less experience, there is the possibility of reduced annotation quality. In this study, we evaluate the quality of diabetic macular edema (DME) intraretinal fluid (IRF) biomarker image annotations on OCT B-scans from five clinicians with a range of experience. We also assess the effectiveness of annotating across multiple sessions following a training session led by an expert clinician. Our investigation shows a notable variance in annotation performance, with a correlation that depends on the clinician's experience with OCT image interpretation of DME, and that having multiple annotation sessions has a limited effect on the annotation quality.

Patient-Reported Outcome Measure Use in Guidelines Published by the American Academy of Ophthalmology: A Review.

TOPIC: We reviewed the use of patient-reported outcome measures (PROMs) in the treatment of ophthalmologic conditions as recommended by the Clinical Practice Guidelines (CPGs) published by the American Academy of Ophthalmology (AAO). CLINICAL RELEVANCE: Patient-reported outcome measures are standardized instruments that provide information regarding a patient's health status or health-related quality of life. Patient-reported outcome measures are increasingly used to inform study end points in ophthalmology studies. However, the extent to which PROMs are ultimately informing patient management recommendations in ophthalmology as part of CPGs remains an area of evidence gap. METHODS: We included all CPGs published by the AAO from inception to June 2022. We also included all primary studies and systematic reviews cited in the treatment sections of the CPGs evaluating treatment of an ophthalmic condition. The primary outcome was the frequency of PROMs discussed in CPGs and in cited studies evaluating treatment. Secondary outcomes included frequency of minimal important difference (MID) use to contextualize PROM results and percentage of strong and discretionary recommendations supported by PROMs. We published a study protocol a priori on PROSPERO (CRD42022307427). Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We assessed risk of bias using the Appraisal of Guidelines, Research and Evaluation II (AGREE II) instrument. RESULTS: We identified 24 eligible CPGs, providing 2458 cited studies (2191 primary, 267 secondary) evaluating treatment of eye conditions. Ten CPGs (41.7%) reported consideration of PROMs. Of these, 31 of 94 (33%) recommendations were informed by studies evaluating a PROM as an outcome. Across all studies cited in the development of CPGs, 221 (9.0%) used PROMs as a primary or secondary outcome, of which 4 PROM results (1.8%) were interpreted using an empirically determined MID. Overall, the risk of bias was low for all CPGs. CONCLUSIONS: Overall, outcomes of PROMs are seldom used in ophthalmology CPGs published by the AAO and in cited primary and secondary research on treatments. When PROMs were considered, their interpretation was seldom based on an MID. To improve patient care, guideline developers may consider incorporating PROMs and applicable MIDs to inform key outcomes when formulating treatment recommendations. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Expansile gas kinetics for pneumatic retinopexy.

PURPOSE: To study the behaviour of expansile intravitreal gases and air used in treating rhegmatogenous retinal detachment. METHODS: A validated mathematical model of gas expansion and absorption in human eyes was used to simulate the effect of varying volumes of pure air, SF6, C2F6 and C3F8 injected into the vitreous cavity. Variation in axial length was accounted for by using three different vitreous cavity volumes to represent hypermetropic, emmetropic and myopic eyes. RESULTS: The time course of varying volumes of pure air and fluorinated gases injected into the vitreous cavity were tabulated, with calculated parameters including volume of gas, percentage gas fills and corresponding retinal contact angles at different time points. CONCLUSION: We produced a comprehensive compilation of expansive gas kinetics aiming to facilitate surgeon selection of the most suitable choice of gas and volume to use, tailored to an individual patient's clinical need.

Stratifying the risk of re-detachment: variables associated with outcome of vitrectomy for rhegmatogenous retinal detachment in a large UK cohort study.

INTRODUCTION: To identify variables associated with primary anatomical outcome following vitrectomy and internal tamponade for rhegmatogenous retinal detachment (RD). METHODS: A retrospective analysis of prospectively collected data, using a database of RD treated with vitrectomy and internal tamponade. Collected data complied with the RCOphth Retinal Detachment Dataset. The main outcome measure was anatomical failure within six months of surgery. RESULTS: There were 6377 vitrectomies. 869 eyes were excluded, either because no outcome was recorded, or inadequate follow up, leaving 5508 operations for analysis. 63.9% of patients were male, and the median age was 62. Primary anatomical failure occurred in 13.9%. On multivariate analysis, the following were associated with increased risk of failure: age <45, or >79, inferior retinal breaks, total detachment, one quadrant or greater inferior detachment, low density silicone oil, and presence of proliferative vitreoretinopathy. C2F6 tamponade, cryotherapy, and 25 G vitrectomy, were associated with reduced risk of failure. The area under the receiver operator curve was 71.7%. According to this model, 54.3% of RD are at low risk (<10%), 35.6% are at moderate risk (10-25%), and 10.1% are at high risk (>25%) of failure. CONCLUSIONS: Previous attempts to identify high risk RD have been limited by small numbers, the inclusion of both scleral buckling and vitrectomy, or by excluding some types of RD. This study examined outcomes in unselected RD, treated by vitrectomy. Identification of the variables associated with anatomical outcome after RD surgery enables accurate risk stratification, which is valuable for patient counselling and selection, and for future clinical trials.

Diabetic retinopathy progression in patients under monitoring for treatment or vision loss: external validation and update of a multivariable prediction model.

INTRODUCTION: The number of people with diabetes mellitus is increasing globally and consequently so too is diabetic retinopathy (DR). Most patients with diabetes are monitored through the diabetic eye screening programme (DESP) until they have signs of retinopathy and these changes progress, requiring referral into hospital eye services (HES). Here, they continue to be monitored until they require treatment. Due to current pressures on HES, delays can occur, leading to harm. There is a need to triage patients based on their individual risk. At present, patients are stratified according to retinopathy stage alone, yet other risk factors like glycated haemoglobin (HbA1c) may be useful. Therefore, a prediction model that combines multiple prognostic factors to predict progression will be useful for triage in this setting to improve care.We previously developed a Diabetic Retinopathy Progression model to Treatment or Vision Loss (DRPTVL-UK) using a large primary care database. The aim of the present study is to externally validate the DRPTVL-UK model in a secondary care setting, specifically in a population under care by HES. This study will also provide an opportunity to update the model by considering additional predictors not previously available. METHODS AND ANALYSIS: We will use a retrospective cohort of 2400 patients with diabetes aged 12 years and over, referred from DESP to the NHS hospital trusts with referable DR between 2013 and 2016, with follow-up information recorded until December 2021.We will evaluate the external validity of the DRPTVL-UK model using measures of discrimination, calibration and net benefit. In addition, consensus meetings will be held to agree on acceptable risk thresholds for triage within the HES system. ETHICS AND DISSEMINATION: This study was approved by REC (ref 22/SC/0425, 05/12/2022, Hampshire A Research Ethics Committee). The results of the study will be published in a peer-reviewed journal, presented at clinical conferences. TRIAL REGISTRATION NUMBER: ISRCTN 10956293.

INTRAOCULAR EMULSION OF SILICONE OIL (ITEMS) GRADING SYSTEM: An Evidence-Based Expert-Led Consensus.

PURPOSE: To propose the InTraocular EMulsion of Silicone oil (ITEMS) grading system for the assessment of silicone oil (SiO) emulsion, applicable in a routine clinical setting and validated through an expert-led consensus procedure. METHODS: Seven experts on intraocular liquid tamponades, led by a facilitator, performed a literature review on the detection of SiO emulsion. Based on the proposed ideas, a questionnaire was developed and submitted to the experts on the methods to detect SiO emulsion and the items to grade. After 2 rounds of individual ranking using a 9-point scale and related discussion, the final grading system was developed including items that reached consensus (score ≥7 from ≥75% of members). RESULTS: The agreed ITEMS grading system includes the identification of SiO microbubbles and large SiO bubbles through slit-lamp biomicroscopy, gonioscopy, fundus examination under mydriasis, or ultra-wide-field fundus photography. Moreover, macular and disk optical coherence tomography are used to detect SiO-associated hyperreflective dots. CONCLUSION: An evidence-based expert-led consensus was conducted to develop grading system of SiO emulsion, allowing, for the first time, homogenous collection of data on SiO emulsion. This has the potential to improve the understanding of the role and clinical relevance of SiO emulsion, allowing comparisons between different studies.