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María Dolores Pinazo-Durán,1,* Roberto Gallego-Pinazo,2,* Jose Javier García-Medina,1,3,* Vicente Zanón-Moreno,1,4 Carlo Nucci,5 Rosa Dolz-Marco,2 Sebastián Martínez-Castillo,2 Carmen Galbis-Estrada,1 Carla Marco-Ramírez,1 Maria Isabel López-Gálvez,6,* David J Galarreta,6,* Manuel Díaz-Llópis4,*1Ophthalmic Research Unit "Santiago Grisolía", Valencia, Spain; 2Department of Ophthalmology, Macula Section, The University and Polytechnic Hospital La Fe, Valencia, Spain; 3Department of Ophthalmology, University Hospital Reina Sofia, Murcia, Spain; 4Faculty of Medicine, University of Valencia, Spain; 5University of Rome Tor Vergata, Rome, Italy; 6Instituto de Oftalmobiología Aplicada (IOBA), Valladolid, Spain *Members of the Spanish Net of Ocular Pathology of the Instituto de Salud Carlos III (Madrid), OFTAREDBackground: Oxidative stress (OS) and its biomarkers are the biochemical end point of the imbalance between reactive oxygen species (ROS) production and the ability of the antioxidant (AOX) biological systems to fight against oxidative injury.Objective: We reviewed the role of OS and its downstream signaling in aging eyes.Methods: A search of the literature and current knowledge on the physiological and pathological mechanisms of OS were revisited in relation to the eyes and the aging process. Most prevalent ocular diseases have been analyzed herein in relation to OS and nutraceutic supplements, such as dry-eye disorders, glaucoma, age-related macular degeneration, and diabetic retinopathy.Results: Clinical, biochemical, and molecular data from anterior and posterior eye segment diseases point to OS as the common pathogenic mechanism in the majority of these ocular disorders, many of which are pathologies causing visual impairment, blindness, and subsequent loss of life quality. Studies with nutraceutic supplements in aging eye-related pathologies have also been reviewed.Conclusion: OS, nutritional status, and nutraceutic supplements have to be considered within the standards of care of older ophthalmologic patients. OS biomarkers and surrogate end points may help in managing the aging population with ocular diseases.Keywords: oxidative stress, eyes, aging, ophthalmic diseases, antioxidants, epidemiology

Ester Carreño1, Alejandro Portero2, David J Galarreta1,3, José M Herreras1,31Ocular Immunology Unit-IOBA (Instituto Universitario de Oftalmobiología), University of Valladolid, Campus Miguel Delibes, Valladolid, Spain; 2Ocular Immunology Unit, Hospital La Zarzuela, Madrid, Spain; 3Ocular Immunology Unit, Hospital Clínico Universitario de Valladolid, Valladolid, SpainAbstract: Ophthalmic bromfenac sodium sesquihydrate is a topically applied selective cyclooxygenase (COX)-2 inhibitor. It is similar to amfenac, except for a bromine atom at the C4 of the benzoyl ring position, which markedly affects its in vitro and in vivo potency, extends the duration of anti-inflammatory activity, and enhances its inhibitory effect on COX-2 absorption across the cornea and penetration into ocular tissues. The United States Food and Drug Administration approved bromfenac in 2005 for the treatment of postoperative inflammation and the reduction of ocular pain in patients who have undergone cataract surgery. Nonsteroidal anti-inflammatory drugs (NSAIDs), and among them bromfenac, could be even more effective than steroids at reestablishing the blood–aqueous barrier, as revealed by flare on slit-lamp examination and as quantitatively measured using ocular fluorophotometry. Similar to other NSAIDs, it has a role in inhibiting intraoperative miosis during cataract surgery. However, bromfenac also seems to be useful in other situations, such as refractive surgery, allergic conjunctivitis (not useful in dry eye), choroidal neovascularization, and even ocular oncology. No reports of systemic toxicity have been published and bromfenac has good topical tolerance with a low incidence of adverse effects.Keywords: bromfenac, ophthalmic nonsteroidal anti-inflammatory drugs, inflammation, cataract surgery

Purpose: Keratoconus affects patients' quality of life. No study has assessed the multivariate determinants of quality of life using the keratoconus end points assessment questionnaire (KEPAQ)., Methods: This study included patients with keratoconus with no history of ocular surgery, who underwent clinical evaluation and tomographic imaging using a dual Scheimpflug/Placido device (Galilei G6). Emotional and functional quality of life was assessed using the KEPAQ. Multiple linear regression models were constructed for each KEPAQ subscale to adjust for confounding variables., Results: A total of 140 surgery-naïve patients with keratoconus were included, with a median age of 39 years and a male predominance (57.1%). For the KEPAQ-E subscale, the multivariate model was significant [F(84,10) = 2.79; adjusted R2 = 0.160, P = 0.005], showing that female sex (β = -0.41) and worse corrected distance visual acuity in the better-seeing eye (β = -0.29) were associated with lower quality of life. Including the functional subscale score significantly enhanced the model's performance (adjusted R2 = 0.464, β = 0.60). For the KEPAQ-F subscale, the model was also significant [F(84,10) = 2.37; adjusted R2 = 0.127, P = 0.016], with corneal astigmatism in the better-seeing eye (β = -0.30) reducing quality of life. Adding the emotional subscale score improved the model (adjusted R2 = 0.442, β = 0.62)., Conclusions: Female sex, reduced vision, and corneal astigmatism negatively affect quality of life in patients with keratoconus. Nonetheless, patients' perceived impairment as measured in 1 subscale is a stronger predictor of overall quality of life than clinical and tomographic factors alone., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To carry out a methodologically complete validation of the Spanish version of the Keratoconus End-Points Assessment Questionnaire (KEPAQ) in a Spanish population with keratoconus., Methods: Analytical, prospective study, including patients with keratoconus without previous surgical history, in which a measurement of quality of life was performed using the KEPAQ questionnaire, a complete exploration of the anterior pole and a corneal elevation topography with the Galilei G6 topographer. The evaluation of the psychometric characteristics of the scale in the studied population was carried out using Rasch modeling., Results: A total of 140 patients with keratoconus were included, with a median age of 26.0 years, the majority (57.6%) being men. For the KEPAQ-E subscale, the median score was 69.3, with a reliability of 0.85 and an eigenvalue of the first contrast of 2.34. For the KEPAQ-F, the median score was 56.4, with a reliability of 0.88 and an eigenvalue of 2.00. All infit and outfit parameters were within normal limits for both subscales. A significant evaluation was found between the evaluations of both subscales (rho = 0.696; p < 0.001). The evaluations of the subscales and various clinical and tomographic characteristics showed a significant classification between them (p value between 0.048 y 0.001)., Conclusion: The KEPAQ is a psychometrically robust and valid scale to evaluate quality of life in the Spanish population with keratoconus. This questionnaire can be easily used for both clinical and research aims., (Copyright © 2024 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Keratoconus (KC) is a corneal ectasia characterized by structural changes, resulting in progressive thinning and biomechanical weakening that can lead to worsening visual acuity due to irregular astigmatism. Corneal collagen Crosslinking (CXL) and Intracorneal Ring Segment (ICRS) are widely used treatments in KC disease, but the alterations they cause in biomechanical mediators are still poorly understood. The aim of this study was to analyze the tear proteome profile before and after treatments to identify biomarkers altered by surgery., Materials and Methods: An observational, prospective, case-control pilot study was conducted, analyzing tear samples from KC patients by nano-liquid chromatography-mass spectrometry (nLC-MS/MS). Data are available via ProteomeXchange with identifier PXD035655. Patients with KC who underwent ICRS surgery ( n = 4), CXL ( n = 4), and healthy subjects (Ctrl, n = 4) were included in this study. Clinical parameters were measured and tear samples were collected before and 18 months after surgery. Proteins with ≥2 expression change and p -value < 0.05 between groups and times were selected to study their role in post-operative corneal changes., Results: These analyses led to the identification of 447 tear proteins, some of which were dysregulated in KC patients. In comparisons between the two surgical groups and Ctrls, the biological processes that were altered in KC patients at baseline were those that were dysregulated as a consequence of the disease and not of the surgical intervention. Among the biological processes seen to be altered were: immune responses, cytoskeleton components, protein synthesis and metabolic reactions. When comparing the two treatment groups (ICRS and CXL), the process related to cytoskeleton components was the most altered, probably due to corneal thinning which was more pronounced in patients undergoing CXL., Conclusion: The changes observed in tears after 18 months post-operatively could be due to the treatments performed and the pathology. Among the deregulated proteins detected, A-kinase anchor protein 13 (AKAP-13) deserves special attention for its involvement in corneal thinning, and for its strong overexpression in the tears of patients with more active KC and faster disease progression. However, it should be kept in mind that this is a pilot study conducted in a small number of patients., 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 © 2022 Goñi, Martínez-Soroa, Ibarrondo, Azkargorta, Elortza, Galarreta and Acera.)

Purpose: The keratoconus end-points assessment questionnaire (KEPAQ) is a disease-specific scale designed to evaluate the quality of life in keratoconus patients and provides the measurement of both functional and emotional compromise in keratoconus. It was previously developed, tested, and validated and now we want to evaluate the test-retest reliability of the KEPAQ, in an effort to contribute evidence on its internal consistency and capability of measuring clinical state with minimal inference of random chance., Methods: This is a prospective analytical study, designed to evaluate the test-retest reliability of the KEPAQ through the repeated application of the questionnaire to a group of clinically stable individuals. A number of patients with a confirmed diagnosis of keratoconus underwent double application of the KEPAQ, seven days apart. Mean KEPAQ score was obtained through Rasch analysis, while test-retest reliability was evaluated through Spearman rank-order correlation and intraclass correlation coefficient. Rasch analysis was performed in JMetrik version 4.1.1 (Psychomeasurement Systems LLC; Charlottesville, VA, USA) in a MacBook Air computer running macOS Catalina version 10.15.2 (Apple Inc.; Cupertino, CA, USA)., Results: A total of 100 patients were included. For KEPAQ-E, Spearman correlation was R = 0.963 while ICC was 0.981 (95% confidence interval 0.972-0.987). For KEPAQ-F, Spearman correlation was R = 0.921 while ICC was 0.952 (95% confidence interval 0.929-0.968)., Conclusion: The KEPAQ is a robust, well-developed, extremely reliable scale which can be confidently used for clinical and research endeavors., Competing Interests: None

Purpose: To study corneal innervation in eyes with history of herpetic keratitis and its correlation with corneal sensitivity and biomechanical properties., Methods: A total of 56 eyes were included, of which 16 had a history of unilateral immune stromal herpetic keratitis, 16 were their contralateral eyes, and 20 were healthy controls. Structural analysis of corneal nerve plexus was performed by confocal microscopy. Biomechanical properties were measured with the Ocular Response Analyzer. Corneal sensitivity was assessed by contact (Cochet-Bonnet) and non-contact (Belmonte) esthesiometry., Results: The eyes with a history of herpetic keratitis had reduced sensitivity for mechanical stimuli when compared to healthy eyes (1441.88 ± 83 ml/min vs. 67.9 ± 7.86 ml/min). Nerve fiber density in the corneas with a history of herpetic disease was lower (4.13 ± 2.19 U/image) than in the contralateral eyes (7.44 ± 2.9 U/image, p value = 0.01) and than in healthy controls (10.35 ± 2.01, p value < 0.0001). The best structural and functional correlation was established between the total length of nerves per section and mechanic threshold assessed by Belmonte esthesiometer (Coef. -0.58 p value < 0.0001) and between total length of nerves and corneal resistance factor (CRF) (Coef. -0.64, p value < 0.0001)., Conclusions: The corneal sensitivity impairment in eyes with immune stromal herpetic keratitis can be explained by the loss of nerve fibers. Biomechanical corneal properties are affected as well. Corneal hysteresis (CH) and CRF are lower for the eyes with a history of herpetic keratitis, and also for the contralateral eye when compared to healthy controls.

Purpose: To evaluate and compare the efficacy of a lipid-based lubricant eyedrop formulation (hydroxypropyl guar/propylene glycol/phospholipid [HPG/PG/PL]) with preservative-free saline for the treatment of dry eye., Methods: This was a prospective, multicenter, randomized, single-masked, parallel-group phase 4 clinical study. Patients ≥18 years diagnosed with dry eye received 1 drop of saline 4 times daily (QID) for 15 days during a run-in phase, followed by randomization. Patients then instilled HPG/PG/PL or saline QID through day 35 and as needed through day 90. Change in tear film break-up time (TFBUT), change in total ocular surface staining (TOSS) score, and Impact of Dry Eye on Everyday Life (IDEEL) were evaluated on day 35., Results: Increase in TFBUT from baseline to day 35 was assessed during the interim and final analyses. Mean ± SE difference between the HPG/PG/PL (n = 110) and saline groups (n = 100) was 1.3 ± 0.4 seconds (interim analysis; 95% confidence interval [CI] 0.5-2.1 seconds; p = 0.0012) and 1.0 ± 0.3 seconds (final analysis; 95% CI 0.4-1.6 seconds; p = 0.0011), demonstrating the superiority of HPG/PG/PL. The mean ± SE difference between the HPG/PG/PL and saline groups for IDEEL treatment effectiveness scores was 16.0 ± 3.6 (95% CI 8.9-23.1; p<0.0001). No significant differences in TOSS scores or IDEEL inconvenience scores were observed between treatment groups., Conclusions: Thirty-five days of QID HPG/PG/PL treatment resulted in a statistically significant improvement in TFBUT and IDEEL treatment effectiveness scores compared with saline but not in TOSS or IDEEL treatment inconvenience scores. HPG/PG/PL was well-tolerated by patients.

Purpose: To evaluate mRNA levels of the ocular mucins MUC1, MUC2, MUC4, MUC5AC, and MUC7 in conjunctival impression cytology samples from patients with moderate to severe dry eye syndrome (DES) compared with a population of healthy subjects; and to investigate the use of the levels of these mucin genes as biomarkers of DES and subsequently as a potential diagnostic test for DES., Methods: This prospective study commenced in the year 2000 and ended in the year 2009. Thirty-eight patients with DES and 43 age- and sex-matched healthy subjects completed the initial part of the study. Investigations were repeated at a later stage in 16 healthy subjects and 30 patients with DES, which were used as external validation data. Conjunctival impression cytology was performed in all subjects to test gene expression of ocular mucin genes MUC1, MUC2, MUC4, MUC5AC, and MUC7. Statistical analysis was performed to determine whether there was a difference in the levels of mucin gene expression between the two groups of subjects. Sensitivity and specificity of mucin gene expression for the diagnosis of DES was calculated., Results: Expressions of MUC1, MUC2, MUC4, and MUC5AC (P < 0.0001) were significantly lower in conjunctival epithelium of patients with DES compared with that in normal subjects. These results were replicated in the external control subject and patient groups. MUC1 expression levels demonstrated the greatest sensitivity (83.3%) and specificity (87.5%) among all genes tested., Conclusions: The data strongly suggest that the expression levels of MUC1 may be used as a diagnostic test in DES for investigational and selective clinical trials.

Purpose: To review cases of culture-positive fungal keratitis seen at Moorfields Eye Hospital over a 13-year period to January 2007., Methods: Isolates were identified retrospectively from laboratory reports. The clinical records were reviewed. The fungal type, risk factors for infection, in vitro sensitivity, and clinical outcome were recorded., Results: There were 66 isolates from 65 patients (men, 53.8%). Forty (60.6%) of the isolates were subspecies of Candida. The average interval from the onset of keratitis to confirmation of fungal infection was 3.4 weeks (median, 1.0 week; range, 0-16 weeks). Prior ocular surface disease (OSD) or a penetrating keratoplasty (PK) was present in 38 (97.4%) patients with Candida infection, and 29 (74.4%) patients with Candida infection were using topical steroid at the time of diagnosis. The principal risk factors for filamentary fungal infection were trauma (8 cases, 30.8%) or cosmetic contact lens wear (8 cases, 30.8%), with OSD or a prior PK each present in 5 (19.2%) cases. The difference in the proportions of risk factors between the 2 fungal groups was statistically significant (P < 0.000). The visual outcome was similar between groups, and at final review, 27 (41.5%) eyes had a visual acuity of < or = 1/60 and 3 (4.6%) eyes were eviscerated. In vitro sensitivity testing showed full or part sensitivity in 100% of 55 isolates tested against econazole, 87.9% of 58 isolates tested against amphotericin, 75% of 40 isolates tested against itraconazole, and 100% of 20 isolates tested against voriconazole., Conclusions: Candida was the principal isolate, usually from eyes with OSD or a prior PK treated with topical steroids.

Purpose: The ocular surface epithelia express at least five mucin genes of the total of 17 human mucin genes that have been identified so far. This study was designed to determine the expression profile of mucin genes in conjunctival impression cytology (CIC) samples from healthy subjects., Methods: Two polyethersulfone filters were applied to the superior conjunctiva of both eyes from eight healthy donors. Polymerase chain reaction (PCR) was performed using isolated and retrotranscripted total RNA obtained from the CIC samples to study the expression of all known human mucin genes. Following amplification, PCR products were electrophoresed on 1.5% agarose gel and stained with ethidium bromide to confirm that only a single band was obtained when amplifying all cDNAs with the convenient primers., Results: Transcripts of the previously reported conjunctival mucin genes MUC1, MUC2, MUC4, MUC5AC, and MUC7 were detected in all samples. In addition, transcripts of MUC13, MUC15, MUC16 and MUC17 mucin genes also were detected. Amplified products by conventional PCR showed the expected amplicon size. Transcripts of MUC3A, MUC3B, MUC5B, MUC6, MUC8, MUC11, and MUC12 mucin genes were not detected., Conclusion: The expression of four additional mucin mRNA (MUC13, MUC15, MUC16, and MUC17) has been proved in human conjunctival epithelium from healthy donors for the first time. The function of these genes remains to be further elucidated.