Review: Emerging Eye-Based Diagnostic Technologies for Traumatic Brain Injury.

The study of ocular manifestations of neurodegenerative disorders, Oculomics, is a growing field of investigation for early diagnostics, enabling structural and chemical biomarkers to be monitored overtime to predict prognosis. Traumatic brain injury (TBI) triggers a cascade of events harmful to the brain, which can lead to neurodegeneration. TBI, termed the "silent epidemic" is becoming a leading cause of death and disability worldwide. There is currently no effective diagnostic tool for TBI, and yet, early-intervention is known to considerably shorten hospital stays, improve outcomes, fasten neurological recovery and lower mortality rates, highlighting the unmet need for techniques capable of rapid and accurate point-of-care diagnostics, implemented in the earliest stages. This review focuses on the latest advances in the main neuropathophysiological responses and the achievements and shortfalls of TBI diagnostic methods. Validated and emerging TBI-indicative biomarkers are outlined and linked to ocular neuro-disorders. Methods detecting structural and chemical ocular responses to TBI are categorised along with prospective chemical and physical sensing techniques. Particular attention is drawn to the potential of Raman spectroscopy as a non-invasive sensing of neurological molecular signatures in the ocular projections of the brain, laying the platform for the first tangible path towards alternative point-of-care diagnostic technologies for TBI.

Automating Large-scale Health Care Service Feedback Analysis: Sentiment Analysis and Topic Modeling Study.

BACKGROUND: Obtaining patient feedback is an essential mechanism for health care service providers to assess their quality and effectiveness. Unlike assessments of clinical outcomes, feedback from patients offers insights into their lived experiences. The Department of Health and Social Care in England via National Health Service Digital operates a patient feedback web service through which patients can leave feedback of their experiences in structured and free-text report forms. Free-text feedback, compared with structured questionnaires, may be less biased by the feedback collector and, thus, more representative; however, it is harder to analyze in large quantities and challenging to derive meaningful, quantitative outcomes. OBJECTIVE: The aim of this study is to build a novel data analysis and interactive visualization pipeline accessible through an interactive web application to facilitate the interrogation of and provide unique insights into National Health Service patient feedback. METHODS: This study details the development of a text analysis tool that uses contemporary natural language processing and machine learning models to analyze free-text clinical service reviews to develop a robust classification model and interactive visualization web application. The methodology is based on the design science research paradigm and was conducted in three iterations: a sentiment analysis of the patient feedback corpus in the first iteration, topic modeling (unigram and bigram)-based analysis for topic identification in the second iteration, and nested topic modeling in the third iteration that combines sentiment analysis and topic modeling methods. An interactive data visualization web application for use by the general public was then created, presenting the data on a geographic representation of the country, making it easily accessible. RESULTS: Of the 11,103 possible clinical services that could be reviewed across England, 2030 (18.28%) different services received a combined total of 51,845 reviews between October 1, 2017, and September 30, 2019. Dominant topics were identified for the entire corpus followed by negative- and positive-sentiment topics in turn. Reviews containing high- and low-sentiment topics occurred more frequently than reviews containing less polarized topics. Time-series analysis identified trends in topic and sentiment occurrence frequency across the study period. CONCLUSIONS: Using contemporary natural language processing techniques, unstructured text data were effectively characterized for further analysis and visualization. An efficient pipeline was successfully combined with a web application, making automated analysis and dissemination of large volumes of information accessible. This study represents a significant step in efforts to generate and visualize useful, actionable, and unique information from free-text patient reviews.

Public perceptions of eye symptoms and hospital services during the first UK lockdown of the COVID-19 pandemic: a web survey study.

OBJECTIVE: This study aimed to explore the British public's healthcare-seeking beliefs concerning eye symptoms, and assess how the first COVID-19 lockdown influenced these. METHODS AND ANALYSIS: An anonymous web-based survey was disseminated through mailing lists and social media between June and August 2020. The survey sought participants' views on the severity and urgency of the need for medical review for four ophthalmic and two general medical scenarios on a five-point scale. Participants were asked to answer questions twice: once ignoring the COVID-19 pandemic, and once taking this into account, with additional questions asked to identify factors influencing the decision to seek medical attention and ward admission. RESULTS: A total of 402 participants completed the survey (mean age 61.6 years, 63.1% female and 87.7% of white ethnicity). Scores for symptom severity and urgency of medical review increased significantly with the severity of the clinical scenario (both p<0.001). However, participants gave significantly lower scores for the urgency of medical attention when accounting for the COVID-19 pandemic (compared with no pandemic) for all scenarios (all p<0.001). Younger age, greater deprivation and non-white ethnicity were correlated with a lower perception of seriousness and urgency of medical attention. CONCLUSIONS: During the first UK lockdown of the COVID-19 pandemic, reduced urgency of medical review for ocular and systemic pathologies was reported in response to the pandemic, which represents a barrier to healthcare-seeking behaviour. This has the potential to critically delay medical review and timely management, negatively impacting patient outcomes.

The impact of the COVID-19 pandemic on microbial keratitis presentation patterns.

BACKGROUND: Microbial keratitis (MK) is the most common non-surgical ophthalmic emergency, and can rapidly progress, causing irreversible sight-loss. This study explored whether the COVID-19 (C19) national lockdown impacted upon the clinical presentation and outcomes of MK at a UK tertiary-care centre. METHODS: Medical records were retrospectively reviewed for all patients with presumed MK requiring corneal scrapes, presenting between 23rd March and 30th June in 2020 (Y2020), and the equivalent time windows in 2017, 2018 and 2019 (pre-C19). RESULTS: In total, 181 and 49 patients presented during the pre-C19 and Y2020 periods, respectively. In Y2020, concurrent ocular trauma (16.3% vs. 5.5%, p = 0.030) and immunosuppression use (12.2% vs 1.7%, p = 0.004) were more prevalent. Despite proportionately fewer ward admissions during the pandemic (8.2% vs 32.6%, p<0.001), no differences were observed in baseline demographics; presenting visual acuity (VA; median 0.6 vs 0.6 LogMAR, p = 0.785); ulcer area (4.0 vs 3.0mm2, p = 0.520); or final VA (0.30 vs 0.30 LogMAR, p = 0.990). Whilst the overall rates of culture positivity were similar in Y2020 and pre-C19 (49.0% vs. 54.7%, p = 0.520), there were differences in the cultures isolated, with a lower rate of poly-microbial cultures in Y2020 (8.3% vs. 31.3%, p = 0.022). CONCLUSIONS: Patient characteristics, MK severity and final visual outcomes did not appear to be affected in the first UK lockdown, despite fewer patients being admitted for care. Concurrent trauma and systemic immunosuppression use were greater than in previous years. The difference in spectra of isolated organisms may relate to behavioural changes, such as increased hand hygiene.

Effectiveness of matching human leukocyte antigens (HLA) in corneal transplantation: a systematic review protocol.

BACKGROUND: Corneal transplantation is the most frequently performed transplantation in the UK. Despite this, the therapeutic value of matching human leukocyte antigen (HLA) subtypes for transplanted corneas remains controversial. Ocular immune privilege was originally deemed to render matching unnecessary; however, more recently, matching has demonstrated improved outcomes including graft success, amongst others. This systematic review aims to evaluate the effectiveness of major and minor antigen matching on graft outcomes in corneal transplantation. METHODS: Standard systematic review methodology will be used to identify, select and extract data from observational studies and clinical trials assessing the effects of HLA matching on corneal graft outcomes. Bibliographic databases (Cochrane Library, EMBASE, MEDLINE, Web of Science, Scopus), clinical trial registers, abstract and conference proceedings, in addition to dissertation, thesis and grey literature will be searched. Neither date of publication nor language will be restricted, and non-English articles will be translated where necessary. The primary outcome will be to assess corneal graft success for different degrees of HLA matching/mismatching. The precise end outcome measure varies amongst studies and includes graft rejection, immunoreaction, failure and survival. Therefore, data will be extracted across all relevant outcome parameters and grouped for subsequent statistical tests. Risk of bias assessment will be completed, appropriate to each study design. Study selection, data extraction and risk of bias assessment will be independently completed by two reviewers. Data will be tabulated, and a narrative synthesis presented. Meta-analysis will be performed where there is sufficient homogeneity between studies to warrant its effective completion. Subgroup and sensitivity analysis will be undertaken if appropriate. DISCUSSION: Many studies have investigated the effectiveness of HLA matching for corneal transplantation. A systematic review is needed to collate and analyse this evidence. Findings of this systematic review may form the basis of evidence-based recommendations on pre-operative HLA typing and matching of corneal grafts for transplantation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO reference CRD42020198882.

Human leukocyte antigen B*0702 is protective against ocular Stevens-Johnson syndrome/toxic epidermal necrolysis in the UK population.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are part of a disease continuum of vesiculobullous mucocutaneous reactions affecting the skin and mucous membranes including the ocular surface. Manifestations of disease range from mild dry eye to progressive conjunctival cicatrisation, limbal epithelial stem cell failure and corneal blindness. In Far Eastern and South East Asian populations where SJS/TEN is prevalent, numerous human leukocyte antigen (HLA) gene variants at the A, B and C loci have been identified as risk factors for developing SJS/TEN with severe ocular complications (SOC). By contrast, the incidence of SJS/TEN with SOC in European countries is relatively low. To date, ocular SJS/TEN risk altering alleles have not been widely investigated in European populations. In this study, we analysed the association of HLA -A, -B and -C alleles with SJS/TEN in 33 patients residing in the UK with age matched controls. The data showed statistically significant novel negative allele association with HLA-B*0702 and a trend with HLA-C*0702 in the patient group, indicating these alleles are protective. Further characterisation of protective and risk alleles in other ethnic groups is required to fully elucidate the putative role of these alleles in the susceptibility of SJS/TEN with or without severe ocular complications in patients in the UK.

Using the West Midlands CONCERT to characterise regional incidence of acute-onset post cataract surgery endophthalmitis.

BACKGROUND: Whilst research and innovation is embedded within the UK's National Health Service (NHS) constitution, Doctors-in-training have little opportunity to contribute to designing, leading and recruiting into clinical trials or cohort studies. We formed the West Midlands Collaborative Ophthalmology Network for Clinical Effectiveness & Research by Trainees (The West Midlands CONCERT) and undertook a characterisation of post cataract surgery endophthalmitis as a proof-of-concept study to test the feasibility of the CONCERT model. METHODS: Doctors-in-training formed a collaborative working group to test the concept of delivering a pan-regional clinical effectiveness study across multiple hospital sites by performing retrospective analyses of post cataract endophthalmitis over a 6-year period. RESULTS: Overall, 157,653 cataract surgeries were performed by participating centres accredited to deliver the Royal College of Ophthalmologists training curriculum. Thirty-eight cases of post cataract endophthalmitis were identified, giving an incidence of 2.41 per 10,000 cases (0.0241%). A further 15 endophthalmitis cases presented who had surgery in non-training centres, giving a total of 53 cases. The most common organisms were S. epidermidis (14 (51.9%)) and P. aeruginosa (5 (18.5%)). Anterior-chamber and vitreous sampling yielded positive culture in 33.3% (6/18) and 50.9% (27/53), respectively. At 6 months follow-up, 19 (51.4%) patients achieved visual acuities of ≤0.5 LogMAR. Repeat intravitreal injections (11 (20.8%)) and vitrectomy (n = 22 (41.5%)) were not associated with better outcomes. CONCLUSIONS: Using post cataract endophthalmitis as a pilot cohort, this study highlights the feasibility of using the CONCERT model for studies across multiple sites. A UK-CONCERT could provide a powerful infrastructure enabling characterisation of patient cohorts and a platform for high-quality interventional studies, improving patient care.

Rapid assessment of ocular drug delivery in a novel ex vivo corneal model.

Drug delivery by topical application has higher patient acceptance and lower morbidity than intraocular injection, but many ophthalmic treatments are unable to enter the eye or reach the posterior segment after topical application. The first stage towards posterior segment delivery after topical application is ocular surface penetration and existing models are in vivo or use large quantities of tissue. We therefore developed a novel ex vivo model using discs of porcine and human cornea and sclera (5 mm diameter) to assess penetration of a candidate neuroprotective siRNA. siRNA against caspase 2 or control solutions of known penetrance were applied to the corneal epithelial surface and trans-corneal penetration and corneal adsorbance measured at fixed time points. To demonstrate that leakage did not occur, we applied dextran blue, which should not penetrate the intact cornea and did not do so in our model. Fluorescein penetration (0.09%) was less than rhodamine B (6.98%) at 60 min. siCASP2 penetration was 0.01% by 60 min. When the applied siCASP2 was washed off after 2 min, (representing lacrimal drainage) 0.071% penetrated porcine cornea by 60 min and 0.0002% penetrated human cornea and 0.001% penetrated human sclera. Our ex vivo model rapidly and cost-effectively assesses transcorneal penetration of candidate topical therapies, allowing rates of trans-corneal penetration for potential therapies such as siRNA to be evaluated with small quantities of human or animal tissue.

Sustained release of decorin to the surface of the eye enables scarless corneal regeneration.

Disorganization of the transparent collagenous matrix in the cornea, as a consequence of a variety of infections and inflammatory conditions, leads to corneal opacity and sight-loss. Such corneal opacities are a leading cause of blindness, according to the WHO. Public health programs target prevention of corneal scarring, but the only curative treatment of established scarring is through transplantation. Although attempts to minimize corneal scarring through aggressive control of infection and inflammation are made, there has been little progress in the development of anti-scarring therapies. This is owing to eye drop formulations using low viscosity or weak gelling materials having short retention times on the ocular surface. In this study, we report an innovative eye drop formulation that has the ability to provide sustained delivery of decorin, an anti-scarring agent. The novelty of this eye drop lies in the method of structuring during manufacture, which creates a material that can transition between solid and liquid states, allowing retention in a dynamic environment being slowly removed through blinking. In a murine model of Pseudomonas keratitis, applying the eye drop resulted in reductions of corneal opacity within 16 days. More remarkably, the addition of hrDecorin resulted in restoration of corneal epithelial integrity with minimal stromal opacity endorsed by reduced α-smooth muscle actin (αSMA), fibronectin, and laminin levels. We believe that this drug delivery system is an ideal non-invasive anti-fibrotic treatment for patients with microbial keratitis, potentially without recourse to surgery, saving the sight of many in the developing world, where corneal transplantation may not be available.

Topical Coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension.

Coenzyme Q10 (CoQ10) is a mitochondrial-targeted antioxidant with known neuroprotective activity. Its ocular effects when co-solubilised with α-tocopherol polyethylene glycol succinate (TPGS) were evaluated. In vitro studies confirmed that CoQ10 was significantly protective in different retinal ganglion cell (RGC) models. In vivo studies in Adult Dark Agouti (DA) rats with unilateral surgically-induced ocular hypertension (OHT) treated with either CoQ10/TPGS micelles or TPGS vehicle twice daily for three weeks were performed, following which retinal cell health was assessed in vivo using DARC (Detection of Apoptotic Retinal Cells) and post-mortem with Brn3a histological assessment on whole retinal mounts. CoQ10/TPGS showed a significant neuroprotective effect compared to control with DARC (p<0.05) and Brn3 (p<0.01). Topical CoQ10 appears an effective therapy preventing RGC apoptosis and loss in glaucoma-related models.