PHOTORECEPTOR DAMAGE IN TERSON SYNDROME.

PURPOSE: To describe photoreceptor damage in patients with Terson syndrome as a potential cause for inconsistent clinical outcomes. METHODS: Clinical evaluation and retinal imaging in six patients. RESULTS: Four patients were women and two men, with an average age of 46.8 years (SD 8.9). Four patients suffered aneurysmal subarachnoid hemorrhage, one vertebral artery dissection, and one superior sagittal sinus thrombosis. In 11 eyes, a consistent pattern of outer retinal changes within the central retina affecting the ellipsoid zone and the outer nuclear layer was observed, indicating photoreceptor damage. Areas of photoreceptor damage showed poor spatial correlation with intraocular hemorrhage, particularly subinternal limiting membrane hemorrhage. The observed retinal abnormalities demonstrated incomplete recovery over long-term follow-up 3.5 to 8 years posthemorrhage, irrespective of surgical or conservative treatment strategy, and had variable impact on the patients' visual function. CONCLUSION: The observations suggest that photoreceptor damage in Terson syndrome likely represents a distinct manifestation of this condition, which could be caused by transient ischemia of the outer retina secondary to acute rise in intracranial pressure.

A Network Meta-Analysis of Retreatment Rates following Bevacizumab, Ranibizumab, Aflibercept, and Laser for Retinopathy of Prematurity.

TOPIC: To compare bevacizumab, ranibizumab, aflibercept, and laser treatment as primary therapies for retinopathy of prematurity (ROP) in terms of retreatment rate. CLINICAL RELEVANCE: Anti-VEGF agents are increasingly used as primary treatment for ROP and may provide superior outcomes compared with laser in posterior disease. Head-to-head comparisons between different anti-VEGFs are lacking. METHODS: We searched CENTRAL, Embase, MEDLINE, and CINAHL databases for randomized controlled trials and nonrandomized comparative studies that had been reported as of March 2022. We included studies that used bevacizumab, ranibizumab, aflibercept or laser for ROP with comparable cohorts and treatment criteria. Studies were evaluated by the Grading of Recommendations, Assessment, Development and Evaluation framework, and those with biased case selection, nonrandomized case-control, or lack of control group were excluded. Frequentist meta-analyses of proportions determined the absolute primary retreatment rate of each modality and Bayesian network meta-analyses compared pairs of treatments in type 1 and Zone I ROP. RESULTS: In all, 30 studies (4686 eyes) were included in the network meta-analyses. For type 1 ROP, single-treatment success rates (i.e., likelihood of needing no further treatment) were 89.3% (95% confidence interval [CI]: 83.8%-93.8%; n = 1552) for laser, 87.0% (95% CI: 78.6%-93.8%; n = 2081) for bevacizumab, 80.7% (95% CI: 62.0%-94.4%; n = 326) for aflibercept, and 74.0% (95% CI: 62.7%-84.1%; n = 727) for ranibizumab. Bayesian network meta-analysis indicates that laser treatment is associated with a significant 62% (95% credible interval [CrI]: 16%-83%) reduction in retreatment risk compared with ranibizumab, while no significant difference was found among other pairwise comparisons. The mean ± standard error of the mean times to secondary treatment following primary aflibercept (12.96 ± 0.47 weeks) and bevacizumab (11.36 ± 0.54 weeks) therapy were significantly longer than that for primary ranibizumab (9.29 ± 0.43weeks) therapy (P = 7 × 10-7 and P = 9 × 10-3, respectively). For Zone I ROP, single-treatment success rates were 91.2% (95% CI: 83.6-96.9; n = 231) for bevacizumab, 78.3% (95% CI: 61.4-91.9; n = 100) for ranibizumab, and 65.9% (95% CI: 41.4-87.2; n = 158) for laser treatment. In this case, Bayesian network meta-analysis suggests that primary bevacizumab is associated with a significant 67% (95% CrI:10%-90%) reduction in retreatment risk compared with laser treatment. CONCLUSIONS: Laser was associated with a lower rate of retreatment than ranibizumab in type 1 ROP (Zones I and II combined), while bevacizumab was associated with a lower rate of retreatment than laser in Zone I ROP. Aflibercept and bevacizumab demonstrate longer duration of action than ranibizumab for ROP.

The Impact of Progressive Visual Field Constriction on Reading Ability in an Inherited Retinal Degeneration.

BACKGROUND: The ability to read is an important factor in the quality of life. Choroideremia is an inherited retinal degeneration presenting with gradual, progressive constriction of the central visual field, providing a useful disease model to investigate the impact of the visual field on reading ability. OBJECTIVE: The aim of this study was to provide practical guidance on the usefulness of measuring reading ability in patients. METHOD: The Radner Reading Test was administered to 33 patients (65 eyes with choroideremia). To quantify the residual retinal area, the patients underwent microperimetry and imaging. The visual angle subtended by the largest letter read by each subject was calculated using Emsley's Model Eye. RESULTS: A minimum of 1 letter must be seen to allow the eye to read, with preservation of foveal sensitivity. The relationship between reading speed and acuity varies with the visual field. The reading speed is higher in eyes with an intact fovea (p < 0.001 right eye, p = 0.06 left eye). Qualitative analysis of the direction of the intact retina did not indicate any directional impact on measurements. CONCLUSIONS: In order to read, an eye must have enough retinal width close to the fovea to see at least 1 full letter. Direction of print does not impact the ability to read, allowing results from different languages to be combined in clinical trials.

Immunomodulatory Effects of Hydroxychloroquine and Chloroquine in Viral Infections and Their Potential Application in Retinal Gene Therapy.

Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine are anti-malarial drugs that have been successfully used in the treatment of autoimmune diseases. Evidence suggests that at high concentrations, hydroxychloroquine and chloroquine can impact viral infection and replication by increasing endosomal and lysosomal pH. This effect has led to investigations into the potential benefits of these drugs in the treatment of viral infections, including human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2. However, at lower concentrations, hydroxychloroquine and chloroquine appear to exert immunomodulatory effects by inhibiting nucleic acid sensors, including toll-like receptor 9 and cyclic GMP-AMP synthase. This dose-dependent effect on their mechanism of action supports observations of increased viral infections associated with lower drug doses. In this review, we explore the immunomodulatory activity of hydroxychloroquine and chloroquine, their impact on viral infections, and their potential to improve the efficacy and safety of retinal gene therapy by reducing AAV-induced immune responses. The safety and practicalities of delivering hydroxychloroquine into the retina will also be discussed.

Assessment of the Electronic Retinal Implant Alpha AMS in Restoring Vision to Blind Patients with End-Stage Retinitis Pigmentosa.

PURPOSE: To report the initial efficacy results of the Retina Implant Alpha AMS (Retina Implant AG, Reutlingen, Germany) for partial restoration of vision in end-stage retinitis pigmentosa (RP). DESIGN: Prospective, single-arm, investigator-sponsored interventional clinical trial. Within-participant control comprising residual vision with the retinal implant switched ON versus OFF in the implanted eye. PARTICIPANTS: The Retina Implant Alpha AMS was implanted into the worse-seeing eye of 6 participants with end-stage RP and no useful perception of light vision. Eligibility criteria included previous normal vision for ≥12 years and no significant ocular or systemic comorbidity. METHODS: Vision assessments were scheduled at 1, 2, 3, 6, 9, and 12 months postimplantation. They comprised tabletop object recognition tasks, a self-assessment mobility questionnaire, and screen-based tests including Basic Light and Motion (BaLM), grating acuity, and greyscale contrast discrimination. A full-field stimulus test (FST) was also performed. MAIN OUTCOME MEASURES: Improvement in activities of daily living, recognition tasks, and assessments of light perception with the implant ON compared with OFF. RESULTS: All 6 participants underwent successful implantation. Light perception and temporal resolution with the implant ON were achieved in all participants. Light localization was achieved with the implant ON in all but 1 participant (P4) in whom the chip was not functioning optimally because of a combination of iatrogenic intraoperative implant damage and incorrect implantation. Implant ON correct grating detections (which were at chance level with implant OFF) were recorded in the other 5 participants, ranging from 0.1 to 3.33 cycles/degree on 1 occasion. The ability to locate high-contrast tabletop objects not seen with the implant OFF was partially restored with the implant ON in all but 1 participant (P4). There were 2 incidents of conjunctival erosion and 1 inferotemporal macula-on retinal detachment, which were successfully repaired, and 2 incidents of inadvertent damage to the implant during surgery (P3 and P4). CONCLUSIONS: The Alpha AMS subretinal implant improved visual performance in 5 of 6 participants and has exhibited ongoing function for up to 24 months. Although implantation surgery remains challenging, new developments such as OCT microscope guidance added refinements to the surgical technique.

Real-world refractive outcomes of toric intraocular lens implantation in a United Kingdom National Health Service setting.

BACKGROUND: With increasing availability of toric intraocular lenses (IOL) for cataract surgery, real-world refractive outcome data is needed to aid the counselling of patients regarding lens choice. We aim to assess the outcomes of toric intraocular lens use in the non-specialist environment of a typical United Kingdom NHS cataract service. METHODS: A retrospective cohort study conducted at the Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, UK. All patients who received a toric IOL implant over a 10 months period. Patients underwent pre-operative corneal marking, phacoemulsification and toric IOL implantation. Biometry was obtained using a Zeiss IOLMaster 500 and the toric IOLs were selected using the manufacturers' online calculators. Post-operative refractions were obtained from optometrist's manifest refraction or by autorefraction. The outcome measures were post-operative unaided visual acuity (UVA), spherical equivalent refraction, cylindrical correction and all complications. RESULTS: Thirty-two eyes of 24 patients aged 21-86 years (mean 66.4, SD 14.5) were included. UVA was superior to pre-operative best-corrected visual acuity (BCVA) in 81% of eyes, same in 16% and inferior in 3%, resulting in a median improvement of 0.20 LogMAR (IQR 0.10 to 0.30). 56%, 81%, 94% and 100% of eyes were within ±0.5, ±1.0, ±1.5 and ±2.0 D of predicted spherical equivalent, respectively. Three (9%) eyes required further surgery to rectify significant IOL rotation. CONCLUSIONS: Reduced cylindrical correction and improved UVA could be expected in the majority of patients undergoing toric IOL implantation. Patients should be counselled about the risk of lens rotation.

Effects of pupil dilation on MAIA microperimetry.

BACKGROUND: Macular Integrity Assessment microperimetry assesses macular sensitivity to projected point light sources and maps eye movements to assess fixation stability. Although microperimetry is gaining prominence as an assessment tool in clinical and research settings, there is no consensus on whether it should be performed before or after pupil dilation. No studies to date have examined the effect of pupil dilation on results. The aim of this project was to elucidate the effect of pupil dilation on microperimetry outcomes. DESIGN: Prospective audit. PARTICIPANTS: Twenty healthy patients from postoperative cataract clinic and 10 patients with choroideremia to simulate a disease with peripheral visual field loss. METHODS: Subjects underwent 10-2 68-point field testing using the Macular Integrity Assessment microperimeter on each eye. Subjects then underwent randomized dilation of one eye, and the test was repeated in both eyes. MAIN OUTCOME MEASURES: We compared changes in threshold sensitivity and fixation stability pre-pupil and post-pupil dilation. The undilated eye was analysed for any learning or fatigue effect caused by test repetition. RESULTS: Dilation produced no significant effect on threshold sensitivity (dilation effect: -0.29 decibels, P = 0.23) or fixation stability in healthy controls or in choroideremia patients (dilation effect: +0.08log bivariate contour ellipse area, P = 0.14). There was also no significant learning effect seen in the undilated eye, with no improvement in threshold sensitivity (order of eye testing: +0.03log bivariate contour ellipse area, P = 0.71). CONCLUSIONS: In the clinical setting, patients may be tested for 10 degree microperimetry with or without pupil dilation, as both scenarios yield consistent and interchangeable results.

Interaction between antibody-diversification enzyme AID and spliceosome-associated factor CTNNBL1.

Activation-induced deaminase (AID) deaminates deoxycytidine residues in immunoglobulin genes, triggering antibody diversification. Here, by use of two-hybrid and coimmunoprecipitation assays, we identify CTNNBL1 (also known as NAP) as an AID-specific interactor. Mutants of AID that interfere with CTNNBL1 interaction yield severely diminished hypermutation and class switching. Targeted inactivation of CTNNBL1 in DT40 B cells also considerably diminishes IgV diversification. CTNNBL1 is a widely expressed nuclear protein that associates with the Prp19 complex of the spliceosome, interacting with its CDC5L component. The results, therefore, identify residues in AID involved in its in vivo targeting and suggest they might act through interaction with CTNNBL1, giving possible insight into the linkage between AID recruitment and target-gene transcription.

Meta-analysis of the adjunctive use of mitomycin C in primary and revision, external and endonasal dacryocystorhinostomy.

PURPOSE: To determine whether application of the anti-proliferation agent, mitomycin C (MMC), to the osteotomy site during dacryocystorhinostomy (DCR) surgery increases surgical success rates. METHOD: We conducted a comprehensive meta-analysis of randomised controlled clinical studies relating to the adjunctive use of MMC in primary and revision, as well as external (EX-DCR) and endonasal DCR (EN-DCR). RESULTS: 15 studies met our inclusion criteria with a total of 850 DCR procedures. The mean concentration of MMC used was 0.3 mg/ml (range 0.02-0.75 mg/ml) and mean duration of application 18 min (range 2-30 min). MMC significantly reduced the failure rate of primary EX-DCR (risk ratio, RR, 0.51; 95% confidence interval, CI, 0.31-0.86) and revision EN-DCR (RR 0.43; 95% CI 0.21-0.89). The adjunctive use of MMC in primary EN-DCR, however, did not confer a significant reduction in failure rate compared with control (RR 0.94; 95% CI 0.44-2.04). We found a deficiency of evidence regarding the potential benefit of MMC in revision EX-DCR. Only two cases of adverse effects relating to the use of MMC were reported among the studies, both of which related to delayed wound healing. CONCLUSIONS: Application of MMC to the osteotomy site is a safe and effective way of increasing surgical success rate in primary EX-DCR and revision EN-DCR, but does not provide any significant benefit in primary EN-DCR. Further studies are required to evaluate the potential effect of MMC in revision EX-DCR.

Robot-Assisted Eye Surgery: A Systematic Review of Effectiveness, Safety, and Practicality in Clinical Settings.

Purpose: Surgical innovation in ophthalmology is impeded by the physiological limits of human motion, and robotic assistance may facilitate an expansion of the surgical repertoire. We conducted a systematic review to identify ophthalmic procedures in which robotic systems have been trialled, evaluate their performance, and explore future directions for research and development of robotic techniques. Methods: The Cochrane Library, Embase, MEDLINE, Scopus, and Web of Science were searched. Screening adhered to five criteria: (1) English language; (2) primary research article; (3) human patients; (4) ophthalmological surgery; and (5) robot-assisted surgery. Quality assessment was conducted with Joanna Briggs Institute Tools for Critical Appraisal. The study protocol was registered prospectively (PROSPERO ID CRD42023449793). Results: Twelve studies were included. In comparative studies, there was no difference in the occurrence of ocular harms in robot-assisted procedures and conventional surgery. However, robotic assistance did not demonstrate consistent benefits over manual surgery in terms of effectiveness or practicality, likely reflecting the learning curve associated with these systems. Single studies indicated the potential of robotic assistance to improve the consistency of subretinal drug infusion and efficiency of instrument manipulation in vitreoretinal surgery. Conclusions: Proof-of-concept studies have demonstrated the potential of robotic assistance to facilitate procedures otherwise infeasible or impractical, and may broaden access to surgery. However, robot-assisted surgery has not yet demonstrated any significant benefits over standard surgical practice. Improving the speed and reducing perioperative requirements of robot-assisted surgery are particular priorities for research and innovation to improve the practicality of these novel techniques. Translational Relevance: This systematic review summarizes the potential and limitations of robotic systems for assisting eye surgery and outlines what is required for these systems to benefit patients and surgeons.

Age-related macular degeneration: suitability of optogenetic therapy for geographic atrophy.

Age-related macular degeneration (AMD) is a growing public health concern given the aging population and it is the leading cause of blindness in developed countries, affecting individuals over the age of 55 years. AMD affects the retinal pigment epithelium (RPE) and Bruch's membrane in the macula, leading to secondary photoreceptor degeneration and eventual loss of central vision. Late AMD is divided into two forms: neovascular AMD and geographic atrophy (GA). GA accounts for around 60% of late AMD and has been the most challenging subtype to treat. Recent advances include approval of new intravitreally administered therapeutics, pegcetacoplan (Syfovre) and avacincaptad pegol (Iveric Bio), which target complement factors C3 and C5, respectively, which slow down the rate of enlargement of the area of atrophy. However, there is currently no treatment to reverse the central vision loss associated with GA. Optogenetics may provide a strategy for rescuing visual function in GA by imparting light-sensitivity to the surviving inner retina (i.e., retinal ganglion cells or bipolar cells). It takes advantage of residual inner retinal architecture to transmit visual stimuli along the visual pathway, while a wide range of photosensitive proteins are available for consideration. Herein, we review the anatomical changes in GA, discuss the suitability of optogenetic therapeutic sensors in different target cells in pre-clinical models, and consider the advantages and disadvantages of different routes of administration of therapeutic vectors.

Retinal imaging: what the neurologist needs to know.

With the advent of confocal microscopy and optical coherence tomography, high-resolution multimodal imaging of the retina and optic nerve head can now be obtained routinely, providing new diagnostic clues in a variety of neuro-ophthalmological conditions. In this review, we provide an overview of these imaging advances and their clinical applications.

Erratum: Enhancement of Adeno-Associated Virus-Mediated Gene Therapy Using Hydroxychloroquine in Murine and Human Tissues.

[This corrects the article DOI: 10.1016/j.omtm.2019.05.012.].

The Role of Inflammation in Age-Related Macular Degeneration-Therapeutic Landscapes in Geographic Atrophy.

Age-related macular degeneration (AMD) is the leading cause of vision loss and visual impairment in people over 50 years of age. In the current therapeutic landscape, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have been central to the management of neovascular AMD (also known as wet AMD), whereas treatments for geographic atrophy have lagged behind. Several therapeutic approaches are being developed for geographic atrophy with the goal of either slowing down disease progression or reversing sight loss. Such strategies target the inflammatory pathways, complement cascade, visual cycle or neuroprotective mechanisms to slow down the degeneration. In addition, retinal implants have been tried for vision restoration and stem cell therapies for potentially a dual purpose of slowing down the degeneration and restoring visual function. In particular, therapies focusing on the complement pathway have shown promising results with the FDA approved pegcetacoplan, a complement C3 inhibitor, and avacincaptad pegol, a complement C5 inhibitor. In this review, we discuss the mechanisms of inflammation in AMD and outline the therapeutic landscapes of atrophy AMD. Improved understanding of the various pathway components and their interplay in this complex neuroinflammatory degeneration will guide the development of current and future therapeutic options, such as optogenetic therapy.

Optimized glycemic control of type 2 diabetes with reinforcement learning: a proof-of-concept trial.

The personalized titration and optimization of insulin regimens for treatment of type 2 diabetes (T2D) are resource-demanding healthcare tasks. Here we propose a model-based reinforcement learning (RL) framework (called RL-DITR), which learns the optimal insulin regimen by analyzing glycemic state rewards through patient model interactions. When evaluated during the development phase for managing hospitalized patients with T2D, RL-DITR achieved superior insulin titration optimization (mean absolute error (MAE) of 1.10 ± 0.03 U) compared to other deep learning models and standard clinical methods. We performed a stepwise clinical validation of the artificial intelligence system from simulation to deployment, demonstrating better performance in glycemic control in inpatients compared to junior and intermediate-level physicians through quantitative (MAE of 1.18 ± 0.09 U) and qualitative metrics from a blinded review. Additionally, we conducted a single-arm, patient-blinded, proof-of-concept feasibility trial in 16 patients with T2D. The primary outcome was difference in mean daily capillary blood glucose during the trial, which decreased from 11.1 (±3.6) to 8.6 (±2.4) mmol L-1 (P < 0.01), meeting the pre-specified endpoint. No episodes of severe hypoglycemia or hyperglycemia with ketosis occurred. These preliminary results warrant further investigation in larger, more diverse clinical studies. ClinicalTrials.gov registration: NCT05409391 .

Deep-learning-enabled protein-protein interaction analysis for prediction of SARS-CoV-2 infectivity and variant evolution.

Host-pathogen interactions and pathogen evolution are underpinned by protein-protein interactions between viral and host proteins. An understanding of how viral variants affect protein-protein binding is important for predicting viral-host interactions, such as the emergence of new pathogenic SARS-CoV-2 variants. Here we propose an artificial intelligence-based framework called UniBind, in which proteins are represented as a graph at the residue and atom levels. UniBind integrates protein three-dimensional structure and binding affinity and is capable of multi-task learning for heterogeneous biological data integration. In systematic tests on benchmark datasets and further experimental validation, UniBind effectively and scalably predicted the effects of SARS-CoV-2 spike protein variants on their binding affinities to the human ACE2 receptor, as well as to SARS-CoV-2 neutralizing monoclonal antibodies. Furthermore, in a cross-species analysis, UniBind could be applied to predict host susceptibility to SARS-CoV-2 variants and to predict future viral variant evolutionary trends. This in silico approach has the potential to serve as an early warning system for problematic emerging SARS-CoV-2 variants, as well as to facilitate research on protein-protein interactions in general.

The in vivo pattern of AID targeting to immunoglobulin switch regions deduced from mutation spectra in msh2-/- ung-/- mice.

Immunoglobulin (Ig) class switching is initiated by deamination of C-->U within the immunoglobulin heavy chain locus, catalyzed by activation-induced deaminase (AID). In the absence of uracil-DNA glycosylase (UNG) and the homologue of bacterial MutS (MSH)-2 mismatch recognition protein, the resultant U:G lesions are not processed into switching events but are fixed by replication allowing sites of AID-catalyzed deamination to be identified by the resulting C-->T mutations. We find that AID targets cytosines in both donor and acceptor switch regions (S regions) with the deamination domains initiating approximately 150 nucleotides 3' of the I exon start sites and extending over several kilobases (the IgH intronic enhancer is spared). Culturing B cells with interleukin 4 or interferon gamma specifically enhanced deamination around Sgamma1 and Sgamma2a, respectively. Mutation spectra suggest that, in the absence of UNG and MSH2, AID may occasionally act at the mu switch region in an apparently processive manner, but there is no marked preference for targeting of the transcribed versus nontranscribed strand (even in areas capable of R loop formation). The data are consistent with switch recombination being triggered by transcription-associated, strand-symmetric AID-mediated deamination at both donor and acceptor S regions with cytokines directing isotype specificity by potentiating AID recruitment to the relevant acceptor S region.