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.

Real-world service costs for neovascular-AMD clinics in the United Kingdom: structured literature review and scenario analysis.

OBJECTIVE: Current cost-effectiveness analyses (CEA) emphasize drug costs as the differentiator between NICE recommended anti-VEGF treatments but may neglect real-world non-drug costs of running nAMD services in the UK. To address this, this study identified real-world non-drug service cost items relevant to UK NHS nAMD clinics, including costs arising from operational strain (demand exceeding capacity). METHODS: Cost items were identified by a structured literature review of peer-reviewed and grey literature, and an expert panel of 10 UK-based ophthalmologists with relevance to real-world practice. These items underwent meta-synthesis and were then determined in a consensus exercise. RESULTS: Of 237 cost items identified, 217 (91.6%) met the consensus threshold of >0.51 and were included in the nAMD Service Non-Drug Cost Instrument (nAS). Sensitivity of cost items taken from UK Health Technology Assessment (HTA) using the nAS as the reference standard was low (HTAmin: 1.84%, 95% CI 0.50-4.65%; HTAmax: 70.51%, 95% CI 63.96-76.49%). False negative rates showed variable likelihood of misclassifying a service by cost burden depending on prevalence. Scenario analysis using cost magnitudes estimated annual per-patient clinic cost at £845 (within capacity) to £13,960 (under strain) compared to an HTAmin estimate of £210. Accounting for cost of strain under an assumed 50% increase in health resource utilization influenced cost-effectiveness in a hypothetical genericisation scenario. CONCLUSION: Findings suggested that HTA underestimates UK NHS nAMD clinic cost burden with cost of strain contributing substantial additional unmeasured expense with impact on CEA. Given potential undertreatment due to strain, durability is suggested as one of the relevant factors in CEA of nAMD anti-VEGF treatments due to robustness under limited capacity conditions affecting UK ophthalmology services.

When considering how well treatments work versus how much they cost, the focus is usually only on the price of the medicine itself. However, other real-world costs exist. In the UK, when treating certain eye problems such as neovascular age-related macular degeneration (nAMD), there are additional expenses related to running clinics and managing treatments that often go unnoticed. To get a better understanding of these hidden costs, the study examined factors like clinic workload and the extra expenses that come with it. Ten eye doctors in the UK were consulted for their expert opinions and numerous research papers were reviewed to identify these additional costs. The study grouped different costs in a tool called the nAMD Service Non-Drug Cost Instrument (nAS). When the findings of the nAS tool were compared to the usual methods of calculating costs, it was found that the conventional approach overlooked many of the actual expenses. Busy clinics face unique challenges, such as higher operational costs associated with staffing for extended hours, emergency appointments, extended waiting times and the potential to miss optimal treatment windows. This can lead to disease progression and the onset of comorbidities, which require more complex and costly treatments. Recognizing these real costs is crucial when making decisions about treatments, especially when treatments require more frequent visits to eye clinics. This study emphasizes the importance of considering all expenses, not just the obvious ones like medication and doctor visits when determining the most effective way to manage eye conditions like nAMD in the UK.

Outcomes in PIC-Related CNV: Pooled Analysis of Individual Participant Data.

Choroidal neovascularization (CNV) affects 64-75% of eyes with punctate inner choroidopathy (PIC). Although anti-VEGF agents are considered first-line therapy, there is controversy regarding other modalities, such as immunosuppression. We performed a systematic review of individual participant data (IPD) and generated a dataset of 278 eyes with PIC-related CNV from 45 studies. Forty-two percent presented with moderate visual loss (MVL) or worse. Four different treatment modalities (anti-VEGF, photodynamic therapy, local immunosuppression, and systemic immunosuppression) and most combinations among them were represented. Anti-VEGF injections decreased the likelihood of MVL (Odds Ratio 0.3, p = .027), an effect moderated by presenting visual acuity and patient age. Eyes receiving more than 3 injections were more likely to receive additional therapeutic modalities. Increasing number of modalities was associated with longer follow-up time and did not improve vision. The beneficial effect of anti-VEGF injections persisted when controlling for presenting visual acuity and follow-up time.

Vitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease.

The first discovered vitamin, vitamin A, exists in a range of forms, primarily retinoids and provitamin carotenoids. The bioactive forms of vitamin A, retinol and retinoic acid, have many critical functions in body systems including the eye and immune system. Vitamin A deficiency is associated with dysfunctional immunity, and presents clinically as a characteristic ocular syndrome, xerophthalmia. The immune functions of vitamin A extend to the gut, where microbiome interactions and nutritional retinoids and carotenoids contribute to the balance of T cell differentiation, thereby determining immune status and contributing to inflammatory disease around the whole body. In the eye, degenerative conditions affecting the retina and uvea are influenced by vitamin A. Stargardt's disease (STGD1; MIM 248200) is characterised by bisretinoid deposits such as lipofuscin, produced by retinal photoreceptors as they use and recycle a vitamin A-derived chromophore. Age-related macular degeneration features comparable retinal deposits, such as drusen featuring lipofuscin accumulation; and is characterised by parainflammatory processes. We hypothesise that local parainflammatory processes secondary to lipofuscin deposition in the retina are mediated by T cells interacting with dietary vitamin A derivatives and the gut microbiome, and outline the current evidence for this. No cures exist for Stargardt's or age-related macular degeneration, but many vitamin A-based therapeutic approaches have been or are being trialled. The relationship between vitamin A's functions in systemic immunology and the eye could be further exploited, and further research may seek to leverage the interactions of the gut-eye immunological axis.

Collaborative Research and Development of a Novel, Patient-Centered Digital Platform (MyEyeSite) for Rare Inherited Retinal Disease Data: Acceptability and Feasibility Study.

BACKGROUND: Inherited retinal diseases (IRDs) are a leading cause of blindness in children and working age adults in the United Kingdom and other countries, with an appreciable socioeconomic impact. However, by definition, IRD data are individually rare, and as a result, this patient group has been underserved by research. Researchers need larger amounts of these rare data to make progress in this field, for example, through the development of gene therapies. The challenge has been how to find and make these data available to researchers in the most productive way. MyEyeSite is a research collaboration aiming to design and develop a digital platform (the MyEyeSite platform) for people with rare IRDs that will enable patients, doctors, and researchers to aggregate and share specialist eye health data. A crucial component of this platform is the MyEyeSite patient application, which will provide the means for patients with IRD to interact with the system and, in particular, to collate, manage, and share their personal specialist IRD data both for research and their own health care. OBJECTIVE: This study aims to test the acceptability and feasibility of the MyEyeSite platform in the target IRD population through a collaborative patient-centered study. METHODS: Qualitative data were generated through focus groups and workshops, and quantitative data were obtained through a survey of patients with IRD. Participants were recruited through clinics at Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and the National Institute for Health Research (NIHR) Moorfields Biomedical Research Centre through their patient and public involvement databases. RESULTS: Our IRD focus group sample (n=50) highlighted the following themes: frustration with the current system regarding data sharing within the United Kingdom's NHS; positive expectations of the potential benefits of the MyEyeSite patient application, resulting from increased access to this specialized data; and concerns regarding data security, including potentially unethical use of the data outside the NHS. Of the surveyed 80 participants, 68 (85%) were motivated to have a more active role in their eye care and share their data for research purposes using a secure technology, such as a web application or mobile app. CONCLUSIONS: This study demonstrates that patients with IRD are highly motivated to be actively involved in managing their own data for research and their own eye care. It demonstrates the feasibility of involving patients with IRD in the detailed design of the MyEyeSite platform exemplar, with input from the patient with IRD workshops playing a key role in determining both the functionality and accessibility of the designs and prototypes. The development of a user-centered technological solution to the problem of rare health data has the potential to benefit not only the patient with IRD community but also others with rare diseases.

Development and application of the ocular immune-mediated inflammatory diseases ontology enhanced with synonyms from online patient support forum conversation.

BACKGROUND: Unstructured text created by patients represents a rich, but relatively inaccessible resource for advancing patient-centred care. This study aimed to develop an ontology for ocular immune-mediated inflammatory diseases (OcIMIDo), as a tool to facilitate data extraction and analysis, illustrating its application to online patient support forum data. METHODS: We developed OcIMIDo using clinical guidelines, domain expertise, and cross-references to classes from other biomedical ontologies. We developed an approach to add patient-preferred synonyms text-mined from oliviasvision.org online forum, using statistical ranking. We validated the approach with split-sampling and comparison to manual extraction. Using OcIMIDo, we then explored the frequency of OcIMIDo classes and synonyms, and their potential association with natural language sentiment expressed in each online forum post. FINDINGS: OcIMIDo (version 1.2) includes 661 classes, describing anatomy, clinical phenotype, disease activity status, complications, investigations, interventions and functional impacts. It contains 1661 relationships and axioms, 2851 annotations, including 1131 database cross-references, and 187 patient-preferred synonyms. To illustrate OcIMIDo's potential applications, we explored 9031 forum posts, revealing frequent mention of different clinical phenotypes, treatments, and complications. Language sentiment analysis of each post was generally positive (median 0.12, IQR 0.01-0.24). In multivariable logistic regression, the odds of a post expressing negative sentiment were significantly associated with first posts as compared to replies (OR 3.3, 95% CI 2.8 to 3.9, p < 0.001). CONCLUSION: We report the development and validation of a new ontology for inflammatory eye diseases, which includes patient-preferred synonyms, and can be used to explore unstructured patient or physician-reported text data, with many potential applications.

Differentiating Multifocal Choroiditis and Punctate Inner Choroidopathy: A Cluster Analysis Approach.

PURPOSE: To develop a robust approach to clinical phenotyping of multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC). DESIGN: Cross-sectional and longitudinal observational study. METHODS: This multicenter study included sites in the United Kingdom and Israel. The study population included 343 eyes of 185 subjects with hospital record diagnoses of MFC or PIC. Eyes were observed over a period of 5 years for clinically relevant characteristics, including demographics and multimodal imaging features, by observers masked to the original diagnoses. Multivariate 2-step cluster analysis was used to identify clusters of eyes in the database with similar clinical phenotypes, which were then analyzed for between-group differences. The primary outcome measure was the difference between clinical phenotype clusters identified using clinical criteria from the multivariate cluster analysis. RESULTS: Subjects ranged from 11 to 89 years of age, with a baseline best-corrected visual acuity of 2.3 to -0.2 logarithm of minimal angle of resolution. Eighty-two percent of eyes were from females, 74% were myopic with a refractive error of +3.00 to -17.00 diopters (spherical equivalent). Cluster analysis prioritized clinical criteria of chorioretinal lesion location and intraocular inflammation and identified 2 distinct phenotype clusters resembling the original descriptions of MFC and PIC. During the 5-year period of observation, the initial clinical diagnosis remained stable for most eyes and only 1 eye (0.3%) changed diagnosis from PIC to MFC because of newly developed peripheral lesions. There were significant between-group differences in clinical characteristics, for example, in choroidal neovascular membrane development and treatment received. CONCLUSIONS: Cluster analysis of this large cohort of eyes identified peripheral lesions and intraocular inflammation as distinct clinical phenotypes of MFC and PIC. The initial diagnosis remained stable for most eyes. This methodology could be useful for future uveitis classification and management.

Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT.

Background: Non-infectious uveitis can cause chronic relapsing and remitting ocular inflammation, which may require high dose systemic immunosuppression to prevent severe sight loss. It has been classically described as an autoimmune disease, mediated by pro-inflammatory Th1 and Th17 T-cell subsets. Studies suggest that natural immunosuppressive CD4+CD25+FoxP3+ T-regulatory cells (Tregs) are involved in resolution of inflammation and may be involved in the maintenance of clinical remission. Objective: To investigate whether there is a peripheral blood immunoregulatory phenotype associated with clinical remission of sight-threatening non-infectious uveitis by comparing peripheral blood levels of Treg, Th1, and Th17, and associated DNA methylation and cytokine levels in patients with active uveitic disease, control subjects and patients (with previously active disease) in clinical remission induced by immunosuppressive drugs. Methods: Isolated peripheral blood mononuclear cells (PBMC) from peripheral blood samples from prospectively recruited subjects were analyzed by flow cytometry for CD3, CD4, FoxP3, TIGIT, T-bet, and related orphan receptor γt. Epigenetic DNA methylation levels of FOXP3 Treg-specific demethylated region (TSDR), FOXP3 promoter, TBX21, RORC2, and TIGIT loci were determined in cryopreserved PBMC using a next-generation sequencing approach. Related cytokines were measured in blood sera. Functional suppressive capacity of Treg was assessed using T-cell proliferation assays. Results: Fifty patients with uveitis (intermediate, posterior, and panuveitis) and 10 control subjects were recruited. The frequency of CD4+CD25+FoxP3+ Treg, TIGIT+ Treg, and T-bet+ Treg and the ratio of Treg to Th1 were significantly higher in remission patients compared with patients with active uveitic disease; and TIGIT+ Tregs were a significant predictor of clinical remission. Treg from patients in clinical remission demonstrated a high level of in vitro suppressive function compared with Treg from control subjects and from patients with untreated active disease. PBMC from patients in clinical remission had significantly lower methylation levels at the FOXP3 TSDR, FOXP3 promoter, and TIGIT loci and higher levels at RORC loci than those with active disease. Clinical remission was also associated with significantly higher serum levels of transforming growth factor ß and IL-10, which positively correlated with Treg levels, and lower serum levels of IFNγ, IL-17A, and IL-22 compared with patients with active disease. Conclusion: Clinical remission of sight-threatening non-infectious uveitis has an immunoregulatory phenotype characterized by upregulation of peripheral Treg, polarized toward T-bet and TIGIT. These findings may assist with individualized therapy of uveitis, by informing whether drug therapy has induced phenotypically stable Treg associated with long-term clinical remission.

Risk Factors for Developing Choroidal Neovascular Membrane and Visual Loss in Punctate Inner Choroidopathy.

PURPOSE: To examine a large cohort of subjects with punctate inner choroidopathy (PIC) looking at risk factors for development of choroidal neovascular membrane (CNVM) and visual loss. DESIGN: Retrospective case series. PARTICIPANTS: A total of 203 participants (318 eyes) with PIC seen at Moorfields Eye Hospital between 1996 and 2016. METHODS: Information was gathered from the clinical notes of all subjects identified with PIC. MAIN OUTCOME MEASURES: Development of CNVM, moderate visual loss (MVL) (≤20/50), and severe visual loss (SVL) (≤20/200). RESULTS: Participants were predominantly young (median age at presentation, 32.9 years; interquartile range [IQR], 26.1-42.2), myopic (91.5%), female (87.2%), and white (75.9%). Disease was bilateral at presentation in 115 participants (56.7%), and CNVM was present at presentation in 152 eyes (47.8%). Median follow-up was 8.4 years. New CNVM occurred in 58 eyes (33.5% of affected eyes and 4.3% of initially unaffected eyes). An increased risk of developing CNVM was associated with the presence of a CNVM in the fellow eye (P < 0.0005; hazard ratio [HR], 2.73), and previous oral corticosteroid treatment was associated with halving of the risk of developing CNVM (P = 0.035; HR, 0.45). No difference was observed in visual outcome with oral corticosteroids, but subjects treated with anti-VEGF had better visual outcomes (12-month median visual acuity, logarithm of the minimum angle of resolution [logMAR] 0.00 with anti-VEGF and 0.20 without; P = 0.018). Median best-corrected visual acuity (BCVA) was 20/30 at presentation (IQR, 0.00-0.50) and remained at 20/30 throughout all follow-up periods. Moderate visual loss occurred in 40 eyes (12.6%), with an incidence of 0.01 per eye-year, and SVL occurred in 49 eyes (15.4%), with an incidence of 0.01 per eye-year. Female participants were half as likely as male participants to develop MVL (P = 0.030; HR, 0.448), and participants with CNVM had a higher risk of MVL (P = 0.003; HR, 21.074). CONCLUSIONS: Visual loss is common in subjects with PIC, predominantly secondary to late development of CNVM. Treatment with oral corticosteroids may help to reduce the risk of CNVM development, and anti-VEGF therapy for CNVM was associated with better clinical outcomes.

Statins as anti-inflammatory agents: A potential therapeutic role in sight-threatening non-infectious uveitis.

In addition to the known lipid-lowering effects, statins are now widely accepted to have anti-inflammatory and immunomodulatory effects. Adjunctive use of statins has proven beneficial in the context of a wide range of inflammatory diseases, including rheumatoid arthritis. Evidence also suggests that statins may also have utility in the management of uveitis, a form of sight threatening inflammation which occurs in the eye. In this article, we outline our rationale behind a clinical trial of simvastatin as a steroid-sparing agent in uveitis, to which patient recruitment started last year. Potential risks associated with the clinical use of statins, including putative effects on the eyes, are discussed.

New nurses need to be urged to apply for various posts.

Jemma Rhodes' letter (September 15) gives the impression that I endured an unsatisfactory placement in a nursing home, when this was not the case.