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Juan J Pérez-Santonja,1 José Luis Güell,2 Oscar Gris,2 Xose Manuel Vázquez Dorrego,3 Esther Pellicer,4 Jose Manuel Benítez-Del-Castillo5– 7 1Department of Ophthalmology, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain; 2Department of Cornea and Refractive Surgery, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain; 3Department of Ophthalmology, Hospital Municipal de Badalona, Badalona (Barcelona), Spain; 4EPT Servicios Científicos, Barcelona, Spain; 5Department of Ophthalmology, Hospital Clínico San Carlos de Madrid, Madrid, Spain; 6Universidad Complutense de Madrid, Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Madrid, Spain; 7Clínica Rementería, Madrid, SpainCorrespondence: Jose Manuel Benítez-Del-Castillo, Hospital Clinico San Carlos, C/ Martin Lagos s/n, Madrid, 28040, Spain, Tel +34 913303000, Fax +34 913941359, Email benitezcastillo@gmail.comAbstract: Ozonated oil has shown antimicrobial, anti-inflammatory and regenerative properties that make it useful in the prevention of infectious diseases and also as an adjuvant in wound-healing management. This review brings together most aspects of the use of liposomal ozonated oil for ocular infections and regeneration of the ocular surface. A search was performed in PubMed, Medline, Web of Science and Cochrane Library for studies published by June 2021. Search terms were combined to sort out papers on the properties and use of ozonated oil in ocular infections. A total of 25 publications were selected for this review on the composition, mechanism of action, restorative action, and preclinical and clinical studies of liposomal ozonated oil focused on ocular infections. In patients with complicated corneal pathology, liposomal ozonated oil has been found to restore corneal ulcers and improve keratitis. In patients with ocular pathologies involving inflammation and infections, liposomal ozonated oil has been found to improve and almost completely restore the signs of vernal, granulomatous and even adenoviral conjunctivitis. Liposomal ozonated oil has also been found to be effective in reducing ocular microbial flora. In conclusion, liposomal ozonated oil has an antiseptic and regenerative effect on corneoconjunctival tissues. It has demonstrated efficacy and safety profile for its use in ocular infections and can be considered as a suitable supportive strategy both alone and combined with other antimicrobial agents.Keywords: antifungal, antimicrobial, antiviral, liposomal ozonated oil, restorative action

Pasquale Aragona,1 Jose M Benítez-del-Castillo,2 Minas T Coroneo,3 Subhanjan Mukherji,4 Jacqueline Tan,5 Evelien Vandewalle,6 Algis Vingrys,7 Haixia Liu,8 Cindy Carlisle-Wilcox,8 Joseph Vehige,8 Peter A Simmons5,8 1Department of Biomedical Sciences, Università di Messina, Messina, Italy; 2Department of Ophthalmology, Hospital Clinico de Madrid, Universidad Complutense, Madrid, Spain; 3M.T. Coroneo Pty. Ltd, Randwick, NSW, Australia; 4Department of Ophthalmology, James Paget University Hospital, Great Yarmouth, UK; 5Optometry and Vision Science, UNSW Sydney, Sydney, NSW, Australia; 6Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium; 7University of Melbourne EyeCare Clinic, Carlton, VIC, Australia; 8Allergan, an AbbVie company, Irvine, CA, USACorrespondence: Peter A SimmonsPCS Research, 16611 Camille Place, Yorba Linda, CA, USATel + 1-714-743-3352Email pasimmons17@gmail.comPurpose: To compare the efficacy and safety of an artificial tear combining the polymers carboxymethylcellulose (CMC) and hyaluronic acid (HA), to a formulation of CMC alone in subjects with dry eye.Methods: A preservative-free artificial tear (CMC-HA) was compared with an existing artificial tear (CMC). Subjects with mild-to-severe signs and symptoms of dry eye were enrolled in this double-masked, randomized, multicenter trial, and dosed at least twice daily for 90 days, with follow-up visits at Days 7, 30, 60, and 90. Ocular Surface Disease Index (OSDI) was the primary outcome measure. Secondary outcome measures were tear break-up time (TBUT), ocular surface staining, Schirmer test with anesthesia, and visual analog scale (VAS) scores of dry eye symptom severity and formulation acceptability. Safety measures included adverse events, biomicroscopy, and visual acuity.Results: A total of 460 subjects were enrolled across 45 sites (38 in Europe; 7 in Australia), of whom 454 were randomized to receive treatment. The per-protocol (PP) population consisted of 394 subjects, 364 (92.4%) of whom completed the study. In the PP population, the mean ± SD change from baseline in OSDI score at the primary timepoint, Day 90, was − 16.9± 17.5 for CMC-HA and − 16.0± 16.1 for CMC. CMC-HA was non-inferior to CMC based upon a confidence interval method. Both treatments significantly improved (P< 0.001) OSDI, symptom VAS scores, TBUT, and ocular surface staining from baseline at all follow-up visits, with minimal differences between groups. Greater reduction of overall ocular pain/discomfort was reported in subjects using CMC-HA versus CMC (P=0.048). Approximately 10% of subjects in each group reported treatment-related adverse events of generally mild to moderate severity.Conclusion: The new CMC-HA formulation was effective and well tolerated, and demonstrates a greater potential for symptom relief compared with CMC. These data support implementation of this formula for the management of dry eye patients.Keywords: carboxymethylcellulose, hyaluronic acid, artificial tears, dry eye

Jose M Benitez-del-CastilloOcular Surface and Inflammation, Department Ophthalmology, Hospital Clinico San Carlos, Madrid, SpainAbstract: Disorders of the lacrimal functional unit are common in ophthalmological practice, with meibomian gland dysfunction, blepharitis, and dry eye forming a significant part of the general ophthalmologist's practice. The eyelid and its associated structures form a complex organ designed to protect the fragile corneal surface and improve visual acuity. This organ is subject to a number of disorders, including meibomian gland dysfunction, dry eye syndrome, anterior blepharitis, allergic and dermatological conditions, and disorders associated with contact lens use. Although commonly described separately, disorders of the lacrimal function unit are better considered as a group of interacting pathologies that have inflammatory mediators as a central feature. Eyelid hygiene, in the sense of routine cleansing and massage of the eyelids, is well accepted in the management of many disorders of the eyelid. However, a broader concept of eyelid health may be appropriate, in which eyelid cleansing is but a part of a more complete program of care that includes screening and risk assessment, patient education, and coaching. The ophthalmologist has an important role to play in helping patients persist with routine eyelid care that may be long-term or lifelong. A number of preparations exist to make routine eyelid care both more effective and more pleasant, and might also improve compliance. Several such preparations have been devised, and are being assessed in clinical studies, and appear to be effective and preferred by patients over traditional soap and water or baby shampoo.Keywords: eyelid, disorders, health, lacrimal functional unit

Purpose of Review: The aim of this review, is to present an updated revision of topical management of SAC and PAC, based on the available scientific evidence and focused on the impact of ophthalmic solution formulations on eye surface., Recent Findings: Physicians treating ocular allergy should be aware of tear film and tear film disruption in SAC and PAC, and how eye drop composition and additives affect the physiology of the allergic eye. Seasonal and perennial allergic conjunctivitis (SAC and PAC) are the most frequent causes of ocular allergy (OA), and both conditions are underdiagnosed and undertreated. SAC and PAC are immunoglobulin E (IgE)-mediated hypersensitivity reactions. The additional tear film disruption caused by the release of inflammatory mediators increases and exacerbates the impact of signs and symptoms and may trigger damage of the ocular surface. Comorbidities are frequent, and dry eye disease in particular must be considered. Clinical guidelines for the management of SAC and PAC recommend topical therapy with antihistamines, mast cells stabilizers or dualaction agents as first-line treatment, but care should be taken, as many medications contain other compounds that may contribute to ocular surface damage., (© 2024. The Author(s).)

Purpose: To analyze the efficacy of liposomal ozonated oil (Ozonest®) treatment, in patients with blepharitis or blepharoconjunctivitis, in improving the signs and symptoms of the pathology., Methods: Exploratory, open-label, prospective, single-arm, pre-post comparative pilot study in usual clinical practice, in 20 patients with blepharitis/blepharoconjunctivitis, receiving treatment with liposomal ozonated oil, one drop in each eye, 4 times a day, for 28 days. Main purpose was to assess whether there was a clinically improvement in the blepharitis specific BLISS questionnaire score. Changes in the 12-item OSDI, in eyelid signs of blepharitis assessed by the physicians were also evaluated among other tests, and there was also a subjective evaluation of the treatment by patients., Results: The BLISS score significantly improved from 16.4 before treatment to 11.8 after treatment ( p  < 0.05). The OSDI score was also significantly improved from 27.5 before treatment to 20.5 after treatment ( p  < 0.05). All tests conducted before and after treatment showed significant improvement ( p  < 0.05), except for NIBUT. The treatment received a score of 7 out of 10 by the patients. There were no adverse events in any patient., Conclusion: Liposomal ozonated oil treatment showed good efficacy in improving the signs and symptoms of blepharitis/blepharoconjunctivitis, satisfaction of patients, and good safety and tolerability., Competing Interests: Declaration of conflicting interestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Compounded insulin eye drops were prepared at 1 IU/mL from commercially available subcutaneous insulin by dilution in saline solution or artificial tears. Physicochemical characterization and in vitro tolerance testing in human and conjunctival cells were followed by a 28-day short-term stability study under various conditions. The formulations were isotonic (280-300 mOsm/L), had a pH close to neutral (7-8), medium surface-tension values (<56 MN/m -1 ), and low (≈1 mPa·s) and medium (≈5 mPa·s) viscosities (compounded normal saline solution and artificial tear-based preparation, respectively). These values remained stable for 28 days under refrigeration. Microbiological stability was also excellent. Insulin potency remained in the 90-110% range in the compounded formulations containing normal saline solution when stored at 2-8 °C for 28 days, while it decreased in those based on artificial tears. Although both formulations were well tolerated in vitro, the compounded insulin diluted in a normal saline solution exhibited better cell tolerance. Preliminary data in humans showed that insulin in saline solution was an effective and safe treatment for persistent corneal epithelial defects. Compounded insulin eye drops diluted in normal saline solution could, therefore, constitute an emergent therapy for the treatment of persistent corneal epithelial defects., Competing Interests: The authors declare no conflicts of interest in any of the matters addressed in this paper. Furthermore, this research did not receive any specific grants from funding agencies operating in the public, commercial, or not-for-profit sectors.

Purpose: To determine the safety and feasibility of human autologous adipose tissue-derived adult mesenchymal stem cells (ASCs) for ocular surface regeneration in patients with bilateral limbal stem-cell deficiency (LSCD)., Methods: A phase IIa clinical trial was designed (https://Clinicaltrials.gov, NCT01808378) with 8 patients, 3 of whom had aniridia, 2 meibomian glands diseases, 2 multiple surgeries and 1 chronic chemical injury. The therapeutic protocol was as follows: 6-mm of central corneal epithelium was removed, 400,000 ASCs were injected into each limboconjunctival quadrant, 400,000 ASCs were suspended over the cornea for 20 min, and finally the cornea was covered with an amniotic membrane patch., Results: No adverse events were detected after a mean of 86,5 months of follow-up. One year after surgery, 6 of the 8 transplants were scored as successful, five patients had improved uncorrected visual acuity (mean of 12 letters), two patients presented epithelial defects (also present at baseline) and the mean percentage of corneal neovascularization was of 28.75% (36.98%, at baseline). Re-examination 24 months after treatment disclosed preserved efficacy in 4 patients. At the last visit (after a mean of 86,5 months of follow up) epithelial defects were absent in all patients although improvement in all of the variables was only maintained in patient 3 (meibomian glands agenesia)., Conclusion: ASCs are a feasible and conservative therapy for treating bilateral LSCD. The therapeutic effect differs between etiologies and diminishes over time.

Background: Ocular surface alterations causing dry eye disease (DED) can be described as a vicious circle consisting of different consecutive stages. Among the factors involved, the ocular surface immune-inflammatory response has been established as a key player in the pathogenesis of the vicious circle of DED. Thus, the prompt recognition of the disruption of the immunoregulatory mechanisms is crucial for properly managing the ocular surface alterations. To increase awareness and knowledge of the identification and clinical interpretation of immunological mechanisms of dry eye in clinical practice, we present two clinical cases related to DED patients to provide a practical example of clinical examination application and interpretation of diagnostic parameters in daily practice. Moreover, a literature overview of the available clinical examinations to assess the immunological involvement in DED patients, with a particular focus on the correlation between diagnostic parameters and pathogenesis of clinical signs, is provided with an educational intent., Case Presentation: The presented clinical experiences suggested that in ocular surface pathologies, knowledge of the immune-inflammatory pathogenetic mechanisms underlying the observed clinical sign is of great help for understanding what is being observed in the patient and, consequently, for the choice of appropriate therapy. Literature evidence suggests that many different clinical examinations can be used to assess inflammation in DED patients, such as the assessment of hyperemia, staining of the ocular surface and measurement of hyperosmolarity and MMP-9 levels. The combination of impression cytology and flow cytometry to assess for markers of inflammation is considered the best technique to quantify the level of inflammation on the ocular surface, even if not always applicable in clinical practice., Conclusions: Literature evidence and clinical experiences suggest that basic diagnostic approaches (assessment of hyperemia, MMP-9 levels, and staining of the ocular surface with Lissamine green or fluorescein) represent useful tools to assess the inflammatory component of DED in everyday practice, providing a guide to establish the correct therapeutic strategy.

Purpose: This study evaluates the efficacy and tolerability of cyclosporine A cationic emulsion (CsA-CE) in patients ≥4 years of age with moderate-to-severe vernal keratoconjunctivitis (VKC)., Methods: This Phase II/III, multicenter, double-masked, dose-ranging study had 2 treatment periods: a 4-week, randomized, vehicle-controlled period in which patients received 0.05% CsA-CE, 0.1% CsA-CE, or vehicle eye drops 4 times daily (period 1) and a 3-month period in which patients received 0.05% CsA-CE or 0.1% CsA-CE 2 or 4 times daily (period 2). The primary efficacy end point was rating of subjective symptoms at day 28 in period 1 per the BenEzra scale., Findings: All groups showed improvement in subjective VKC symptoms at day 28, without a statistically significant difference between 0.05% or 0.1% CsA-CE vs vehicle. Both CsA-CE doses produced statistically significant improvements in corneal fluorescein staining scores vs vehicle at day 28; improvements were evident as early as week 1 and continued through month 1. Progressive reduction in subjective itching was evident after week 1 and continued through month 1. Treatment for an additional 3 months further improved subjective symptoms and objective signs of VKC in both CsA-CE groups. Improvement was most notable with 0.1% CsA-CE in patients with severe keratitis. The safety and tolerability profile is favorable., Implications: Although treatment with 0.05% and 0.1% CsA-CE showed clinical efficacy in alleviating keratitis and itching as early as week 1, with sustained benefit through 1 month, the primary efficacy end point was not met. These findings informed the design of the Phase III trial of 0.1% CsA-CE (Vernal Keratoconjunctivitis Study)., Clinicaltrials: gov identifier: NCT00328653., Competing Interests: Declaration of Competing Interest Andrea Leonardi is a consultant for Alcon, AstraZeneca, FAES Farma, FIDIA, Santen Pharmaceutical Co. Ltd., SIFI, and Laboratoires Théa, and URSAPHARM; Pierre-Jean Pisella has nothing to disclose; José Manuel Benítez-del Castillo is a consultant for Alcon, Allergan, Bausch + Lomb, Brill, Santen Pharmaceutical Co. Ltd., and Laboratoires Théa; Mourad Amrane is an employee of Santen SAS; Dahlia Ismail is an employee of Santen SAS; Serge Doan is a consultant for Horus Pharma, Santen Pharmaceutical Co. Ltd., Alcon, Allergan, Bausch + Lomb, and Laboratoires Théa; Dominique Bremond-Gignac is a consultant for Novartis, Santen Pharmaceutical Co. Ltd., Alcon, Allergan, Bausch + Lomb, Horus Pharma, and Laboratoires Théa., (Copyright © 2023. Published by Elsevier Inc.)

The chronic use of hypotensive agents eventually leads to ocular surface damage and poor patient compliance during glaucoma management. Thus, new sustained drug delivery systems are needed. This work aimed to develop osmoprotective latanoprost-loaded microemulsion formulations as new potential glaucoma treatments with ocular surface protective properties. The microemulsions were characterized and latanoprost encapsulation efficacy determined. In-vitro tolerance, osmoprotective efficacy, cell internalization as well as cell-microemulsion interactions and distribution were performed. In vivo hypotensive activity was conducted in rabbits to assess intraocular pressure reduction and relative ocular bioavailability. Physicochemical characterization showed nanodroplet sizes within 20-30 nm, being in vitro tolerance within 80 and 100% viability in corneal and conjunctival cells. Besides, microemulsions exhibited higher protection under hypertonic conditions than untreated cells. Cell fluorescence lasted for 11 days after short exposure to coumarin-loaded microemulsions (5 min) showing extensive internalization in different cell compartments by electronic microscopy. In vivo studies exhibited that a single instillation of latanoprost-loaded microemulsions reduced the intraocular pressure for several days (4-6 days without polymer and 9-13 days with polymers). Relative ocular bioavailability was 4.5 and 19 times higher than the marketed formulation. These findings suggest the use of these microemulsions as potential combined strategies for extended surface protection and glaucoma treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in any subjects treated in the present work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Dry eye disease (DED) is a worldwide, multifactorial disease mainly caused by a deficit in tear production or increased tear evaporation with an increase in tear osmolarity and inflammation. This causes discomfort and there is a therapeutic need to restore the homeostasis of the ocular surface. The aim of the present work was to develop a biodegradable and biocompatible liposomal formulation from the synthetic phospholipids 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) that is able to reduce the effects of hypertonic stress by helping to restore the lipid layer of the tear film. Liposomes were made using the lipid film hydration method with synthetic phospholipids (10 mg/mL) with and without 0.2% HPMC. They were characterised in terms of size, osmolarity, pH, surface tension, and viscosity. Additionally, the in vitro toxicity of the formulation at 1 and 4 h in human corneal epithelial cells (hTERT-HCECs) and human conjunctival cells (IM-HConEpiC) was determined. Furthermore, osmoprotective activity was tested in a corneal model of hyperosmolar stress. In vivo acute tolerance testing was also carried out in albino New Zealand rabbits by topical application of the ophthalmic formulations every 30 min for 6 h. All the assayed formulations showed suitable physicochemical characteristics for ocular surface administration. The liposomal formulations were well-tolerated in cell cultures and showed osmoprotective activity in a hyperosmolar model. No alterations or discomfort were reported when they were topically administered in rabbits. According to the results, the osmoprotective liposomal formulations developed in this work are promising candidates for the treatment of DED.

Introduction and Objective: Digital evolution represents an opportunity for ophthalmology to adapt to new care models. This study aimed to find out how the pandemic has modified the clinical practice and training activities of the ophthalmologist specialised in ocular surface, as well as to analyse emerging trends and needs., Materials and Methods: This study was carried out through an online survey. A committee of 3 specialists developed a questionnaire of 25 questions structured in: 1) Participant profile; 2) Impact of the pandemic on patient management and professional activities; 3) Trends and needs., Results: 68 clinical ophthalmologists participated. There was a high degree of agreement (90%) that the pandemic has delayed ophthalmological follow-up visits and diagnosis. The participants agreed that the frequency of patients with dry eye disease (75%), stye/chalazion (62%) and blepharitis (60%) has increased. According to 28%, remote monitoring of pathologies such as dry eye, glaucoma, diabetes, conjunctivitis, hyposphagmas, styes, etc., will be common, especially in the young population. This will be especially relevant in chronic or mild pathologies of the ocular surface, and in the follow-up of patients after cataract and diabetic retinopathy interventions., Conclusions: During the pandemic, an increase in the incidence of certain ocular surface diseases has been perceived. The telematic follow-up of chronic or mild pathologies of the ocular surface entails the need to provide specific training for both the patient and the healthcare professional, in addition to screening and referral protocols that would optimise the flow of care., (Copyright © 2023 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: To identify factors affecting the response rate to immunosuppressive drugs (ISDs) in patients with non-infectious uveitis (NIU)., Methods: This longitudinal retrospective cohort study included patients from the Hospital Clinico San Carlos Uveitis Clinic diagnosed with NIU from 1992 to 2016. Subjects were followed up from ISD prescription until the achievement of good therapeutic response (GTR), ISD treatment change, or up to 12 months. GTR was defined as the complete resolution of the eye inflammatory manifestations with a corticosteroid dose ≤ 10 or ≤ 5 mg per day of prednisone or equivalent (GTR10 and GTR5, respectively) maintained for at least 28 days. Kaplan-Meier curves were estimated for GTR. Demographic, clinical, and treatment-related factors were analyzed using Cox robust regression., Results: A total of 73 patients (100 episodes of ISD prescription) were analyzed. In 44 and 41 episodes, GTR10 and GTR5 were achieved, respectively. A lower hazard for both GTRs was associated with uveitic macular edema at prescription and with a higher "highest oral corticosteroid dose prescribed in the year before ISD prescription". GTR10 was higher if cyclosporine was prescribed (compared to other ISDs), and if a higher number of ISDs had been previously prescribed. GTR5 hazard was lower for patients with posterior uveitis or if the ISDs were prescribed before 2008, and higher if periocular corticosteroids had been administered before ISD prescription, or if the duration of the posterior segment activity was shorter., Conclusions: Factors associated with GTR to ISDs may help to identify patients with NIUs who could benefit from a thorough follow-up., (© 2022. The Author(s).)

Purpose: To evaluate whether the use of masks has an effect on the measurement of corneal topographic parameters., Methods: A study including healthy patients with no previous ocular diseases or surgeries was conducted. Corneal topography was evaluated with an elevation topography Pentacam Scheimpflug. Four measurements were taken: two measurements with face mask and another two measurements after 10 min without wearing the face mask. The following parameters were evaluated: anterior topographic flat meridian (K1), anterior topographic steepest meridian (K2), mean keratometry (Km) and maximum keratometric point (Kmax)., Results: Thirty-five eyes of thirty-five healthy individuals were included; with a mean age of 33.5 ± 13.8 years (range 24-66) and 26 (74%) being female. Mean time with face-mask was 3.8 ± 2.2 h (range 1-8). No differences in mean K1, K2, Km and Kmax with and without face-mask were noted (paired t-test, all, p > 0.05). Intraclass correlation coefficients (ICC) were excellent for all four analyzed parameters (ICC > 0.914), although they were lower when measurements with face-mask were considered., Conclusions: Although tear film alterations with the use of face-mask have been described in the literature, no significant differences can be noted in topographic variables.

Competing Interests: The authors declare that they have no conflict of interest.

Self-emulsified osmoprotective ophthalmic microemulsions (O/A) were prepared by combining betaine/leucine, clusterin/oleanolic acid, and hyaluronic acid or Dextran. The microemulsions contained an internal oily phase (1.2%), an external aqueous phase (96.3%), cosolvents (1%), and surfactants (1.5%). Physicochemical characterization and in vivo and in vitro tolerance were analyzed. The formulations' osmoprotective in vitro activity was assayed in a hyperosmolar model in human corneal cells. Average internal phase sizes were 16-26 nm for the microemulsions including Dextran. Addition of hyaluronic acid increased the size range (25-39 nm). Addition of osmoprotectants did not change nanodroplet size. The formulations were isotonic (280-290 mOsm/L) with neutral pH (≈7) and zeta potential (-10 to 0 mV), low surface tension (≈35-40mN·m -1 ), and low viscosity (≈1 mPa·s), except for the microemulsions containing hyaluronic acid (≈4-5 mPa·s). SEM and cryo-TEM showed that all formulations exhibited sphere-shaped morphology with good cell tolerance (≈100%) and were stable at 8 °C for 9 months. Osmoprotective formulations were well tolerated in vitro and in vivo, protecting cells from hypertonic stress. We therefore developed stable microemulsions compatible with the ocular surface that could constitute a novel tool for treatment of ophthalmic diseases., (Copyright © 2022. Published by Elsevier B.V.)

Glaucoma is a group of chronic irreversible neuropathies that affect the retina and the optic nerve. It is considered one of the leading causes of blindness in the world. Although it can be due to various causes, the most important modifiable risk factor is the elevated intraocular pressure (IOP). In this case, the treatment of choice consists of instilling antihypertensive formulations on the ocular surface. The chronicity of the pathology, together with the low bioavailability of the drugs that are applied on the ocular surface, make it necessary to instill the formulations very frequently, which is associated, in many cases, with the appearance of dry eye disease (DED). The objective of this work is the design of topical ocular formulations capable of treating glaucoma and, at the same time, preventing DED. For this, two liposome formulations, loaded with brimonidine or with travoprost, were Tadeveloped using synthetic phospholipids and enriched by the addition of compounds with osmoprotective activity. The proposed formulations not only presented physicochemical characteristics (size, pH, osmolarity, surface tension, and viscosity) and encapsulation efficiency values (EE% of 24.78% and ≥99.01% for brimonidine and travoprost, respectively) suitable for ocular surface administration, but also showed good tolerance in human corneal and conjunctival cell cultures, as well as an in vitro osmoprotective activity. The hypotensive effect of both liposomal formulations was evaluated in normotensive albino New Zealand rabbits, showing a faster and longer lasting reduction of intraocular pressure in comparison to the corresponding commercialized products used as control. According to these results, the hypotensive liposomal formulations combined with osmoprotective agents would result in a very promising platform for the treatment of glaucoma and the simultaneous protection of the ocular surface.

Purpose: To describe the clinical and epidemiological characteristics of patients with Vogt-Koyanagi-Harada (VKH) disease in Spain., Methods: This was a retrospective multicenter analysis of data from VKH patients followed for at least 6 months. The data collected were related to demographics, clinical manifestations, treatments, and complications., Results: Participants were 112 patients (224 eyes), from 13 tertiary referral centers, of mean age 37.5 ± 14.7 years; 83.9% were women. Ethnicities were 61.6% Caucasian and 30.4% Hispanic. The disease was classified as complete in 16.1%, incomplete in 55.4%, and probable in 28.6%. When seen for the first time, the clinical course was acute in 69.6%, recurrent chronic in 15.2%, and chronic in 14.3%. The most frequent treatment was corticosteroids (acute stage 42.2%, maintenance stage 55.6%). The most common complications were cataract (41.1%) and ocular hypertension (16.1%). In most eyes, visual acuity was improved (96.7%) or remained stable at the end of follow up., Conclusion: VKH in Spain mostly affects women and presents as incomplete acute stage disease. Visual prognosis is good. Cataract and glaucoma are the two most frequent complications.

Purpose: The SARS-CoV-2 virus, which causes COVID-19 disease, is transmitted by aerosols or by contact with infected surfaces. The route of entry to the body is through the nasal, oral or conjunctival mucosa. Health workers must use effective protection measures against the entry of the virus into mucous membranes, both physical and antiseptic filters. There is an antiseptic used in Ophthalmology that we believe could have virucidal action against the SARS-CoV-2 virus, formulated based on 0.01% hypochlorous acid., Methods: An exhaustive search has been carried out in the databases of Pubmed and Web of Science to identify relevant articles on the virucidal activity of hypochlorous acid in different concentrations until October 4, 2020., Results: There is evidence of the virucidal efficacy of 0.01% hypochlorous acid against SARS-CoV-2. According to the different scientific publications reviewed, hypochlorous acid has virucidal efficacy against different viruses, among them, SARS-CoV-2., Conclusions: The 0.01% hypochlorous acid could act as an effective antiseptic against SARS-CoV-2, exerting a barrier on the mucosa to prevent COVID-19 infection. It can be used on the eyes, nose and mouth. We consider it necessary to assess its use in the protocol for patient health care in ophthalmology consultations, as well as to recommend its use to the general population to reduce viral load and/or prevent transmission of infection. Additional in vivo studies would be required to confirm its antiseptic action., (Copyright © 2021 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Congenital aniridia is a multisystemic genetic disease due to a mutation in PAX6 gene which severely affects the development and functionality of the human eyes. In patients affected by the mutation, aside from the absence or defects of iris tissue formation, abnormalities in position or opacities of the crystalline lens, macular hypoplasia, ocular surface disease is the main cause of visual loss and the deterioration of the quality of life of most patients. Limbal stem cell deficiency combined with tear film instability and secondary dry eye cause aniridic keratopathy which, in advanced stages, ends up in corneal opacification. In this paper, the actual knowledge about congenital aniridia keratopathy physiopathology and medical and surgical treatment options and their efficacy are discussed. Indications and results of topical treatments with artificial tears and blood-derivatives in its initial stages, and different surgical techniques as limbal stem cell transplantation, keratoplasty and keratoprostheses are reviewed. Finally, recent advances and results in regenerative medicine techniques with ex vivo stem cell cultivation or other types of cultivated cells are presented., (Copyright © 2021 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: To develop an easy-to-perform combined model in human corneal epithelial cells (HCECs) and Balb/c mice macrophages J774.A1 (MP) for preliminary screening of potential ophthalmic therapeutic substances., Methods: HCECs were exposed to different osmolarities (350-500 mOsm/L) and MTT assay was employed for cell survival and flow cytometry to assess apoptosis-necrosis and relative cell size (RCS) distribution. Effectiveness of Betaine, L-Carnitine, Taurine at different concentrations (ranging from 20 mM to 200 mM) was studied. Also, mucoadhesive polymers such as Hyaluronic acid (HA) and Hydroxypropylmethylcellulose (HPMC) (0.4 and 0.8%) were evaluated. Cells were pre-incubated with the compounds (8h) and then exposed to hyperosmotic stress (470 mOsm/L) for 16h. Moreover, anti-inflammatory activity was performed in LPS-stimulated MP., Results: Exposure to hyperosmotic solutions between 450 and 500 mOsm/L promoted the highest cell death after 16h exposures (p < 0.0001) with a drop in viability to 34.96% ± 11.77 for 470 mOsm/L. Pre-incubation with Betaine at 150 mM and 200 mM provided the highest cell survival against hyperosmolarity (66.01% ± 3.65 and 65.90% ± 0.78 respectively) while HA 0.4% was the most effective polymer in preventing cell death (42.2% ± 3.60). Flow cytometry showed that Betaine and Taurine at concentrations between 150-200 mM and 20-80 mM respectively presented the highest anti-apoptotic activity. Also, HA and HPMC polymers reduced apoptotic-induced cell death. All osmoprotectants modified RCS, and polymers increased their value over 100%. L-Carnitine 50 mM, Taurine 40 mM and HA 0.4% presented the highest TNF-α inhibition activity (60%) albeit all of them showed anti-inflammatory inhibition percentages higher than 20% CONCLUSIONS: HCECs hyperosmolar model combined with inflammatory conditions in macrophages allows the screening of osmoprotectants by simulating chronic hyperosmolarity (16h) and inflammation (24h)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Meibomian gland dysfunction (MGD) is a major cause of signs and symptoms related to dry eyes (DE) and eyelid inflammation. We investigated the composition of human tears by metabolomic approaches in patients with aqueous tear deficiency and MGD., Methods: Participants in this prospective, case-control pilot study were split into patients with aqueous tear deficiency and MGD (DE-MGD [n = 15]) and healthy controls (CG; n = 20). Personal interviews, ocular surface disease index (OSDI), and ophthalmic examinations were performed. Reflex tears collected by capillarity were processed to 1H nuclear magnetic resonance (NMR) spectroscopy and quantitative data analysis to identify molecules by spectra comparison to library entries of purified standards and/or unknown entities. Statistical analyses were made by the SPSS 22.0 program., Results: Chemometric analysis and 1H NMR spectra comparison revealed the presence of 60 metabolites in tears. Differentiating features were evident in the NMR spectra of the 2 clinical groups, characterized by significant upregulation of phenylalanine, glycerol, and isoleucine, and downregulation of glycoproteins, leucine, and -CH3 lipids, as compared to the CG. The 1H NMR metabolomic analyses of human tears confirmed the applicability of this platform with high predictive accuracy/reliability., Conclusions: Our key distinctive findings support that DE-MGD induces tear metabolomics profile changes. Metabolites contributing to a higher separation from the CG can presumably be used, in the foreseeable future, as DE-MGD biomarkers for better managing the diagnosis and therapy of this disease., (© 2020 S. Karger AG, Basel.)

Purpose: To create a new list of medical procedures in ophthalmology based on the International Classification of Diseases ICD-9-CM. To establish the general principles that define criteria, quantitative indicators, and scales. To develop the algorithms needed to calculate fees for medical procedures., Methods: The out-of-date processes were removed from the list, and new techniques were added, descriptors were modified, procedures with similar descriptions were grouped together, and others were relocated to other group according to surgical complexity conditions. The criteria to calculate the medical fees were defined: training and complexity (U), proficient responsibility (R), and health value (V), with their respective quantitative indicators: period of training necessary to master a technique, frequency of complications that worsen the preoperative situation, and days of incapacity for work due to the process. The Relative Value Unit (RVU) was defined as the score sum of R, V and U. The final fee per medical procedure was calculated as the product of the RVU by its unit cost and by the weighting coefficient (WC)., Results: A new catalogue was prepared with 161 medical procedures, grouped into consultations, diagnostic procedures (DX.PR), therapeutic procedures (TX.PR), and surgical interventions, increasing in complexity from group 0 to group 8. The following characters were described for each one of the procedures: OMC and ICD-9-MC code, descriptor term, group, proposed modification: no changes or minimums in the descriptors, grouping of acts by similar definitions, change of origin group, new procedures, and procedures removed. The indicators for assessment were also scored: U between 1-4 points, and R and V between 0-3 points. Using their sum, the number of RVUs per medical procedure (between 1 and 10) was calculated which, together with the unit cost of the RVU and the WC (between 0.05 and 1), will determine the final rate., Conclusions: The new standardised ophthalmological nomenclature updates and improves the old classification, adapting the procedures to the descriptors included in the ICD-9-CM, and incorporating all the new techniques. Additionally, the declaration of the general principles allows defining new criteria, quantitative indicators, rating scales, and algorithms to calculate fees for medical procedures., (Copyright © 2020 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: The purpose of this study was to evaluate the frequency and clinical presentation of conjunctivitis in hospitalized patients with COVID-19., Methods: A cross-sectional study was conducted at the Hospital Clinico San Carlos of Madrid, Spain. A total of 301 subjects from the COVID admission unit with laboratory-confirmed SARS-CoV-2 infection were included. The presence and clinical characteristics of conjunctivitis were evaluated. Laboratory, radiological, and clinical results in patients with and without conjunctivitis stratified by sex were analyzed., Results: Of the 301 subjects included, 180 patients (59.8%) were male and the median age was 72 years (IQ 59-82). Overall, 35 patients (11.6%) were diagnosed with acute conjunctivitis. We found no relationship between the COVID-19 severity score and the presence of conjunctivitis (P = 0.17). However, conjunctivitis was more frequent in males with moderate clinical severity and in women classified as clinically mild. The natural history of the disease seems to be a rapid self-limited conjunctivitis that improves without treatment and does not affect visual acuity nor associate short-term complications., Conclusions: Approximately, 1 out of 10 hospitalized non-critical COVID-19 patients presents conjunctivitis during the disease. Compared with other viral conjunctivitis, we found distinctive clinical findings that could guide defining and differentiating conjunctivitis in COVID-19 patients., Trial Registration Number: 20/336&#95;E&#95;COVID.

Objective: To evaluate the effects and safety of topical drops of perfluorohexyloctane (F6H8) on the ocular surface and the corneal endothelium., Methods: Forty-five patients (90 eyes) diagnosed with dry eye disease were recruited and prescribed treatment with F6H8 as part of a six-month prospective multicentre study. Variables in corneal staining were documented using the National Eye Institute/Industry Workshop scale. The conjunctival variables included using the Oxford scale, as well as corneal parameters, such as central corneal thickness, cell density, coefficient of variation, hexagonality, and mean cell area, at the start of the study, and at 3months and 6months. Compliance and satisfaction with the treatment were measured., Results: F6H8 drops reduced mean corneal staining based on the NEI scale in compliant patients to a mean of -0.84 ± 1.95 at 3months (P=.001) and to -1.65 ± 2.42 at 6months (P<.001). Conjunctival staining at 6months showed a mean decrease of -0.13 (P=.319). The endothelial parameters did not show a significant difference, in contrast to the central corneal thickness that showed a statistically significant decrease (545.30 ± 32.25 at the start of the study to 538.40 ± 31.36 after 6months, P=.009). At the end of the study, 46% of patients reported feeling subjectively better, 40.5% felt the same, and 13.5% felt subjectively worse., Conclusions: Topical treatment with F6H8 for dried eye disease did not alter the measured variables of the corneal endothelium, but showed improvement in corneal staining and satisfaction., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

Purpose: Neurotrophic corneal ulcers are difficult to treat, and the conventional treatment often results in failure. A new matrix regenerating agent ("ReGeneraTing Agents"), Cacicol® (Laboratoires Théa), has demonstrated good results over the last few years. Therefore, the aim of this study was to evaluate the response to Cacicol® in a series of cases with neurotrophic corneal ulcers., Methods: Retrospective case series looking at 11 patients with corneal ulcers unresponsive to conventional therapy that underwent treatment with Cacicol®. One cycle included 1 drop every two days for 5 days., Results: The range of conventional therapy prior to Cacicol® was 0-91 days. On introducing Cacicol® 82% (9/11) of the cases were cured, and 18% (2/11) failed, requiring an amniotic membrane transplant or penetrating keratoplasty. The healing only required one cycle of Cacicol® in 67% (6/9) of the patients. More than one cycle of Cacicol® was needed in 45% (5/11) patients. One corneal bacterial ulcer responded favourably and one case related to Acanthamoeba did not respond. Most of the patients improved or maintained their visual acuity., Conclusion: Cacicol® was a useful therapy in a high number of difficult neurotrophic corneal ulcers, including corneal infections. Some cases may require more than one cycle of Cacicol® or used as first-line treatment in order to achieve the desired result., (Copyright © 2020 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Anecdotal evidence suggests that eyelid disorders are common, although estimates of prevalence vary. The current study determines the prevalence of eyelid disorders, meibomian gland dysfunction (MGD) and related diseases (specifically ocular surface disease) in a population of patients presenting for routine ophthalmologic consultations., Methods: This cross-sectional epidemiologic survey evaluated patients presenting for routine ophthalmic visits. During the consultation an ophthalmologist completed a questionnaire, and each patient underwent an ophthalmic examination and completed a quality of life questionnaire., Results: Three hundred forty-nine ophthalmologists, recruited from 11 countries, provided data on 6525 patients. Patients were predominantly females (61.6%). The mean age of the study population was 57.0 ± 17.6 years. Eyelid disorders were diagnosed in 5109 (78.3%) patients and were statistically associated with: atopic dermatitis, seborrheic dermatitis, dry eye, age-related macular degeneration, diabetes, cataract, allergy and MGD (P < 0.05, all associations). Eyelid abnormalities were identified in 59.6% of patients; conjunctival or corneal abnormalities were observed in 64.9% and 28.1% of patients, respectively. MGD was diagnosed in 54.3% patients and was statistically significantly associated with the presence of eyelid disorders and eyelid margin abnormalities (P < 0.001, both comparisons). Dry eye was diagnosed in 61.8% of patients. Concurrent dry eye and MGD were present in 67.6% of patients. Most patients reported some degree of impaired vision and daily/work activities related to dry eye. Impact on contact lens usage, emotions and quality of sleep was also reported. The effects on daily life were associated with the presence of MGD., Conclusion: In conclusion, eyelid disorders were highly prevalent in this 'real-world' population of patients from ophthalmology clinics. Routine ophthalmologic consultations provide an opportunity to improve patient quality of life and to modify topical therapy in patients who may be predisposed to eyelid disorders.

Purpose: To assess the relationship between the meibomian gland loss (MGL) and relevant ocular surface clinical parameters as well as the influence of age in this relationship., Methods: A total of 161 participants (mean age; 42±17 years) were enrolled in this study. Infrared meibography was performed using Keratograph 5M (K5M; Oculus GmbH, Wetzlar). Participants were divided into five groups according to total meiboscore and the ocular surface parameters of each MGL group were studied. In addition, the relationship between MGL and the ocular surface parameters was established including age as covariant., Results: Both eyelids were taken into account since no association between the MGL from upper and lower eyelid was found (k value=0.2; p=0.3) despite they were significantly correlated (r= 0.3; p<0.001). No statistically significant differences were found in symptomatology among different MGL groups. Statistically significant differences were found among MGL groups in tear osmolarity (p=0.02), bulbar redness (p=0.04), corneal and conjunctival staining (p=0.01 and p=0.004, respectively). Despite this, only corneal staining showed a significant correlation with MGL when age was covariant (r=0.2; p=0.04)., Conclusions: MGL higher than 50% seems to be accompanied by signs on the ocular surface. Furthermore, age demonstrated to be a relevant factor when assessing MGL. For this reason, future studies should compare age-matched groups in order to know the contribution of the MGL on the ocular surface and establish valid cut-off values for dry eye diagnosis., (Copyright © 2019 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: To compare visual, topographic and topometric outcomes in patients subjected to deep anterior lamellar keratoplasty or penetrating keratoplasty showing a high or low risk of graft rejection., Setting: Complejo Hospitalario La Mancha Centro, Ciudad Real, Spain., Materials and Methods: Data were reviewed for consecutive patients with a corneal stroma disease undergoing deep anterior lamellar keratoplasty or penetrating keratoplasty over the period 2009-2015 at our centre by the same surgeon. The outcome measures examined were 2-year follow-up best-corrected visual acuity, refractive error, topographic astigmatism, intraocular pressure, endothelial cell density and central corneal thickness., Results: Of 115 eyes enrolled, 46 underwent deep anterior lamellar keratoplasty (15 low risk, 31 high risk) and 69 penetrating keratoplasty (23 low risk, 46 high risk). Mean postoperative best-corrected visual acuity (logMAR) in the low- and high-risk groups, respectively, were 0.31 and 0.26 for deep anterior lamellar keratoplasty (p = 0.32) and 0.40 and 0.51 for penetrating keratoplasty (p = 0.28). The values for the high-risk deep anterior lamellar keratoplasty versus high-risk penetrating keratoplasty patients were 0.26 and 0.51, respectively (p = 0.004). Mean postoperative spherical equivalents were -2.60 D for low-risk deep anterior lamellar keratoplasty versus -2.29 D for high-risk deep anterior lamellar keratoplasty (p = 0.19), and -0.41 D for low-risk penetrating keratoplasty versus -0.13 D for high-risk penetrating keratoplasty (p = 0.51)., Conclusion: Final best-corrected visual acuity and visual acuity gains were better for deep anterior lamellar keratoplasty, mainly in corneas with a high rejection risk. Despite a better corneal thickness recorded in the deep anterior lamellar keratoplasty group, the other variables examined were comparable. Deep anterior lamellar keratoplasty emerged as an effective alternative to penetrating keratoplasty for patients with a disease affecting the corneal stroma.