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Introduction: It remains uncertain whether Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping only (DSO) yields better outcomes in patients with symptomatic Fuchs endothelial corneal dystrophy (FECD). This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial II (DETECT II), a multicentre, outcome-masked, randomised, placebo-controlled, clinical trial comparing DMEK to DSO with ripasudil (DSO-R) for this patient population., Methods and Analysis: A total of 60 patients with endothelial dysfunction due to symptomatic FECD will be enrolled from seven participating sites in the USA. The patients will be randomly assigned in a 1:1 ratio to one of the following treatment groups: group 1-DMEK plus topical placebo and group 2-DSO plus topical ripasudil 0.4%. The enrolment period is 24 months. The primary outcome is best spectacle-corrected visual acuity at 12 months. Secondary outcomes include peripheral and central endothelial cell density, visual acuity, vision-related quality of life and Pentacam Scheimpflug tomography. Study outcomes will be analysed using mixed effects linear regression. Adverse events, including rebubble procedures, endothelial failure and graft rejection, will be documented and analysed using appropriate statistical methods. DETECT II aims to provide evidence on the comparative effectiveness of DMEK and DSO-R. The results of this trial will contribute to optimising the treatment of FECD, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation., Ethics and Dissemination: A data and safety monitoring committee has been empanelled by the National Eye Institute. All study protocols will be subject to review and approval by WCG IRB as the single IRB of record. This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request., Trial Registration Number: NCT05275972., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Combining cataract surgery with endothelial keratoplasty (triple EK) is a common practice and may be safer because it commits the patient to only one surgery. This study aimed to determine whether outcomes of pseudophakic endothelial keratoplasty and triple EK have similar outcomes., Methods: This was a non-prespecified secondary analysis of a multicenter, double-masked, randomized, controlled clinical trial. Enrollment centers included the Casey Eye Institute at Oregon Health and Sciences University and the Byers Eye Institute at Stanford University. Patients with damaged or diseased endothelium and were considered good candidates for either Descemet membrane endothelial keratoplasty or ultrathin Descemet stripping automated endothelial keratoplasty were randomized to one of the two surgeries 1-2 days prior to surgery. If the patient had a cataract, they underwent simultaneous cataract surgery. The primary outcome was visual acuity at 6 months. Visual acuity at 3, 12, and 24 months, 3, 6, 12, and 24 month endothelial cell density and intraoperative and postoperative complications were also recorded., Results: Those who had pseudophakic EK generally were older, more likely to be male, and more likely to have worse baseline vision with higher corneal densitometry values. After controlling for baseline visual acuity and type of keratoplasty, those that underwent Triple-EK had 0.09 better LogMAR lines better visual acuity at 6 (95% CI -0.17 to -0.10; P = 0.02) and 12 months (95% CI -0.21 to -0.07; P = 0.03). Although those receiving Triple- EK had nearly one-half LogMAR line better visual acuity at 24 months, it was no longer statistically significant (95% CI -0.20 to -0.05; P = 0.36). There was no statistically significant difference in ECD between groups at any timepoint. Those undergoing triple EK were more likely to have at least one adverse event (P = 0.02)., Conclusions: Earlier intervention with Triple-EK may improve visual acuity outcomes after endothelial keratoplasty compared with staged procedures, but may also increase the risks of adverse events including the need for re-bubble., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study developed machine learning (ML) classifiers of postoperative corneal endothelial cell images to identify postkeratoplasty patients at risk for allograft rejection within 1 to 24 months of treatment., Methods: Central corneal endothelium specular microscopic images were obtained from 44 patients after Descemet membrane endothelial keratoplasty (DMEK), half of whom had experienced graft rejection. After deep learning segmentation of images from all patients' last and second-to-last imaging, time points prior to rejection were analyzed (175 and 168, respectively), and 432 quantitative features were extracted assessing cellular spatial arrangements and cell intensity values. Random forest (RF) and logistic regression (LR) models were trained on novel-to-this-application features from single time points, delta-radiomics, and traditional morphometrics (endothelial cell density, coefficient of variation, hexagonality) via 10 iterations of threefold cross-validation. Final assessments were evaluated on a held-out test set., Results: ML classifiers trained on novel-to-this-application features outperformed those trained on traditional morphometrics for predicting future graft rejection. RF and LR models predicted post-DMEK patients' allograft rejection in the held-out test set with >0.80 accuracy. RF models trained on novel features from second-to-last time points and delta-radiomics predicted post-DMEK patients' rejection with >0.70 accuracy. Cell-graph spatial arrangement, intensity, and shape features were most indicative of graft rejection., Conclusions: ML classifiers successfully predicted future graft rejections 1 to 24 months prior to clinically apparent rejection. This technology could aid clinicians to identify patients at risk for graft rejection and guide treatment plans accordingly., Translational Relevance: Our software applies ML techniques to clinical images and enhances patient care by detecting preclinical keratoplasty rejection.

Purpose: The purpose of this study was to evaluate outcomes of Descemet stripping automated endothelial keratoplasty comparing exchange with fresh intermediate-term cold storage solution after lenticule preparation versus reuse of the original solution in the Cornea Preservation Time Study., Methods: In the Cornea Preservation Time Study, 508 donor corneas had lenticules prepared by the eye bank with fresh solution exchange (Fresh group) and 283 with reuse of the original solution (Original group). Storage time for all donors was ≤11 days. Graft success rates, central endothelial cell loss at 3 years, and frequency of positive donor rim cultures were compared between the 2 groups., Results: The 3-year graft success rate (95% confidence interval) was 93.4% (90.7%-95.3%) in the Fresh group and 95.2% (91.8%-97.2%) in the Original group (adjusted hazard ratio for graft failure = 0.64, 95% confidence interval, 0.33-1.24, P = 0.19). The mean percentage endothelial cell loss was significantly greater in the Fresh group versus Original group (45% ± 22% vs. 38% ± 20%, respectively, P = 0.004). Cultures were positive in 4 (1.5%) of 267 donor rims (3 fungal and 1 bacterial) in the Fresh group and in 4 (2.5%) of 158 in the Original group ( P = 0.57). There were 2 postoperative infections in the Original group and none in the Fresh group., Conclusions: The use of the original intermediate-term cold storage solution did not reduce the 3-year graft success rate compared with exchanging with fresh solution after lenticule preparation for Descemet stripping automated endothelial keratoplasty, while the frequency of positive donor rim cultures did not significantly differ between groups., Competing Interests: The following authors have financial disclosures with companies that manufacture corneal storage solutions (considered relevant to this work): M. Terry (Bausch & Lomb) and W. B. Lee (Bausch & Lomb) (part of CPTS Study Group but not authors on this paper). These authors are employed by eye banks: M. Soper (VisionFirst), and M. S. Titus (Eversight). J. H. Lass is a voluntary board member of Eversight and the Cleveland Eye Bank Foundation. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To identify donor and recipient factors, including eye bank tissue observations, predictive of operative complications in the Cornea Preservation Time Study., Methods: One thousand three hundred thirty study eyes undergoing Descemet stripping automated endothelial keratoplasty for Fuchs dystrophy or pseudophakic/aphakic corneal edema were randomized to receive a donor cornea with preservation time (PT) of 0 to 7 days (N = 675) or 8 to 14 days (N = 655). Donor factors included demographics, prelamellar corneal and postlamellar lenticule dissection thickness, central endothelial cell density, and tissue processing time. Recipient factors included demographics, intraocular pressure, and glaucoma medications or surgery (trabeculectomy, laser trabeculoplasty). Eye bank observations included donor tissue folds, pleomorphism/polymegethism, and endothelial cell abnormalities. Possible tissue-related operative complications were recorded including difficult donor lenticule unfolding and positioning. Multivariable logistic regression with backward selection was used to identify statistically significant (P < 0.01) associations between factors and operative complications., Results: The only factor predictive of operative complications [58 (4.4%) of 1330 surgeries] was prelamellar dissection donor corneal thickness (P = 0.002). For every 50 μm of donor corneal thickness prior to lamellar dissection, operative complication odds increased by 40% (odds ratio [99% confidence interval (CI)]: 1.40 [1.06-1.83]) adjusting for PT and whether the epithelium was on or off. The estimated mean prelamellar dissection donor corneal thickness for PT 0 to 7 days was 537 μm (99% CI: 516 μm-558 μm) compared with 567 μm (99% CI: 546 μm-588 μm) for PT 8 to 14 days (P < 0.001)., Conclusions: Thicker donor tissue (prelamellar dissection) is associated with operative complications and should be considered in tissue selection for Descemet stripping automated endothelial keratoplasty lenticule preparation.

Purpose: To determine whether preoperative endothelial cell density (ECD) and postoperative ECD after Descemet stripping automated endothelial keratoplasty (DSAEK) are associated with late endothelial graft failure (LEGF) in the Cornea Preservation Time Study (CPTS)., Design: Cohort study within a multicenter, randomized clinical trial., Participants: A total of 1007 individuals (1223 study eyes), mean age 70 years, undergoing DSAEK for Fuchs' dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (PACE) (6% of eyes) and followed for up to 5 years., Methods: Central ECD was determined by a central image analysis reading center. Preoperative ECD was determined for 1209 eyes that did not fail and 14 eyes that experienced LEGF. The ECD at 6 and 12 months after DSAEK, the change in ECD from preoperative to 6 and 12 months, surgeon-reported operative complications, and postoperative graft dislocation were investigated for an association with LEGFs unrelated to other postoperative events. Univariable and multivariable Cox proportional hazards regression models were used to assess associations., Main Outcome Measures: Late endothelial graft failure and its associations with pre- and postoperative ECD and operative complications., Results: The cumulative probability of LEGF was 1.3% (95% confidence interval [CI], 0.8%-2.4%). Median (interquartile range [IQR]) preoperative ECDs were similar for eyes with LEGF (2523; 2367-3161) cells/mm 2 ) and eyes without failure (2727; 2508-2973) cells/mm 2 ) (P = 0.34). The ECD at 6 months was associated with LEGF (P < 0.001) in time-to-event analyses, whereas preoperative ECD was not (P = 0.55). The cumulative incidence (95% CI) of LEGF was 6.5% (3.0%, 14.0%) for 97 grafts with a 6-month ECD less than 1200 cells/mm 2 , 0.3% (0.0%, 2.4%) for 310 grafts with a 6-month ECD between 1200 and 2000 cells/mm 2 , and 0.6% (0.1%, 2.7%) for 589 grafts with a 6-month ECD greater than 2000 cells/mm 2 . In multivariable analyses, ECD at 6 months and operative complications were both associated with LEGF (P = 0.002 and P = 0.01, respectively), whereas graft dislocation was not (P = 0.61)., Conclusions: In eyes undergoing DSAEK, preoperative ECD is unrelated to LEGF, whereas lower ECD at 6 months is associated with LEGF. Early endothelial cell loss after DSAEK and intraoperative complications should be minimized to improve graft survival., (Copyright © 2019 American Academy of Ophthalmology. All rights reserved.)

Purpose: To examine the association of donor, recipient, and operative factors on graft dislocation after Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS) as well as the effects of graft dislocation and elevated IOP on graft success and endothelial cell density (ECD) 3 years postoperatively., Design: Cohort study within a multi-center, double-masked, randomized clinical trial., Methods: 1090 individuals (1330 study eyes), median age 70 years, undergoing DSAEK for Fuchs endothelial corneal dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (6% of eyes). Recipient eyes receiving donor corneal tissue randomized by preservation time (PT) of 0-7 days (N = 675) or 8-14 days (N = 655) were monitored for early or late graft failure through 3 years. Donor, recipient, operative, and postoperative parameters were recorded including graft dislocation (GD), partial detachment, and pre- and post-operative IOP. Pre- and postoperative central donor ECD were determined by a central image analysis reading center. Proportional hazards, mixed effects, and logistic regression models estimated risk ratios and (99% confidence intervals)., Results: Three independent predictive factors for GD were identified: a history of donor diabetes (odds ratio [OR]: 2.29 [1.30, 4.02]), increased pre-lamellar dissection central corneal thickness (OR: 1.13 [1.01, 1.27] per 25µ increase), and operative complications (OR: 2.97 [1.24, 7.11]). Among 104 (8%) eyes with GD, 30 (28.9%) developed primary donor or early failure and 5 (4.8%) developed late failure vs. 15 (1.2%; P < .001) and 29 (2.4%; P = .04), respectively, of 1226 eyes without GD. 24 (2%) of 1330 study eyes had early acutely elevated postoperative IOP that was associated with a higher risk of graft failure through 3 years (hazard ratio: 3.42 [1.01, 11.53]), but not with a lower mean 3-year ECD (mean difference 61 (-479, 601) cells/mm 2 , P = .77). History of elevated postoperative IOP beyond 1 month was not significantly associated with 3-year graft success or ECD., Conclusions: Donor diabetes, increased donor corneal thickness, and intraoperative complications were associated with an increased risk of GD. Early acutely elevated postoperative IOP and GD significantly increased the risk for graft failure following DSAEK., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Determining factors associated with endothelial cell loss after Descemet stripping automated endothelial keratoplasty (DSAEK) could improve long-term graft survival., Objective: To evaluate the associations of donor, recipient, and operative factors with endothelial cell density (ECD) 3 years after DSAEK in the Cornea Preservation Time Study., Design, Setting, and Participants: This cohort study was a secondary analysis of data collected in a multicenter, double-masked, randomized clinical trial. Forty US clinical sites with 70 surgeons participated, with donor corneas provided by 23 US eye banks. Individuals undergoing DSAEK for Fuchs dystrophy or pseudophakic/aphakic corneal edema were included., Interventions: The DSAEK procedure, with random assignment of a donor cornea with a preservation time of 0 to 7 days or 8 to 14 days., Main Outcomes and Measures: Endothelial cell density at 3 years as determined by a reading center from eye bank and clinical specular or confocal central endothelial images., Results: The study included 1090 participants (median age, 70 years) with 1330 affected eyes (240 bilateral cases [22.0%]), who underwent DSAEK for Fuchs dystrophy (1255 eyes [94.4%]) or pseudophakic/aphakic corneal edema (PACE) (75 eyes [5.6%]). Of these, 801 eyes (60.2%) belonged to women and 1207 (90.8%) to white individuals. A total of 749 participants (913 eyes; 164 [21.9%] bilateral cases) had functioning grafts with acceptable endothelial images preoperatively and at 3 years postoperatively and were included in this analysis. Factors associated with a lower ECD at 3 years (estimated effect with 99% CI) in the final multivariable model included donors with diabetes (-103 [-196 to -9] cells/mm2), lower screening ECD (-234 [-331 to -137] per 500 cells/mm2), recipient diagnosis of PACE (-257 [-483 to -31] in cells/mm2), and operative complications (-324 [-516 to -133] in cells/mm2). Endothelial cell loss (ECL) from a preoperative measurement to a 3-year postoperative measurement was 47% (99% CI, 42%-52%) for participants receiving tissue from donors with diabetes vs 43% (99% CI, 39%-48%) without diabetes; it was 53% (99% CI, 44%-62%) for participants diagnosed with PACE vs 44% (99% CI, 39%-49%) for those diagnosed with Fuchs dystrophy, and 55% (99% CI, 48%-63%) in participants who experienced operative complications vs 44% (99% CI, 39%-48%) in those who did not. No other donor, recipient, or operative factors were significantly associated with 3-year ECD., Conclusions and Relevance: Donor diabetes, lower screening ECD, a PACE diagnosis in the recipient, and operative complications were associated with lower ECD at 3 years after DSAEK surgery and may be associated with long-term graft success. While causation cannot be inferred, further studies on the association of donor diabetes and PACE in recipients with lower 3-year ECD warrant further study.

Purpose: To identify factors related to graft rejection following Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS)., Design: Cohort study within a multicenter randomized clinical trial., Methods: A total of 1330 eyes of 1090 subjects undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0-7 days (n = 675) or 8-14 days (n = 655) and followed for 3 years. Central endothelial cell density (ECD) was determined by a central image analysis reading center. Multivariable Cox models adjusted for PT, recipient diagnosis, and surgeon effect were used to identify factors associated with rejection., Results: Cumulative probability of definite graft rejection was 3.6% (99% confidence interval 2.5%-5.3%). Younger recipient age was associated with graft rejection (P < .001; hazard ratio: 0.53 [0.33, 0.83] per decade). PT, donor-recipient sex mismatch, recipient diagnosis, recipient race, graft size, discontinuation of topical corticosteroids and immune-modulators, prior immunizations within 3 months, and prior glaucoma surgery were not associated with rejection (P > .01). Among clear grafts with an ECD measurement at baseline and 3 years (n = 913), endothelial cell loss (ECL) was greater in eyes that experienced a rejection episode (n = 27) than in those that did not (n = 886) (48% vs 38%, P = .03). Twelve of 44 eyes (27%) with definite graft rejection subsequently failed, comprising 15% of the 79 failures in the CPTS., Conclusions: Graft rejection is uncommon after DSAEK and more likely with younger age, in a study cohort mostly > 50 years old. Rejection increases ECL, but it is not a leading cause of DSAEK failure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Demonstrating that endothelial cell loss following Descemet stripping automated endothelial keratoplasty (DSAEK) is independent of donor cornea preservation time (PT) could increase the pool of corneal tissue available for keratoplasty., Objective: To determine whether endothelial cell loss 3 years after successful DSAEK is related to PT., Design, Setting, and Participants: A multicenter, double-masked, randomized clinical trial included 40 clinical sites (70 surgeons) in the United States, with donor corneas provided by 23 US eye banks. A total of 945 eyes of 769 participants were included in the Cornea Preservation Time Study that had not experienced graft failure 3 years after DSAEK, performed primarily for Fuchs endothelial corneal dystrophy (96% of the cohort). The study was conducted from April 16, 2012, to June 5, 2017., Interventions: DSAEK with random assignment of a donor cornea with PT of 0 to 7 days (0-7d PT) or 8 to 14 days (8-14d PT)., Main Outcomes and Measures: Endothelial cell density (ECD) at 3 years determined by a central image analysis reading center from clinical specular or confocal central endothelial images., Results: Nine hundred forty-five eyes of 769 participants (median age, 70 years [range, 42-90 years], 60.8% women, 93.0% white) in the Cornea Preservation Time Study that had not experienced graft failure 3 years after DSAEK were included. At the initial eye bank tissue screening, mean (SD) central ECD was 2746 (297) cells/mm2 in the 0-7d PT group (n = 485) and 2723 (284) cells/mm2 in the 8-14d PT group (n = 460). At 3 years, the mean (SD) ECD decreased from baseline by 37% (21%) in the 0-7d PT group and 40% (22%) in the 8-14d PT group to 1722 (626) cells/mm2 and 1642 (631) cells/mm2, respectively (mean difference, 73 cells/mm2; 95% CI, 8-138 cells/mm2; P = .03). When analyzed as a continuous variable (days), longer PT was associated with lower ECD (mean difference by days, 15 cells/mm2; 95% CI, 4-26 cells/mm2; P = .006). Endothelial cell loss (ECL) was comparable from 4 to 13 days’ PT (n = 878; 36%-43% when tabulated by day). Available extension study ECD results at 4 years mirrored those at 3 years in the 203 eyes in the 0-7d PT group (mean [SD] ECD, 1620 [673] cells/mm2 and mean [SD] ECL, 41% [23%]) and 209 eyes in the 8-14d PT group (mean [SD] ECD, 1537 [683] cells/mm2 and mean [SD] ECL, 44% [23%]) (mean difference, 112 cells/mm2; 95% CI, 5-219 cells/mm2; P = .04)., Conclusions and Relevance: Although ECL 3 years after Descemet stripping automated endothelial keratoplasty is greater with longer PT, the effect of PT on ECL is comparable from 4 to 13 days’ PT.

Purpose: To evaluate a single eye bank's measurement of endothelial cell density (ECD) of Descemet membrane endothelial keratoplasty (DMEK) grafts before and after preparation using 2 separate counting methods., Methods: A series of 60 donor tissues were prepared for DMEK surgery. One to 4 specular images of the central endothelium were taken both before and after preparation, and ECDs were evaluated for a total of 345 unique images. Images were then masked and provided to the Cornea Image Analysis Reading Center (CIARC) for independent analysis., Results: Before preparation, average eye bank-determined ECD with the center method was 2678 ± 259 cells/mm and was 2599 ± 280 cells/mm CIARC-determined by the variable frame method (P < 0.001, n = 176). After preparation, eye bank-determined ECD was 2719 ± 265 cells/mm and CIARC-determined ECD was 2615 ± 344 cells/mm (P < 0.001, n = 169). The difference in ECD before and after DMEK preparation was not found to be statistically significant when evaluated using either analysis method (P = 0.19; P = 0.64) before and after preparation, respectively., Conclusions: Although the absolute ECD value may differ by the analysis method statistically, pre- and post-DMEK preparation ECDs did not significantly change by either analysis method. Other methods such as vital staining to assess tissue damage after preparation in conjunction with specular microscopy are suggested.

Purpose: The aim of this study was to compare endothelial cell loss and graft success 6 months after endothelial keratoplasty (EK) with paired donor corneas stored in Optisol GS and Life4°C solutions and their associated storage chambers., Methods: Donor pairs were stored, one in Optisol GS and the other in Life4°C, and prepared for Descemet stripping automated EK or Descemet membrane EK. Matched pairs of recipients with Fuchs dystrophy were randomized to 1 member of each donor pair. Clarity of recipient stroma, intraocular pressure, and complications were followed for 6 months. Central endothelial images of the donor cornea at screening and 3 and 6 months after EK were analyzed by a masked central reading center. Dual grading of endothelial cell density was performed using the center method. Differences in endothelial cell density and cell loss were examined by paired analysis., Results: Thirty-two pairs were enrolled, and 27 were analyzed (5 had improper matching or loss to follow-up). Donor age was 59 ± 14 years, median death-to-surgery time was 4 days (range, 2-9 days), 6 recipient pairs had Descemet membrane EK, and 21 had Descemet stripping automated EK. Recipient age was comparable in the Optisol GS and Life4°C groups (70 vs. 68 years, respectively, P = 0.46). Six-month central endothelial cell loss did not differ significantly between the Life4°C and Optisol GS groups (18 ± 18% vs. 20 ± 20%, respectively, P = 0.55). All recipient corneas were clear at 6 months in both groups., Conclusions: Endothelial cell loss and graft success were comparable at 6 months for paired donor corneas stored in Optisol GS and Life4°C.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01657500.