The Role of VASOGRADE as a Simple Grading Scale to Predict Delayed Cerebral Ischemia and Functional Outcome After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The VASOGRADE is a simple aneurysmal subarachnoid hemorrhage (aSAH) grading scale that combines the modified Fisher scale (mFisher) and the World Federation of Neurological Societies (WFNS) grading system, allowing the stratification of delayed cerebral ischemia (DCI) risk. However, the VASOGRADE accuracy in predicting functional outcomes is still to be determined. METHODS: We retrospectively evaluated a multiethnic cohort of consecutive patients with aSAH admitted to a high-volume center in Brazil from January 2016 to January 2019. Patients were classified according to the severity of the clinical presentation (WFNS), the amount of blood in the initial head computerized tomography (mFisher) scan, and the VASOGRADE (green, yellow, red). The primary outcome was to detect DCI-related cerebral infarction, and the secondary outcome was the functional outcome at hospital discharge according to the modified Rankin scale (mRs). Univariate and multivariate logistic regression models were employed. RESULTS: A total of 212 patients (71.7% female, mean age 52.7 ± 12.8) were included. Sixty-nine patients were classified as VASOGRADE-Green (32.5%), 98 patients as VASOGRADE-Yellow (46.9%), and 45 patients as VASOGRADE-Red (20.6%). DCI-related infarction was present in 39 patients (18.9%). The proportions of patients in the VASOGRADE-Green, VASOGRADE-Yellow, and VASOGRADE-Red categories with DCI-related infarction were 7.7, 61.5, and 30.8%, respectively. After a multivariable analysis including age, sex, aneurysm location, and the VASOGRADE classification as variables, both VASOGRADE-Yellow and VASOGRADE-Red were independently associated with DCI-related infarction (odds ratio [OR] 7.69, 95% confidence interval [CI] 2.13-27.8, and OR 8.07, 95% CI 2.03-32.11, respectively) and unfavorable outcome (OR 4.16, 95% CI 1.33-13.03, and OR 25.57, 95% CI 4.45-147.1, respectively). The VASOGRADE discrimination performance for DCI-related infarction (area under the receiver operating characteristic curve) was 0.67 ± 0.04 (95% CI 0.58-0.75; p = 0.001). VASOGRADE-Red had 97.5% specificity for predicting an unfavorable mRs score at discharge (95% CI 92.8-99.5%). Conversely, VASOGRADE-Green had an excellent specificity for predicting favorable outcome at discharge (mRs score 0-2, 95% CI 82.6-95.5%). CONCLUSIONS: In conclusion, in a multiethnic cohort of patients with aSAH, VASOGRADE-Green predicted the absence of DCI and good clinical outcome at discharge with very high specificity, and patients in this category might be selected for early intensive care unit (ICU) discharge, minimizing costs and medical complications associated with prolonged hospital stay. On the other hand, patients categorized as VASOGRADE-Yellow and VASOGRADE-Red were at the highest risk for DCI. They should, therefore, be selected as a priority for care in high-volume aSAH centers, being aggressively monitored for DCI at the ICU. Such stratification methods are crucial, especially in countries with low financial resources and high health care services demand.

NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy.

Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from ß-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.

Autologous Retinal Transplantation for Primary and Refractory Macular Holes and Macular Hole Retinal Detachments: The Global Consortium.

PURPOSE: To report the anatomic and functional outcomes of autologous retinal transplantation (ART). DESIGN: Multicenter, retrospective, interventional, consecutive case series. PARTICIPANTS: One hundred thirty eyes of 130 patients undergoing ART for the repair of primary and refractory macular holes (MHs), as well as combined MH-rhegmatogenous retinal detachment (MH-RRD), between January 2017 and December 2019. METHODS: All patients underwent pars plana vitrectomy and ART, with surgeon modification of intraoperative variables. A large array of preoperative, intraoperative, and postoperative data was collected. Two masked reviewers graded OCT images. Multivariate statistical analysis and subgroup analysis were performed. MAIN OUTCOME MEASURES: Macular hole closure rate, visual acuity (VA), external limiting membrane and ellipsoid zone (EZ) band integrity, and alignment of neurosensory layers (ANL) on OCT. RESULTS: One hundred thirty ART surgeries were performed by 33 vitreoretinal surgeons worldwide. Patient demographics were: mean age of 63 ± 6.3 years, 58% female, 41% White, 23% Black, 19% Asian, and 17% Latino. Preoperative VA was 1.37 ± 0.12 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, approximately 20/500), which improved significantly to 1.05 ± 0.09 logMAR (Snellen equivalent, approximately 20/225; P < 0.001) after surgery (mean follow-up, 8.6 ± 0.8 months). Autologous retinal transplantation was performed for primary MH repair in 27% of patients (n = 35), for refractory MH in 58% of patients (n = 76; mean number of previous surgeries, 1.6 ± 0.2), and for MH-RRD in 15% of patients (n = 19). Mean maximum MH diameter was 1470 ± 160 µm, mean minimum diameter was 840 ± 94 µm, and mean axial length was 24.6 ± 3.2 mm. Overall, 89% of MHs closed (78.5% complete; 10% small eccentric defect), with a 95% closure rate in MH-RRD (68.4% complete; 26.3% small eccentric defect). Visual acuity improved by at least 3 lines in 43% of eyes and by at least 5 lines in 29% of eyes. Reconstitution of the EZ (P = 0.02) and ANL (P = 0.01) on OCT were associated with better final VA. Five cases of ART graft dislocation (3.8%), 5 cases of postoperative retinal detachment (3.8%), and 1 case of endophthalmitis (0.77%) occurred. CONCLUSIONS: In this global experience, patients undergoing ART for large primary and refractory MHs and MH-RRDs achieved good anatomic and functional outcomes, with low complication rates despite complex surgical pathologic features.

Non-invasive in vivo measurement of ocular rigidity: Clinical validation, repeatability and method improvement.

Ocular rigidity (OR) is thought to play a role in the pathogenesis of glaucoma, but the lack of reliable non-invasive measurements has been a major technical challenge. We recently developed a clinical method using optical coherence tomography time-lapse imaging and automated choroidal segmentation to measure the pulsatile choroidal volume change (ΔV) and calculate OR using Friedenwald's equation. Here we assess the validity and repeatability of this non-invasive technique. We also propose an improved mathematical model of choroidal thickness to extrapolate ΔV from the pulsatile submacular choroidal thickness change more accurately. The new mathematical model uses anatomical data accounting for the choroid thickness near the equator. The validity of the technique was tested by comparing OR coefficients obtained using our non-invasive method (OROCT) and those obtained with an invasive procedure involving intravitreal injections of Bevacizumab (ORIVI) in 12 eyes. Intrasession and intersession repeatability was assessed for 72 and 8 eyes respectively with two consecutive measurements of OR. Using the new mathematical model, we obtained OR values which are closer to those obtained using the invasive procedure and previously reported techniques. A regression line was calculated to predict the ORIVI based on OROCT, such that ORIVI = 0.655 × OROCT. A strong correlation between OROCT and ORIVI was found, with a Spearman coefficient of 0.853 (p < 0.001). The intraclass correlation coefficient for intrasession and intersession repeatability was 0.925, 95% CI [0.881, 0.953] and 0.950, 95% CI [0.763, 0.990] respectively. This confirms the validity and good repeatability of OR measurements using our non-invasive clinical method.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Catheter-guided suprachoroidal buckling of rhegmatogenous retinal detachments secondary to peripheral retinal breaks.

PURPOSE: To evaluate functional and anatomic outcomes of eyes undergoing suprachoroidal buckling (SCB) using a specially designed catheter for the management of rhegmatogenous retinal detachment (RRD) secondary to peripheral retinal breaks. METHODS: Retrospective cohort study of 62 eyes of 62 patients. Subjects underwent SCB for the management of RRD secondary to single or multiple retinal breaks. Suprachoroidal indentation was achieved through the introduction of viscoelastic material in the suprachoroidal space overlying the break using an illuminated, 450 µm-wide, flex-tip catheter. This allowed for the creation of a suprachoroidal dome and chorio-retinal apposition. Forty-seven eyes (80 %) underwent SCB alone, while 15 eyes (20 %) were combined with 25-G pars-plana vitrectomy. Cryopexy and laserpexy were used in 38 (61 %) and 24 of eyes (39 %) respectively. RESULTS: Mean pre-operative best-corrected visual acuity (BCVA) improved from logMAR 0.82 (20/132) to 0.22 (20/33) (p < 0.0001). The single surgery reattachment rate was 92 % (57/62.) Final retinal reattachment was achieved in all eyes (100 %). No significant difference was observed in single-surgery anatomic success rates when stratified by lens status, macular involvement, or break location. There were no major intra- or post-operative complications. CONCLUSION: Suprachoroidal buckling using a special-design, flexible catheter is a safe and effective procedure for the management of RRD secondary to peripheral retinal breaks.

Evaluation of the vitreous microbial contamination rate in office-based three-port microincision vitrectomy surgery using Retrector technology.

BACKGROUND: To perform a microbiological contamination analysis of the vitreous during office-based micro-incision vitrectomy surgery (MIVS) assessing whether the bacteria detected correlated with patient's ocular conjunctival flora. METHODS: This is a prospective, interventional, nonrandomized case series of patients undergoing office-based MIVS, anti-VEGF, and dexamethasone intravitreal injections (triple therapy) for the treatment of wet age-related macular degeneration (AMD) and diabetic macular edema (DME).All patients were operated at a small procedure room in an ambulatory clinic of the Department of Ophthalmology, University of Montreal, Quebec, Canada. Conjunctival samples were done before placing the sclerotomies. The MIVS was done with a 23-gauge retractable vitrector, a 27-gauge infusion line, and a 29-gauge chandelier. Undiluted and diluted vitreous were collected for aerobic, anaerobic and fungal cultures. Outcomes measured were bacterial species identification within samples collected from the conjunctiva and the vitreous. RESULTS: Thirty-seven patients (37 eyes) were recruited and completed over 17 months of follow-up. Twenty-eight had wet AMD and nine had DME. There were 13 men and 24 women, with a mean age of 78 years. Eighteen patients (46%) had culture positive conjunctival flora. Twenty-six bacterial colonies were tabulated in total from the conjunctival swabs. All bacteria detected were gram-positive bacteria (100%), most commonly: Staphylococcus epidermitis in 11 (42%) and Corynebacterium sp. in 6 (23%). Only 1/18 patients had more than 3 species isolated, 6/18 patients had 2 species and 11/18 patients had 1 species identified on the conjunctival swab. Only 1 of the 37 undiluted midvitreous samples was culture positive, equating to a contamination rate of 2.7%. None of the diluted vitreous samples were culture positive. All cultures were negative for fungus. No serious postoperative complications occurred, including bacterial endophthalmitis, choroidal detachment, and retinal detachment. CONCLUSION: This preliminary study of office-based MIVS gives us insights on the ocular surface microbial profile and vitreous contamination rate of performing such procedures outside the OR-controlled environment. Our initial results seem to indicate that there is little risk of bacterial translocation and contamination from the conjunctiva into the vitreous. Therefore, if endophthalmitis occurs post-operatively, the source may likely arise after the procedure. Larger studies are needed to confirm our data.

Impact of Medical and Neurologic Complications on the Outcome of Patients with Aneurysmal Subarachnoid Hemorrhage in a Middle-Income Country.

OBJECTIVE: Almost two thirds of the world's aneurysmal subarachnoid hemorrhage (aSAH) are in low- and middle-income countries. Herein, we aimed to evaluate the impact of complications on the outcome of aSAH in a middle-income country. METHODS: Baseline data (age, sex, World Federation of Neurosurgical Society, time ictus-treatment, treatment modality) and medical and neurologic complications from a cohort in Brazil (2016-2019) were evaluated: delayed cerebral ischemia; hydrocephalus; meningitis; seizures; intracranial hypertension; infections (pneumonia, bloodstream, urinary tract infection infection of undetermined source); sodium disturbances; acute kidney injury; and cardiac and pulmonary complications. The primary outcome was the modified Rankin scale (mRS) at hospital discharge. Univariate and multivariate models were employed. RESULTS: From 212 patients (71.7% female, age 52.7 ± 12.8), 92% developed at least 1 complication (any infection-43.9%, hydrocephalus-34.4%, intracranial hypertension-33%, infection of undetermined source-20.8%, hypernatremia-20.8%, hyponatremia-19.8%, delayed cerebral ischemia-related infarction-18.7%, pneumonia-18.4%, acute kidney injury-16.5%, and seizures-11.8%). In unadjusted analysis, all but hyponatremia and urinary tract infection were associated with mRS 3-6 at discharge; however, complications explained only 12% of the variation in functional outcome (mRS). Most patients were treated by clipping (66.5%), and 15.6% (33 patients) did not receive a definitive treatment. The median time ictus-admission and ictus-treatment were 5 and 9 days, respectively. CONCLUSIONS: While medical and neurologic complications are a recognized opportunity to improve aSAH care, low- and middle-income countries comprise 70% of the world population and still encounter difficulties concerning early definitive aneurysm treatment, rebleeding, and human and material resources.

Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

Outcomes of Pars Plana Vitrectomy and 4-Point Sutured Scleral Fixation of Akreos AO60 Intraocular Lens in Clinical Settings: A Case Series.

PURPOSE: To determine the long-term anatomic outcomes and surgical complications of pars plana vitrectomy (PPV) and 4-point Gore-Tex-sutured Akreos AO60 intraocular lens (IOL) scleral fixation. DESIGN: Retrospective, multicenter, multisurgeon case series. PARTICIPANTS: Ninety-seven patients in tertiary eye care centers. METHODS: The patients underwent PPV and intraocular fixation of the Akreos AO60 IOL using Gore-Tex CV-8 sutures between January 2015 and April 2020. The inclusion criteria were aphakia, no capsular support, and a minimal 1 year of follow-up. MAIN OUTCOME MEASURES: Uncorrected visual acuity (VA), complication rates or types, and refraction. RESULTS: Data from 101 eyes of the 97 patients were analyzed (mean follow-up duration, 33.4 months; range, 12-62 months). The mean ± standard deviation uncorrected logarithm of the minimum angle of resolution VA improved from 1.04 ± 0.73 (20/200 Snellen equivalent) before surgery to 0.66 ± 0.65 (20/80) at 6 months after surgery (P < 0.001). The most prevalent complications included hypotony (12.9%), ocular hypertension (12.9%), corneal edema (8.9%), cystoid macular edema (6.9%), and vitreous hemorrhage (5.9%). Refraction was measured between 3 and 6 months after surgery, and 61.8% of the patients had spherical equivalent of ± 2.0 diopters. Most complications occurred in the first postoperative month and resolved spontaneously or with medical treatment. CONCLUSIONS: The results demonstrated that this surgical technique is well tolerated by the eyes, with a low complication rate in the long term. The rates of IOL opacification were infrequent for up to 62 months of follow-up.

Surgical classification for large macular hole: based on different surgical techniques results: the CLOSE study group.

BACKGROUND: The CLOSE study group proposes an updated surgical classification for large macular holes based on a systematic review of new treatments. Recently, many new techniques have been introduced to treat large full-thickness macular holes (FTMH); although the indications are not clear. An updated surgical classification is needed to help surgical decision-making. METHODS: We gathered published series by the CLOSE Study Group members and from literature search until June 2021. Techniques included: internal limiting membrane peeling (ILM peeling), ILM flaps, macular hydrodissection (macular hydro), human amniotic membrane graft (hAM), and autologous retinal transplantation (ART). Within each technique, chi-square test assessed association between the minimal linear diameter (MLD) (in µm) and closure rate; the postoperative best-corrected visual acuity (BCVA) gains were compared among groups. RESULTS: Data extraction included 31 published articles: total of 1135 eyes. Eyes were divided into the following groups: ILM peel (n: 683), ILM Flap (n: 233), macular hydrodissection (n: 64), hAM (n: 59), and ART (n: 96). The initial BCVA and size were heterogenous between the groups. ILM peel showed the best results in large FTMH ≤ 535 µm (closure rate 96.8%); adjusted mean BCVA: 0.49 (LogMAR) with a statistical difference among groups. Large FTMH between 535 and 799 µm: ILM flap technique showed better results (closure rate 99.0%); adjusted mean BCVA: 0.67(LogMAR); also with a statistical difference. For large FTMH ≥ 800 µm more invasive techniques are required. Use of hAM, macular hydrodissection and ART showed higher closure rates for this category (100%, 83.3% and 90.5% respectively), and adjusted mean BCVA varied from 0.76 to 0.89. Although there was no statistical difference between those techniques for this group due to the smaller number of cases. CONCLUSIONS: The CLOSE study group demonstrated the potential usefulness of a new surgical classification for large FTMHs and propose OCT biomarkers for use in clinical practice and future research. This new classification demonstrated that Large (400-550 µm) and X-Large (550-800 µm) holes can be treated highly successfully with ILM peel and ILM flap techniques, respectively. Further studies are necessary for the larger FTMHs (XX-Large and Giant), using the CLOSE classification, in order to determine which technique is better suited for each hole size and characteristics.

Transconjunctival drainage of serous and hemorrhagic choroidal detachment.

PURPOSE: To describe a novel surgical technique for drainage of bullous serous and hemorrhagic choroidal detachments. METHODS: A prospective, consecutive case series of 6 eyes with serous and/or hemorrhagic choroidal detachments secondary to intraocular surgery was documented to evaluate the feasibility of using the 25-gauge and 20-gauge transconjunctival trocar/cannula systems to drain choroidal detachments. Two eyes had expulsive hemorrhagic choroidal detachments and 4 eyes had serous choroidal detachments after glaucoma surgeries. A 25-gauge infusion line was placed in the anterior chamber. A 20-gauge (in eyes with hemorrhagic choroidal detachments) or a 25-gauge (in eyes with serous detachments) trocar/cannula system was inserted into the suprachoroidal space 7.0 mm from limbus. After drainage, the cannulas were removed and no sutures were placed. Pars plana vitrectomy was performed only in eyes with concomitant pathology that demanded the additional procedure. The primary outcome measure was presence of choroidal detachment at 1 week, 2 weeks, and 1 month postoperatively. Secondary outcome measures were visual acuity at 6 months and intraocular pressure at 1 week and 1, 3, and 6 months postoperatively. RESULTS: Drainage of hemorrhagic choroidal detachments resulted in resolution of the detachments by 1 month postoperatively. In eyes with serous detachments, resolution was achieved by 1 week postdrainage. In both groups, intraocular pressure increased to at least 10 mmHg by postoperative Week 1. The visual acuity improved in all eyes. No complications related to the transconjunctival technique were noted. CONCLUSION: Transconjunctival drainage of serous and hemorrhagic choroidal detachments seems to be a feasible and simple surgical option with minimal scleral and conjunctival damage. Pars plana vitrectomy may not be necessary when draining choroidal detachments in this manner.

Risk factors for epiretinal membrane formation and peeling following pars plana vitrectomy for primary rhegmatogenous retinal detachment, an OCT guided analysis.

BACKGROUND: To evaluate the rate and risk factors of epiretinal membrane (ERM) formation and need for ERM peeling after pars plana vitrectomy (PPV) for uncomplicated primary rhegmatogenous retinal detachment (RRD). METHODS: Retrospective, single-center, cohort study of 119 consecutive patients (119 eyes) that underwent RRD repair using PPV. The primary outcomes were ERM formation, classified using an optical coherence tomography grading system, and the rate of ERM peeling. Visual acuity, postoperative complications, and risk factors for ERM formation and peeling were also identified. RESULTS: Postoperative ERM formation occurred in 69 eyes (58.0%); 56 (47.1%) were stage 1, 9 (7.6%) stage 2, 3 (2.5%) stage 3, and 1 (0.8%) stage 4. Only 6 (5.0%) eyes required secondary PPV for a visually significant ERM, with a mean time to reoperation of 488 ± 351 days. Risk factors for ERM formation included intraoperative cryotherapy, more than 1000 laser shots, 360° laser photocoagulation, and choroidal detachment (p < 0.01). Eyes with more than 3 tears had a trend towards increased ERM surgery (p = 0.10). CONCLUSIONS: Visually significant ERM formation following PPV for primary RRD was uncommon in this cohort (5%). Half of the ERMs were detected after the first post-operative year, indicating that this complication may be underreported in studies with only 1-year follow-up.

Triglyceride-derived fatty acids reduce autophagy in a model of retinal angiomatous proliferation.

Dyslipidemia and autophagy have been implicated in the pathogenesis of blinding neovascular age-related macular degeneration (NV-AMD). VLDL receptor (VLDLR), expressed in photoreceptors with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acids. Since fatty acid uptake is reduced in Vldlr-/- tissues, more remain in circulation, and the retina is fuel deficient, driving the formation in mice of neovascular lesions reminiscent of retinal angiomatous proliferation (RAP), a subtype of NV-AMD. Nutrient scarcity and energy failure are classically mitigated by increasing autophagy. We found that excess circulating lipids restrained retinal autophagy, which contributed to pathological angiogenesis in the Vldlr-/- RAP model. Triglyceride-derived fatty acid sensed by free fatty acid receptor 1 (FFAR1) restricted autophagy and oxidative metabolism in photoreceptors. FFAR1 suppressed transcription factor EB (TFEB), a master regulator of autophagy and lipid metabolism. Reduced TFEB, in turn, decreased sirtuin-3 expression and mitochondrial respiration. Metabolomic signatures of mouse RAP-like retinas were consistent with a role in promoting angiogenesis. This signature was also found in human NV-AMD vitreous. Restoring photoreceptor autophagy in Vldlr-/- retinas, either pharmacologically or by deleting Ffar1, enhanced metabolic efficiency and suppressed pathological angiogenesis. Dysregulated autophagy by circulating lipids might therefore contribute to the energy failure of photoreceptors driving neovascular eye diseases, and FFAR1 may be a target for intervention.

A Smart Vitrector Equipped by a Fiber-Based OCT Sensor Mitigates Intentional Attempts at Creating Iatrogenic Retinal Breaks During Vitrectomy in Pigs.

Purpose: The occurrence of iatrogenic retinal breaks (RB) in pars plana vitrectomy (PPV) is a complication that compromises the overall efficacy of the surgery. A subset of iatrogenic RB occurs when the retina (rather than the vitreous gel) is cut accidentally by the vitrector. We developed a smart vitrector that can detect in real-time potential iatrogenic RB and activate promptly a PPV machine response to prevent them. Methods: We fabricated the smart vitrectors by attaching a miniaturized fiber-based OCT sensor on commercial vitrectors (25G). The system's response time to an iatrogenic RB onset was measured and compared to the literature reported physiologically limited response time of the average surgeon. Two surgeons validated its ability to prevent simulated iatrogenic RB by performing PPV in pigs. Note that the system is meant to control the PPV machine and requires no visual or audio signal interpretation by the surgeons. Results: We found that the response time of the system (28.9 ± 6.5 ms) is 11 times shorter compared to the literature reported physiologically limited reaction time of the average surgeon (P < 0.0001). Ex vivo validation (porcine eyes) showed that the system prevents 78.95% (15/19) (95% confidence interval [CI] 54.43-93.95) of intentional attempts at creating RB, whereas in vivo validation showed that the system, prevents 55.68% (30/54) (95% CI 41.40-69.08), and prevents or mitigates 70.37% (38/54) (95% CI 56.39-82.02) of such attempts. A subset of failures was classified as "early stop" (i.e., false positive), having a prevalence of 5.26% (1 /19) in ex vivo tests and 24.07% (13/54) in in vivo tests. Conclusions: Our results indicate the smart vitrector can prevent iatrogenic RB by providing seamless intraoperative feedback to the PPV machine. Importantly, the use of the smart vitrector requires no modifications of the established PPV procedure. It can mitigate a significant proportion of iatrogenic RB and thus improve the overall efficacy of the surgery. Translational Relevance: Potential clinical adoption of the smart vitrector can reduce the incidence of iatrogenic RB in PPV and thus increase the therapeutic outcome of the surgery.

Stellate nonhereditary idiopathic foveomacular retinoschisis resolution after vitreomacular adhesion release.

PURPOSE: To present a case of stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) resolution associated with vitreomacular adherence (VMA) release and propose a potential contributing association between SNIFR and vitreomacular interactions. OBSERVATIONS: A 67-year-old female patient was diagnosed and followed for SNIFR in OD with spectral-domain optical coherence tomography (SD-OCT) scans at presentation and subsequent visits at 3, 6, 16 and 22 months. VMA and foveomacular retinoschisis remained unchanged on SD-OCT during the first 6 months of the follow-up. At 16-month follow-up visit, SD-OCT revealed VMA release and an important improvement of the macular schisis. At 22 months of follow-up, SNIFR cavities completely resolved in the presence of posterior hyaloid separation from the macular area without any adjunct treatment. The authors could not identify any other possible cause to justify the resolution of SNIFR other than VMA release in this case. Patient did not undergo any treatment for OD other than phacoemulsification 3 months after initial visit. CONCLUSION: The present case illustrates with SD-OCT scans a possible association between SNIFR resolution and VMA release, highlighting a potential tractional component of the posterior vitreous on the internal limiting membrane and consequent glial cells stretching with schisis formation.

Correlation of ocular rigidity with intraocular pressure spike after intravitreal injection of bevacizumab in exudative retinal disease.

BACKGROUND/AIMS: To evaluate the non-invasive measurement of ocular rigidity (OR), an important biomechanical property of the eye, as a predictor of intraocular pressure (IOP) elevation after anti-vascular endothelial growth factor (anti-VEGF) intravitreal injection (IVI). METHODS: Subjects requiring IVI of anti-VEGF for a pre-existing retinal condition were enrolled in this prospective cross-sectional study. OR was assessed in 18 eyes of 18 participants by measurement of pulsatile choroidal volume change using video-rate optical coherence tomography, and pulsatile IOP change using dynamic contour tonometry. IOP was measured using Tono-Pen XL before and immediately following the injection and was correlated with OR. RESULTS: The average increase in IOP following IVI was 19±9 mm Hg, with a range of 7-33 mm Hg. The Spearman correlation coefficient between OR and IOP elevation following IVI was 0.796 (p<0.001), showing higher IOP elevation in more rigid eyes. A regression line was also calculated to predict the IOP spike based on the OR coefficient, such that IOP spike=664.17 mm Hg·µL×OR + 4.59 mm Hg. CONCLUSION: This study shows a strong positive correlation between OR and acute IOP elevation following IVI. These findings indicate that the non-invasive measurement of OR could be an effective tool in identifying patients at risk of IOP spikes following IVI.

Human amniotic membrane for the treatment of large and refractory macular holes: a retrospective, multicentric, interventional study.

BACKGROUND: The purpose of the current study is to report the anatomical and functional results of off-label human amniotic membrane graft as primary intervention to repair large to giant macular holes and in reoperations when wide internal limiting membrane peeling was unsuccessful. METHODS: Retrospective chart review was carried out in five different centers to identify all cases that had undergone off-label human amniotic membrane graft for the treatment of large or failed macular holes (MH). Data collected included age, gender, other concomitant diagnosis, symptoms duration, lens status, number of previous surgeries, macular hole measurements (minimum and base linear diameters), mean post-operative follow-up (months), and pre- and post-operative best corrected visual acuity (BCVA). Main outcome measures were anatomical MH closure rates and final BCVA (in logMAR). Nonparametric Wilcoxon rank-sum test was used because the data was not normally distributed, a P values < 0.05 were considered statistically significant. RESULTS: Nineteen eyes of 19 patients were identified and included in the study. Mean age was 66.21 ± 14.96 years and predominantly females (84%). All eyes had successfully closed MH with a single intervention with no recurrences during a mean of 9 ± 3.87 months follow-up. The median BCVA in logMAR preoperative was 1.30 ± 0.44 (0.80-2.0), approximately 20/400 on Snellen chart and the median BCVA in logMAR postoperative was 1.0 ± 0.72 (0.4-3.0) approximately 20/200 (p < 0.0001) with median of three lines of visual improvement. CONCLUSION: The use of human amniotic membrane graft seems to be a viable and effective alternative for the treatment of large and persistent macular holes. However, further larger prospective controlled studies are necessary to confirm our preliminary results of this new surgical technique.