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Brandon D Ayres,1 Marc R Bloomenstein,2 Jennifer Loh,3 Thomas Chester,4 Bobby Saenz,5,6 Julio Echegoyen,7 Shane R Kannarr,8 Victor L Perez,9 Tomasita C Rodriguez,10 Jaime E Dickerson Jr10,11 1Private Practice, Philadelphia, PA, USA; 2Schwartz Laser Eye Center, Scottsdale, AZ, USA; 3Loh Ophthalmology Associates, Miami, FL, USA; 4Cleveland Eye Clinic, Brecksville, OH, USA; 5Rosenberg School of Optometry, University of the Incarnate Word, San Antonio, TX, USA; 6LASIK San Antonio, Kerrville, TX, USA; 7Gordon Schanzlin New Vision Institute, La Jolla, CA, USA; 8Kannarr Eye Care, Pittsburg, KS, USA; 9Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA; 10Sight Sciences, Menlo Park, CA, USA; 11North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USACorrespondence: Jaime E Dickerson Jr, Email jdickerson@sightsciences.comPurpose: We compare outcomes in eyes with dry eye disease (DED) treated with TearCare (TC) or topical cyclosporine 0.05% (RESTASIS; CsA).Setting: Nineteen ophthalmic and optometric practices in 11 US states.Design: Multicenter, randomized, assessor-masked, controlled IRB-approved trial. Eligible subjects: ≥ 22 years of age, dry eye symptoms within 3– 6 months, Tear Break-up Time (TBUT) ≥ 1 to ≤ 7 s, Meibomian Gland Secretion Score (MGSS) ≤ 12, Ocular Surface Disease Index (OSDI) of 23– 79. Randomized (1:1) to TC or CsA. TC subjects treated at baseline and month 5; CsA was twice daily for 6 months.Methods: Follow-up visits were scheduled for Day 1, Week 1, Months 1, 3, and 6 with primary inference at Month 6. Primary outcomes: TBUT and OSDI; secondary outcomes: MGSS, conjunctival and corneal staining, eye dryness score (EDS), symptoms assessment in dry eye (SANDE) score, and Schirmer tear score (STS). Safety assessments included adverse events, best corrected visual acuity, intraocular pressure, and slit-lamp findings.Results: Overall, 345 subjects, 172 TC and 173 CsA. TBUT improved at all time points in both groups (p< 0.0001), with statistically greater improvement for TC versus CsA (p=0.0006). OSDI improved significantly at all time points in both groups (p< 0.0001) with no significant differences between treatments. MGSS and other measures of meibomian gland function improved significantly more with TC eyes versus CsA; other secondary outcomes showed significant improvements in both groups with no difference between groups. Treatment-related adverse events were uncommon (10 total, 8 in the CsA group consistent with prior CsA studies); most (9/10) mild.Conclusion: TC provides statistically superior and sustained improvement in TBUT and multiple measures of meibomian gland secretion, and non-inferior improvement in OSDI, corneal and conjunctival staining, SANDE, EDS, and STS versus CsA. TC should be a preferred treatment for DED associated with MGD.Keywords: dry eye disease, meibomian gland dysfunction, restasis, TearCare, cyclosporine

Brandon D Ayres,1 Marc R Bloomenstein,2 Jennifer Loh,3 Thomas Chester,4 Bobby Saenz,5,6 Julio Ehegoyen,7 Shane R Kannarr,8 Victor L Perez,9 Tomasita C Rodriguez,10 Jaime E Dickerson Jr10,11 1Private Practice, Philadelphia, PA, USA; 2Schwartz Laser Eye Center, Scottsdale, AZ, USA; 3Loh Ophthalmology Associates, Miami, FL, USA; 4Cleveland Eye Clinic, Brecksville, OH, USA; 5Rosenberg School of Optometry, San Antonio, TX, USA; 6LASIK San Antonio, Kerrville, TX, USA; 7Gordon Schanzlin New Vision Institute, La Jolla, CA, USA; 8Kannarr Eye Care, Pittsburg, KS, USA; 9Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA; 10Sight Sciences, Menlo Park, CA, USA; 11North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USACorrespondence: Jaime E Dickerson Jr, Email jdickerson@sightsciences.com

Allister Gibbons,1 Ella H Leung,1 Luis J Haddock,1 Carlos A Medina,1 Viviana Fernandez,2 Jean-Marie A Parel,1,2 Heather A Durkee,2 Guillermo Amescua,1 Eduardo C Alfonso,1 Victor L Perez1,3 1Bascom Palmer Eye Institute/University of Miami Miller School of Medicine, Miami, FL, 2Ophthalmic Biophysics Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 3Ocular Surface Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Purpose: To determine the indications, long-term clinical and visual outcomes, and complications of the aphakic snap-on type I Boston keratoprosthesis (KPro). Design: Retrospective, non-comparative case series. Methods: Forty-five eyes of 43 patients with type I aphakic snap-on KPros with at least 1 year of follow-up were included. The past medical histories, preoperative indications, best-corrected visual acuities (BCVAs), postoperative complications, and retention rates were analyzed. Results: The most common indication for KPro implantation was a failed corneal graft (89%). The mean preoperative BCVA was count fingers–hand motion (2.14±0.45 logarithm of minimum angle of resolution [logMAR]), which initially improved to 20/200 (1.04±0.85 logMAR; P

Marwan Raymond Atallah, Sotiria Palioura, Victor L Perez, Guillermo Amescua Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Abstract: Regeneration of the corneal surface after an epithelial insult involves division, migration, and maturation of a specialized group of stem cells located in the limbus. Several insults, both intrinsic and extrinsic, can precipitate destruction of the delicate microenvironment of these cells, resulting in limbal stem cell deficiency (LSCD). In such cases, reepithelialization fails and conjunctival epithelium extends across the limbus, leading to vascularization, persistent epithelial defects, and chronic inflammation. In partial LSCD, conjunctival epitheliectomy, coupled with amniotic membrane transplantation, could be sufficient to restore a healthy surface. In more severe cases and in total LSCD, stem cell transplantation is currently the best curative option. Before any attempts are considered to perform a limbal stem cell transplantation procedure, the ocular surface must be optimized by controlling causative factors and comorbid conditions. These factors include adequate eyelid function or exposure, control of the ocular surface inflammatory status, and a well-lubricated ocular surface. In cases of unilateral LSCD, stem cells can be obtained from the contralateral eye. Newer techniques aim at expanding cells in vitro or in vivo in order to decrease the need for large limbal resection that may jeopardize the “healthy” eye. Patients with bilateral disease can be treated using allogeneic tissue in combination with systemic immunosuppressive therapy. Another emerging option for this subset of patients is the use of noncorneal cells such as mucosal grafts. Finally, the use of keratoprosthesis is reserved for patients who are not candidates for any of the aforementioned options, wherein the choice of the type of keratoprosthesis depends on the severity of the disease. In summary, limbal stem cell transplantation improves both vision and quality-of-life in patients with ocular surface disorders associated with LSCD, and overall, the use of autologous tissue offers the best results. Future studies aim at improving cellular expansion and finding different sources of stem cells. Keywords: limbal stem cell deficiency (LSCD), simple limbal epithelial transplantation (SLET), cultivated limbal epithelial transplantation (CLET), keratolimbal allograft (KLAL)

Volkan Hurmeric,1 Pravin Vaddavalli,1 Anat Galor,1,2 Victor L Perez,1 Janika San Roman,1 Sonia H Yoo11Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL, USA; 2Miami Veterans Affairs Medical Center, Miami, FL, USAPurpose: To assess the effect of single versus multiple subconjunctival ranibizumab injections in patients with an early pterygium recurrence.Setting: Single-center, academic practice.Study population: Nine patients with early pterygium recurrence.Observational procedure: Subconjunctival ranibizumab (0.5 mg/0.05 mL) was administered adjacent to pterygium recurrence. Group 1 (n = 5) received one injection; group 2 (n = 4) received three injections (time points 0, 2, and 4 weeks) with the ability to retreat as needed.Main outcome measures: Effect of ranibizumab on conjunctival hyperemia and corneal neovascular area over a 6-month follow-up period.Results: In the single injection group, a decrease in conjunctival hyperemia was noted in all patients on postinjection day 1. At follow up, hyperemia grade fluctuated, although all patients had less hyperemia than at baseline. In the recurrent injection group, the median number of injections was 8.5 (range 7 to 9) over the 6 months. In spite of the repeated injections, the pattern of conjunctival hyperemia was similar to that of the single injection group. In group 1, corneal neovascularization remained relatively unchanged over the 6-month period in four patients and decreased in one patient by 24%. In group 2, corneal neovascularization increased in one patient by 39%, remained stable in one patient, and decreased in two patients by 34% and 44%.Conclusion: This is the first study to evaluate the role of ranibizumab in the treatment of an early pterygium recurrence and the first to compare multiple versus single injections. Recurrent injections did not appear to be superior to a single injection with regards to conjunctival hyperemia.Keywords: pterygium, recurrence, ranibizumab, conjunctival hyperemia, corneal neovascularization

Jianhua Wang,1 Lele Cui,1 Meixiao Shen,1 Victor L Perez,1 Michael R Wang21Bascom Palmer Eye Institute, University of Miami Leonard M Miller School of Medicine, 2Electrical and Computer Engineering, University of Miami, Miami, FL, USAPurpose: This study was designed to determine the ability of ultra-high-resolution optical coherence tomography (UHR-OCT) to monitor tear meniscus volume after dry eye treatment with Restasis® (0.05% cyclosporine).Methods: UHR-OCT was used to image the upper and lower tear menisci (height and volume) in 14 consecutive dry eye patients at baseline. The treatment group was initiated on daily Restasis and measurements were repeated at 1 and 2 months while on treatment. All measurements were performed immediately after a blink.Results: The baseline tear meniscus volumes were 0.40 ± 0.19 µL (upper) and 0.43 ± 0.18 µL (lower). In the treatment group, tear meniscus heights showed significant increases of both upper (post-hoc test with Bonferroni correction: P = 0.003) and lower (P = 0.0003) tear menisci, after 1 month on Restasis. The tear meniscus volumes in the treatment group after 1 month of Restasis showed significant increases of both upper (P = 0.007) and lower (P = 0.007) tear menisci. At 2 months, the increase of the tear meniscus was still evident in all measured variables compared with baseline (P < 0.05).Conclusion: UHR-OCT offers a promising tool for monitoring dry eye treatment. With this method, a measurable increase in tear meniscus volume was evident after 1 month of treatment with Restasis in dry eye patients.Keywords: tear menisci, UHR-OCT, tear dynamics, dry eye, Restasis®

The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD) includes long-term pharmacological immune suppression frequently accompanied by unwanted side effects. Advances in targeted immunotherapies regulating alloantigen responses in the recipient continue to reduce the need for pan-immunosuppression. Here, in vivo targeting of the TNF superfamily receptor 25 (TNFRSF25) and the high affinity IL-2 receptor with a TL1A-Ig fusion protein and low dose IL-2, respectively, was used to pretreat recipient mice prior to allogeneic-HSCT (aHSCT). Pretreatment induced Treg expansion persisting early post-aHSCT leading to diminished GVHD and improved transplant outcomes. Expansion was accompanied by an increase in frequency of stable and functionally active Tregs as evidenced by in vitro assays using cells from major GVHD target tissues including colon, liver, and eye. Importantly, pretreatment supported epithelial cell function/integrity, a diverse microbiome including reduction of pathologic bacteria overgrowth and promotion of butyrate producing bacteria, while maintaining physiologic levels of obligate/facultative anaerobes. Notably, using a sphingosine 1-phosphate receptor agonist to sequester T cells in lymphoid tissues, we found that the increased tissue Treg frequency included resident CD69 + CD103 + FoxP3 + hepatic Tregs. In contrast to infusion of donor Treg cells, the strategy developed here resulted in the presence of immunosuppressive target tissue environments in the recipient prior to the receipt of donor allo-reactive T cells and successful perseveration of GVL responses. We posit strategies that circumvent the need of producing large numbers of ex-vivo manipulated Tregs, may be accomplished through in vivo recipient Treg expansion, providing translational approaches to improve aHSCT outcomes.

Competing Interests: Financial disclosures/conflicts of interest: This work was supported in part by an unrestricted grant from Research to Prevent Blindness (RPB), National Eye Institute (NEI): center grant P30-EY026877 (Duke, Stanford), R01EY030283 (VLP), R01EY024485 (VLP), UG1 EY030417 (JRN), UG1 EY028518 (JRN), K23 EY025025 (JRN). Funding for the Steroids for Corneal Ulcers Trial (SCUT) was provided by the NEI U10 EY015114 (TML), K23 EY017897 (NRA), EY02162 (UCSF), and a Research to Prevent Blindness Award. SCUT was registered at clinicaltrials.gov (NCT00324168). Funding for the Mycotic Ulcer Treatment Trial (MUTT) I and II were provided by: U10 EY018573 (TML), K23 EY017897 (NRA), K23 EY025025 (JRN), grants from That Man May See, the Harper/Inglis Trust, the South Asia Research Foundation, and Research to Prevent Blindness. MUTT I was registered at clinicaltrials.gov (NCT00996736). MUTT II was registered at clinicaltrials.gov (NCT00997035). V.L. Perez has financial relationships with Alcon, Dompe, EyeGate, Kala, Trefoil, Novartis, and Oculis. The remaining authors have no conflicts of interest to disclose.

Non-immune hydrops fetalis (NIHF) is a rare entity characterized by excessive accumulation of fluid within the fetal extravascular compartments and body cavities. Here we present two intrauterine fetal demises with NIHF presenting with oligohydramnios, cystic hygroma, pleural effusion, and generalized hydrops with predominance of subcutaneous edema. The fetuses also presented with ascites, severe and precocious IUGR and skeletal anomalies. Whole exome sequencing was applied in order to screen for a possible genetic cause. The results identified biallelic variants in MYBBP1A in both fetuses. A previous report described another case with a similar phenotype having compound heterozygous variants in the same gene. The protein encoded by MYBBP1A is involved in several cellular processes including the synthesis of ribosomal DNA, the response to nucleolar stress, and tumor suppression. Our functional protein analysis through immunohistochemistry indicates that MYBBP1A is a gene expressed during fetal stages. Altogether, we concluded that MYBBP1A is associated with the development of hydrops fetalis. More cases and further studies are necessary to understand the role of this gene and the mechanism associated with NIHF., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Primarily, to evaluate the repeatability and reproducibility of the new noncontact esthesiometer (NCE) in healthy subjects. Secondarily, the corneal sensitivity threshold measurements of the NCE were compared with those of the Cochet-Bonnet esthesiometer (CBE)., Design: Assessment reliability study., Methods: Two examiners measured bilateral corneal sensitivity thresholds by NCE and CBE. Triple NCE measurements were performed per eye at all 5 levels, whereas single CBE measurements were performed per eye. When appropriate, NCE (mBar) and CBE (mm) measurements were converted to millinewtons (mN) for direct comparison between devices. The NCE measurement variations were calculated with the intra-class correlation coefficients (ICC) for the primary objective. For the secondary objective, Bland-Altman plots with 95% limits of agreement (95%-LoA) and Spearman's rank correlation coefficients were used to evaluate the level of agreement and linear relationship between the corneal sensitivity thresholds obtained with both devices. Generalized estimating equation models were used to account for the inter-eye correlation of the same study participant., Results: Fifty subjects (100 eyes) aged 29 years (median) were included. There were no statistically significant differences in the pressure measured by both observers at each NCE level (all P > .05). There was a high intra-observer and inter-observer repeatability of the NCE measurements (ICC > 0.90) and a strong linear correlation (rho > 0.7) at each NCE level. The difference between the mean corneal sensitivity thresholds (mN) measured with the NCE (0.052 ± 0.021 mN) and CBE (0.046 ± 0.005 mN) was statistically significant (P = .001). Bland-Altman analysis revealed a differential bias of +0.00578 mN (95%-LoA -0.03677 - +0.04833 mN) between threshold measurements., Conclusions: The NCE provides reliable user-independent corneal sensitivity measurements. The NCE and CBE do not yield similar values. Thus, both devices cannot be used interchangeably., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To evaluate the incidence of chronic cicatrizing conjunctivitis (CCC) and its associated risk factors in the context of chronic ocular graft-vs-host disease (coGVHD)., Methods: A retrospective chart review of individuals diagnosed with coGVHD following hematopoietic stem cell transplantation (HSCT) who were seen at the Bascom Palmer Eye Institute between May 2010 and November 2021 was performed. Data regarding baseline demographic characteristics, systemic co-morbidities, lid margin abnormalities, ocular cicatricial changes, transplant information, immunosuppressive therapy, and GVHD severity assessments were collected. The incidence of cicatricial conjunctivitis was estimated with Kaplan-Meier survival analysis. A Cox regression model was used to assess the contribution of demographic and systemic variables to the development of CCC., Results: 167 individuals were included (53.9 ± 14.7 years old; 60.5 % male). 65 individuals presented with features suggestive of CCC an average of 60.9 ± 53.8 months after HSCT, with 60-month and 120-month incidences of 29.3 % and 48.9 %, respectively. Multivariable analysis demonstrated that age younger than 50 at the time of the first eye visit was associated with a higher chance of CCC development (Hazard Ratio (HR): 2.14, 95 % Confidence Interval (CI): 1.16-3.97, p = 0.02)., Conclusion: Clinically detected cicatrizing conjunctivitis is an ocular manifestation of coGVHD, with an incidence that increases over time. Younger individuals may be at higher risk for CCC development., (Published by Elsevier Inc.)

Purpose: To evaluate and compare subbasal corneal nerve parameters of the inferior whorl in patients with dry eye disease (DED), neuropathic corneal pain (NCP), and controls using a novel deep-learning-based algorithm to analyze in-vivo confocal microscopy (IVCM) images., Methods: Subbasal nerve plexus (SNP) images of the inferior whorl of patients with DED (n = 49, 77 eyes), NCP (n = 14, 24 eyes), and controls (n = 41, 59 eyes) were taken with IVCM and further analyzed using an open-source artificial intelligence (AI)-based algorithm previously developed by our group. This algorithm automatically segments nerves, immune cells, and neuromas in the SNP. The following parameters were compared between groups: nerve area density, average nerve thickness, average nerve segment tortuosity, junction point density, neuroma density, and immune cell density., Results: 160 eyes of 104 patients (63 % females), aged 56.8 ± 15.4 years, were included. The mean nerve area density was significantly lower in the DED (P = 0.012) and NCP (P < 0.001) groups compared to the control group. The junction point density was lower in the NCP group compared with control (P = 0.001) and DED (P = 0.004) groups. The immune cell density was higher in the DED group compared with controls (P < 0.001)., Conclusions: Deep-learning-based analysis of IVCM images of the corneal SNP inferior whorl distinguished a decreased mean nerve area density in patients with DED and NCP compared with controls and an increased immune cell density in patients with oGVHD- and SS-associated DED. These findings suggest that the inferior whorl could be used as landmark to distinguish between patients with DED and NCP., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Evaluate the response to adalimumab (ADA) in pediatric chronic anterior uveitis (pCAU)., Methods: Retrospective chart review of pCAU patients treated with ADA. Outcomes evaluated included the proportion of patients achieving zero ocular inflammation and discontinuation of topical corticosteroids, visual outcomes, and incidence of uveitis recurrences after ≥ 12 months of prescribing ADA. Incidence and risk factors for developing anti-adalimumab antibodies (AAAs) were also evaluated., Results: Of 27 children aged 11 years, 16 (59%) were Caucasian and 6 (22%) African Americans. Thirteen (48%) patients had idiopathic pCAU, 12 (44%) had juvenile idiopathic arthritis (JIA) related pCAU, and 2 (7%) had tubulointerstitial nephritis and uveitis syndrome. At baseline, African American children had worse visual acuity (p = 0.026). At 1 year, 21 (78%) children achieved zero ocular inflammation (remission). Risk factors associated with non-remission were being African American (20% vs. 94%, p = 0.003) and experiencing ≥ 1 episode of uveitis recurrence (100% vs. 0%, p < 0.001). Six episodes of uveitis recurrence were documented in five children, four of whom were African American. Topical corticosteroids were discontinued in 83% of children, and visual acuity remained stable for 1 year. Twelve children were tested for AAAs due to arthritis or uveitis flare-ups, with five (42%) being positive. No significant factors were associated with the development of AAAs., Conclusions: We found that ADA is effective in controlling inflammation, reducing the need for topical corticosteroids, and maintaining visual acuity in pCAU. There appears to be racial differences in African American children who had worse baseline disease and poorer outcomes. Studies are necessary to understand better and address these disparities., (© 2024. The Author(s).)

Introduction: This study aimed to analyze corneal sensitivity with a new noncontact and handheld esthesiometer (Brill Engines, Spain) in patients with dry eye disease (DED) and patients on hypotensive drops, and to compare it with healthy subjects., Methods: A total of 31 patients (57 eyes) with DED, 23 patients (46 eyes) with glaucoma, and 21 healthy patients (33 eyes) were recruited. In all patients, corneal sensitivity was measured. Subsequently, a keratography test (Keratograph 5M, Oculus) was carried out to measure tear meniscus height (TMH), non-invasive breakup time (NIBUT), bulbar redness (Jenvis scale), and corneal staining (CS, Oxford scale). Both corneal sensitivity and ocular surface parameters were compared between DED, glaucoma, and healthy subjects. Linear mixed models were constructed to utilize data from both eyes of patients. An alpha level of 0.05 was considered statistically significant., Results: The mean age was 56.1 ± 16.1 years in the DED group, 69.5 ± 11.7 years in the glaucoma group, and 37.190 ± 11.677 years in the control group. After adjustment for age and sex, corneal sensitivity was significantly reduced in DED and glaucoma vs control group (P = 0.02 and P = 0.009, respectively). NIBUT was lower in DED and glaucoma groups (P < 0.001 and P = 0.001, respectively). Redness and CS values were higher in the DED group (P = 0.04 and P = 0.001, respectively). TMH was lower in the glaucoma group (P = 0.03)., Conclusions: Corneal sensitivity measured with a novel noncontact esthesiometer was reduced in DED and glaucoma groups compared to controls. In clinical practice, this esthesiometer could be an easy-to-use device to screen for patients with subclinical neurotrophic keratopathy., (© 2024. The Author(s).)

Purpose: Analyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP)., Design: Retrospective multicenter study., Participants: Patients with OMMP seen at the Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990 to 2022., Methods: Data at presentation on demographics, direct immunofluorescence, ocular findings, sites of extraocular manifestations (EOMs), and previous treatments in patients with a clinical or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes., Main Outcome Measures: (1) Inflammatory control (no conjunctival inflammation in both eyes at 3 months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥ 1 cicatrizing stage progression in either eye); and (4) vision loss (≥ 2 Snellen lines)., Results: A total of 117 patients (234 eyes), 61% (71/117) of whom were women, with a mean age of 66.6 (SD: 12.4) years (range: 37-97 years) and median follow-up of 34 months (interquartile range: 16-66 months; range: 3-265 months), were enrolled. Inflammatory control was achieved in 57% of patients (67/117), with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital involvement (adjusted odds ratio [aOR]: 12.51; 95% confidence interval [CI]: 2.61-59.99; P = 0.002) and corneal scarring (aOR: 3.06; 95% CI, 1.15-8.14; P = 0.025), as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% of patients (23/117), 12% of patients (14/117), and 27% of patients (32/117), respectively. Baseline corneal scarring was a risk factor for relapse (adjusted hazard ratio: 4.14; 95% CI: 1.61-10.62; P = 0.003), progression (aOR: 11.46; 95% CI: 1.78-73.75; P = 0.010), and vision loss (aOR: 3.51; 95% CI: 1.35-9.10; P = 0.010). HR-EOM was associated with stage progression (aOR, 34.57; 95% CI, 6.57-181.89; P<0.001) and vision loss (aOR, 8.42; 95% CI, 2.50-28.42; P = 0.001). No significant differences were found between IMT regimes and relapse (P = 0.169)., Conclusions: Ocular mucous membrane pemphigoid presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Several gaps and barriers remain for transplanting stem cells into the eye to treat ocular disease, especially diseases of the retina. While the eye has historically been considered immune privileged, recent thinking has identified the immune system as both a barrier and an opportunity for eye stem cell transplantation. Recent approaches leveraging scaffolds or cloaking have been considered in other tissues beyond immune suppression. This perspective paper outlines approaches for transplantation and proposes opportunities to overcome barriers of the immune system in stem cell transplantation in the eye., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To analyze the clinical course and outcomes of autoimmune vs. non-autoimmune surgically induced scleral necrosis (SISN)., Methods: Multicentric, retrospective, comparative cohort study. Eighty-two eyes of 70 patients with SISN were classified according to pathogenic mechanism into autoimmune vs. non-autoimmune. Main outcome measures included necrosis onset, type of surgery, associated systemic disease, visual acuity, and treatment were analysed in patients followed for ≥ 6 months., Results: Forty-six (65.7%) patients were women, and the median age was 66 (range: 24-90) years. Most patients (82.9%) had unilateral disease. The median time between surgery and SISN onset was 58 (1-480) months. Thirty-one (37.8%) eyes were classified as autoimmune, and 51 (62.2%) as non-autoimmune SISN. Autoimmune SISN was associated with a shorter time between the surgical procedure and SISN onset than non-autoimmune cases (median of 26 vs. 60 months, p  = 0.024). Also, autoimmune SISN was associated with cataract extraction (93.5% vs. 25.5%, p  < 0.001), severe scleral inflammation (58.1% vs. 17.6%, p  < 0.001), and higher incidence of ocular complications (67.7% vs. 33.3%, p  = 0.002) than non-autoimmune cases. Remission was achieved with medical management alone in 44 (86.3%) eyes from the non-autoimmune and in 27 (87.1%) from the autoimmune group ( p  = 0.916). Surgical management was required in 11 (13.4%) eyes, including two requiring enucleations due to scleral perforation and phthisis bulbi ., Conclusions: Eyes with autoimmune SISN had a higher rate of cataract surgery, severe scleral inflammation, and ocular complications. Early SISN diagnosis and appropriate management, based on clinical features and pathogenic mechanisms, are critical to avoid sight-threatening complications.

Abstract: The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a "time zero," meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a "time zero" allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjögren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the "time zero" concept in the study of oGVHD., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Contact Lens Association of Ophthalmologists.)

Meibomian gland dysfunction (MGD) is a leading cause of dry eye disease and one of the most common ophthalmic conditions encountered in eye clinics worldwide. These holocrine glands are situated in the eyelid, where they produce specialized lipids, or meibum, needed to lubricate the eye surface and slow tear film evaporation - functions which are critical to preserving high-resolution vision. MGD results in tear instability, rapid tear evaporation, changes in local microflora, and dry eye disease, amongst other pathological entities. While studies identifying the mechanisms of MGD have generally focused on gland obstruction, we now know that age is a major risk factor for MGD that is associated with abnormal cell differentiation and renewal. It is also now appreciated that immune-inflammatory disorders, such as certain autoimmune diseases and atopy, may trigger MGD, as demonstrated through a T cell-driven neutrophil response. Here, we independently discuss the underlying roles of gland and immune related factors in MGD, as well as the integration of these two distinct mechanisms into a unified perspective that may aid future studies. From this unique standpoint, we propose a revised model in which glandular dysfunction and immunopathogenic pathways are not primary versus secondary contributors in MGD, but are fluid, interactive, and dynamic, which we likened to the Yin and Yang of MGD., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: BA, MB, JL, TC, BS, JE, and SK were Investigators and received research support for the study. BA is a consultant for Allergan and Sight Sciences. MB is a consultant for and reports honoraria from Allergan and Sight Sciences. JL is a consultant for Allergan and Sight Sciences and reports personal fees from Sun Ophthalmics, Alcon, and Bausch and Lomb, outside the submitted work. TC reports grant support, consulting, and speaking for Sight Sciences. BS is a consultant and speaker for Sight Sciences and Allergan. SK is a consultant and speaker for Allergan and a consultant for Sight Sciences. VP reports consulting fees from Sight Sciences, grants from Alcon; stock options from Claris; grants, personal fees from Novartis; personal fees from Dompe, Oyster Point, Oculis, Novaliq, Sun Pharma, Quidel, BrightStar and Kala; stock options from Trefoil; personal fees, stock options from Kuria, outside the submitted work. JD and TR are employees of Sight Sciences. There are no other relevant conflicts of interest in this communication.

Purpose: To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation., Design: Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial., Participants: The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus., Methods: Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks., Main Outcome Measures: Vessel and invasion area of vessels in the corneal graft and host beds., Results: This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P  = 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P  = 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients., Conclusions: In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Purpose: The aim of this study was to validate the C-DU(KE) calculator as a predictor of treatment outcomes on a data set derived from patients with culture-positive ulcers., Methods: C-DU(KE) criteria were compiled from a data set consisting of 1063 cases of infectious keratitis from the Steroids for Corneal Ulcer Trial (SCUT) and Mycotic Ulcer Treatment Trial (MUTT) studies. These criteria include corticosteroid use after symptoms, visual acuity, ulcer area, fungal etiology, and elapsed time to organism-sensitive therapy. Univariate analysis was performed followed by multivariable logistic regressions on culture-exclusive and culture-inclusive models to assess for associations between the variables and outcome. The predictive probability of treatment failure, defined as the need for surgical intervention, was calculated for each study participant. Discrimination was assessed using the area under the curve for each model., Results: Overall, 17.9% of SCUT/MUTT participants required surgical intervention. Univariate analysis showed that decreased visual acuity, larger ulcer area, and fungal etiology had a significant association with failed medical management. The other 2 criteria did not. In the culture-exclusive model, 2 of 3 criteria, decreased vision [odds ratio (OR) = 3.13, P < 0.001] and increased ulcer area (OR = 1.03, P < 0.001), affected outcomes. In the culture-inclusive model, 3 of 5 criteria, decreased vision (OR = 4.9, P < 0.001), ulcer area (OR = 1.02, P < 0.001), and fungal etiology (OR = 9.8, P < 0.001), affected results. The area under the curves were 0.784 for the culture-exclusive model and 0.846 for the culture-inclusive model which were comparable to the original study., Conclusions: The C-DU(KE) calculator is generalizable to a study population from large international studies primarily taking place in India. These results support its use as a risk stratification tool assisting ophthalmologists in patient management., Competing Interests: V.L. Perez has financial relationships with Alcon, Dompe, EyeGate, Kala, Trefoil, Novartis, and Oculis. The remaining authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: We compare outcomes in eyes with dry eye disease (DED) treated with TearCare (TC) or topical cyclosporine 0.05% (RESTASIS; CsA)., Setting: Nineteen ophthalmic and optometric practices in 11 US states., Design: Multicenter, randomized, assessor-masked, controlled IRB-approved trial. Eligible subjects: ≥22 years of age, dry eye symptoms within 3-6 months, Tear Break-up Time (TBUT) ≥1 to ≤7 s, Meibomian Gland Secretion Score (MGSS) ≤12, Ocular Surface Disease Index (OSDI) of 23-79. Randomized (1:1) to TC or CsA. TC subjects treated at baseline and month 5; CsA was twice daily for 6 months., Methods: Follow-up visits were scheduled for Day 1, Week 1, Months 1, 3, and 6 with primary inference at Month 6. Primary outcomes: TBUT and OSDI; secondary outcomes: MGSS, conjunctival and corneal staining, eye dryness score (EDS), symptoms assessment in dry eye (SANDE) score, and Schirmer tear score (STS). Safety assessments included adverse events, best corrected visual acuity, intraocular pressure, and slit-lamp findings., Results: Overall, 345 subjects, 172 TC and 173 CsA. TBUT improved at all time points in both groups (p<0.0001), with statistically greater improvement for TC versus CsA (p=0.0006). OSDI improved significantly at all time points in both groups (p<0.0001) with no significant differences between treatments. MGSS and other measures of meibomian gland function improved significantly more with TC eyes versus CsA; other secondary outcomes showed significant improvements in both groups with no difference between groups. Treatment-related adverse events were uncommon (10 total, 8 in the CsA group consistent with prior CsA studies); most (9/10) mild., Conclusion: TC provides statistically superior and sustained improvement in TBUT and multiple measures of meibomian gland secretion, and non-inferior improvement in OSDI, corneal and conjunctival staining, SANDE, EDS, and STS versus CsA. TC should be a preferred treatment for DED associated with MGD., Competing Interests: BA, MB, JL, TC, BS, JE, and SK were Investigators and received research support for the study. BA is a consultant for Allergan and Sight Sciences. MB is a consultant for and reports honoraria from Allergan and Sight Sciences. JL is a consultant for Allergan and Sight Sciences and reports personal fees from Sun Ophthalmics, Alcon, and Bausch and Lomb, outside the submitted work. TC reports grant support, consulting, and speaking for Sight Sciences. BS is a consultant and speaker for Sight Sciences and Allergan. SK is a consultant and speaker for Allergan and a consultant for Sight Sciences. VP reports consulting fees from Sight Sciences, grants from Alcon; stock options from Claris; grants, personal fees from Novartis; personal fees from Dompe, Oyster Point, Oculis, Novaliq, Sun Pharma, Quidel, BrightStar and Kala; stock options from Trefoil; personal fees, stock options from Kuria, outside the submitted work. JD and TR are employees of Sight Sciences. There are no other relevant conflicts., (© 2023 Ayres et al.)

Purpose: The aim of this study was to perform automated segmentation of corneal nerves and other structures in corneal confocal microscopy (CCM) images of the subbasal nerve plexus (SNP) in eyes with ocular surface diseases (OSDs)., Methods: A deep learning-based 2-stage algorithm was designed to perform segmentation of SNP features. In the first stage, to address applanation artifacts, a generative adversarial network-enabled deep network was constructed to identify 3 neighboring corneal layers on each CCM image: epithelium, SNP, and stroma. This network was trained/validated on 470 images of each layer from 73 individuals. The segmented SNP regions were further classified in the second stage by another deep network as follows: background, nerve, neuroma, and immune cells. Twenty-one-fold cross-validation was used to assess the performance of the overall algorithm on a separate data set of 207 manually segmented SNP images from 43 patients with OSD., Results: For the background, nerve, neuroma, and immune cell classes, the Dice similarity coefficients of the proposed automatic method were 0.992, 0.814, 0.748, and 0.736, respectively. The performance metrics for automatic segmentations were statistically better or equal as compared to human segmentation. In addition, the resulting clinical metrics had good to excellent intraclass correlation coefficients between automatic and human segmentations., Conclusions: The proposed automatic method can reliably segment potential CCM biomarkers of OSD onset and progression with accuracy on par with human gradings in real clinical data, which frequently exhibited image acquisition artifacts. To facilitate future studies on OSD, we made our data set and algorithms freely available online as an open-source software package., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To describe the long-term management of bilateral limbal stem cell deficiency secondary to a severe chemical burn., Methods: Descriptive case report., Importance: This case highlights the importance of early intervention in ocular chemical burns for the preservation of tissue integrity and avoidance of perforation. We also review the use of proper ocular surface reconstructive techniques to restore the function of the limbal area, as well as the immunomodulatory strategies and follow-up needed for these interventions.

Graft versus host disease (GVHD) remains a major and serious complication of allogeneic hematopoietic stem cell transplantation. Based on the time of onset, clinical phenotypes, progression kinetics, and pathophysiology, GVHD is stratified into acute, chronic, and overlapping types. The eyes are among the most commonly affected organs in GVHD. Mouse models have played an important role in understanding the several key elements of GVHD pathobiology. The current review discusses the immunology, pathology, and key phenotypic features of mouse models of systemic GVHD. Furthermore, a critical appraisal of mouse models of ocular GVHD (oGVHD) is provided. The disease mechanisms underlying the ocular surface, meibomian gland, and lacrimal gland injury in these models are reviewed, and the relevance of oGVHD murine models to clinical oGVHD is also included., Competing Interests: Declaration of competing interest Authors do not have any financial conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Surgically induced scleral necrosis (SISN) is an uncommon complication of ocular procedures. Cosmetic eye-whitening surgery involves conjunctival and Tenon's capsule dissection, cautery, and mitomycin C application. We report the case of a 36-year-old white woman referred to our clinic for severe pain, scleral inflammation, and necrosis in both eyes 9 years after I-BRITE, an elective eye-whitening procedure. An extensive workup yielded negative results. The patient improved with aggressive lubrication and topical and high-dose systemic prednisone (60 mg), with recurrence upon steroid tapering. Concomitant weekly methotrexate was added, resulting in inflammatory control and allowing discontinuance of topical and oral steroids., (Copyright ©2023. All rights reserved. Reproduction in whole or in part in any form or medium without expressed written permission of the Digital Journal of Ophthalmology is prohibited.)

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc -null cells. This proteomic screen confirmed EVC's main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2's Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies., Competing Interests: Author GM was employed by DBGen Ocular Genomics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Barbeito, Martin-Morales, Palencia-Campos, Cerrolaza, Rivas-Santos, Gallego-Colastra, Caparros-Martin, Martin-Bravo, Martin-Hurtado, Sánchez-Bellver, Marfany, Ruiz-Perez and Garcia-Gonzalo.)

Ocular surface disease (OSD), a disorder affecting the lacrimal and meibomian glands and the corneal and conjunctival epithelium, is a well-known complication of topical glaucoma therapy. OSD can present as a new or pre-existing condition that virtually any anti-glaucoma formulation can exacerbate. As such, both glaucoma and OSD frequently coexist. Typical OSD symptoms include ocular discomfort, redness, burning, and dryness, whereas signs include periorbital and eyelid skin pigmentation, conjunctival scarring, and superficial punctate keratitis. Pressure-lowering eyedrops can cause toxic, allergic, and inflammatory reactions on the ocular surface. The latter can result from either preservatives or direct toxicity from the active molecule. Although usually mild, OSD can cause significant symptoms that lead to poor quality of life, decreased compliance to therapy, glaucoma progression, and worse visual outcomes. Given the chronic nature of glaucoma, lack of curative therapy, and subsequent lifelong treatment, addressing OSD is necessary. This manuscript aims to provide an up-to-date overview of OSD's signs, symptoms, and pathogenic mechanisms from glaucoma therapy toxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ruiz-Lozano, Azar, Mousa, Quiroga-Garza, Komai, Wheelock-Gutierrez, Cartes and Perez.)

The cornea is a densely innervated avascular tissue showing exceptional inflammatory and immune responses. The cornea is a site of lymphangiogenic and angiogenic privilege devoid of blood and lymphatic vessels that limits the entry of inflammatory cells from the adjacent and highly immunoreactive conjunctiva. Immunological and anatomical differences between the central and peripheral cornea are also necessary to sustain passive immune privilege. The lower density of antigen-presenting cells in the central cornea and the 5:1 peripheral-to-central corneal ratio of C1 are two main features conferring passive immune privilege. C1 activates the complement system by antigen-antibody complexes more effectively in the peripheral cornea and, thus, protects the central corneas' transparency from immune-driven and inflammatory reactions. Wessely rings, also known as corneal immune rings, are noninfectious ring-shaped stromal infiltrates usually formed in the peripheral cornea. They result from a hypersensitivity reaction to foreign antigens, including those of microorganism origin. Thus, they are thought to be composed of inflammatory cells and antigen-antibody complexes. Corneal immune rings have been associated with various infectious and noninfectious causes, including foreign bodies, contact lens wear, refractive procedures, and drugs. We describe the anatomical and immunologic basis underlying Wessely ring formation, its causes, clinical presentation, and management., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The word "elective" refers to medications and procedures undertaken by choice or with a lower grade of prioritization. Patients usually use elective medications or undergo elective procedures to treat pathologic conditions or for cosmetic enhancement, impacting their lifestyle positively and, thus, improving their quality of life. However, those interventions can affect the homeostasis of the tear film and ocular surface. Consequently, they generate signs and symptoms that could impair the patient's quality of life. This report describes the impact of elective topical and systemic medications and procedures on the ocular surface and the underlying mechanisms. Moreover, elective procedures performed for ocular diseases, cosmetic enhancement, and non-ophthalmic interventions, such as radiotherapy and bariatric surgery, are discussed. The report also evaluates significant anatomical and biological consequences of non-urgent interventions to the ocular surface, such as neuropathic and neurotrophic keratopathies. Besides that, it provides an overview of the prophylaxis and management of pathological conditions resulting from the studied interventions and suggests areas for future research. The report also contains a systematic review investigating the quality of life among people who have undergone small incision lenticule extraction (SMILE). Overall, SMILE refractive surgery seems to cause more vision disturbances than LASIK in the first month post-surgery, but less dry eye symptoms in long-term follow up., Competing Interests: Declaration of competing interest José Alvaro P. Gomes: Alcon (F,C), Allergan (F,C), Johnson & Johnson (F,C), Latinofarma/Cristália (F,C), Ofta Vision Health/EMS (F,C), Bausch-Lomb (F), Novartis (C), Ophthalmos (C). Dimitri T. Azar: Twenty/Twenty Therapeutics (F,I,P,E). Christophe Baudouin: Horus Pharma (F,C), Pharma (F), Santen (F,C), Théa (F,C), Opia (P), Alcon (C), Allergan (C), Oculis (C), Aerie Pharmaceuticals (C). Etty Bitton: Johnson & Johnson Vision (F), I-Med Pharma (F), Shire (F,C), Valeant (F), Alcon (C), Aequus Pharmaceuticals (C), Brio (C), Labtician-Théa (C), Novartis (C), Snell Communications (C). Wei Chen: Santen (C). Farhad Hafezi: Light for Sight Foundation (F), Schwind Eye Tech Solutions (F), VELUX Foundation (F), Gelbert Foundation (F), SOOFT Italia (F), EMAGine AG (I), ELZA Institute (E), GmbH-Switzerland (C). Pedram Hamrah: Novartis (F,C), CooperVision (F), Dompé (F), Oyster Point Pharma (F,C), OKYO (F,C), Noveome (I,F,C), Eyegate Pharma (I,C), Clementia (C), Novaliq (C), Santen (C) Sanofi (C), Astra Zeneca (C), Ocunova (C), Neuroptika (C). Ruth E. Hogg: Okko Healthcare (F), Roche (C). Jutta Horwath-Winter: Bausch + Lomb (C), Allergan (C), CromaPharma (C), MC2 Therapeutics (C), Omnivision (C) Santen (C), Théa (C), TRB Chemedica (C), Ursapharma (C), Shire (C). Georgios A. Kontadakis: None. Jodhbir S. Mehta: UK Network Medical (P,R), Cordlife (P,R), Asia Genomics (P,R), Carl Zeiss Meditec (C), Ziemer (C), Moria (C), Santen (C). Elisabeth M. Messmer: Alcon/Novartis (C), Chiesi (F,C), DMg (C), Dompé (C), Kala (C), Novartis (C), Allergan (C), Santen(C), Shire (C), Sun (C), Sifi (C), Théa (C), TRB Chemedica (C), Ursapharma (C), Visufarma (C). Victor L. Perez: Alcon (F), Heat Biologics (F), Alcon (C), Aldyra (C), Dompé (C), Kala (C), Mallinkrodt (C), Novartis (C), Oculis (C). David Zadok: DiagnosTear Ltd (C), Precise-Bio (C). Mark D.P. Willcox: Alcon (F), Allergan (F), CooperVision (F), Johnson and Johnson Vision (F), Ophtecs (C,F)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: This epidemiologic study evaluates the variance in incidence of Herpes Zoster (HZ) and Herpes Zoster Ophthalmicus (HZO) within a single healthcare system with an aim to analyze their relationship to the COVID-19 pandemic., Methods: All patients attending the Duke University Health System (DUHS) from January 1, 2018, to December 31, 2021, were included. General and COVID-related trends of HZO and HZ were analyzed based on new ICD-9 or ICD-10 diagnosis codes, compared with the total number of patients seen at DUHS during this period, and the number of reported COVID-19 cases in North Carolina obtained using the CDC data tracker., Results: This study included 16,287 cases of HZ of whom 1,294 (7.94%) presented with HZO. The overall incidence of HZO showed an average yearly increase of 5.6%, however HZ incidence decreased by 5.3% per year. When comparing incidence rates of HZO in the 12-months before and after the COVID-19 pandemic onset in the United States (March 2020), the average incidence from March 2020 to February 2021 was 27.6 ± 11.6 compared to 18.0 ± 2.7 from March 2019 to February 2020 (p = 0.01). Moreover, 10/12 (83.3%) of the months had a higher incidence rate of HZO in the post-COVID onset year compared to their corresponding month in the pre-COVID year., Conclusion: The results show HZO incidence may be increasing, despite an overall lower HZ incidence. This could suggest a distinct mechanism for HZO appearance. The COVID pandemic, directly or indirectly, may have accelerated the already increasing HZO incidence., Competing Interests: Competing Interests: Financial Interests: Authors A through E declare they have no financial or commercial interests. Author F (V.L.P.) declares financial interests with Alcon, Asclepix, Azura, Dompe, Evolve by Nature, Kala, Kiora, Novartis, Oyster Point, Pelican Pharma, Sight Sciences, Sun Pharma.

Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Purpose: To investigate the role of aggressive meibomian gland dysfunction (MGD) in the immune pathogenesis of ocular graft-vs-host disease (GVHD)., Methods: In mice, an allogeneic GVHD model was established by transferring bone marrow (BM) and purified splenic T cells from C57BL/6J mice into irradiated C3-SW.H2b mice (BM+T). Control groups received BM only. Mice were scored clinically across the post-transplantation period. MGD severity was categorized using the degree of atrophy on harvested lids. Immune disease was analyzed using flow cytometry of tissues along with fluorescent tracking of BM cells onto the ocular surface. In humans, parameters from 57 patients with ocular GVHD presenting to the Duke Eye Center were retrospectively reviewed. MGD was categorized using the degree of atrophy on meibographs. Immune analysis was done using high-parameter flow cytometry on tear samples., Results: Compared with BM only, BM+T mice had higher systemic disease scores that correlated with tear fluid loss and eyelid edema. BM+T had higher immune cell infiltration in the ocular tissues and higher CD4+-cell cytokine expression in draining lymph nodes. BM+T mice with worse MGD scores had significantly worse corneal staining. In patients with ocular GVHD, 96% had other organs affected. Patients with ocular GVHD had abnormal parameters on dry eye testing, high matrix metalloproteinase-9 positivity (92%), and abundance of immune cells in tear samples. Ocular surface disease signs were worse in patients with higher MGD severity scores., Conclusions: Ocular GVHD is driven by a systemic, T-cell-dependent process that causes meibomian gland damage and induces a robust form of ocular surface disease that correlates with MGD severity. NOTE: Publication of this article is sponsored by the American Ophthalmological Society., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: The aim of this study was to identify characteristics of infectious keratitis predictive of poor outcome to develop a web-based predictive calculator., Method: A retrospective chart review was performed at the Duke Eye Center. Two hundred fifteen adult patients with culture-proven infectious keratitis presenting between January 1, 2016, and December 31, 2020, were separated into a derivation set (136 patients, 53 positives; 83 controls) and a temporal validation set (79 patients, 26 positives; 53 controls). The poor outcome group consisted of patients requiring penetrating keratoplasty for visually significant scarring, penetrating keratoplasty for ulcer progression, or evisceration/enucleation for endophthalmitis. Univariable analysis was performed followed by stepwise multivariable logistic regression to obtain a predictive model in the derivation data set. Culture-naïve and postculture models were constructed. Discrimination and calibration were assessed using the area under the curve (AUC) and calibration plots, respectively., Results: The culture-naïve model consisted of corticosteroid drop use postsymptom onset [Odds Ratio (OR) = 2.3, P = 0.054], decreased vision (OR = 2.4, P = 0.001), and increased ulcer area (OR = 1.017, P = 0.017). The postculture model additionally included fungal keratitis (OR = 5.4, P = 0.006) and elapsed time from symptoms to organism-sensitive therapy (OR = 1.027, P = 0.014). The models were summarized by the acronym C-DU(KE). The AUCs for the culture-naïve model were 0.794 in the derivation set and 0.850 in the validation set. The AUCs for the postculture model were 0.898 in the derivation set and 0.946 in the validation set. Calibration plots indicated goodness of fit in the data sets for both models. The calculator was deployed under the URL: https://duke-eye-calculator.shinyapps.io/Corneal&#95;Ulcers/ ., Conclusions: The C-DU(KE) calculator permits a data-driven prediction of outcome in infectious keratitis that can supplement clinical judgment., Competing Interests: V. L. Perez—Alcon, Dompe, EyeGate, Kala, Trefoil, Novartis, Oculis, National Institutes of Health/National Eye Institute R01EY030283 (V.L.P.) and R01EY024485 (V.L.P.), Duke NIH Center Core Grant, and Duke Research to Prevent Blindness Unrestricted Grant (V.L.P.). The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Inflammation is an important driver of dry eye disease (DED) pathogenesis. An initial insult that results in the loss of tear film homeostasis can initiate a nonspecific innate immune response that leads to a chronic and self-sustaining inflammation of the ocular surface, which results in classic symptoms of dry eye. This initial response is followed by a more prolonged adaptive immune response, which can perpetuate and aggravate inflammation and result in a vicious cycle of chronic inflammatory DED. Effective anti-inflammatory therapies can help patients exit this cycle, and effective diagnosis of inflammatory DED and selection of the most appropriate treatment are therefore key to successful DED management and treatment. This review explores the cellular and molecular mechanisms of the immune and inflammatory components of DED, and examines the evidence base for the use of currently available topical treatment options. These agents include topical steroid therapy, calcineurin inhibitors, T cell integrin antagonists, antibiotics, autologous serum/plasma therapy, and omega-3 fatty acid dietary supplements.

Riot Control Agents (RCAs) are chemical compounds used by law enforcement agencies to quell violent demonstrations as an alternative to lethal force and as part of police/military training. They are also known as tear gases because of the hallmark ocular irritation and lacrimation they cause. The most common RCAs include oleoresin capsicum (contained in Mace and pepper spray), chlorobenzylidene malononitrile, dibenzoxazepine, and chloroacetophenone (previously the main content of Mace); some of which have been in use for decades. Their immediate incapacitating effects are mediated through polymodal afferent fibers innervating the corneal surface, inducing the release of peptides that cause neurogenic inflammation. Although previously thought to have only transient effects on exposed patients more severe complications such as corneal stromal opacities, corneal neovascularization, neurotrophic keratopathy, conjunctival necrosis, and pseudopterygium can occur. Concerningly, the lack of research and specific therapies restrict the current management to decontamination and symptom-tailored support. This manuscript will provide an overview of the toxic mechanisms of RCAs, their clinical manifestations, and current therapy after exposure to tear gases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Quiroga-Garza, Ruiz-Lozano, Azar, Mousa, Komai, Sevilla-Llorca and Perez.)