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Abstract Background Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections play a key role in treating a range of macular diseases. The effectiveness of these therapies is dependent on patients’ adherence (the extent to which a patient takes their medicines as per agreed recommendations from the healthcare provider) and persistence (continuation of the treatment for the prescribed duration) to their prescribed treatment regimens. The aim of this systematic review was to demonstrate the need for further investigation into the prevalence of, and factors contributing to, patient-led non-adherence and non-persistence, thus facilitating improved clinical outcomes. Methods Systematic searches were conducted in Google Scholar, Web of Science, PubMed, MEDLINE, and the Cochrane Library. Studies in English conducted before February 2023 that reported the level of, and/or barriers to, non-adherence or non-persistence to intravitreal anti-VEGF ocular disease therapy were included. Duplicate papers, literature reviews, expert opinion articles, case studies, and case series were excluded following screening by two independent authors. Results Data from a total of 409,215 patients across 52 studies were analysed. Treatment regimens included pro re nata, monthly and treat-and-extend protocols; study durations ranged from 4 months to 8 years. Of the 52 studies, 22 included a breakdown of reasons for patient non-adherence/non-persistence. Patient-led non-adherence varied between 17.5 and 35.0% depending on the definition used. Overall pooled prevalence of patient-led treatment non-persistence was 30.0% (P = 0.000). Reasons for non-adherence/non-persistence included dissatisfaction with treatment results (29.9%), financial burden (19%), older age/comorbidities (15.5%), difficulty booking appointments (8.5%), travel distance/social isolation (7.9%), lack of time (5.8%), satisfaction with the perceived improvement in their condition (4.4%), fear of injection (4.0%), loss of motivation (4.0%), apathy towards eyesight (2.5%), dissatisfaction with facilities 2.3%, and discomfort/pain (0.3%). Three studies found non-adherence rates between 51.6 and 68.8% during the COVID-19 pandemic, in part due to fear of exposure to COVID-19 and difficulties travelling during lockdown. Discussion Results suggest high levels of patient-led non-adherence/non-persistence to anti-VEGF therapy, mostly due to dissatisfaction with treatment results, a combination of comorbidities, loss of motivation and the burden of travel. This study provides key information on prevalence and factors contributing to non-adherence/non-persistence in anti-VEGF treatment for macular diseases, aiding identification of at-risk individuals to improve real-world visual outcomes. Improvements in the literature can be achieved by establishing uniform definitions and standard timescales for what constitutes non-adherence/non-persistence. Systematic review registration PROSPERO CRD42020216205.

Abstract Background An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. Methods We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. Results We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39–1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49–0.76) and ischaemic stroke (HR = 0.27, CI 0.08–0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results. Conclusion We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on ‘patients like me’. We identify the key challenges in offering such an Informatics Consult as a service.

Abstract Background The application of artificial intelligence (AI) in healthcare is an area of immense interest. The high profile of ‘AI in health’ means that there are unusually strong drivers to accelerate the introduction and implementation of innovative AI interventions, which may not be supported by the available evidence, and for which the usual systems of appraisal may not yet be sufficient. Main text We are beginning to see the emergence of randomised clinical trials evaluating AI interventions in real-world settings. It is imperative that these studies are conducted and reported to the highest standards to enable effective evaluation because they will potentially be a key part of the evidence that is used when deciding whether an AI intervention is sufficiently safe and effective to be approved and commissioned. Minimum reporting guidelines for clinical trial protocols and reports have been instrumental in improving the quality of clinical trials and promoting completeness and transparency of reporting for the evaluation of new health interventions. The current guidelines—SPIRIT and CONSORT—are suited to traditional health interventions but research has revealed that they do not adequately address potential sources of bias specific to AI systems. Examples of elements that require specific reporting include algorithm version and the procedure for acquiring input data. In response, the SPIRIT-AI and CONSORT-AI guidelines were developed by a multidisciplinary group of international experts using a consensus building methodological process. The extensions include a number of new items that should be reported in addition to the core items. Each item, where possible, was informed by challenges identified in existing studies of AI systems in health settings. Conclusion The SPIRIT-AI and CONSORT-AI guidelines provide the first international standards for clinical trials of AI systems. The guidelines are designed to ensure complete and transparent reporting of clinical trial protocols and reports involving AI interventions and have the potential to improve the quality of these clinical trials through improvements in their design and delivery. Their use will help to efficiently identify the safest and most effective AI interventions and commission them with confidence for the benefit of patients and the public.

Abstract Background Inflammation in anterior uveitis is characterised by breakdown of the blood-ocular barrier, which allows leakage of blood constituents of higher molecular weight into the aqueous humour. In routine clinical care, increase in aqueous protein levels can be observed at the slit lamp as ‘flare’ and the severity can be graded using various clinical grading systems, of which the Standardization of Uveitis Nomenclature (SUN) grading system is most commonly used. Alternative instrument-based technologies are available, which can detect aqueous protein levels in an objective and quantifiable way. This review will identify instruments capable of measuring anterior chamber inflammation in this way, their level of reliability, and how well the measurements correlate with clinical grading and/or actual aqueous protein concentration. Methods Standard systematic review methodology will be used to identify, select and extract data from studies that report the use of any instrument-based technology in the assessment of aqueous protein levels. Searches will be conducted through bibliographic databases (MEDLINE, EMBASE and Cochrane Library), clinical trial registries and the grey literature. No restrictions will be placed on language or year of publication. The outcomes of interest are the level of correlation between identified instrument-based test measurements, clinical grading and/or actual aqueous protein concentration, as well as the reliability of each index test identified. Study quality assessment will be based on QUADAS2. Correlation and reliability outcomes will be pooled and meta-analysed if appropriate. Discussion The assessment of inflammation in anterior chamber protein levels currently relies on crude and subjective clinical examination. The findings of this review will identify non-invasive technologies which show good correlation with actual protein concentration, which could be used in routine clinical practice for objective monitoring of AC inflammation. Systematic review registration PROSPERO CRD42017084167. Study screening stage has just been completed.

Abstract Background Childhood uveitis is a collection of chronic rare inflammatory eye disorders which result in visual loss in at least one eye of one fifth of affected children. Despite the introduction of novel systemic immunochemotherapies, it remains a blinding disease. We have undertaken a systematic review of outcome measures used in interventional trials of children with, or at risk of uveitis, in order to investigate metric quality and heterogeneity, as possible barriers to the translation of clinical research into improved outcomes. Methods Systematic review of trials registered within databases approved by the International Committee of Medical Journal Editors (ICMJE). Eligible trials for were those which involved participants aged under 18 years with or at risk of non-infectious uveitis. Data on date of study commencement, uveitis site, inclusion age criteria, and outcome measure characteristics including type, dimension and quality were extracted independently by two authors. Quality was determined using the reproducibility, validity and age-appropriateness of the metric. Results Of 917 identified trials, 57 were eligible for inclusion. Twenty different domains across five dimensions were used as primary outcome measures. The structure most commonly used was multiple separate outcome measures. In a quarter of studies, outcomes were assessed less than 3 months following the intervention. Disease activity was the most commonly assessed dimension, with only 30 studies (60%) using reproducible methodologies to assess activity. Only 2/12 (18%) studies on intermediate or posterior uveitis used reproducible activity grading schemes. Of 18 studies involving children aged under 6 years old which used outcome measures related to visual function, only 8/18 (44%) described the use of age-appropriate acuity assessment measures. None of the studies used a vision related quality of life metrics which had been validated for use in childhood. Conclusion This review of outcome measures in childhood uveitis interventional trials has identified under-utilisation of reproducible or child appropriate measures, and considerable heterogeneity in metric type, and structure. Clinicians and researchers interested in improving outcomes for affected children must identify a patient and family centred core outcome set, and work to validate both objective and patient (or proxy) reported disease age appropriate outcome measures.

Abstract Background Uveitis describes a group of inflammatory conditions affecting the eye. The ability to monitor inflammatory changes in anterior uveitis is crucial in clinical practice for making treatment decisions and in clinical trials for testing therapeutic agents. The current standard for quantifying anterior segment inflammation is clinical slit-lamp examination findings classified using the Standardisation of Uveitis Nomenclature (SUN) grading system. Such clinical grading systems rely on a subjective estimation using the slit lamp and are often non-linear and non-continuous scales, with large increases in cell count between each grade. Novel instrument-based technologies have emerged over the last few decades, which can provide objective and quantifiable measurements. This review will evaluate the reliability of such technologies and their level of agreement with anterior chamber (AC) cell count using clinical slit-lamp examination. Methods Standard systematic review methodology will be used to identify, select and extract data from studies that report the use of any instrument-based technology in the assessment of AC cells. Searches will be conducted through bibliographic databases (MEDLINE, EMBASE and Cochrane Library), clinical trial registries and the grey literature. No restrictions will be placed on language or year of publication. The outcomes of interest are the correlation of index test measurements of AC cells with clinical grading systems using slit-lamp examination and the reliability of each index test identified. Quality assessment will be undertaken using QUADAS2. Degree of correlation between the index and reference test measures will be pooled and meta-analysed if appropriate. Discussion A number of instrument-based tools are available for measuring AC cells. This review will evaluate the technologies available and measure the level of correlation of these alternative methods with clinical grading systems as well as their performance in reliability and repeatability. The findings of this review will identify those objective, instrument-based technologies which show good utility for measuring AC cells in a quantifiable way and which warrant further exploration for their sensitivity and reliability over the current standard. Systematic review registration PROSPERO CRD42017084156 (Liu X, Moore DJ, Denniston AK). Instrument-based tests for measuring anterior chamber (AC) cells in uveitis: a systematic review. 2017). Study screening stage is complete. Data extraction stage has not yet commenced.

Abstract Background Non-infectious uveitis represents a sub-type of intraocular inflammation often associated with disorders of immune dysregulation. If untreated, the intraocular inflammation may progress to severe visual impairment and blindness. Current treatment is heavily reliant on systemic corticosteroid, often at doses associated with severe side effects. There is a need for efficacious corticosteroid-sparing immunomodulatory therapy for these patients. Current immunomodulators include various immunosuppressants and biologics but mammalian target of rapamycin (mTOR) inhibitors (such as sirolimus and everolimus) may also be contenders for this role. The systematic review proposed here will evaluate the evidence for the use of sirolimus and everolimus in the context of non-infectious uveitis. Method/design Standard systematic review methodology will be used to identify, select and extract data from any comparative or non-comparative study of mTOR inhibitors in patients with non-infectious uveitis excluding case reports. Searches of bibliographic databases (MEDLINE, EMBASE, The Cochrane Library and CINAHL) and clinical trials registers will be performed, with no restriction on language or date of publication. Translation of non-English language articles will be undertaken where necessary. The primary outcome of interest will be uveitis activity as measured by vitreous haze. Secondary outcomes will include other pre-specified measures of uveitis activity (such as anterior chamber cells or central macular thickness) best corrected visual acuity, heath-related quality of life, requirement for concurrent treatment and adverse events. Risk of bias assessment will be performed appropriate to each study design. Study selection, data extraction and risk of bias assessment will be undertaken by two reviewers independently. Data will be grouped, tabulated and narratively synthesised. Meta-analysis will be undertaken where appropriate clinical and methodological homogeneity exists. The review will be published according to PRISMA guidance. Discussion Studies of various designs have investigated the clinical use of mTOR inhibitors for non-infectious uveitis, and a large international randomised controlled trail of sirolimus for non-infectious uveitis is due to report. The findings of this systematic review will help inform ophthalmologists and aid the improvement of treatment protocols for non-infectious uveitis with regard to the use of mTOR inhibitors. Systematic review registration PROSPERO CRD42017056390

Abstract Background To compare visual function and structural improvements in pseudophakic eyes with diabetic macular oedema (DMO) treated with the 0.19mg Fluocinolone Acetonide (FAc) intravitreal implant (IluvienTM) in a ‘real world’ setting. Methods A single centre retrospective evaluation of patients with DMO unresponsive to conventional treatment treated with the FAc implant according to UK guidelines. Primary efficacy endpoint was best corrected visual acuity (BCVA); secondary endpoints included optical coherence tomography evaluations of the macula (a) central retinal and (b) peak macular thickness collected at annual time points. Primary safety endpoint was new rise in IOP >27mmHg or glaucoma surgery. Patients with

Abstract Background Uveitis, a group of disorders characterised by intraocular inflammation, causes 10–15% of total blindness in the developed world. The most sight-threatening uveitis affects the posterior segment of the eye (posterior-segment involving uveitis (PSIU)). Numerous different outcomes have been used in clinical trials evaluating alternative treatments for uveitis, limiting inter-trial comparison and aggregation of data. We aim to develop a core outcome set (COS) that would provide a standardised set of outcomes to be measured and reported in all effectiveness trials for PSIU. Methods A three-phase design will be used informed by recommendations from the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Phase 1: a comprehensive list of outcomes will be identified through both a systematic review of effectiveness trials of PSIU and qualitative research with stakeholders. The qualitative study will comprise focus groups with patients and their carers in parallel with one-to-one telephone interviews with health professionals and policy-makers. In the focus groups, patients will be grouped according to whether or not their uveitis is complicated by the sight-threatening condition uveitic macular oedema (UMO) since it is hypothesised that the presence of UMO may significantly impact on patient experience of PSIU. Phase 2: Delphi methodology will be used to reduce the range of potential outcomes for the core set. Up to three Delphi rounds will be used through an online survey. Participants will be asked to rate the importance of each outcome on a 9-point Likert scale where 9 is most important. Phase 3: a consensus meeting will be held with key stakeholders to discuss the Delphi results and ratify the final outcomes to be included in the COS. Discussion The development of an agreed COS for PSIU would help ensure that outcomes which matter to key stakeholders are captured and reported in a consistent way. A COS for PSIU would allow greater comparison and aggregation of data across trials for the better evaluation of established and emerging therapies through evidence synthesis and meta-analysis to inform clinical guidelines and health policy. Trial registration COMET. http://comet-initiative.org/studies/details/640 . August 2015.

Abstract Background Congenital colour vision deficiency (CVD), commonly called ‘colour blindness’, affects around 8% of men and 0.4% of women. Although many aspects of health (e.g. change in colour of urine) and healthcare (e.g. coloured medication, colour-coded diagnostic tests), and modern life depend upon colour coding (e.g. graphs, maps, signals), the impact of colour blindness on everyday life is not generally considered a topic of importance. This study is the first to create and validate a questionnaire measuring the quality of life (QoL) impact of being colour blind. Methods This study consisted of two phases. Firstly, the questionnaire design and development phase was led by an expert panel and piloted on a focus group. Secondly, an online sample of 128 men and 291 women filled in the questionnaire, and the psychometric properties of the questionnaire were analysed using principal components analysis (PCA). The scores of colour blind (CB) participants and normal-sighted controls, controlling for age and sex, were compared using matched t-tests. Results The PCA resulted in a questionnaire with three domains (or subscales): QoL for Health & Lifestyle, QoL for Work, and QoL for Emotions. Controlling for age, there was a significantly greater negative impact on QoL for CB people than normal-sighted controls in regards to confusion over colour in various aspects of their health (p = 5 × 10−7), work (p = 1.3 × 10−7), and emotional life (p = 6 × 10−5). Conclusion Colour blindness can significantly impact quality of life for health, emotions, and especially careers. The tool developed here could be useful in future clinical studies to measure changes in CBQoL in response to therapy in conditions where colour vision is affected. We also discuss ways in which everyday problems related to colour vision might be reduced, for example, workplaces could avoid colour coding where a non-colour alternative is possible.

Abstract ᅟ Behçet’s disease (BD) is a systemic vasculitis characterised by a relapsing remitting course, affecting multiple organ systems. In the eye, it is a cause of potentially blinding inflammation in the form of uveitis. Management of uveitis in BD often requires the use of systemic immunosuppression, in order to reduce disease activity and prevent accumulation of irreversible damage. Whilst corticosteroids remain the mainstay of treatment, long-term use is limited by the development of adrenocorticotrophic side effects. There has therefore been significant interest in the use of corticosteroid-sparing immunosuppressive agents, and more recently, biologic therapies. Recent publications have demonstrated biologic therapy to have beneficial effects both on overall disease control, and quality of life for patients with BD. Widespread use of such agents is however limited, partly by the lack of high quality research evidence, and partly by the prohibitive cost of biologic treatments. In this review, we discuss the most recent research investigating the use of biologic therapy in uveitis due to BD, with consideration of health economics and quality of life outcomes.

Abstract Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare oculorenal inflammatory condition that was first described in 1975. In 2001 a major review identified 133 cases in the world literature and proposed key diagnostic criteria for the condition. Although acknowledged as rare, the limited data available prevented reliable estimates of the prevalence of the condition, and hampered elucidation of the relationship between genetic and environmental factors that contribute to its pathogenesis. In this review we have performed a systematic search on the epidemiology, demographics and proposed risk factors for TINU. Estimates of prevalence based on studies that explicitly report TINU cases suggest that it is diagnosed in 0.2–2% of patients attending specialist uveitis services, with variation reflecting a number of factors including level of diagnostic certainty required. The prevalence of uveitis in patients with tubulointerstitial nephritis (TIN) may be higher than currently recognised, particularly in the paediatric population. The prevalence of TINU is higher in younger age groups and there is a female preponderance although this gender effect appears weaker than suggested by early studies. Although important genetic contributions have been proposed, the small size of studies and variation between reports currently preclude identification of a ‘pro-TINU’ haplotype. Drugs and infections have been proposed as the leading acquired risk factors for the development of TINU; whilst the small size of TINU cohorts and issues of study design limit interpretation of many studies. Larger datasets from the renal literature suggest that the majority of these cases are precipitated by a drug-induced hypersensitivity reaction; however in many ophthalmic cases no clear precipitant is identified.