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The Tat-NR2B9c peptide has shown clinical efficacy as a neuroprotective agent in acute stroke. Tat-NR2B9c is designed to prevent nitric oxide (NO) production by preventing postsynaptic density protein 95 (PSD-95) binding to N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase; however, PSD-95 is a scaffolding protein that also couples NMDA receptors to other downstream effects. Here, using neuronal cultures, we show that Tat-NR2B9c also prevents NMDA-induced activation of neuronal NADPH oxidase, thereby blocking superoxide production. Given that both superoxide and NO are required for excitotoxic injury, the neuroprotective effect of Tat-NR2B9c may alternatively be attributable to uncoupling neuronal NADPH oxidase from NMDA receptor activation.

Purpose: To evaluate the reproducibility of SIMPLE (Single field Image Multi Parameters defined Lesions Extent), a new Diabetic Retinopathy (DR) classification for screening of 45° single field fundus pictures of patients with diabetes (PwDM), assessing DR, Diabetic Maculopathy (DMac) and referral rate agreement and comparing it to current Italian Guidelines (IG)., Materials and Methods: We conducted a retrospective, observational, multicentre study, collecting 1000 retinal 45° single field images of PwDM obtained during routine visits in two diabetes clinics. Three ophthalmologists evaluated each image, determining the presence and number of specific DR lesions and then assigning a stage according to the current IG for screening. SIMPLE staging was performed automatically via Excel software, based on the pre-specified DR characteristics observed by the graders. We analysed intra-centre, inter-centre and total inter-grader agreement for DR and DMac stage and referral rate of the two classifications., Results: Agreement amongst the three graders was consistently higher when using SIMPLE classification than when using current IG classification. For DR, kappa (k) was 0.86 with IG and 0.95 with SIMPLE classification; for DMac, k-IG was 0.78, while k-SIMPLE was 0.96; concordance on the referral rate was 0.91 with IG and 0.99 with SIMPLE. Similar results were obtained in sub-analyses for the evaluation of intra-centre and inter-centre concordance., Conclusions: Our results suggest that the new SIMPLE classification has an excellent reproducibility amongst graders, comparable or superior to the current IG for DR screening proposed in 2015, improving the standardisation of the decision on referability., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Hereditary transthyretin (ATTRv) amyloidosis is a heterogeneous, progressive, multisystemic disease with a life-threatening course if left untreated. Given the current availability of effective therapies, close follow-up of presymptomatic TTR mutation carriers is essential to recognize disease onset at the earliest sign. In addition to routine techniques, in recent years several novel tools have been proposed, although a consensus on their use has not been reached yet. In this paper, we aimed to evaluate possible markers of neuropathic disease onset intended to discriminate clinically asymptomatic carriers from early symptomatic patients, thus allowing timely treatment initiation., Methods: Thirty-eight presymptomatic carriers were enrolled. Clinical and electrophysiological findings at first evaluation and follow-up were collected. All carriers underwent an extensive clinical and instrumental evaluation according to the standard clinical practice. One or more non-routine investigations, whose use in this field is not yet validated (henceforth "unconventional"), were additionally assessed in a subgroup of individuals., Results: Based on the exclusive use of routine investigations, it was possible to define disease onset in 4/38 carriers during the follow-up. Employing additionally one or more "unconventional" tests, abnormal findings, indicative of a possible "conversion" to symptomatic disease, were detected in further 12 cases. More than half of our study cohort showed findings suggestive of small nerve fiber (SF) involvement at either invasive or non-invasive tests., Conclusions: A close, multidisciplinary monitoring of presymptomatic TTR mutation carriers is fundamental, and diagnostic workup should include both routine and "unconventional" tests. Assessment of SF involvement is important also in non-endemic countries., (© 2023. The Author(s).)

Introduction: In this work, our aim is to report the functional outcomes of cataract surgery with smaller-incision new-generation miniature telescope (SING IMT) implantation followed by rehabilitation training in patients with central visual loss due to late-stage age-related macular degeneration (AMD)., Methods: This retrospective study included patients who were monocularly implanted with SING IMT and then followed a rehabilitation program based on 6 biweekly sessions focused on visual abilities, reading, writing, visual motor integration and mobility. A total of 11 participants were included in this study. Reading acuity (RA), reading speed (RS), and fixation stability (FS) were assessed biweekly at 6-, 8-, 10-, 12-, 14-, and 16-week follow-up visits after SING IMT implantation and at a final assessment at 24 weeks. Best-corrected distance visual acuity (BCDVA) was also measured at baseline and at the same postoperative timepoints., Results: Mean baseline BCDVA was 12.5 ± 8.6 letter score. Both RA and RS were found to be significantly improved from the first rehabilitation session (6 weeks after surgery) to the last session (24 weeks after surgery). At the end of the rehabilitation program, mean RA was 0.45 ± 0.19 LogMAR and mean RS was 30.9 ± 17.6 words per minute. Moreover, all patients achieved a FS of 15 s or more after the last rehabilitation session. Most patients (55%) achieved an improvement of 15 letters in BCDVA at the end of the study., Conclusions: This study suggests that rehabilitation training can improve visual functions of patients with late-stage AMD implanted with SING IMT in real-world tasks such as reading skills., (© 2023. The Author(s).)

Purpose: to report a case of bilateral macular edema (ME) secondary to Rituximab infusions in a woman affected by IgG4-Related Disease and to review of prior cases of ME related to Rituximab., Observations: ME completely resolved after Intravitreal Dexamethasone Implant (IDI)., Conclusions and Importance: ME is a rare complication after Rituximab infusions and very few cases are reported in the literature. Usually, ME occurs a few weeks after systemic administration and is probably related to a local release of cytokines. It resolves with oral, subtenon or intravitreal steroids. Our case is the first showing that IDI is a safe and effective treatment in ME secondary to Rituximab. Rituximab is not required to be discontinued if treatment for ME is started., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: to evaluate long-term effectiveness and safety of fluocinolone acetonide (FAc) implant used as second-line treatment in patients with persistent diabetic macular edema (DME)., Methods: retrospective data chart review of 241 pseudophakic eyes of 178 patients treated with FAc from July 2017 to December 2021 in 10 medical retinal units in Italy. The primary endpoint was the change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 2 years. A Student's paired t-test was used. Additional therapies for DME and intraocular pressure (IOP)-related events were also evaluated., Results: efficacy of FAc was assessed in a subset of 111 eyes with at least 24 months of follow-up. Mean BCVA increased at 2 years by 5.1 ETDRS letters (95%CI = 2.6-7.5; p  < 0.001) while mean CMT decreased by 189 µm (95% CI 151-227; p  < 0.001). Thirty-eight of these eyes (34.2%) needed additional intravitreal treatments, mainly anti-VEGF. Safety was evaluated on the entire cohort of 241 eyes treated with FAc. Overall, 66 eyes (27.4%) required emergent IOP-lowering medications (typically within the first-year post FAc) while 14 eyes (5.8%) underwent trabeculectomy, mostly during the second year of follow-up., Conclusion: FAc implant provides a substantial long-term functional and anatomical benefit when used as second-line treatment in eyes with DME. IOP rise can be adequately managed with topical agents although some eyes may require IOP-lowering surgery., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Exposure to blue light has seriously increased in our environment since the arrival of light emitting diodes (LEDs) and, in recent years, the proliferation of digital devices rich in blue light. This raises some questions about its potential deleterious effects on eye health. The aim of this narrative review is to provide an update on the ocular effects of blue light and to discuss the efficiency of methods of protection and prevention against potential blue light-induced ocular injury., Methods: The search of relevant English articles was conducted in PubMed, Medline, and Google Scholar databases until December 2022., Results: Blue light exposure provokes photochemical reactions in most eye tissues, in particular the cornea, the lens, and the retina. In vitro and in vivo studies have shown that certain exposures to blue light (depending on the wavelength or intensity) can cause temporary or permanent damage to some structures of the eye, especially the retina. However, currently, there is no evidence that screen use and LEDs in normal use are deleterious to the human retina. Regarding protection, there is currently no evidence of a beneficial effect of blue blocking lenses for the prevention of eye diseases, in particular age-related macular degeneration (AMD). In humans, macular pigments (composed of lutein and zeaxanthin) represent a natural protection by filtering blue light, and can be increased through increased intake from foods or food supplements. These nutrients are associated with lower risk for AMD and cataract. Antioxidants such as vitamins C, E, or zinc might also contribute to the prevention of photochemical ocular damage by preventing oxidative stress., Conclusion: Currently, there is no evidence that LEDs in normal use at domestic intensity levels or in screen devices are retinotoxic to the human eye. However, the potential toxicity of long-term cumulative exposure and the dose-response effect are currently unknown., (© 2023. The Author(s).)

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy with a wide range of manifestations including retinal vasculopathy. This study aimed to analyse retinal vascular involvement in FSHD patients using fundus photographs and optical coherence tomography-angiography (OCT-A) scans, evaluated through artificial intelligence (AI). Thirty-three patients with a diagnosis of FSHD (mean age 50.4 ± 17.4 years) were retrospectively evaluated and neurological and ophthalmological data were collected. Increased tortuosity of the retinal arteries was qualitatively observed in 77% of the included eyes. The tortuosity index (TI), vessel density (VD), and foveal avascular zone (FAZ) area were calculated by processing OCT-A images through AI. The TI of the superficial capillary plexus (SCP) was increased ( p < 0.001), while the TI of the deep capillary plexus (DCP) was decreased in FSHD patients in comparison to controls ( p = 0.05). VD scores for both the SCP and the DCP results increased in FSHD patients ( p = 0.0001 and p = 0.0004, respectively). With increasing age, VD and the total number of vascular branches showed a decrease ( p = 0.008 and p < 0.001, respectively) in the SCP. A moderate correlation between VD and EcoRI fragment length was identified as well (r = 0.35, p = 0.048). For the DCP, a decreased FAZ area was found in FSHD patients in comparison to controls (t (53) = -6.89, p = 0.01). A better understanding of retinal vasculopathy through OCT-A can support some hypotheses on the disease pathogenesis and provide quantitative parameters potentially useful as disease biomarkers. In addition, our study validated the application of a complex toolchain of AI using both ImageJ and Matlab to OCT-A angiograms.

Background: Eyes shut homolog (EYS) gene mutations are estimated to affect at least 5% of patients with autosomal recessive retinitis pigmentosa. Since there is no mammalian model of human EYS disease, it is important to investigate its age-related changes and the degree of central retinal impairment., Methods: A cohort of EYS patients was studied. They underwent full ophthalmic examination as well as assessment of retinal function and structure, by full-field and focal electroretinograms (ERGs) and spectral domain optical coherence tomography (OCT), respectively. The disease severity stage was determined by the RP stage scoring system (RP-SSS). Central retina atrophy (CRA) was estimated from the automatically calculated area of the sub-retinal pigment epithelium (RPE) illumination (SRI)., Results: The RP-SSS was positively correlated with age, showing an advanced severity score (≥8) at an age of 45 and a disease duration of 15 years. The RP-SSS was positively correlated with the CRA area. LogMAR visual acuity and ellipsoid zone width, but not ERG, were correlated with CRA., Conclusions: In EYS-related disease, the RP-SSS showed advanced severity at a relative early age and was correlated with the central area of the RPE/photoreceptor atrophy. These correlations may be relevant in view of therapeutic interventions aimed at rescuing rods and cones in EYS-retinopathy.

Purpose: To predict improvement of best-corrected visual acuity (BCVA) 1 year after pars plana vitrectomy for epiretinal membrane (ERM) using artificial intelligence methods on optical coherence tomography B-scan images., Methods: Four hundred and eleven (411) patients with Stage II ERM were divided in a group improvement (IM) (≥15 ETDRS letters of VA recovery) and a group no improvement (N-IM) (<15 letters) according to 1-year VA improvement after 25-G pars plana vitrectomy with internal limiting membrane peeling. Primary outcome was the creation of a deep learning classifier (DLC) based on optical coherence tomography B-scan images for prediction. Secondary outcome was assessment of the influence of various clinical and imaging predictors on BCVA improvement. Inception-ResNet-V2 was trained using standard augmentation techniques. Testing was performed on an external data set. For secondary outcome, B-scan acquisitions were analyzed by graders both before and after fibrillary change processing enhancement., Results: The overall performance of the DLC showed a sensitivity of 87.3% and a specificity of 86.2%. Regression analysis showed a difference in preoperative images prevalence of ectopic inner foveal layer, foveal detachment, ellipsoid zone interruption, cotton wool sign, unprocessed fibrillary changes (odds ratio = 2.75 [confidence interval: 2.49-2.96]), and processed fibrillary changes (odds ratio = 5.42 [confidence interval: 4.81-6.08]), whereas preoperative BCVA and central macular thickness did not differ between groups., Conclusion: The DLC showed high performances in predicting 1-year visual outcome in ERM surgery patients. Fibrillary changes should also be considered as relevant predictors.

The present study aimed to investigate ocular findings in hereditary transthyretin amyloidosis (ATTRv) pre-symptomatic carriers. Fourteen ATTRv pre-symptomatic carriers, who are patients with positive genetic testing but without signs or symptoms of the disease, were retrospectively evaluated. Retinal morphology was assessed using optical coherence tomography (OCT) and OCT-angiography. Retinal function was evaluated using cone b-wave and photopic negative response (PhNR). Pupillometry and in vivo corneal confocal microscopy (IVCM) were performed. ATTRv pre-symptomatic carriers presented a significantly reduced central macular thickness (CMT) ( p = 0.01) and outer nuclear layer (ONL) thickness ( p = 0.01) in comparison to normal controls. No differences were found when analyzing sub-foveal choroidal thickness, retinal nerve fiber layer and ganglion cell complex. In comparison to healthy controls, pre-symptomatic carriers presented an attenuated superficial retinal vascular network and a significantly augmented PhNR amplitude ( p = 0.01). However, PhNR implicit times, B-wave amplitude and B-wave peak time did not show significant differences in comparison to controls. No differences were found for pupillometric values. All the examined eyes presented alterations in the IVCM. Preclinical ocular structural and functional abnormalities can be found in ATTRv pre-symptomatic carriers. Thus, an extensive ophthalmological evaluation should be included at the baseline visit and during follow-up. Considering the availability of new drugs potentially able to prevent or delay disease progression, the identification of new disease biomarkers appears to be particularly promising.

Introduction: The aim of this study was to explore the early efficacy and safety of treatment with intravitreal injections (IVIs) of brolucizumab in patients presenting with neovascular age-related macular degeneration (nAMD) in a real-world setting., Methods: This retrospective study included 194 eyes of 180 patients with nAMD treated with standard 6-mg IVIs of brolucizumab in our clinic between March 11, 2021, and June 15, 2022. Both treatment-naive (33 eyes) and switch therapy patients (161 eyes) were included in the study. Best corrected visual acuity (BCVA), central subfield thickness (CST), retinal fluid distribution (classified as intraretinal, subretinal, under the pigmented epithelium), treatment intervals, and adverse event rates were collected for analysis., Results: Average follow-up time was 37.2 ± 16.6 weeks. Mean baseline BCVAs were 38.1 ± 4.5 and 41.9 ± 6.7 letters in the treatment-naive and switch therapy groups, with a final gain of 16.0 ± 4.9 (p &lt; 0.0001) and 10.7 ± 5.9 (p &lt; 0.0001) letters in the two groups, respectively. Throughout the study period, CST significantly decreased in both treatment naïve (from 352.0 ± 129.4 to 284.2 ± 93.8 µm; p = 0.0015) and switch therapy (from 369.9 ± 140.5 to 307.4 ± 123.5 µm; p &lt; 0.0001). Significant fluid control rates were achieved at the end of the study period (45% and 27% eyes were completely free of fluid in naïve and switch groups, respectively). Five eyes (2.6%) developed adverse events with different grades of intraocular inflammation and visual outcomes., Conclusion: Brolucizumab IVI showed very good anatomical and functional outcomes in both naive and switch patients in this real-world experience. Nevertheless, even showing a favorable risk/benefit profile, clinicians and patients should be aware of the possibility of a small rate of severe complications., (© 2023 S. Karger AG, Basel.)

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a treatable multisystemic disease with great phenotypic heterogeneity. Among extra-neurological features, pupillary abnormalities have been reported, either related to amyloid deposition in the eye or to a progressive autonomic neuropathy., Objective: To evaluate the role of automated pupillometry, a non-invasive and rapid test able to provide objective and reproducible data on pupil size and reactivity, as a marker of disease severity in late-onset ATTRv patients., Patients and Methods: We performed automated pupillometry on a cohort of ATTRv patients and pre-symptomatic TTR mutation carriers and compared results to healthy controls. An exhaustive clinical and instrumental evaluation was performed on all enrolled subjects., Results: A statistically significant difference in most pupillometry parameters was found in ATTRv patients as compared to both carriers and healthy controls. Moreover, in ATTRv patients, we found a significant correlation between many pupillometry findings and disease duration, as well as widely accepted clinical scales and investigations (NIS, Sudoscan from feet, and Norfolk QoL-DN questionnaire)., Conclusions: We suggest pupillometry may play a role as a reliable and non-invasive biomarker to evaluate ATTRv disease severity and monitor its progression.

The long-term effect of intravitreal Fluocinolone acetonide (FAc) on retinal morphology and function in diabetic macular edema (DME) was investigated. Seventeen eyes of twelve consecutive DME patients, treated by intravitreal FAc, were retrospectively evaluated. Retinal morphology was assessed with central macular thickness (CMT). Retinal function was assessed by best-corrected visual acuity (BCVA) and cone b-wave and photopic negative response (PhNR). The main outcome was a mean change in CMT at month 24. The secondary outcomes were changes in cone b-wave and PhNR at month 24. The incidence of adverse events was also recorded. Mean CMT decreased from 406.52 µm (±138.74) at baseline to 310 µm (±130.39) at 24 months (p = 0.008). No significant changes in the other parameters were found. At baseline, BCVA and PhNR amplitude were negatively correlated (r = −0.55) with CMT. At the end of follow-up, the change in CMT was negatively correlated with baseline CMT (r = −0.53, p = 0.03) and positively correlated with baseline PhNR amplitude (r = 0.58, p < 0.01). A significant, long-term reduction in CMT was observed in DME patients after FAc implant. The anti-edema effect tended to be stronger in patients with the poorest baseline retinal morphology (CMT) and function (PhNR). Structure/function correlations might help to characterize the patients who may benefit from this treatment.

Acute posterior syphilitic placoid chorioretinopathy (ASPPC) is a rare ocular manifestation of syphilis characterized by outer retinal layers involvement and drop in visual acuity. The current work documents outer retinal layer involvement in this pathology and their reconstitution with treatment by means of adaptive optics (AO). Three eyes of two patients together with four controls eyes were included in the study. Patients underwent optical coherence tomography (OCT) and OCT angiography (OCTA) scan centered on fovea, where vessel density (VD) and vessel perfusion (VP) were calculated. AO images centered on fovea were acquired and cone density (CD) and cone spacing (CS) were measured and compared to control group. Multimodal imaging was performed at presentation, at 10 days, and at 2-month follow-up. All eyes improved in visual acuity, with reconstitution in outer retinal layers at 2-month follow-up. Overall choriocapillary layer VD and VP improved. AO imaging was able to identify outer retinal alterations at presentation and at follow-ups, with improvement in tissue architecture. CD and CS was respectively lower and greater than controls at all follow-ups and improved within patients at the 2-month follow-up. In conclusion, AO was able to document outer retinal alterations in ASPPC at presentation and improvement over the follow-up, representing a tool to study photoreceptor layer involvement in this pathology.

Introduction: Choroidal thickness (CT) plays an important role in the pathogenesis of various ocular diseases, including neovascular age-related macular degeneration (nAMD). Previous studies evaluated the CT variations after anti-vascular endothelial growth factor (VEGF) injections in patients with nAMD, but the results are still controversial. The present study aimed to evaluate the CT at different times (15, 30, 60, 90, and 365 days) after intravitreal aflibercept injections and its correlation with the baseline CT in treatment-naïve patients with nAMD. Secondly, the study evaluated the correlation between CT variation at 365 days and the number of intravitreal injections received., Methods: This was a prospective, open-label, single-arm pilot study. Twenty-one treatment-naïve nAMD eyes were enrolled. The study population underwent three monthly aflibercept injections (loading phase) and additional injections as needed (pro re nata regimen). A complete ophthalmological examination, including optical coherence tomography (OCT) was performed at each visit. CT was measured manually by two independent observers. All patients were evaluated at baseline and at 15, 30, 60, 90, and 365 days after the first intravitreal injection., Results: CT showed a statistically significant reduction at days 15, 90, and 365 in comparison to baseline. However, the major reduction of CT was observed at day 15 and in eyes with a thicker choroid at baseline. No significant correlation between CT variation and the number of injections performed was found., Conclusion: Our findings contribute to clarifying the role of aflibercept injections in choroidal vasculature, confirming its effect after the first 2 weeks. Moreover, CT can be considered as a potential biomarker, as it reflects the pharmacological effect of anti-VEGF drugs., (© 2022. The Author(s).)

Purpose: The objectives of this study were the creation and validation of a screening tool for age-related macular degeneration (AMD) for routine assessment by primary care physicians, ophthalmologists, other healthcare professionals, and the general population., Methods: A simple, self-administered questionnaire (Simplified Théa AMD Risk-Assessment Scale [STARS] version 4.0) which included well-established risk factors for AMD, such as family history, smoking, and dietary factors, was administered to patients during ophthalmology visits. A fundus examination was performed to determine presence of large soft drusen, pigmentary abnormalities, or late AMD. Based on data from the questionnaire and the clinical examination, predictive models were developed to estimate probability of the Age-Related Eye Disease Study (AREDS) score (categorized as low risk/high risk). The models were evaluated by area under the receiving operating characteristic curve analysis., Results: A total of 3854 subjects completed the questionnaire and underwent a fundus examination. Early/intermediate and late AMD were detected in 15.9% and 23.8% of the patients, respectively. A predictive model was developed with training, validation, and test datasets. The model in the test set had an area under the curve of 0.745 (95% confidence interval [CI] = 0.705-0.784), a positive predictive value of 0.500 (95% CI = 0.449-0.557), and a negative predictive value of 0.810 (95% CI = 0.770-0.844)., Conclusions: The STARS questionnaire version 4.0 and the model identify patients at high risk of developing late AMD., Translational Relevance: The screening instrument described could be useful to evaluate the risk of late AMD in patients >55 years without having an eye examination, which could lead to more timely referrals and encourage lifestyle changes.

Two-hundred and thirty-four Italian patients with a clinical diagnosis of macular, cone and cone-rod dystrophies (MD, CD, and CRD) were examined using next-generation sequencing (NGS) and gene sequencing panels targeting a specific set of genes, Sanger sequencing and-when necessary-multiplex ligation-dependent probe amplification (MLPA) to diagnose the molecular cause of the aforementioned diseases. When possible, segregation analysis was performed in order to confirm unsolved cases. Each patient's retinal phenotypic characteristics were determined using focal and full-field ERGs, perimetry, spectral domain optical coherence tomography and fundus autofluorescence. We identified 236 potentially causative variants in 136 patients representing the 58.1% of the total cohort, 43 of which were unpublished. After stratifying the patients according to their clinical suspicion, the diagnostic yield was 62.5% and 53.8% for patients with MD and for those with CD/CRD, respectively. The mode of inheritance of all cases confirmed by genetic analysis was 70% autosomal recessive, 26% dominant, and 4% X-linked. The main cause (59%) of both MD and CD/CRD cases was the presence of variants in the ABCA4 gene, followed by variants in PRPH2 (9%) and BEST1 (6%). A careful morpho-functional evaluation of the phenotype, together with genetic counselling, resulted in an acceptable diagnostic yield in a large cohort of Italian patients. Our study emphasizes the role of targeted NGS to diagnose MDs, CDs, and CRDs, as well as the clinical usefulness of segregation analysis for patients with unsolved diagnosis., (© 2022. The Author(s).)

The term microbiome means not only a complex ecosystem of microbial species that colonize our body but also their genome and the surrounding environment in which they live. Recent studies support the existence of a gut-retina axis involved in the pathogenesis of several chronic progressive ocular diseases, including age-related macular disorders. This review aims to underline the importance of the gut microbiome in relation to ocular health. After briefly introducing the characteristics of the gut microbiome in terms of composition and functions, the role of gut microbiome dysbiosis, in the development or progression of retinal diseases, is highlighted, focusing on the relationship between gut microbiome composition and retinal health based on the recently investigated gut-retina axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scuderi, Troiani and Minnella.)

Background: Early identification of AMD can lead to prompt and more effective treatment, better outcomes, and better final visual acuity; several risk scores have been devised to determine the individual level of risk for developing AMD. Herein, the Delphi method was used to provide recommendations for daily practice regarding preventive measures and follow-up required for subjects at low, moderate, and high risk of AMD evaluated with the Simplified Test AMD Risk-assessment Scale (STARS ® ) questionnaire., Methods: A steering committee of three experts drafted and refined 25 statements on the approach to be recommended in different clinical situations [general recommendations ( n = 2), use of evaluation tools ( n = 4), general lifestyle advice ( n = 3), and AREDS-based nutritional supplementation ( n = 5)] with the help of a group of international experts, all co-authors of this paper. Thirty retinal specialists from Europe and the US were chosen based on relevant publications, clinical expertise, and experience in AMD, who then provided their level of agreement with the statements. Statements for which consensus was not reached were modified and voted upon again., Results: In the first round of voting, consensus was reached for 24 statements. After modification, consensus was then reached for the remaining statement., Conclusion: An interprofessional guideline to support preventive measures in patients at risk of AMD based on STARS ® scoring has been developed to aid clinicians in daily practice, which will help to optimize preventive care of patients at risk of AMD.

Background: Systemic vascular involvement in COVID-19 has been identified in several patients: not only endothelial derangement and increased permeability are reported to be early hallmarks of organ damage in patients with COVID-19 but are also the most important cause of worsening of clinical conditions in severe cases of SARS-CoV-2 infection. There are several reasons to hypothesize that the eye, and the retina in particular, could be a target of organ damage in SARS-CoV-2 infection., Methods: This cohort observational study analyzes OCT angiography and structural OCT of 70 post-COVID-19 patients evaluated at 1-month hospital discharge and 22 healthy control subjects. Primary outcomes were macular vessel density (VD) and vessel perfusion (VP); structural OCT features were evaluated as secondary outcomes. In addition, patients and healthy volunteers were evaluated for best corrected visual acuity, slit lamp photograph, and fundus photo image., Results: VD and VP in 3 × 3 and 6 × 6 mm scans for SCP and DCP showed no significant differences between the groups. Similarly, CMT and GCL did not reveal significant differences between post-COVID-19 and healthy patients. Nine patients (12.9%) featured retinal cotton wool spots and 10 patients had vitreous fibrillary degeneration. The prevalence of epiretinal membrane and macular hole was similar in the two groups. One case of extra papillary focal retinal hemorrhage was reported in the post-COVID-19 group., Conclusions: Macula and perimacular vessel density and perfusion resulted unaltered in mild post-COVID-19 patients at 1-month hospital discharge, suggesting no or minimal retinal vascular involvement by SARS-CoV-2., (© 2021. The Author(s).)

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

Hereditary transthyretin amyloidosis (hATTR) is a rare disease caused by a point mutation in the transthyretin (TTR) gene and inherited in an autosomal dominant fashion. TTR is a plasma protein that functions as a carrier for thyroxine (T4) and retinol (vitamin A). Ophthalmological manifestations are due to both the hepatic and ocular production of mutated TTR. In this case series, we report the ocular manifestations of hATTR in eighteen eyes of nine consecutive patients. Corneal nerve abnormalities as well as morphological and functional changes in the retina were investigated. The study was a single-center, retrospective, observational, clinical case series. In all patients, corneal confocal microscopy (CCM), multimodal imaging of the retina, including fundus photography and Optical Coherence Tomography (OCT), as well as rod and cone electroretinography (ERG) were performed. Eight patients had active disease and one was an unaffected carrier. In all study eyes, corneal nerve plexa examined with CCM were poorly represented or absent. Mixed rod-cone and cone ERG b-wave amplitudes were reduced, and photopic b-wave responses were significantly delayed. Photopic Negative Response (PhNR) amplitude was significantly reduced, while PhNR latency was significantly augmented. In 13/18 eyes, vitreous opacities and abnormalities of vitreo-retinal interface were found. The current results highlight the presence of corneal nerve damage. Functional retinal abnormalities, detected by ERG, can be found even in the presence of minimal or absent structural retinal damage. These findings support the use of CCM and ERGs to detect early biomarkers for primary hATTR.

Purpose: To evaluate morpho-functional outcomes of the intravitreal fluocinolone acetonide (FAc) implant., Methods: Retrospective, observational, single-center study. Primary endpoint was the mean change in central macular thickness (CMT) from baseline to month 1-3. Secondary endpoints included mean CMT change from baseline to month 4-8 and 9-14 and mean best corrected visual acuity (BCVA), photopic negative response (PhNR) and b-wave of flash full-field electroretinogram (ERG) changes from baseline to month 1-3, 4-8, and 9-14., Results: Fourteen patients (18 eyes) were included. Mean (standard deviation) CMT decreased from 473 (196) µm at baseline to 371 (163) µm at month 1-3 (mean difference - 102.3 ± 98.35 µm, 95% CI ± 46.4 µm; p < 0.0001) and this decrease tended to endure up to month 9-14. BCVA did not change significantly. There was an improvement in mean PhNR amplitude from 2.76 (1.65) µV at baseline to 3.73 (2.32) µV at month 1-3 (mean difference 0.91 (1.14) µV, 95% CI ± 0.54 µV, p = 0.003); b-wave amplitude improved from 8.83 (4.52) µV at baseline versus 10.05 (5.04) µV at month 1-3 (mean difference 1.22 (2.23) µV, 95% CI ± 1.08 µV, p = 0.0384). These ERG positive changes tended to endure up to month 9-14, although they did not reach statistical significance after month 3., Conclusions: Intravitreal FAc implant significantly improved anatomic as well as functional outcomes related to middle and inner retinal layers, known to be altered in diabetic retinopathy. Our findings support the hypothesis that intravitreal FAc implant may exert a protective effect in diabetic retinas with diabetic macular edema.

Usher syndrome type 2A ( USH2A ) is a genetic disease characterized by bilateral neuro-sensory hypoacusia and retinitis pigmentosa (RP). While several methods, including electroretinogram (ERG), describe retinal function in USH2A patients, structural alterations can be assessed by optical coherence tomography (OCT). According to a recent collaborative study, RP can be staged considering visual acuity, visual field area and ellipsoid zone (EZ) width. The aim of this study was to retrospectively determine RP stage in a cohort of patients with USH2A gene variants and to correlate the results with age, as well as additional functional and morphological parameters. In 26 patients with established USH2A genotype, RP was staged according to recent international standards. The cumulative staging score was correlated with patients' age, amplitude of full-field and focal flicker ERGs, and the OCT-measured area of sub-Retinal Pigment Epithelium (RPE) illumination (SRI). RP cumulative score (CS) was positively correlated (r = 0.6) with age. CS was also negatively correlated (rho = -0.7) with log10 ERG amplitudes and positively correlated (r = 0.5) with SRI. In USH2A patients, RP severity score is correlated with age and additional morpho-functional parameters not included in the international staging system and can reliably predict their abnormality at different stages of disease.

Purpose: To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in prior ranibizumab-treated patients with neovascular age-related macular degeneration (nAMD) enrolled in the LUMINOUS™ study., Patients and Methods: LUMINOUS, a 5-year, prospective, multicenter, observational study, recruited 30,138 adult patients (treatment-naïve or prior ranibizumab-treated or other ocular treatments) across all approved indications for ranibizumab. Patients were treated as per local ranibizumab label of participating countries. Here we report the mean change in visual acuity (VA) at Year 1, treatment exposure, overall incidence of ocular, non-ocular adverse events (AEs) and serious AEs (SAEs) in prior ranibizumab-treated nAMD patients (n = 16,167)., Results: At baseline, the mean (standard deviation [SD]) age of patients was 78.4 (9.0) years, 59.0% were female, and 80.0% were Caucasian. At Year 1 (n = 10,168), the mean (SD) VA change was -1.6 (12.6) letters (baseline VA: 58.3 [19.0] letters) with a mean (SD) of 4.7 (3.1) ranibizumab injections. Stratified by duration of prior ranibizumab treatment of <1 (n = 4,112), 1 to <2 (n = 2,095), 2 to <3 (n = 1,506), 3 to <4 (n = 1,123), 4 to <5 (n = 689), and ≥5 (n = 256) years, the mean (SD) VA change at Year 1 were -1.2 (13.5), -2.0 (12.3), -2.0 (11.3), -1.9 (11.8), -2.5 (10.9), and 0.0 (11.2) letters, respectively. Mean (SD) VA change in patients who received ≤6 and >6 injections over 1 year was -1.8 (13.8) and +0.5 (12.5) letters, respectively. The rate of ocular/non-ocular AEs and SAEs across all prior ranibizumab-treated patients over 5 years were 13.29%/23.02% and 0.84%/13.66%, respectively., Conclusions: Overall, regardless of the prior ranibizumab-treatment duration, VA was maintained in these patients at Year 1, and those receiving ≥6 injections showed a trend towards gaining letters. There were no new safety signals. These results may help inform routine clinical practice to appropriately treat nAMD patients with ranibizumab to achieve optimal visual outcomes., Competing Interests: Prof. Frank G Holz is a consultant for Acucela, Alcon, Bayer, Boehringer-Ingelheim, Galimedix, Genentech, Heidelberg Engineering, Khanghong, Lin-Bioscience, Novartis, Oxurion, Roche, Zeiss; receives grants from Bayer, Centervue, Genentech/Roche, Heidelberg Engineering, Novartis, and Zeiss. Prof. Angelo M Minnella is a consultant for Theà Laboratoire; receives grants (travel and meeting) from Allergan, Bayer Healthcare, Novartis Pharmaceutical, Theà Laboratoire. Dr. Raman Tuli is a member of advisory boards in Bayer, Novartis; receives grants from Apelis, Novartis, Roche. Prof. Pradeepa Yoganathan receives honoraria from Alimera Sciences, Genentech, and Knight Therapeutics including non-financial support from Bayer and Novartis. Dr. Soumil Parikh is an employee of Novartis Pharma AG, Basel, Switzerland. Dr. Robin Hamilton is a consultant for Allergan, Bayer Healthcare, Novartis Pharmaceuticals, and Roche; receives grants from Bayer Healthcare, Novartis Pharmaceuticals and Roche; receives lecture fees from Allergan, Bayer Healthcare, Novartis Pharmaceuticals and Roche. We state that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Cataract surgery can be associated with vision-threatening complications in patients with diabetes. This study aimed to assess the functional and anatomic outcomes of the intravitreal dexamethasone (DEX) implant, administered at the time as cataract surgery, in patients with diabetic retinopathy and diabetic macular edema (DME)., Methods: This was a retrospective, observational, and single-center study. The primary endpoint was the mean change in central macular thickness (CMT) from baseline to month 1. Secondary endpoints included mean change in best corrected visual acuity (BCVA) from baseline to month 1 and 3, mean change in CMT from baseline to month 3, the photopic negative response (PhNR) and the b wave of flash full-field electroretinogram from baseline to month 1, and the incidence of adverse events., Results: Twenty-four eyes of 21 patients were included in the study. The mean (range) age of patients was 69 (63-87) years and 13 (61.9%) were men. Mean (standard deviation) CMT significantly decreased from 447 (134) µm at baseline to 341 (134) µm at month 1 (mean difference - 106 ± 134 µm, 95% CI - 183.9 to - 28.1 µm; p = 0.0087). BCVA significantly improved from 46 (20) ETDRS letters at baseline to 59 (22) ETDRS letters at month 1 (mean difference 13 ± 21 letters, 95% CI 0.8-25.2 letters; p = 0.0375). Regarding electrophysiology, there was a statistically significant reduction in mean PhNR from 5.24 (1.67) µV at baseline to 3.73 (1.19) µV at month 1 (mean difference - 1.51 ± 0.42 µV, 95% CI - 2.4 to - 0.7 µV, p = 0.0008); whereas b wave amplitude did not change (12.69 ± 6.89 µV at baseline versus 12.29 ± 6.30 µV at month 1; p = 0.8347). Four (16.7%) eyes developed ocular hypertension over the course of follow-up, which was successfully controlled with topical hypotensive medication., Conclusion: Perioperative DEX implant significantly improved both anatomic and functional outcomes in patients with DME who underwent cataract surgery.

Vitreomacular traction (VMT) syndrome has only been surgically treated for a long time. Recently, enzymatic vitreolysis with ocriplasmin has emerged as a possible option to release VMT and, in some cases, close full thickness macular holes (FTMHs). Despite its clinical relevance, gathering information about the ocriplasmin-induced alterations of the Inner Limiting Membrane (ILM) of the retina in a clinical study is a complex task, mainly because of the inter-individual variability among patients. To obtain more insights into the mechanism underlying the drug action, we studied in-vitro the mechanical and morphological changes of the ILM using Atomic Force Microscopy (AFM). To this aim, we measured the ILM average Young's modulus (YM), hysteresis (H) and adhesion work (A) over time under ocriplasmin treatment. Our data unveil a time-dependent increase in the membrane YM of 19% of its initial value, along with changes in its adhesive and dissipative behavior. Such modifications well correlate with the morphological alterations detected in the AFM imaging mode. Taken all together, the results here presented provide more insights into the mechanism underlying the ocriplasmin action in-vivo, suggesting that it is only able to alter the top-most layer of the vitreal side of the membrane, not compromising the inner ILM structure., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Early detection of retinal dysfunction in age-related macular degeneration (AMD) may be important for both prevention and treatment. The aim of this study was to evaluate in early and intermediate AMD the correlation of macular function, assessed by the focal electroretinogram (fERG), with the Simplified Thea Risk Assessment Scale (STARS), a simple 13-item self-administered questionnaire., Methods: We recorded a fERG (18°, 41 Hz) in 84 patients with AMD (40 male and 44 female, age 55-87 years, visual acuity 20/40-20/20), who had undergone a 5-year clinical ophthalmic and general follow-up. Sixty-six patients had early and 17 patients intermediate AMD. Fifty healthy subjects, in a comparable age range, served as controls. The fERG amplitude (in microVolts) was the main outcome variable. STARS was calculated for each patient., Results: Compared with controls, fERG amplitudes were significantly reduced, on average, in both early and intermediate patients with AMD ( P < 0.01). In both groups, fERG amplitudes tended to decrease with age and to increase with visual acuity and were negatively correlated with STARS (early r = -0.6, P < 0.01; intermediate, r = -0.50, P < 0.05). fERG losses were greatest in patients with a STARS score of greater than 20., Conclusions: In early and intermediate AMD, STARS robustly predicted central retinal function, as assessed by fERG, supporting the combined use of both parameters to estimate the clinical risk of visual function loss., Translational Relevance: The STARS may predict macular function in AMD and could be used in the daily clinical practice to estimate the risk of visual function loss in early disease stages., Competing Interests: Disclosure: A.M. Minnella, Allergan, Bayer, Novartis, Thea Laboratoires; M. Piccardi, None; G. Placidi, None; A. García-Layana, Allergan, Bayer, Novartis, Roche, Thea Laboratoires; C. Delcourt, Allergan, Bausch+Lomb, Thea Laboratoires, Novartis; P. Valentini, None; B. Falsini, None, (Copyright 2020 The Authors.)

The purpose of this study was to investigate the relationship between the retinal pigment epithelium (RPE) and outer retina changes, expressed in terms of sub-RPE illumination (SRI) on optical-coherence tomography (OCT), and central retinal function, measured by visual acuity and focal electroretinogram (fERG), in patients with non-exudative age-related macular degeneration (neAMD). In this retrospective study, 29 eyes of 29 patients affected by early (24.14%), intermediate (41.38%), and advanced (34.48%) neAMD were evaluated. All enrolled eyes were studied with OCT to measure the total area of SRI, by using an automated standardized algorithm. Visual acuity and fERG were assessed. The area of SRI was negatively correlated with fERG amplitude (r ≤ -0.4, p ≤ 0.02) and best-corrected visual acuity (BCVA) (r ≤ 0.4, p ≤ 0.04). Our results indicate that the severity of retinal pigment epithelium and outer retina atrophy (RORA), indirectly quantified through the detection of SRI areas by commercial OCT algorithms, is correlated with central retinal dysfunction, as determined by visual acuity and fERG, supporting the combined use of structural exams and functional tests as valid tools to detect the extent of RPE and photoreceptors' disruption.

Objective: To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in treatment-naïve patients with branch retinal vein occlusion (BRVO) enrolled in the LUMINOUS™ study., Study Design: A 5-year, global, prospective, multicenter, observational, open-label study conducted in a clinical practice (real-world) setting at outpatient ophthalmology clinics that recruited 30,138 consenting adult patients from all approved indications for ranibizumab across 42 countries. Patients with BRVO were treated according to the local ranibizumab label of the participating countries. Mean change in visual acuity (VA) in Early Treatment Diabetic Retinopathy Study letters from baseline to Year 1, treatment exposure during Year 1, and adverse events (AEs) over 5 years were assessed., Results: Of the 1366 recruited BRVO patients, 405 were treatment-naïve at baseline with a mean (standard deviation [SD]) age of 67.9 (12.5) years, 57.5% were female, and 71.8% were White. At Year 1 (n = 189), the mean (SD) VA gain was 11.9 (17.66) letters from a baseline of 49.2 (±20.32) letters with a mean (SD) of 5.0 (2.34) injections. VA gains were higher in patients (n = 83) who received 6-9 injections (13.6 [20.16] letters) than in those who received 2-5 injections (n = 92, 11.7 [15.43] letters), or 1 injection (n = 14, 3.6 [13.72] letters). Patients with baseline VA <23 letters had numerically highest VA gains (n = 20, 31.1 [24.48] letters). Over 5 years, the rate of ocular/non-ocular AEs was 7.4%/9.1% and serious AEs was 0.3%/4.4% in treatment-naïve BRVO patients (n = 405)., Conclusions: One year results from the LUMINOUS real-world study showed a clinically meaningful VA improvement with ranibizumab in treatment-naïve patients with BRVO; numerically higher VA gains were achieved in patients who received more injections and those with poor baseline VA. No new safety signals were observed., Competing Interests: Ian Pearce is a consultant for Alcon Pharma, Allergan, Bayer Healthcare, Novartis Pharmaceuticals, and Roche; receives lecture fees from Alcon Pharma, Allergan, Bayer Healthcare, Novartis Pharmaceuticals, and Roche. Andreas Clemens and Cornelia Dunger-Baldauf are employees and shareholders of Novartis Pharma AG, Basel, Switzerland. Michael H Brent receives research support from Novartis, Bayer, Roche and in advisory boards of Bayer, Novartis, and Roche. Lin Lu has nothing to disclose. Roberto Gallego-Pinazo is a consultant for Novartis and Roche, speaker for Bloss, Heidelberg Engineering, Indo, Novartis, Novo Nordisk, Roche, and have received grant support from Boehringer-Ingelheim, Novartis, Roche, and Thrombogenics. Angelo Maria Minnella is a consultant for Theà Laboratoire and receives travel and meeting grant from Allergan, Bayer Healthcare, Novartis Pharmaceuticals, and Theà Laboratoire. Catherine Creuzot-Garcher is a consultant for Allergan, Alcon, Bausch & Lomb, Bayer, Novartis, Roche, and Thea. Georg Spital reports personal fees from Allergan, Bayer, Heidelberg Engineering, Novartis, and Zeiss, outside the submitted work. Taiji Sakamoto is a consultant for Bausch & Lomb, Bayer Healthcare, Novartis Pharmaceuticals, Roche, Santen, and Senju; receives grants from Bayer Healthcare, Novartis Pharmaceuticals, Otsuka Pharmaceuticals, Santen and Senju; receives lecture fees from Bausch & Lomb, Bayer Healthcare, Novartis Pharmaceuticals, Santen, and Senju. Ian McAllister is an advisory board member for Bayer and Novartis. The aforementioned disclosures for all authors does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: To assess the one-year effectiveness and safety of ranibizumab 0.5 mg in treatment- naïve patients with diabetic macular edema (DME) enrolled in the real-world LUMINOUS study., Patients and Methods: A 5-year, prospective, observational, open-label, global study which recruited 30,138 patients across all approved indications. Consenting patients (≥18 years) who were treatment-naïve or previously treated with ranibizumab or other ocular treatments were treated as per the local ranibizumab label. Here, we present the change in visual acuity (VA) (Early Treatment Diabetic Retinopathy Study letter score; primary treated eye) at Year 1, as well as the change in VA based on injection frequencies (≤4 and ≥5), treatment exposure, and the overall adverse events (AEs) and serious AEs (SAEs) in treatment-naïve DME patients., Results: Of the 4,710 DME patients enrolled in the study, 1,063 were treatment-naïve. At baseline, mean age was 64.5 years, 54.7% were male, and 69.2% were white. At 1 year, mean VA letter score improved by +3.5 (n = 502) from a baseline of 57.7 with a mean of 4.5 injections. Presented by injection frequencies ≤4 and ≥5, VA letter score gains were 0.5 (n = 264) and 6.9 (n = 238) from baseline letter scores of 56.6 and 59.0, respectively. Over 5 years, the incidence of ocular/non-ocular AEs and SAEs was 7.2%/10.1% and 0.3%/5.8%, respectively. No endophthalmitis cases were reported., Conclusions: The LUMINOUS study included patients with DME with more diverse baseline characteristics than those in randomized clinical trials. The 1-year data showed improvement in VA with low number of injections in treatment- naïve patients with DME. Greater VA gains were observed in patients who received ≥5 injections. No new safety findings were identified. LUMINOUS confirms the effectiveness and safety of ranibizumab for the treatment of patients with DME in a real-world clinical practice., Competing Interests: Financial disclosures: Paul Mitchell: Consultant − Abbott, Allergan, Bayer, Genentech, Novartis, Roche. Tom G. Sheidow: Research support – Novartis, Pfizer; Advisory board – Novartis, Alcon, Bayer Michel E. Farah: Consultant: Allergan, Bayer, Novartis, Alcon, Zeiss; Advisor: Cristália, Latinofarma; Research grant: Fapesp, Capes, CNPq Sajjad Mahmood: Research Grant – Bayer, and Novartis; Personal Fees – Alcon, Allergan, Bayer, and Novartis. Angelo M. Minnella: Consultant – Theà Laboratoire; Travel and meeting grant- Allergan, Bayer, Novartis, Theà. Nicole Eter: Consultant – Allergan, Alimera, Bausch & Lomb, Bayer, Heidelberg Engineering, Novartis, Roche. Bora Eldem: Consultant – Alcon Laboratories, Bayer Healthcare, and Novartis. Hassan Al-Dhibi: Consultant –Bayer, AbbVie and Novartis. Wayne Macfadden: Employee of Novartis Pharma AG, Basel, Switzerland at the time of development of the manuscript. Soumil Parikh: Employee of Novartis Pharma AG, Basel, Switzerland. Cornelia Dunger-Baldauf: Employee of Novartis Pharma AG, Basel, Switzerland. Mohamed M. Mahgoub: Nothing to declare. Ursula Schmidt-Erfurth: Consultant – Alcon, Bayer, Boeringher-Ingelheim GmbH, and Novartis. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

The high-energy demands of the retina are thought to contribute to its particular vulnerability to mitochondrial dysfunction. Photoreceptors are the cells with the higher oxygen consumption within the retina, and among these, the cones contain more mitochondria and have a higher energy demand than rods. A cohort of twenty-two patients with genetically-defined mitochondrial diseases (MDs) were enrolled to determine if the macula is functionally and anatomically impaired in these metabolic disorders. Visual acuity and fERG amplitude of patients with primary mitochondrial dysfunction were reduced compared to controls. Furthermore, SD-OCT layer segmentation showed a reduction of retinal and outer nuclear layer (ONL) volume in the macula of the patients. fERG amplitude showed a positive correlation with both ONL volume and thickness. A negative relationship was noted between fERG amplitude and disease severity assessed with Newcastle Mitochondrial Disease Adult Scale. In conclusion, MDs are associated with functional and anatomical alteration of macular cone system, characterized by its strong correlation with clinical disease severity suggesting a role as a potential biomarker of primary mitochondrial disorders.

Purpose: To assess the 1-year effectiveness, safety, and treatment patterns of ranibizumab in patients with myopic choroidal neovascularization (mCNV) enrolled in the LUMINOUS study., Methods: This 5-year, prospective, multicenter, observational, study enrolled 30,138 patients across all approved ranibizumab indications from outpatient ophthalmology clinics. 297 consenting patients (≥18 years) with mCNV who were treatment-naïve or prior-treated with ranibizumab or other ocular treatments were enrolled, and treated with ranibizumab according to the local product label. The main outcomes are visual acuity (VA; Early Treatment Diabetic Retinopathy Study letters or equivalent), adverse events during the study, and treatment exposure over 1 year. Results are presented by prior treatment status of the study eye and injection frequency., Results: Of the 297 mCNV patients recruited in the study, 108 were treatment-naïve and 175 were prior ranibizumab-treated. At baseline, the mean age of patients was 57.6 years, and 59.0 years and 80.6% and 65.7% were female in the treatment-naïve and prior ranibizumab-treated groups, respectively. Most were Caucasian (treatment-naïve, 88.9%; prior ranibizumab-treated, 86.9%). The mean (±standard deviation [SD]) VA letter changes to 1 year were +9.7 (±17.99) from 49.5 (±20.51) and +1.5 (±13.15) from 58.5 (±19.79) and these were achieved with a mean (SD) of 3.0 (±1.58) and 2.6 (±2.33) injections in the treatment-naïve and prior ranibizumab-treated groups, respectively. Presented by injection frequencies 1-2, 3-4 and ≥5 injections in Year 1, the mean (SD) VA changes were +15.0 (±14.70), +7.7 (±19.91) and -0.7 (±16.05) in treatment-naïve patients and +1.5 (±14.57), +3.1 (±11.53) and -3.6 (±11.97) in prior ranibizumab-treated patients, respectively. The safety profile was comparable with previous ranibizumab studies., Conclusions: Ranibizumab treatment for mCNV showed robust VA gains in treatment-naïve patients and VA maintenance in prior ranibizumab-treated patients in a clinical practice setting, consisting mainly of Caucasians. No new safety signals were observed during the study., Competing Interests: Mr. Hamilton is a consultant for Allergan, Bayer Healthcare, Novartis Pharmaceuticals, and Roche; receives grants from Bayer Healthcare, Novartis Pharmaceuticals and Roche; receives lecture fees from Allergan, Roche, Bayer Healthcare, and Novartis Pharmaceuticals Drs Clemens and Dunger-Baldauf are employees and shareholders of Novartis Pharma AG, Basel, Switzerland. Dr. Minnella is a consultant for Theà Laboratoire and receives travel and meeting grant from Allergan, Bayer Healthcare, Novartis Pharmaceutical, Theà Laboratoire Dr Lai is a Consultant for Allergan, Bayer Healthcare, Boehringer Ingelheim, Genentech, Novartis Pharmaceuticals, and Roche; receives grants from Bayer Healthcare, Novartis Pharmaceuticals and Roche; receives lecture fees from Allergan, Bausch & Lomb, Bayer Healthcare, and Novartis Pharmaceuticals. Dr Dai receives research grants and non-financial support from Novartis. Dr. Sakamoto is a Consultant for Bayer Healthcare, Novartis Pharmaceuticals, Roche, Bausch & Lomb, Senju and Santen; receives grants from Bayer Healthcare, Santen, Otsuka Pharmaceuticals, Novartis Pharmaceuticals, and Senju; receives lecture fees from Bausch & Lomb, Bayer Healthcare, and Novartis Pharmaceuticals, Santen, and Senju. Dr Cheung receives consulting fees from Bayer, Novartis and Boehringer-Ingelheim, Roche. Dr Ngah receives research grants for the study and lecture fees from Bayer, Novartis and Allergan. Prof Dr Holz receives grants from Bayer, Centervue, Genentech/Roche, Heidelberg Engineering, Novartis, and Zeiss, and is a consultant for Acucela, Alcon, Bayer, Boehringer-Ingelheim, Galimedix, Genentech, Heidelberg Engineering, Lin-Bioscience, Novartis, Roche, and Zeiss. These competing interests of the authors does not alter their adherence to PLOS ONE policies on sharing data and materials.

Retinal oxidative damage, associated with an ATP-binding cassette, sub-family A, member 4, also known as ABCA4 gene mutation, has been implicated as a major underlying mechanism for Stargardt disease/fundus flavimaculatus (STG/FF). Recent findings indicate that saffron carotenoid constituents crocins and crocetin may counteract retinal oxidative damage, inflammation and protect retinal cells from apoptosis. This pilot study aimed to evaluate central retinal function following saffron supplementation in STG/FF patients carrying ABCA4 mutations., Methods: in a randomized, double-blind, placebo-controlled study (clinicaltrials.gov: NCT01278277), 31 patients with ABCA4-related STG/FF and a visual acuity >0.25 were randomly assigned to assume oral saffron (20 mg) or placebo over a six month period and then reverted to P or S for a further six month period. Full ophthalmic examinations, as well as central 18° focal electroretinogram (fERG) recordings, were performed at baseline and after six months of either saffron or placebo. The fERG fundamental harmonic component was isolated by Fourier analysis. Main outcome measures were fERG amplitude (in µV) and phase (in degrees). The secondary outcome measure was visual acuity., Results: supplement was well tolerated by all patients throughout follow-up. After saffron, fERG amplitude was unchanged; after placebo, amplitude tended to decrease from baseline (mean change: -0.18 log µV, p < 0.05). Reverting the treatments, amplitude did not change significantly. fERG phase and visual acuity were unchanged throughout follow-up., Conclusions: short-term saffron supplementation was well tolerated and had no detrimental effects on the electroretinographic responses of the central retina and visual acuity. The current findings warrant further long-term clinical trials to assess the efficacy of saffron supplementation in slowing down the progression of central retinal dysfunction in ABCA4-related STG/FF.

Background: Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the BEST1 gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium., Methods: Here we describe the spectrum of BEST1 variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands., Results: Thirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All BEST1 variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual BEST1 variants., Conclusions: Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.

Many ocular diseases are associated with an alteration of the mechanical and the material properties of the eye. These mechanically-related diseases include macular hole and pucker, two ocular conditions due to the presence of abnormal physical tractions acting on the retina. A complete relief of these tractions can be obtained through a challenging microsurgical procedure, which requires the mechanical peeling of the internal limiting membrane of the retina (ILM). In this paper, we provide the first comparative study of the nanoscale morphological and mechanical properties of the ILM in macular hole and macular pucker. Our nanoscale elastic measurements unveil a different bio-mechanical response of the ILM in the two pathologies, which correlates well to significant differences occurring during microsurgery. The results here presented pave the way to the development of novel dedicated microsurgical protocols based on the material ILM properties in macular hole or pucker. Moreover, they contribute to clarify why, despite a common aetiology, a patient might develop one disease or the other, an issue which is still debated in literature., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Fabry disease (FD) is a multiorgan X-linked condition characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in a progressive intralysosomal deposit of globotriaosylceramide. The aim of this study was to evaluate the macular ultrastructure of the vascular network using optical coherence tomography angiography (OCTA) and to evaluate macular function using focal electroretinography (fERG) in Fabry patients (FPs)., Methods: A total of 20 FPs (38 eyes, mean age 57 ± 2.12 SD, range of 27-80 years) and 17 healthy controls (27 eyes, mean age 45 years ± 20.50 SD, range of 24-65 years) were enrolled in the study. Color fundus photography, swept-source optical coherence tomography (SS-OCT), OCTA and fERG were performed in all subjects. The OCTA foveal avascular zone (FAZ), vasculature structure, superficial and deep retinal plexus densities (images of 4.5 × 4.5 mm) and fERG amplitudes were measured. Group differences were statistically assessed by Student's t-test and ANOVA., Results: In the FP group, the FAZ areas of the superficial and deep plexuses were enlarged (P = 0.036, t = 2.138; P < 0.001, t = -3.889, respectively), the vessel density was increased in the superficial plexus, and the fERG amplitude was reduced (P < 0.001, t = -10.647) compared with those in healthy controls. No significant correlations were found between the structural and functional data., Conclusions: OCTA vascular abnormalities and reduced fERG amplitudes indicate subclinical signs of microangiopathy with early retinal dysfunction in FPs. This study highlights the relevance of OCTA imaging analysis in the identification of abnormal macular vasculature as an ocular hallmark of FD.