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PurposeThe aim of this study was to assess the effect of donor and recipient factors on corneal allograft rejection and evaluate whether a rejection event was associated with graft failure.MethodsOne thousand ninety subjects undergoing penetrating keratoplasty for a moderate risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) were followed for up to 12 years. Associations of baseline recipient and donor factors with the occurrence of a rejection event were assessed in univariate and multivariate proportional hazards models.ResultsAmong 651 eyes with a surviving graft at 5 years, the 10-year graft failure (±99% confidence interval) rates were 12% ± 4% among eyes with no rejection events in the first 5 years, 17% ± 12% in eyes with at least 1 probable, but no definite rejection event, and 22% ± 20% in eyes with at least 1 definite rejection event. The only baseline factor significantly associated with a higher risk of definite graft rejection was a preoperative history of glaucoma, particularly when previous glaucoma surgery had been performed and glaucoma medications were being used at the time of transplant (10-year incidence 35% ± 23% compared with 14% ± 4% in eyes with no history of glaucoma/intraocular pressure treatment, P = 0.008).ConclusionsPatients who experienced a definite rejection event frequently developed graft failure raising important questions as to how we might change acute and long-term corneal graft management. Multivariate analysis indicated that previous use of glaucoma medications and glaucoma filtering surgery was a significant risk factor related to a definite rejection event.

ObjectiveTo examine the effect of donor age and other perioperative factors on long-term endothelial cell loss after penetrating keratoplasty (PKP).DesignMulticenter, prospective, double-masked clinical trial.ParticipantsWe included 176 participants from the Cornea Donor Study cohort who had not experienced graft failure ≥ 10 years after PKP for a moderate risk condition (principally Fuchs' dystrophy or pseudophakic/aphakic corneal edema).MethodsCorneas from donors 12 to 75 years old were assigned to participants using a randomized approach, without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons' usual routines. Images of the central endothelium were obtained preoperatively and at intervals for 10 years postoperatively. Images were analyzed by a central image analysis reading center to determine endothelial cell density (ECD).Main outcome measuresEndothelial cell density at 10 years.ResultsAmong study participants with a clear graft at 10 years, the 125 who received a cornea from a donor 12 to 65 years old experienced a median cell loss of 76%, resulting in a 10-year median ECD of 628 cells/mm(2) (interquartile range [IQR], 522-850 cells/mm(2)), whereas the 51 who received a cornea from a donor 66 to 75 years old experienced a cell loss of 79%, resulting in a median 10-year ECD of 550 cells/mm(2) (IQR, 483-694 cells/mm(2); P adjusted for baseline ECD = 0.03). In addition to younger donor age, higher ECD values were significantly associated with higher baseline ECD (P1000 cells/mm(2).ConclusionsSubstantial cell loss occurs in eyes with a clear graft 10 years after PKP, with the rate of cell loss being slightly greater with older donor age. Greater preoperative ECD and larger donor tissue size are associated with higher ECD at 10 years.

ObjectiveTo determine whether the 10-year success rate of penetrating keratoplasty for corneal endothelial disorders is associated with donor age.DesignMulticenter, prospective, double-masked clinical trial.ParticipantsA total of 1090 participants undergoing penetrating keratoplasty at 80 sites for Fuchs' dystrophy (62%), pseudophakic/aphakic corneal edema (34%), or another corneal endothelial disorder (4%) and followed for up to 12 years.MethodsForty-three eye banks provided corneas from donors aged 12 to 75 years, using a randomized approach to assign donor corneas to study participants without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons' usual routines.Main outcome measuresGraft failure defined as a regraft or, in the absence of a regraft, a cloudy cornea that was sufficiently opaque to compromise vision for 3 consecutive months.ResultsIn the primary analysis, the 10-year success rate was 77% for 707 corneas from donors aged 12 to 65 years compared with 71% for 383 donors aged 66 to 75 years (difference, +6%; 95% confidence interval, -1 to +12; P = 0.11). When analyzed as a continuous variable, higher donor age was associated with lower graft success beyond the first 5 years (P

Parasitic filarial nematodes infect more than 200 million individuals worldwide, causing debilitating inflammatory diseases such as river blindness and lymphatic filariasis. Using a murine model for river blindness in which soluble extracts of filarial nematodes were injected into the corneal stroma, we demonstrated that the predominant inflammatory response in the cornea was due to species of endosymbiotic Woibachia bacteria. In addition, the inflammatory response induced by these bacteria was dependent on expression of functional Toll-like receptor 4 (TLR4) on host cells., Wolbachia bacteria are essential symbionts of the major pathogenic filarial nematode parasites of humans, including Brugia malayi and Wuchereria bancrofti, which cause lymphatic filariasis, and Onchocerca volvulus, which causes river [...]

Fuchs endothelial corneal dystrophy (FECD) is the most common late-onset, vision-threatening corneal dystrophy in the United States, affecting about 4% of the population. Advanced FECD involves a thickening of the cornea from stromal edema and changes in Descemet membrane. To understand the relationship between FECD and central corneal thickness (CCT), we characterized common genetic variation in COL8A2 and TCF4, genes previously implicated in CCT and/or FECD. Other genes previously associated with FECD (PITX2, ZEB1, SLC4A11), and genes only known to affect CCT (COL5A1, FOXO1, AVGR8, ZNF469) were also interrogated. FECD probands, relatives and controls were recruited from 32 clinical sites; a total of 532 cases and 204 controls were genotyped and tested for association of FECD case/control status, a 7-step FECD severity scale and CCT, adjusting for age and sex. Association of FECD grade with TCF4 was highly significant (OR = 6.01 at rs613872; p = 4.8x10-25), and remained significant when adjusted for changes in CCT (OR = 4.84; p = 2.2x10-16). Association of CCT with TCF4 was also significant (p = 6.1x10-7), but was abolished with adjustment for FECD grade (p = 0.92). After adjusting for FECD grade, markers in other genes examined were modestly associated (p ~ 0.001) with FECD and/or CCT. Thus, common variants in TCF4 appear to influence FECD directly, and CCT secondarily via FECD. Additionally, changes in corneal thickness due to the effect of other loci may modify disease severity, age-at-onset, or other biomechanical characteristics. [ABSTRACT FROM AUTHOR]

Congenital hydrocephalus is an etiologically diverse, poorly understood, but relatively common birth defect. Most human cases are sporadic with familial forms showing considerable phenotypic and etiologic hetero-geneity. We have studied the autosomal recessive mouse mutation congenital hydrocephalus (ch) to identify candidate human hydrocephalus genes and their modifiers. ch mice have a congenital, lethal hydrocephalus in association with multiple developmental defects, notably skeletal defects, in tissues derived from the cephalic neural crest. We utilized positional cloning methods to map ch in the vicinity of D13Mit294 and confirm that the ch phenotype is caused by homozygosity for a nonsense mutation in a gene encoding a winged helix/forkhead transcription factor (Mf1). Based on linked genetic markers, we performed detailed phenotypic characterization of mutant homozygotes and heterozygotes to demonstrate the pleiotropic effects of the mutant gene. Surprisingly, ch heterozygotes have the glaucoma-related distinct phenotype of multiple anterior segment defects resembling Axenfeld-Rieger anomaly. We also localized a second member of this gene family (Hfh1), a candidate for other developmental defects, ∼470 kb proximal to Mf1. [ABSTRACT FROM AUTHOR]

Purpose: To determine endothelial cell density (ECD) from real-world donor cornea endothelial cell (EC) images using a self-supervised deep learning segmentation model., Methods: Two eye banks (Eversight, VisionGift) provided 15,138 single, unique EC images from 8169 donors along with their demographics, tissue characteristics, and ECD. This dataset was utilized for self-supervised training and deep learning inference. The Cornea Image Analysis Reading Center (CIARC) provided a second dataset of 174 donor EC images based on image and tissue quality. These images were used to train a supervised deep learning cell border segmentation model. Evaluation between manual and automated determination of ECD was restricted to the 1939 test EC images with at least 100 cells counted by both methods., Results: The ECD measurements from both methods were in excellent agreement with rc of 0.77 (95% confidence interval [CI], 0.75-0.79; P < 0.001) and bias of 123 cells/mm2 (95% CI, 114-131; P < 0.001); 81% of the automated ECD values were within 10% of the manual ECD values. When the analysis was further restricted to the cropped image, the rc was 0.88 (95% CI, 0.87-0.89; P < 0.001), bias was 46 cells/mm2 (95% CI, 39-53; P < 0.001), and 93% of the automated ECD values were within 10% of the manual ECD values., Conclusions: Deep learning analysis provides accurate ECDs of donor images, potentially reducing analysis time and training requirements., Translational Relevance: The approach of this study, a robust methodology for automatically evaluating donor cornea EC images, could expand the quantitative determination of endothelial health beyond ECD.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

Purpose: We constructed several mathematical models that predict endothelial cell density (ECD) for patients after penetrating keratoplasty (PK) for a moderate-risk condition (principally Fuchs' dystrophy or pseudophakic/aphakic corneal edema)., Methods: In a subset (n = 591) of Cornea Donor Study participants, postoperative ECD was determined by a central reading center. Various statistical models were considered to estimate the ECD trend longitudinally over 10 years of follow-up. A biexponential model with and without a logarithm transformation was fit using the Gauss-Newton nonlinear least squares algorithm. To account for correlated data, a log-polynomial model was fit using the restricted maximum likelihood method. A sensitivity analysis for the potential bias due to selective dropout was performed using Bayesian analysis techniques., Results: The three models using a logarithm transformation yield similar trends, whereas the model without the transform predicts higher ECD values. The adjustment for selective dropout turns out to be negligible. However, this is possibly due to the relatively low rate of graft failure in this cohort (19% at 10 years). Fuchs' dystrophy and pseudophakic/aphakic corneal edema (PACE) patients had similar ECD decay curves, with the PACE group having slightly higher cell densities by 10 years., Conclusions: Endothelial cell loss after PK can be modeled via a log-polynomial model, which accounts for the correlated data from repeated measures on the same subject. This model is not significantly affected by the selective dropout due to graft failure. Our findings warrant further study on how this may extend to ECD following endothelial keratoplasty., (© ARVO.)

Purpose: The presence of eosinophilic granulocytes in ocular tissue is a hallmark of the host response to environmental and parasite allergens. Using a mouse model of Onchocerca volvulus-mediated keratitis (river blindness), the present study examined the role of the cytokines interleukin (IL)-4 and IL-13 in regulating recruitment of eosinophils to the cornea through expression of intercellular cell adhesion molecule (ICAM)-1., Methods: C57BL/6 mice received an intrastromal injection of recombinant IL-4 and IL-13 (rIL-4 and IL-13) or were immunized by subcutaneous injection prior to receiving an intrastromal injection of a soluble O. volvulus extract. Expression of ICAM-1 and recruitment of eosinophils to the cornea were monitored by immunohistochemistry., Results: Expression of ICAM-1 was elevated after injection of rIL-4 or IL-13 together with recombinant tumor necrosis factor (rTNF)-alpha. Conversely, expression of ICAM-1 in O. volvulus-mediated keratitis was significantly reduced after subconjunctival injection of a monoclonal antibody (mAb) to IL-4 or IL-13. In addition, combined in vivo neutralization of IL-4 and IL-13 inhibited recruitment of eosinophils, but not of neutrophils, to the corneal stroma., Conclusions: These findings demonstrate that expression of ICAM-1 and recruitment of eosinophils to the cornea are tightly regulated by IL-4 and IL-13, and indicate that these cytokines are a potential target for immune intervention in ocular allergy and parasitic infections of the eye.

Purpose: Bacterial lipopolysaccharide (LPS, endotoxin) is a potent stimulator of inflammatory responses and is likely to contribute to microbial keratitis and to the pathogenesis of sterile corneal ulcers. The purpose of the present study was to identify specific mediators of endotoxin-induced keratitis., Methods: The corneal epithelium of BALB/c, C3H/HeJ, and C3H/HeN mice was abraded, and Pseudomonas aeruginosa endotoxin (10 microg in 1 microL) was added. Stromal thickness and haze were measured by in vivo scanning confocal microscopy, and neutrophil recruitment determined by immunohistochemistry., Results: Pseudomonas endotoxin induced a significant increase in stromal thickness and haze compared with untreated control corneas at each time point examined, and the severity coincided with neutrophil infiltration into the corneal stroma. Furthermore, systemic depletion of neutrophils completely abrogated endotoxin-induced increases in stromal thickness and haze, indicating an essential role for these cells. Expression of platelet endothelial cell adhesion molecule (PECAM)-1 on vascular endothelium and production of macrophage inflammatory protein (MIP)-2 in the corneal stroma were also significantly elevated after exposure to endotoxin, and antibody blockade inhibited neutrophil recruitment to the cornea and abrogated endotoxin-induced increases in stromal thickness and haze. In LPS-hyporesponsive C3H/HeJ mice, PECAM-1 and MIP-2 were not upregulated after exposure to endotoxin, and endotoxin-induced keratitis did not develop in these mice., Conclusions: These findings demonstrate that endotoxin-induced keratitis is regulated by toll-like receptor-4 (TLR4)-dependent expression of PECAM-1 and MIP-2, which are essential for recruitment of neutrophils to this site and for development of endotoxin-induced stromal disease.