The UK clinical eye research strategy: refreshing research priorities for clinical eye research in the UK.

OBJECTIVES: To validate and update the 2013 James Lind Alliance (JLA) Sight Loss and Vision Priority Setting Partnership (PSP)'s research priorities for Ophthalmology, as part of the UK Clinical Eye Research Strategy. METHODS: Twelve ophthalmology research themes were identified from the JLA report. They were allocated to five Clinical Study Groups of diverse stakeholders who reviewed the top 10 research priorities for each theme. Using an online survey (April 2021-February 2023), respondents were invited to complete one or more of nine subspecialty surveys. Respondents indicated which of the research questions they considered important and subsequently ranked them. RESULTS: In total, 2240 people responded to the survey (mean age, 59.3 years), from across the UK. 68.1% were female. 68.2% were patients, 22.3% healthcare professionals or vision researchers, 7.1% carers, and 2.1% were charity support workers. Highest ranked questions by subspecialty: Cataract (prevention), Cornea (improving microbial keratitis treatment), Optometric (impact of integration of ophthalmic primary and secondary care via community optometric care pathways), Refractive (factors influencing development and/or progression of refractive error), Childhood onset (improving early detection of visual disorders), Glaucoma (effective and improved treatments), Neuro-ophthalmology (improvements in prevention, diagnosis and treatment of neurodegeneration affecting vision), Retina (improving prevention, diagnosis and treatment of dry age-related macular degeneration), Uveitis (effective treatments for ocular and orbital inflammatory diseases). CONCLUSIONS: A decade after the initial PSP, the results refocus the most important research questions for each subspecialty, and prime targeted research proposals within Ophthalmology, a chronically underfunded specialty given the substantial burden of disability caused by eye disease.

Proliferative Sickle Cell Retinopathy: A Patient and a Physician's Perspective on Quality of Life and Quality of Eye Care.

The impact of visual impairment in the context of sickle cell disease is poorly understood. Despite the significant advancements over the past three decades in retinal imaging and in the understanding of molecular mechanisms that drive retinal neovascularization, there has been little improvement in the management of proliferative sickle cell retinopathy. This article is co-authored by a patient impacted by proliferative sickle cell retinopathy. She highlights her personal experience of sight loss from proliferative sickle cell retinopathy and the impact on her daily life and mental health. Subsequent to diagnosis and management of proliferative sickle cell retinopathy, she continues to live with irreversible sight loss and provides crucial insight from a patient's perspective into the broad lack of high-quality educational materials online and lack of understanding of the disease within the clinical community. This article aims to provide a strong narrative to emphasize the need for further qualitative and quantitative research in this area, to bring about the holistic step-change required to improve visual outcomes and eyecare for people with sickle cell disease.

Sickle Eye Project: a cross-sectional, non-interventional study of the prevalence of visual impairment due to sickle cell retinopathy and maculopathy in the UK.

INTRODUCTION: Sickle cell disease (SCD) is one of the most common genetic disorders in the UK, with over 15 000 people affected. Proliferative sickle cell retinopathy (SCR) is a well-described complication of SCD and can result in significant sight loss, although the prevalence in the UK is not currently known. There are currently no national screening guidelines for SCR, with wide variations in the management of the condition across the UK. METHODS AND ANALYSIS: The Sickle Eye Project is an epidemiological, cross-sectional, non-interventional study to determine the prevalence of visual impairment due to SCR and/or maculopathy in the UK. Haematologists in at least 16 geographically dispersed hospitals in the UK linked to participating eye clinics will offer study participation to consecutive patients meeting the inclusion criteria attending the sickle cell clinic. The following study procedures will be performed: (a) best corrected visual acuity with habitual correction and pinhole, (b) dilated slit lamp biomicroscopy and funduscopy, (c) optical coherence tomography (OCT), (d) OCT angiography where available, (e) ultrawide fundus photography, (f) National Eye Institute Visual Function Questionnaire-25 and (g) acceptability of retinal screening questionnaire. The primary outcome is the proportion of people with SCD with visual impairment defined as logarithm of the minimum angle of resolution ≥0.3 in at least one eye. Secondary outcomes include the prevalence of each stage of SCR and presence of maculopathy by age and genotype; correlation of stage of SCR and maculopathy to severity of SCD; the impact of SCR and presence of maculopathy on vision-related quality of life; and the acceptability to patients of routine retinal imaging for SCR and maculopathy. ETHICS AND DISSEMINATION: Ethical approval was obtained from the South Central-Oxford A Research Ethics Committee (REC 23/SC/0363). Findings will be reported through academic journals in ophthalmology and haematology.

Patient acceptability of intravitreal complement inhibitors in geographic atrophy (GA): protocol for a UK-based cross-sectional study.

INTRODUCTION: Geographic atrophy (GA) is the advanced form of the non-neovascular ('dry') type of age-related macular degeneration (AMD). Previously untreatable, complement inhibitors delivered by regular intravitreal injections have recently been demonstrated to slow down the progression of GA lesions in phase 3 trials. One such treatment, Syfovre (pegcetacoplan), was approved by the US Food and Drug Administration in February 2023. These therapies slow down, but do not stop or reverse, the progression of GA; they may also increase the risk of developing the neovascular ('wet') type of AMD. In light of these developments, this study aims to quantify the acceptability of these new intravitreal injection treatments to patients with GA in the UK and explore factors that may influence the acceptability of these treatments. METHODS AND ANALYSIS: In this cross-sectional, non-interventional study, the primary objective is to determine the proportion of patients with GA that find regular intravitreal therapy acceptable for slowing the progression of GA. We will use a validated acceptability questionnaire in order to quantify the acceptability of new treatments among patients with GA. The correlation between acceptability and functional and structural biomarkers of GA will be established. We will also explore demographic, general health and ocular factors that may influence acceptability. 180 individuals with a diagnosis of GA will be recruited from 7 to 8 participating National Health Service trusts across the UK. Multiple regression analysis will be conducted to determine the simultaneous effects of multiple factors on patient acceptability. ETHICS AND DISSEMINATION: The study received ethical approval from the Health Research Authority on 14 March 2023 (IRAS Project ID: 324854). Findings will be disseminated through peer-reviewed publications and conference presentations to the medical retina community, as well as through dialogue with patients and macular disease charities.

Piloting a forced-choice task to elicit treatment preferences in geographic atrophy.

OBJECTIVE: Geographic Atrophy (GA) is the advanced form of the non-neovascular ('dry') type of age-related macular degeneration (AMD) and responsible for one-quarter of legal blindness in the UK. New therapies delivered by intravitreal injection are in late-stage development, and two such therapies (pegcetacoplan (Syfovre) and avacincaptad pegol (Izervay)) have now been approved for clinical use by the US Food and Drug Administration. These therapies slow down, but do not stop or reverse, progression of GA and they may also increase the risk of developing the neovascular ('wet') type of AMD. Within a larger study exploring the acceptability of these new treatments to people living with GA, we developed a forced-choice exercise to evaluate how participants weigh up benefits and drawbacks of different treatment regimens. This research note reports quantitative and qualitative findings from this exercise. RESULTS: Twenty-eight participants took part in this exercise. The exercise demonstrated that participants were generally, although not unanimously, in favour of less frequent treatment for GA that was slightly less efficacious in terms of preserving visual function but presented a lower risk of developing wet AMD. Even among a small sample, the exercise demonstrated the highly personal and idiosyncratic decision-making processes influencing participants' choices of preferred hypothetical GA treatment.

Exploring patient acceptability of emerging intravitreal therapies for geographic atrophy: A mixed-methods study.

BACKGROUND/OBJECTIVES: The acceptability of emerging intravitreal therapies for patients with Geographic Atrophy (GA) is currently unknown. This study therefore aimed to investigate the extent to which regular intravitreal injections may be acceptable to GA patients. SUBJECTS/METHODS: Thirty UK-based individuals with GA secondary to age-related macular degeneration (AMD), recruited from two London-based hospitals, were interviewed in April-October 2021 regarding acceptability of new GA treatments. Participants responded to a structured questionnaire, as well as open-ended questions in a semi-structured interview. The Theoretical Framework of Acceptability (TFA) informed framework analysis of the qualitative data. RESULTS: Twenty participants (67%) were female, and median (interquartile range (IQR)) age was 83 (78, 87) years. 37% of participants had foveal centre-involving GA, and better eye median (IQR) logMAR visual acuity was 0.30 (0.17, 0.58). Data suggested that 18 participants (60% (95% CI: 41-79%)) would accept the treatment, despite awareness of potential drawbacks. Eight participants (27% (95% CI: 10-43%) were ambivalent or undecided about treatment, and four (13%) (95% CI: 0-26%) would be unlikely to accept treatment. Reducing the frequency of injections from monthly to every other month increased the proportion of participants who considered the treatments acceptable. Conversely, factors limiting acceptability clustered around: the limited magnitude of treatment efficacy; concerns about side effects or the increased risk of neovascular AMD; and the logistical burden of regular clinic visits for intravitreal injections. Misunderstandings of potential benefits indicate the need for appropriately-designed patient education tools to support decision-making. CONCLUSIONS: Our study suggests a majority of participants would be positive about intravitreal treatment for GA, in spite of potential burdens.

Towards a Therapy for Geographic Atrophy: A Patient's Experience.

Purpose: Geographic atrophy (GA) is the advanced form of the non-neovascular (dry) type of age-related macular degeneration. Presently, GA cannot be treated. However, new therapies administered by intravitreal injection are in late-stage development. These can slow down, but do not stop or reverse, GA progression. The acceptability of these emerging therapies to people with GA is currently unknown. The present case study explores the perspectives of a person living with GA who took part in the terminated Phase 3 clinical trial of Lampalizumab, a candidate intravitreal treatment for GA. We explored this patient's perspective on the retrospective acceptability of regular Lampalizumab injections, and the prospective acceptability of future intravitreal therapies for GA. Patients and Methods: A 78-year-old woman living in the UK was recruited as part of a mixed-methods pilot study and interviewed by telephone, regarding: her experience of the Lampalizumab trial injections; and her thoughts regarding emerging intravitreal therapies for GA. The Framework Method was used for initial inductive analysis of the interview transcript. Subsequently, deductive analysis was undertaken, informed by the Theoretical Framework of Acceptability (TFA). Results: For this participant, intravitreal injections in the Lampalizumab trial were acceptable, although streamlining processes within the clinic would have improved the patient experience. Regarding prospective acceptability of new intravitreal therapies, the participant considered a delay in progression of GA a valuable goal. Potential discomfort, anxiety and inconvenience associated with regular intravitreal injections would be acceptable in the context of preserving her vision for as long as possible. Conclusion: Analysis of one participant's experience demonstrates the value of exploring GA patients' unique views on the acceptability of new intravitreal treatments. Larger prospective studies will provide more insight that help to optimise treatment design and delivery, thereby maximising likelihood of adherence and persistence when these therapies eventually arrive in clinic.

Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease (HERMES): a Cluster Randomised Superiority Trial with a linked Diagnostic Accuracy Study-HERMES study report 1-study protocol.

INTRODUCTION: Recent years have witnessed an upsurge of demand in eye care services in the UK. With a large proportion of patients referred to Hospital Eye Services (HES) for diagnostics and disease management, the referral process results in unnecessary referrals from erroneous diagnoses and delays in access to appropriate treatment. A potential solution is a teleophthalmology digital referral pathway linking community optometry and HES. METHODS AND ANALYSIS: The HERMES study (Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease: a cluster randomised superiority trial with a linked diagnostic accuracy study) is a cluster randomised clinical trial for evaluating the effectiveness of a teleophthalmology referral pathway between community optometry and HES for retinal diseases. Nested within HERMES is a diagnostic accuracy study, which assesses the accuracy of an artificial intelligence (AI) decision support system (DSS) for automated diagnosis and referral recommendation. A postimplementation, observational substudy, a within-trial economic evaluation and discrete choice experiment will assess the feasibility of implementation of both digital technologies within a real-life setting. Patients with a suspicion of retinal disease, undergoing eye examination and optical coherence tomography (OCT) scans, will be recruited across 24 optometry practices in the UK. Optometry practices will be randomised to standard care or teleophthalmology. The primary outcome is the proportion of false-positive referrals (unnecessary HES visits) in the current referral pathway compared with the teleophthalmology referral pathway. OCT scans will be interpreted by the AI DSS, which provides a diagnosis and referral decision and the primary outcome for the AI diagnostic study is diagnostic accuracy of the referral decision made by the Moorfields-DeepMind AI system. Secondary outcomes relate to inappropriate referral rate, cost-effectiveness analyses and human-computer interaction (HCI) analyses. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Bromley Research Ethics Committee (REC 20/LO/1299). Findings will be reported through academic journals in ophthalmology, health services research and HCI. TRIAL REGISTRATION NUMBER: ISRCTN18106677 (protocol V.1.1).

Correction: Aflibercept for treatment-naïve diabetic macula oedema in a multi-ethnic population: Real-world outcomes from North West London.

[This corrects the article DOI: 10.1371/journal.pone.0246626.].

Factors Influencing Response to Aflibercept in Diabetic Macular Oedema Patients in a Diverse North West London Population: A Real-World Study.

BACKGROUND: Diabetic macular oedema (DMO) is the leading cause of sight impairment in working age populations in developed countries. Current first line treatment for centre-involving DMO involves intravitreal anti-VEGF but treatment response can be variable. In this retrospective, real world, multi-centre cohort study, we aim to identify ocular and systemic characteristics that correlate with anatomical and functional outcomes for treatment-naive DMO patients treated with intravitreal aflibercept. METHODS: Retrospective multicentre cohort study of treatment-naive DMO patients initiated on aflibercept at three North West London hospitals between 2016 and 2018. Baseline systemic and ocular factors, best corrected visual acuity (BCVA) and central macular thickness (CMT) at 12 months were determined and statistically analysed. RESULTS: A total of 270 eyes of 221 DMO patients met inclusion criteria. Mean age was 62.8 ± 12.1, mean baseline HbA1c was 67 ± 20 mmol/mol, and mean eGFR was 72 mL/min/1.7m2. Mean number of aflibercept injections at 12 months was 6.2. Better baseline BCVA, lower baseline CMT, and absence of epiretinal membrane (ERM) were associated with better BCVA at 12 months whilst lower baseline CMT and proliferative retinopathy status were associated with lower CMT at 12 months. CONCLUSION: Our study is the largest real-world dataset examining factors influencing functional and anatomical response to aflibercept in DMO in the UK. Older age, lower baseline BCVA, higher baseline CMT and more severe diabetic retinopathy were associated with poorer visual acuity at 12 months and prioritisation of these patients within a pressured healthcare setting is recommended.

Acceptability of intravitreal injections in geographic atrophy: protocol for a mixed-methods pilot study.

INTRODUCTION: Age-related macular degeneration (AMD) is a common cause of visual impairment, affecting central vision. Geographic atrophy (GA) is an advanced form of the non-neovascular (dry) type of AMD. Late-stage clinical trials suggest that intravitreal injections of novel therapeutics may slow down the rate of GA progression by up to 30% in 1 year, thus allowing people with GA to preserve central vision for a longer period. While intravitreal injections have become an established treatment modality for neovascular (wet) AMD, it is unknown whether patients with (more gradually progressing) GA would accept regular injections that slow down, but do not stop or reverse, vision loss. Therefore, this mixed-methods pilot study will aim to explore whether regular intravitreal injections will be acceptable as treatment for patients with GA, and the factors that may affect treatment acceptability. METHODS AND ANALYSIS: A mixed-methods survey has been designed in collaboration with a GA patient advisory group. The survey comprises of structured questionnaires, semi-structured interview questions regarding patients' perceptions of intravitreal injections and the burden of treatment, and a task eliciting preferences between different potential treatments. Due to COVID-19 restrictions, this study will be conducted remotely by telephone. Thirty individuals will be recruited from NHS Medical Retina clinics at Central Middlesex Hospital, London. Half of the participants will be naïve to intravitreal injections, while half will have previous experience of intravitreal injections for neovascular (wet) AMD. Qualitative data analysis will be conducted using the Framework Method of analysis to identify key themes from participants' accounts. ETHICS AND DISSEMINATION: The study received Health Research Authority approval on 23 March 2021 (IRAS Project ID: 287824). Findings will be disseminated through peer-reviewed publications and conference presentations to the medical retina community, as well as through dialogue with patients and macular disease charities.

Aflibercept for treatment-naïve diabetic macula oedema in a multi-ethnic population: Real-world outcomes from North West London.

PURPOSE: To evaluate the clinical outcomes of patients with treatment-naïve diabetic macula oedema (DMO) treated with Aflibercept in routine clinic settings in ethnically diverse North West London (NWL) and compare to outcomes reported in the VIVID and VISTA clinical trials. METHODS: This was a retrospective multicentre interventional case series. Two hundred and seventy eyes of 221 treatment-naïve patients at three NWL hospitals initiated on Aflibercept and who had at least 12 months follow-up were included in the study. Visual acuity, central subfield thickness and macula volume were recorded at baseline, month 3, 6 and 12. RESULTS: There were significant differences between the NWL cohort and participants in the VIVID and VISTA trials at baseline including higher HbA1c and a higher proportion of eyes with proliferative diabetic retinopathy in the NWL cohort. The mean VA, mean CSFT and mean MV at baseline was 66.4 (± 14.6) letters, 417 (± 94) µm and 10.3 (± 1.9) mm3. The mean VA gain at 12 months was 4.0 (± 11.8) letters (p < 0.001); a total of 26% of eyes gained ≥ 10 letters, 15% of eyes gained ≥ 15 letters and 6% lost ≥15 letters. At 12-months, the mean reduction in CSFT was 108 (± 96) µm (p<0.001) and the mean reduction in MV was 1.05 (± 1.21) mm3 (p<0.001). An average of 6.2 (± 2.3) injections was given over 12 months. There was a significant association between functional and anatomical response category at 3 months and response category at 12 months (p<0.001). CONCLUSION: The effectiveness of treatment with Aflibercept for patients in NWL was meaningfully lower than was reported in the VIVID and VISTA clinical trials. A high proportion of patients with good visual acuity at baseline, poorer glycaemic control, worse diabetic retinopathy and under-treatment likely contributed to lower functional and anatomical outcomes.

The relationship between a dissociated optic nerve fibre layer appearance after macular hole surgery and Muller cell debris on peeled internal limiting membrane.

PURPOSE: A dissociated optic nerve fibre layer (DONFL) is a characteristic change noted in inner retinal morphology after internal limiting membrane (ILM) peeling. It is thought to be due to trauma to Muller cells as the ILM is peeled from their attached end plates. In this study, we aimed to determine the extent and size of Muller cell debris on the retinal side of excised ILM and assess whether this correlated with the extent of DONFL observed postoperatively. METHOD: Prospective single centre study of a consecutive series of patients undergoing macular hole surgery. Transmission electron microscopy of the ILM was used to assess Muller cell debris and postoperative spectral domain optical coherence tomography (SD-OCT) to assess the extent of DONFL. A variety of other pre- and postoperative features was also included. RESULTS: Thirty-nine patients were analysed. There were retinal dimples characteristic of DONFL detected on SD-OCT in all 39 eyes. The portion of the retinal side of the ILM specimen covered by cellular debris ranged from 12% to 49%, with a median of 28%. Using linear regression, the percentage of retinal debris, the size of the debris and the postoperative visual acuity were significantly positively associated with the DONFL score. The total R squared for the model was 63.9%. CONCLUSION: The extent of DONFL observed postoperatively can be partly explained by the amount of retinal side cellular debris on the retinal side of the peeled ILM. Surgical strategies which minimize this material could reduce the extent of DONFL.

A Novel Technique for Repositioning of a Migrated ILUVIEN(®) (Fluocinolone Acetonide) Implant into the Anterior Chamber.

INTRODUCTION: Fluocinolone acetonide (FAc) intravitreal implant (ILUVIEN(®); Alimera Sciences Limited, Aldershot, UK) has been approved in the UK for the treatment of chronic diabetic macula edema, insufficiently responsive to available therapies. It is inserted into the vitreous cavity through a 25-gauge needle. Migration of the implant to the anterior chamber (AC) can occur through gaps in the posterior capsule especially in vitrectomized eyes. Early removal of AC-dislocated FAc implant is essential to prevent corneal edema and damage from raised intraocular pressure. AIM: To demonstrate a simple and novel technique, with a previous capsular tear, for removal of AC-migrated FAc implant and reinsertion into the vitreous cavity without compromising implant integrity. METHOD: A side port incision was created with a keratome and an anterior chamber maintainer introduced and secured. Subsequently, a corneal incision was created at 12 o'clock through which a 23-gauge backflush needle (flute needle) was advanced into the anterior chamber and passive suction used to secure the implant. The flute needle was then placed through the defect in the posterior capsule and the exit port blocked, causing loss of suction and allowing the implant to fall into the posterior segment. The sulcus intraocular lens (IOL) was centralized simply by manipulating it approximately 180 degrees to provide adequate anterior capsule support. RESULTS: The FAc implant was successfully removed from AC in two patients and reinserted into the vitreous cavity without damage or complications either for the eye or the implant. IOL in both patients were repositioned to close the gap in posterior capsule. After 2 months, the implant remains in the vitreous cavity. This paper presents data from one of these cases. CONCLUSION: Using 23-gauge flute needle to retrieve dislocated FAc implant is a safe and easy technique. FUNDING: Alimera Sciences Ltd.

The Case Mix of Patients Presenting with Full-Thickness Macular Holes and Progression before Surgery: Implications for Optimum Management.

AIMS: Analysis of pre-operative spectral domain optical coherence tomography (SD-OCT) characteristics of full-thickness macular holes (FTMH) and effect on optimum management. METHODS: We retrospectively reviewed SD-OCT characteristics of a consecutive cohort of patients waitlisted for FTMH surgery and categorized them by current evidence-based treatments. RESULTS: Out of the 106 holes analysed, 36 were small, 40 medium and 30 large. Initially, 33 holes had vitreomacular adhesion (VMA). 41 holes were analysed for change in characteristics with a median duration of 8 weeks between the scans. The number of small or medium holes decreased from 20 to 6 and that of large holes doubled. The number of holes with VMA halved. Smaller hole size (p = 0.014) and being phakic (p = 0.048) were associated with a larger increase in size. The strongest predictor of hole progression into a different surgical management category was the presence of VMA. CONCLUSION: FTMH characteristics can change significantly pre-operatively and affect optimal treatment choice.

ILM peeling technique influences the degree of a dissociated optic nerve fibre layer appearance after macular hole surgery.

PURPOSE: We sought to assess the effect of two different internal limiting membrane [ILM] peeling techniques carried out during surgery for idiopathic macular holes on the postoperative extent of a dissociated optic nerve fibre layer appearance [DONFL]. METHODS: We collected prospective data of surgical records, videos, and pre- and postoperative imaging of a consecutive series of patients undergoing surgery for idiopathic macular hole with one of two surgeons. One surgeon used a forceps pinch-peel technique to peel the ILM, whereas the other surgeon used a diamond dusted membrane scraper. The extent of any DONFL was measured using spectral domain optical coherence tomography and blue reflectance imaging at three months postoperatively. A proportion of the ILMs removed were examined with transmission electron microscopy. RESULTS: Fifty-seven patients were studied, with 41 in the forceps group and 16 in the scraper group. The groups were well matched, with no significant difference in any preoperative parameters. Some degree of DONFL was observed on the 3-month blue reflectance images in 88 % of the forceps group and 100 % of the scraper group [p = 0.14]. There was a significant difference in the total number of depressions in the nerve fibre layer typical of DONFL on OCT between the two groups [p = 0.001], and general regression analysis showed that the peeling technique used had the only significant association with the degree of DONFL observed. Electron microscopy showed large patches of cellular debris on the retinal side of the peeled ILM in 3 out of 4 cases in the scraper group and 1 out of 12 cases in the forceps group. CONCLUSION: ILM peeling technique and possibly other surgeon-specific factors appear to influence the extent of DONFL observed after ILM peeling macular hole surgery.