Myeloid-derived suppressor cells promote allograft survival by suppressing regulatory T cell dysfunction in high-risk corneal transplantation.

Highly inflamed and neovascularized corneal graft beds are known as high-risk (HR) environments for transplant survival. One of the primary factors leading to this rejection is reduction in the suppressive function of regulatory T cells (Treg). Our results show that myeloid-derived suppressor cells (MDSC) counteract interleukin-6-mediated Treg dysfunction by expressing interleukin-10. Additionally, MDSC maintain forkhead box P3 stability and their ability to suppress IFN-γ+ Th1 cells. Administering MDSC to HR corneal transplant recipients demonstrates prolonged graft survival via promotion of Treg while concurrently suppressing IFN-γ+ Th1 cells. Moreover, MDSC-mediated donor-specific immune tolerance leads to long-term corneal graft survival as evidenced by the higher survival rate or delayed survival of a second-party C57BL/7 (B6) graft compared to those of third-party C3H grafts observed in contralateral low-risk or HR corneal transplantation of BALB/c recipient mice, respectively. Our study provides compelling preliminary evidence demonstrating the effectiveness of MDSC in preventing Treg dysfunction, significantly improving graft survival in HR corneal transplantation, and showing promising potential for immune tolerance induction.

Therapeutic Effects of Stimulating the Melanocortin Pathway in Regulating Ocular Inflammation and Cell Death.

Alpha-melanocyte-stimulating hormone (α-MSH) and its binding receptors (the melanocortin receptors) play important roles in maintaining ocular tissue integrity and immune homeostasis. Particularly extensive studies have demonstrated the biological functions of α-MSH in both immunoregulation and cyto-protection. This review summarizes the current knowledge of both the physiological and pathological roles of α-MSH and its receptors in the eye. We focus on recent developments in the biology of α-MSH and the relevant clinical implications in treating ocular diseases.

The Neuropeptide α-Melanocyte-Stimulating Hormone Prevents Persistent Corneal Edema following Injury.

Corneal endothelial cells (CEnCs) regulate corneal hydration and maintain tissue transparency through their barrier and pump function. However, these cells exhibit limited regenerative capacity following injury. Currently, corneal transplantation is the only established therapy for restoring endothelial function, and there are no pharmacologic interventions available for restoring endothelial function. This study investigated the efficacy of the neuropeptide α-melanocyte-stimulating hormone (α-MSH) in promoting endothelial regeneration during the critical window between ocular injury and the onset of endothelial decompensation using an established murine model of injury using transcorneal freezing. Local administration of α-MSH following injury prevented corneal edema and opacity, reduced leukocyte infiltration, and limited CEnC apoptosis while promoting their proliferation. These results suggest that α-MSH has a proregenerative and cytoprotective function on CEnCs and shows promise as a therapy for the prevention and management of corneal endothelial dysfunction.

Prevalence and Economic Burden of Fuchs Endothelial Corneal Dystrophy in the Medicare Population in the United States.

PURPOSE: The aim of this study was to assess the prevalence and economic burden of Fuchs endothelial corneal dystrophy (FECD) in patients older than 65 years in the United States. METHODS: A retrospective analysis of the Medicare data reported to the Vision and Eye Health Surveillance System including patients diagnosed with FECD between 2014 and 2019 was performed. The crude prevalence rate of FECD was assessed and extrapolated to estimate the total case burden in the United States. The prevalence data were further compared between men and women and different racial groups. In addition, the economic burden was computed using inflation-adjusted direct costs of treatment to patients. RESULTS: The Medicare database included 25,432,700 patients older than 65 years. The national prevalence of FECD in this population cohort was calculated to be 1.12% in 2019. In 2019, FECD case burden in Medicare patients older than 65 years was 284,846 and total estimated FECD case count in the country in this age group was 591,226. FECD prevalence was significantly higher in women as compared to men during the 6-year period evaluated in this study. The intergroup comparison revealed that FECD prevalence in the White population was significantly higher than all other racial groups (P < 0.0001). The total inflation-adjusted economic burden of FECD in the United States in 2019 was USD 291.648 million and has increased from USD 243.998 million over the 6-year study period. CONCLUSIONS: The estimated prevalence of FECD in the individuals older than 65 years is 1.12% in the United States. FECD prevalence is significantly higher in women and White population compared with other ethnicities.

Ophthalmic injuries from the beirut blast: Managing long-term consequences.

The 2020 Beirut Port explosion was one of the largest non-nuclear urban explosions in history, and resulted in a plethora of oculofacial injuries. In this retrospective study, we present the two year follow up ophthalmic outcomes of the survivors of the blast. Only 16 out of 39 patients continued follow up at our center, with 13 having delayed complications and 7 requiring further surgery. The most common delayed complications related to the eyelid, lacrimal system, and orbit. Treatment of disfiguring facial and peri-ocular scarring with laser-assisted drug delivery of topical 5-fluorouracil showed great promise and significantly improved patients' functional and well as cosmetic outcomes.

Phacoemulsification with and without iStent: A Systematic Review and Meta-Analysis of Comparative Studies.

BACKGROUND: The iStent (Glaukos Corporation; Laguna Hills, CA, USA) is one of the minimally invasive glaucoma devices. It can be inserted at the time of phacoemulsification or as a stand-alone procedure to lower the intraocular pressure (IOP). OBJECTIVE: Our aim was to conduct a systematic review and meta-analysis comparing the effect of iStent insertion at the time of phacoemulsification with phacoemulsification alone in patients with ocular hypertension or open-angle glaucoma. METHODS: We searched EMBASE, MEDLINE (OVID and PubMed), CINAHL, and Cochrane Library for articles published between 2008 and June 2022 (PRISMA 2020 for the checklist). Studies comparing the IOP-lowering effect of iStent with phacoemulsification versus phacoemulsification alone were included. The endpoints were IOP reduction (IOPR) and the mean reduction in the number of glaucoma drops. A quality-effects model was used to compare both surgical groups. RESULTS: Ten studies were included, reporting on 1,453 eyes. Eight hundred fifty three eyes had the combined iStent and phacoemulsification, and 600 eyes underwent phacoemulsification alone. IOPR was higher in the combined surgery at of 4.7 ± 2 mm Hg compared to 2.8 ± 1.9 mm Hg in phacoemulsification alone. A greater decrease in postoperative eye drops was noted in the combined group having a decrease of 1.2 ± 0.3 eye drops versus of 0.6 ± 0.6 drops in isolated phacoemulsification. The quality effect model showed an IOPR weighted mean difference (WMD) of 1.22 mm Hg (confidence interval [CI]: [-0.43, 2.87]; Q = 315.64; p < 0.01; I2 = 97%) and decreased eye drops WMD 0.42 drops (CI: [0.22, 0.62]; Q = 42.6; p < 0.01; I2 = 84%) between both surgical groups. Subgroup analysis shows that the new generation iStent may be more effective in reducing IOP. CONCLUSION: iStent has a synergetic effect with phacoemulsification. The reduction of IOP and glaucoma eye drops was higher when iStent is combined with phacoemulsification compared with isolated phacoemulsification.

The impact of donor diabetes on corneal transplant immunity.

Corneal transplantation is the most common form of solid tissue grafting, with an approximately 80% to 90% success rate. However, success rates may decline when donor tissues are derived from patients with a history of diabetes mellitus (DM). To evaluate the underlying immunopathologic processes that cause graft rejection, we used streptozotocin-induced type 1 DM (DM1) and transgenic Lepob/ob type 2 DM (DM2) diabetic murine models as donors and nondiabetic BALB/c as recipients. DM resulted in an increased frequency of corneal antigen-presenting cells (APCs) with an acquired immunostimulatory phenotype. Following transplantation, recipients that received either type of diabetic graft showed increased APC migration and T helper type 1 alloreactive cells, impaired functional regulatory T cells, and graft survival. Insulin treatment in streptozotocin-induced diabetic mice led to an increased tolerogenic profile of graft APC, lower T helper type 1 sensitization, and a higher frequency of functional regulatory T cells with high suppressive capacity, reflected in increased graft survival. We conclude that both DM1 and DM2 in donors can impact corneal APC functional phenotype, rendering the tissue more immunogenic and thereby increasing the risk of graft failure.

Descemet Stripping Only Technique for Corneal Endothelial Damage in Mice.

PURPOSE: Descemet stripping only is an emerging surgical technique used to remove central Descemet membrane and corneal endothelial cells in patients with corneal endothelial disease. Here, we describe a murine model of this procedure to help facilitate basic science investigation and evaluation of postoperative outcomes using this surgical technique. METHODS: Slitlamp biomicroscopy, central corneal thickness assessment (by optical coherence tomography), and immunohistochemistry were used to assess the model through 7 weeks of follow-up. RESULTS: Complete removal of the endothelium and Descemet membrane was confirmed by slitlamp biomicroscopy and by histology. Central corneal thickness peaked at day 1 postinjury and then declined over the course of 2 weeks to a stable level of persistent edema. Seven weeks postinjury, immunohistochemical staining for ZO-1 showed the area of Descemet stripping was fully covered by enlarged and dysmorphic corneal endothelial cell. No significant ocular complications were appreciated through the end of the follow-up. CONCLUSIONS: We demonstrate the feasibility of and provide detailed instructions for a murine model of Descemet stripping only. This model provides a potential in vivo platform to investigate the mechanisms and biology of this emerging surgical procedure.

Effect of time to operative repair within twenty-four hours on visual acuity outcomes for open globe injuries.

PURPOSE: Convention is to perform open globe injury (OGI) repair within 24 h to minimize risk of endophthalmitis. However, there are limited data assessing how time to operative repair (OR) within 24 h impacts postoperative visual acuity (VA). METHODS: Manual retrospective chart review of 633 eyes at Massachusetts Eye and Ear (MEE) with a diagnosis of OGI between 2012 and 2022. Inclusion criteria were primary repair ≤ 24 h after injury and ≥1 month follow-up. Multivariate regression analysis was conducted with postoperative VA as primary outcome. RESULTS: Of the subjects, 489 (77.3%) were male and 496 (78.4%) were white. Demographics of OGI wounds included 320 (50.6%) rupture and 313 (49.4%) laceration; 126 (19.9%) with rAPD, 189 (29.9%) zone 3 injuries, 449 (71.2%) uveal prolapse, and 110 (17.4%) intraocular foreign body. Final postoperative LogMAR VAs consisted of 31% with a VA < 1.7, 9% with a VA of 1.9, 18% with a VA of 2.3, 27% with a VA of 2.7, and 11% with a VA of 3.0. Multivariate analysis showed no significant correlation between time to OR and postoperative VA (p = 0.800) [95%CI: -0.01,0.01]. Older age (p < 0.001) [95%CI: 0.00,0.01], worse presenting VA (p < 0.001) [95%CI: 0.17,0.32], rAPD (p < 0.001) [95%CI: 0.65,1.0], mechanism of rupture (p < 0.001) [95%CI: 0.19,0.54], higher zone of injury (p < 0.001) [95%CI: 0.25,0.45], and uveal prolapse (p = 0.003) [95%CI: 0.09,0.42] were significantly associated with worse final VA. CONCLUSIONS: Time to repair of OGIs within 24 h does not influence final VA. Optimization of surgical and patient factors may contribute more significantly to final VA than prioritizing more rapid time to OR.

A Novel Murine Model of Endothelial Keratoplasty.

PURPOSE: The purpose of this study was to establish a murine model of endothelial keratoplasty. METHODS: Endothelial keratoplasty (EK) was performed using C57BL/6 donor and BALB/c recipient mice. The central endothelium and Descemet membrane were removed from the recipient cornea, and a 1.5-mm posterior lamellar donor graft was made adherent to the recipient cornea with a small amount of viscoelastic. Mice were followed through slitlamp microscopy postoperatively, and OCT was used to assess the cornea and anterior chamber and measure central corneal thickness. Histology and immunohistochemistry were performed to confirm graft adherence and endothelial cell morphology. RESULTS: Successfully attached EK grafts were visualized in all transplanted animals. Histology and immunostaining confirmed proper graft orientation and adherence, as well as the presence of donor endothelium on transplanted grafts. We observed maximal corneal edema in all animals at day 1 postoperatively which gradually subsided. EK graft survival was 97% at 8 weeks. CONCLUSIONS: In this study, we describe a novel murine model for EK which we anticipate will enable detailed investigation into the cellular and molecular mechanisms involved in EK pathobiology.

Vaccine-Associated Uveitis after COVID-19 Vaccination: Vaccine Adverse Event Reporting System Database Analysis.

PURPOSE: To assess the risk of vaccine-associated uveitis (VAU) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and evaluate uveitis onset interval and clinical presentations in the patients. DESIGN: A retrospective study from December 11, 2020, to May 9, 2022, using the Centers for Disease Control and Prevention Vaccine Adverse Event Reporting System. PARTICIPANTS: Patients diagnosed with VAU after administration of BNT162b2 (Pfizer-BioNTech, Pfizer Inc/BioNTech SE), mRNA-1273 (Moderna, Moderna Therapeutics Inc), and Ad26.COV2.S (Janssen, Janssen Pharmaceuticals) vaccine worldwide. METHODS: A descriptive analysis of the demographics, clinical history, and presentation was performed. We evaluated the correlation among the 3 vaccines and continuous and categorical variables. A post hoc analysis was performed between uveitis onset interval after vaccination and age, dose, and vaccine type. Finally, a 30-day risk analysis for VAU onset postvaccination was performed. MAIN OUTCOME MEASURES: The estimated global crude reporting rate, observed to expected ratio of VAU in the United States, associated ocular and systemic presentations, and onset duration. RESULTS: A total of 1094 cases of VAU were reported from 40 countries with an estimated crude reporting rate (per million doses) of 0.57, 0.44, and 0.35 for BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively. The observed to expected ratio of VAU was comparable for BNT162b2 (0.023), mRNA-1273 (0.025), and Ad26.COV2.S (0.027). Most cases of VAU were reported in patients who received BNT162b2 (n = 853, 77.97%). The mean age of patients with VAU was 46.24 ± 16.93 years, and 68.65% (n = 751) were women. Most cases were reported after the first dose (n = 452, 41.32%) and within the first week (n = 591, 54.02%) of the vaccination. The onset interval for VAU was significantly longer in patients who received mRNA-1273 (21.22 ± 42.74 days) compared with BNT162b2 (11.42 ± 23.16 days) and rAd26.COV2.S (12.69 ± 16.02 days) vaccines (P < 0.0001). The post hoc analysis revealed a significantly shorter interval of onset for the BNT162b2 compared with the mRNA 1273 vaccine (P < 0.0001). The 30-day risk analysis showed a significant difference among the 3 vaccines (P < 0.0001). CONCLUSIONS: The low crude reporting rate and observed to expected ratio suggest a low safety concern for VAU. This study provides insights into a possible temporal association between reported VAU events and SARS-CoV-2 vaccines; however, further investigations are required to delineate the associated immunological mechanisms.

Doxorubicin-Loaded Extracellular Vesicles Enhance Tumor Cell Death in Retinoblastoma.

Chemotherapy is often used to treat retinoblastoma; however, this treatment method has severe systemic adverse effects and inadequate therapeutic effectiveness. Extracellular vesicles (EVs) are important biological information carriers that mediate local and systemic cell-to-cell communication under healthy and pathological settings. These endogenous vesicles have been identified as important drug delivery vehicles for a variety of therapeutic payloads, including doxorubicin (Dox), with significant benefits over traditional techniques. In this work, EVs were employed as natural drug delivery nanoparticles to load Dox for targeted delivery to retinoblastoma human cell lines (Y-79). Two sub-types of EVs were produced from distinct breast cancer cell lines (4T1 and SKBR3) that express a marker that selectively interacts with retinoblastoma cells and were loaded with Dox, utilizing the cells' endogenous loading machinery. In vitro, we observed that delivering Dox with both EVs increased cytotoxicity while dramatically lowering the dosage of the drug. Dox-loaded EVs, on the other hand, inhibited cancer cell growth by activating caspase-3/7. Direct interaction of EV membrane moieties with retinoblastoma cell surface receptors resulted in an effective drug delivery to cancer cells. Our findings emphasize the intriguing potential of EVs as optimum methods for delivering Dox to retinoblastoma.

Advances in biomaterials for the treatment of retinoblastoma.

Retinoblastoma is the most common primary intraocular malignancy in children. Although traditional chemotherapy has shown some success in retinoblastoma management, there are several shortcomings to this approach, including inadequate pharmacokinetic parameters, multidrug resistance, low therapeutic efficiency, nonspecific targeting, and the need for adjuvant therapy, among others. The revolutionary developments in biomaterials for drug delivery have enabled breakthroughs in cancer management. Today, biomaterials are playing a crucial role in developing more efficacious retinoblastoma treatments. The key goal in the evolution of drug delivery biomaterials for retinoblastoma therapy is to resolve delivery-associated obstacles and lower nonlocal exposure while ameliorating certain adverse effects. In this review, we will first delve into the historical perspective of retinoblastoma with a focus on the classical treatments currently used in clinics to enhance patients' quality of life and survival rate. As we move along, we will discuss biomaterials for drug delivery applications. Various aspects of biomaterials for drug delivery will be dissected, including their features and recent advances. In accordance with the current advances in biomaterials, we will deliver a synopsis on the novel chemotherapeutic drug delivery strategies and evaluate these approaches to gain new insights into retinoblastoma treatment.

Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials.

CONTEXT: The growing number of systematic reviews/meta-analyses (SR/MAs) on vitamin D (±â€…calcium) for fracture prevention has led to contradictory guidelines. OBJECTIVE: This umbrella review aims to assess the quality and explore the reasons for the discrepancy of SR/MAs of trials on vitamin D supplementation for fracture risk reduction in adults. METHODS: We searched 4 databases (2010-2020), Epistemonikos, and references of included SRs/MAs, and we contacted experts in the field. We used A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) for quality assessment. We compared results and investigated reasons for discordance using matrices and subgroup analyses (PROSPERO registration: CRD42019129540). We included 13 SR/MAs on vitamin D and calcium (Ca/D) and 19 SR/MAs on vitamin D alone, compared to placebo/control. RESULTS: Only 2 from 10 SRs/MAs on Ca/D were of moderate quality. Ca/D reduced the risk of hip fractures in 8 of 12 SRs/MAs (relative risk [RR] 0.61-0.84), and any fractures in 7 of 11 SR/MAs (RR 0.74-0.95). No fracture risk reduction was noted in SRs/MAs exclusively evaluating community-dwelling individuals or in those on vitamin D alone compared to placebo/control. Discordance in results between SRs/MAs stems from inclusion of different trials, related to search periods and eligibility criteria, and varying methodology (using intention to treat, per-protocol, or complete case analysis from individual trials). CONCLUSION: Ca/D reduces the risk of hip and any fractures, possibly driven by findings from institutionalized individuals. Individual participant data meta-analyses of patients on Ca/D with sufficient follow-up periods, and subgroup analyses, would unravel determinants for a beneficial response to supplementation.

Novel adaptation of a running suture technique in a mouse model of corneal transplantation.

Several murine models of corneal transplantation have been developed over the years to study the immunopathological processes that lead to the failure of grafted corneas. In all of them, the classic eight interrupted sutures technique is utilized for transplanting the donor cornea on the host bed. However, in clinical practice, a single continuous suture with a single knot is generally performed for corneal transplantation. Here, we describe the adaptation of the single continuous suture technique in a mouse model of corneal transplantation.