Fazal O, Loya A, Muayad J
… +6 more, Alsoudi AF, Bordbar DD, Chaaya C, Weng CY, Rahimy E, Patel NA
Am J Ophthalmol
· 2026 Jun · PMID 42336230
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PURPOSE: Age-related macular degeneration (AMD) is a leading cause of central vision loss worldwide. Emerging evidence suggests that targeting dopaminergic pathways may influence AMD progression. This study evaluates whe...PURPOSE: Age-related macular degeneration (AMD) is a leading cause of central vision loss worldwide. Emerging evidence suggests that targeting dopaminergic pathways may influence AMD progression. This study evaluates whether levodopa ± carbidopa or dopamine receptor D2 (DRD2) agonists are associated with reduced risk of conversion to neovascular AMD (nAMD). DESIGN: Population-based clinical cohort study. PARTICIPANTS: Adults aged ≥18 years diagnosed with non-neovascular AMD between May 2005 and May 2025, within the TriNetX U.S. Collaborative Network, a federated electronic health record database spanning 69 healthcare organizations. METHODS: This retrospective cohort study emulated four distinct target trials comparing new users of (1) levodopa (± carbidopa) or (2) DRD2 agonists (pramipexole, ropinirole, bromocriptine, rotigotine, or cabergoline) to new users of two comparators (pantoprazole or gabapentin). Patients with prior nAMD or prescriptions of other dopamine-enhancing agents (e.g., selegiline, rasagiline, tolcapone) were excluded. Each exposure group was independently matched to comparators using 1:1 propensity score matching for selected demographics, social factors, comorbidities, and AMD stage. MAIN OUTCOME MEASURES: The primary outcome was 3-year risk of conversion from non-neovascular AMD to nAMD. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. An α level of 0.05 was used to determine statistical significance. RESULTS: Patients prescribed levodopa ± carbidopa had a reduced 3-year risk of conversion to nAMD relative to their matched counterparts prescribed pantoprazole (levodopa n=1312, control n=1312; HR 0.67; 95% CI, 0.45-0.98) and gabapentin (levodopa n=1675, control n=1675; HR 0.69; 95% CI, 0.50-0.95). No significant difference was observed in 3-year risk of conversion to nAMD between DRD2 agonists use relative to pantoprazole (DRD2 n=1603, control n=1603; HR 0.81; 95% CI, 0.58-1.13) or gabapentin (DRD2 n=2779, control n=2779; HR 0.92; 95% CI, 0.72-1.19). CONCLUSIONS: In this cohort study, levodopa ± carbidopa use was associated with lower 3-year risk of conversion to nAMD in two independent matched comparisons, whereas DRD2 agonists were not associated with significant differences in risk. These findings suggest dopaminergic signaling may influence AMD progression and warrant further prospective investigation.
Schulgit MJ, Bala S, Bellanda V
… +7 more, Mohan N, Arline A, Kaelber DC, Lin P, Mammo DA, Srivastava SK, Sharma S
Am J Ophthalmol
· 2026 Jun · PMID 42336229
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OBJECTIVE: To evaluate the association between vaccination and the risk of new-onset idiopathic uveitis (NIU). DESIGN: Retrospective cohort study of aggregated electronic health records from multiple health systems acros...OBJECTIVE: To evaluate the association between vaccination and the risk of new-onset idiopathic uveitis (NIU). DESIGN: Retrospective cohort study of aggregated electronic health records from multiple health systems across the United States. SUBJECTS: Subjects who received the coronavirus disease 2019 (COVID-19), human papilloma virus (HPV), varicella, recombinant herpes zoster, or live herpes zoster vaccinations from 2006 to 2025 and propensity-score matched controls. INTERVENTION: Vaccines against COVID-19, HPV, varicella, recombinant herpes zoster, or live herpes zoster. MAIN OUTCOMES AND MEASURES: The main outcome was the incidence of NIU at 3-, 6-, and 12-months following vaccination. Vaccinated patients were compared with matched controls who did not receive the respective vaccines. Analyses were repeated excluding patients with previous diagnosis of the respective viral infection. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated for overall NIU and constituent subtypes (anterior, intermediate, posterior, and panuveitis). RESULTS: All tested vaccinations were associated with reduced risk of NIU through 12 months compared with matched controls. Relative risk reductions were 65% for COVID-19 (RR, 0.35; CI, 0.33-0.37), 56% for HPV (RR, 0.44; CI, 0.35-0.54), 71% for varicella (RR, 0.29; CI, 0.25-0.33), 68% for live zoster (RR, 0.32; CI, 0.23-0.43), and 69% for recombinant zoster vaccination (RR, 0.31; CI, 0.26-0.37). Similar reductions were observed after excluding patients with prior diagnoses of the respective viral infections. CONCLUSIONS: Vaccination was associated with a lower risk of idiopathic uveitis, representing the complex interplay between immune modulation and the development of NIU.
Gou D, Qiu W, Chang V
… +8 more, Weiler L, Mihalache A, Balas M, Ahmed Y, Alsarhani WK, Tao BK, Teichman JC, Popovic MM
Am J Ophthalmol
· 2026 Jun · PMID 42331129
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TOPIC: This systematic review and meta-analysis evaluated the literature-pooled association between statins and dry eye disease (DED). CLINICAL RELEVANCE: Statins, a common treatment modality for dyslipidemia, have been...TOPIC: This systematic review and meta-analysis evaluated the literature-pooled association between statins and dry eye disease (DED). CLINICAL RELEVANCE: Statins, a common treatment modality for dyslipidemia, have been proposed as a potential contributor to DED via their activity in meibomian gland epithelial cells. However, single studies show mixed evidence, and there remains an unmet clinical need to clarify whether statin exposure is associated with DED. METHODS: This review was reported in accordance with the Preferred Reporting Items for Systematic Reviews of Interventions (PRISMA) 2020 statement and was registered a priori on PROSPERO (CRD420251238004). Ovid MEDLINE, Embase, CINAHL, Web of Science, CENTRAL, and the reference lists of relevant reviews were searched from inception to November 2025 for studies reporting the association between statin use and DED. Random-effects meta-analysis using inverse-variance weighting was conducted to pool effect estimates as odds ratios (ORs) with 95% confidence intervals (CIs). Study risk of bias was appraised using the ROBINS-E tool and the certainty of the evidence was reported using the GRADE framework. RESULTS: Six observational studies were included in the meta-analysis (n = 560,821; 356,012/559,141 [63.7%] statin users). The pooled analysis revealed a significant positive association between statins and DED (OR 1.09, 95% CI 1.05 to 1.13, p < 0.001), with an absolute risk difference of 10.2 more DED cases per 1,000 (95% CI 5.5 more to 15.2 more). This result was derived from very low certainty evidence given limitations in study design and serious inconsistency. Subgroup and sensitivity analyses for risk of bias (p = 0.123), method of outcome ascertainment (p = 0.737), type of effect estimate (p = 0.496), and leave-one-out analyses showed no evidence of effect modification and demonstrated consistent direction of association across studies. CONCLUSION: Statin use was associated with a small but statistically significant increase in DED, limited by very low certainty evidence. Physicians should monitor for and educate patients on ocular surface symptoms in patients using statins with pre-existing DED risk factors. Future studies should use standardized DED diagnostic criteria to investigate the impact of statin dose, type, and duration to better characterize this potential association.
Zhou C, Shen Y, Li S
… +28 more, Li Y, Li X, Yang X, Xu Y, Wang X, Yang Q, Sun D, Zhang W, Li S, Zhang H, Lv H, Ma X, Yu H, Song Z, Zhang T, Yu X, Liu Y, Niu T, Yuan R, You Z, Liu Q, Song Y, Cao N, Zhu D, Sun X, Zheng Z, Liu K, Xu X
Am J Ophthalmol
· 2026 Jun · PMID 42331128
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PURPOSE: To describe the visual and anatomical changes after restarting anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema (DME) who returned with stabilized vision after being...PURPOSE: To describe the visual and anatomical changes after restarting anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema (DME) who returned with stabilized vision after being lost to follow-up (LTFU), and to explore the distinct predictors of clinical benefits upon retreatment. DESIGN: Retrospective clinical cohort study. METHODS: In this study, 976 patients who returned after being LTFU for ≥6 months were included. All participants had center-involved DME, and presented with visual acuity (VA) <20/25 and central foveal thickness (CFT) ≥250μm. VA and CFT were assessed before being LTFU, at return, and after retreatment. Patients were stratified into two groups: (I) Patients who returned with stabilized VA (the first VA upon returning was equal to or better than the last recorded VA prior to being LTFU), and (II) Patients who returned with vision decline (the first VA upon returning was worse than the last recorded VA prior to being LTFU). RESULTS: After a median LTFU period of 259 days, 447 patients (45.8%) had stabilized VA, and 529 patients (54.2%) had vision decline. With similar follow-up periods (361 days vs 356 days, p=0.590) after anti-VEGF reinitiation, visual gain was obtained in 32.7% of patients with stabilized VA, significantly lower than in those with vision decline (62.0%, p<0.001). Consistently, CFT reduction by ≥10% was achieved in 56.4% of patients with stabilized vision and in 63.2% of those with decreased vision (p=0.038) over similar follow-up periods (377 days vs 361 days, p=0.375). Multivariate logistic regression analysis indicated that the odds of visual (OR=0.29, 95% CI:0.22-0.38, p<0.001) and anatomical (OR=0.78, 95%CI: 0.59-1.02, p=0.073) improvements were lower in patients who returned with stabilized VA, but increased with more anti-VEGF injections administered during retreatment (both p<0.001). Notably, patients presenting with stabilized VA of 20/50 or better did not obtain vision gain after retreatment despite anatomical improvement. CONCLUSION: Patients who returned with stabilized vision exhibited suboptimal visual and anatomical responses to anti-VEGF retreatment. Those with VA of 20/50 or better did not improve sufficiently in vision despite anatomical improvements. The decision to readminister anti-VEGF therapy in patients returning with stabilized moderate-to-good vision should be weighed carefully, and alternative or combination therapies may be warranted.
Heur M, Brabletz S, Stemmler MP
… +2 more, Brabletz T, Lee J
Am J Ophthalmol
· 2026 Jun · PMID 42323978
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PURPOSE: To investigate the role of Zeb1 in regulating fibrosis in endothelial mesenchymal transition in the cornea. siRNA knockdown of Zeb1 inhibits FGF2-induced mesenchymal transition in the corneal endothelium. Endoth...PURPOSE: To investigate the role of Zeb1 in regulating fibrosis in endothelial mesenchymal transition in the cornea. siRNA knockdown of Zeb1 inhibits FGF2-induced mesenchymal transition in the corneal endothelium. Endothelial cells that undergo mesenchymal transition show increased expression of endothelial-mesenchymal transition associated genes, including COL1, fibronectin and vimentin, and decreased expression of E-cadherin, leading to fibrous retrocorneal membrane formation. METHODS: To address potential off-target effects of siRNA knockdown, Zeb1:UBC-CreERT2 mouse was generated to allow for spatiotemporal control of Zeb1 targeting and studying the role of Zeb1 in the corneal endothelium in vivo. RESULTS: Intracameral injection of 4-hydroxytamoxifen (4-OHT) inhibited Fgf2-induced expression of Zeb1 mRNA and protein in the corneal endothelium of Zeb1:UBC-CreERT2 mouse. Fgf2 and surgical injury-dependent expression of mesenchymal transition-related genes and suppression of E-cadherin were inhibited by conditional targeting of Zeb1 in the mouse corneal endothelium in vivo. Surgical injury led to corneal edema with a central corneal thickness of 189.0 ± 14.6um (injury) vs 92.3 ± 2.8um (control), and injury-induced edema was significantly attenuated by Zeb1 targeting in the corneal endothelium with a central corneal thickness of 182.2 + 15.5um (injury) vs 106.8 ± 11.1um (injury + 4-OHT), F = 120.9, p < 0.00001. Moreover, conditional targeting of Zeb1 also inhibited injury-dependent RCM formation in the mouse corneal endothelium in vivo. CONCLUSION: These results suggest that ZEB1 signaling could be targeted for inhibiting retrocorneal membrane formation and anterior segment fibrosis, and could be leveraged to treat certain forms of corneal blindness without relying on transplantation.
Am J Ophthalmol
· 2026 Jun · PMID 42323976
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PURPOSE: Low systemic blood pressure (BP) has been implicated as a risk factor for glaucoma progression. The purpose of this study was to investigate the association between 24-hour BP and rates of retinal nerve fiber la...PURPOSE: Low systemic blood pressure (BP) has been implicated as a risk factor for glaucoma progression. The purpose of this study was to investigate the association between 24-hour BP and rates of retinal nerve fiber layer (RNFL) loss in eyes with primary open-angle glaucoma (POAG). DESIGN: Prospective cohort study. PARTICIPANTS: Seventy-nine eyes from 42 subjects with glaucoma (mean age, 68.5 ± 7.6 years) enrolled in the Vascular Imaging in Glaucoma Study at the Bascom Palmer Eye Institute. METHODS: Participants underwent 24-hour ambulatory BP monitoring (ABPM) at baseline. Follow-up evaluations were conducted at 4-month intervals and included ophthalmic examination, BP measurement, and peripapillary retinal nerve fiber layer (RNFL) thickness measurement with spectral-domain optical coherence tomography (OCT). The association between BP and RNFL loss over time was assessed using linear mixed-effects models adjusted for age, sex, race, baseline RNFL thickness, central corneal thickness, and IOP. MAIN OUTCOME MEASURES: The effect of baseline 24-hour mean arterial pressure (MAP), systolic BP (SBP), and diastolic BP (DBP) on the rate of average RNFL loss over time. RESULTS: Eyes underwent an average of 13 ± 3 OCT exams over 43 ± 10 months of follow-up. The mean rate of RNFL loss was -0.34 ± 0.64 µm/year (median: -0.32; interquartile range: -0.66 to -0.04 µm/year). After adjusting for confounding factors, every 10 mmHg lower in 24-hour minimum MAP, SBP, and DBP was associated with -0.542 µm/year (P < 0.001), -0.360 µm/year (P = 0.003), and -0.458 µm/year (P = 0.008) faster RNFL loss, respectively. Eyes in the lowest quartile of average 24-hour MAP (81-90 mmHg) and minimum 24-hour DBP (35-47 mmHg) experienced significantly faster progression compared to those in the highest quartile, with differences of -0.68 µm/year (P = 0.017) and -0.63 µm/year (P = 0.030), respectively. CONCLUSIONS: Lower systemic BP, especially minimum MAP, SBP, and DBP measured by 24-hour ABPM, is associated with faster rates of RNFL loss in POAG eyes. 24-hour BP monitoring may help predict glaucoma patients at greater risk of progression.
Xavier JJ, Reed JHA, Bahierathan KS
… +3 more, Kim SB, Talcott KE, Singh RP
Am J Ophthalmol
· 2026 Jun · PMID 42320617
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OBJECTIVE: To determine the predictive value of the Charlson Comorbidity Index (CCI) for outcomes in patients with macular edema secondary to retinal vein occlusion (RVO). DESIGN: Retrospective clinical cohort study. SUB...OBJECTIVE: To determine the predictive value of the Charlson Comorbidity Index (CCI) for outcomes in patients with macular edema secondary to retinal vein occlusion (RVO). DESIGN: Retrospective clinical cohort study. SUBJECTS: Patients seen between 2013-2023 at the Cole Eye Institute, Cleveland Clinic, were included. All patients were >18, diagnosed with RVO (ICD-9 and 10 codes), had a complete CCI score, and had at least one year of ophthalmic follow-up data after their first intravitreal injection (baseline). Patients with ocular surgery, trauma, or panretinal photocoagulation were excluded. METHODS: Age-adjusted CCI scores were calculated for each patient from chart review. For patients with bilateral RVO, one eye was selected randomly. Patients were stratified into tertiles by CCI distribution: tertile 1 (CCI 0-5; mean 3.4), tertile 2 (age-CCI 4.1-6; mean 4.9), and tertile 3 (CCI ≥ 8; mean 9.6). Multivariable linear regression was performed to determine the predictive value of CCI and other covariates on visual and anatomical outcomes. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) and central subfield thickness (CST) at one-year follow-up. RESULTS: A total of 972 patients met all criteria, with an average age-adjusted CCI score of 6.2. Each one-point increase in CCI predicted 0.38 fewer letters in BCVA at follow-up (p < 0.001). Baseline BCVA was a significant predictor of follow-up BCVA in all tertiles (p < 0.001). In the third tertile, each one-point increase in CCI was associated with a 0.72 letter reduction in follow-up BCVA (p <0.001). For CST, baseline CST was strongly predictive of final CST (p < 0.001), while CCI was only significant in the first tertile, where each point increase in CCI predicted a 13.7µm increase in CST (p = 0.02). In RVO subtype interaction models, the age-adjusted CCI × CRVO interaction was not statistically significant for either 1-year BCVA (p = 0.269) or 1-year CST (p = 0.695). CONCLUSION: Higher CCI scores are significantly associated with worse visual outcomes in patients with RVO, particularly in the combined population (CP) and most comorbid patients (Tertile 3). CCI was significantly associated with higher (thicker) CST only among the least comorbid patients (tertile 1).
Qin Y, Qin L, Zhao X
… +3 more, Ding Y, Liu L, Wu M
Am J Ophthalmol
· 2026 Jun · PMID 42320616
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PURPOSE: To evaluate the accuracy of modern intraocular lens (IOL) power calculation formulas and axial length (AL) adjustment methods in eyes with AL ≥ 30.0 mm. DESIGN: Retrospective consecutive cross-sectional study. P...PURPOSE: To evaluate the accuracy of modern intraocular lens (IOL) power calculation formulas and axial length (AL) adjustment methods in eyes with AL ≥ 30.0 mm. DESIGN: Retrospective consecutive cross-sectional study. PARTICIPANTS AND CONTROLS: A total of 308 eyes (308 patients) with AL≥30.00 mm were included. METHODS: Accuracy of modern online formulas, alone or with established AL adjustments methods, was analyzed. Subgroup analyses were performed based on AL, keratometry (K), anterior chamber depth (ACD), lens thickness (LT), and AL-to-corneal radius (AL/R) ratio. MAIN OUTCOME MEASURES: Predictive accuracy was evaluated using the formula performance index (FPI), root mean square absolute prediction error (RMSAE), standard deviation (SD) of prediction error (PE), and percentage of eyes within ± 0.25 and ± 0.50 diopters (D). RESULTS: Overall, Holladay 1 combined with the non-linear polynomial Wang-Koch axial length adjustment (H1-PWK) demonstrated the best overall performance, achieving the lowest SD (0.40), RMSAE (0.40), and highest FPI (0.494). A tendency toward hyperopic error was observed in eyes with AL ≥ 32.0 mm, K ≥ 46.0 D. The AL/R ratio showed a significant positive correlation with PE in the Ladas Super formula, Barrett Universal II, EVO, PEARL-DGS, and Hoffer QST formulas. Spline-based regression analysis indicated that the transition point of AL/R from myopic to hyperopic PE varied across different formulas. CONCLUSIONS: H1-PWK provides robust refractive accuracy in extremely long eyes. The AL/R ratio may provide a useful composite biometric stratification parameter compared to AL alone.
Moshiri A, Kasiri N, Shea M
… +39 more, Ali L, Yang B, Shao A, Clary D, Flenniken AM, Eskandarian M, Amarie OV, Becker L, Sangermano R, Place EM, Bujakowska KM, Huckfeldt RM, Berberovic Z, Bour R, Riet F, Brown SD, D'Souza A, Fuchs H, Gailus-Durner V, Guimond A, Hérault Y, de Angelis MH, Lux A, Mittelhauser C, Nutter LMJ, Palkova M, Lindovsky J, Petit-Demouliere B, Prochazka J, Bradaschia V, Kelsey L, McKerlie C, Raishbrook MJ, Sedlacek R, International Mouse Phenotyping Consortium, Lanoue L, Lloyd KK, Roux MJ, Bermingham-McDonogh O
Am J Ophthalmol
· 2026 Jun · PMID 42309414
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PURPOSE: The purpose of this project was to identify novel Usher syndrome (USH) candidate genes from phenotyping data of 9,139 knockout (KO) mouse lines. METHODS: We evaluated phenotype data for concurrent retinopathy an...PURPOSE: The purpose of this project was to identify novel Usher syndrome (USH) candidate genes from phenotyping data of 9,139 knockout (KO) mouse lines. METHODS: We evaluated phenotype data for concurrent retinopathy and hearing abnormalities in single-gene KO mice generated by the International Mouse Phenotyping Consortium (IMPC). A search was performed to determine if each gene had been previously established in retinopathy and/or deafness in humans. Bioinformatic tools were used to predict protein interactions, molecular functions, signaling pathways, and expression of human orthologs of candidate genes in retina and inner ear. RESULTS: We identified 18 single-gene KO lines exhibiting hearing abnormality and retinopathy after ear and eye examination, respectively, and/or by histopathology. The molecular functions and signaling pathways of the human orthologues of 18 candidate genes partially overlapped with USH genes. Particularly, FER and DYRK1B proteins were predicted to interact with proteins encoded by known ciliopathy genes. ADIPOR1, ATP8B1 and MPDZ were associated with retinal degeneration in humans. CHSY1 and IDUA may be a pathogenic cause of hearing impairment in people. Additionally, CHSY1, CSTB and SPRED1 were located adjacent to unsolved genetic loci related to USH. CONCLUSIONS: A screen of 9,139 KO mouse lines revealed 18 candidate genes exhibiting both retinal and inner ear abnormality consistent with principle clinical features associated with USH. As the observed phenotypes are attributed to gene deletion in mice, these genes warrant further study to determine causation of retinal degeneration and hearing loss in patients.
Am J Ophthalmol
· 2026 Jun · PMID 42303065
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PURPOSE: To review history of Descemet Stripping Only (DSO) in Fuchs Endothelial Corneal Dystrophy (FECD), describe the results of a clinical trial of topical ripasudil after DSO (K-321-201 study), and discuss future dir...PURPOSE: To review history of Descemet Stripping Only (DSO) in Fuchs Endothelial Corneal Dystrophy (FECD), describe the results of a clinical trial of topical ripasudil after DSO (K-321-201 study), and discuss future directions. METHODS: A one-year, phase 2, randomized, placebo-controlled multicenter clinical trial of two doses of K-321 (ripasudil) administered for 12 weeks after DSO surgery in FECD was performed. The primary endpoint, central corneal endothelial cell density (ECD) at 12 weeks after surgery, was determined by an independent reading center that was masked to study group assignment. Duration of corneal edema, need for medical or surgical rescue therapy, corneal thickness, and central ECD throughout the entire study period were also examined. Adverse events and exploratory endpoints were collected. RESULTS: Sixty-five subjects were enrolled (21 in the QID group, 22 in the BID and in the placebo groups). Over 95% of subjects completed the trial. The QID group had a higher central ECD 12 weeks after DSO than the placebo group (531±312 cells/mm vs. 228±298 cells/mm,P=.0065). Corneal edema cleared in 17/21 (81.0%) of the QID group at 12 weeks, compared with 2/22 (9.1%) of the placebo group (P<.0001). Rescue was required in 2/21 (9.5%) subjects in the QID group and 6/22 (27.3%) subjects in the placebo group (P=.0092). Adverse events were mild and did not lead to discontinuation of treatment. CONCLUSIONS: Topical K-321 given QID improves DSO outcomes, as demonstrated by a higher ECD, more rapid resolution of corneal edema and reduced failure rate. The medication was well-tolerated.