Search

Brian J Nguyen,1 Angela S Gupta,1 Jocelyn He,1,2 Gui-Shuang Ying,1,2 Vatinee Y Bunya,1 Ilaria Macchi,1 Mina Massaro-Giordano1 1Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Ophthalmology, Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Mina Massaro-Giordano, Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 North 39th St, Philadelphia, PA, 19104, USA, Email mina@pennmedicine.upenn.eduPurpose: This study was to assess corneal epithelial thickness (CET) in patients with Sjogren’s disease (SjD).Methods: A retrospective chart review was conducted of SjD patients from September 2021 to January 2022. Patient demographics, unanesthetized Schirmer’s test, serologic markers, and symptoms as measured by the Ocular Surface Disease Index (OSDI) were reviewed. Epithelial thickness from both eyes was measured using anterior segment OCT at the central 3mm and concentric 5mm, 7mm, and 9mm zones for the superior, temporal, inferior, and nasal corneal quadrants. Associations between corneal epithelial thickness with patient demographics, clinical characteristics, and symptoms were evaluated using regression models.Results: Fifteen SjD patients (100% female) were included with a mean age of 58.4 years. Patients with Sjogren’s disease had a significantly thinner superior corneal epithelium compared to the inferior epithelium (mean 47.7mm vs 53.1mm, p = 0.001). The epithelial thickness mean standard deviation (MSD) was significantly inversely correlated with the unanesthetized Schirmer test (r=− 0.39, p = 0.005), suggesting that an overall variability of CET correlates with decreased aqueous tear production. SS-A, SS-B, ANA, and RF positivity were not associated with any measures of CET.Conclusion: This pilot study suggests that there is significant superior versus inferior thinning of corneal epithelium in Sjogren’s patients. There was a significant correlation between variability of corneal epithelial thickness and decreased tear production in Sjogren’s patients. Further larger studies are needed to understand the relationship of CET with objective and subjective measurements of ocular surface disease.Keywords: Sjogren’s disease, corneal epithelial thickness, anterior segment OCT

Jennifer B Nadelmann,1,2 Vatinee Y Bunya,1 Gui-Shuang Ying,3 Peiying Hua,3 Mina Massaro-Giordano1 1Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Ophthalmology, Weill Cornell Medicine, New York, NY, USA; 3Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Mina Massaro-Giordano, Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, Tel +1-215-662-8100, Email mina@pennmedicine.upenn.eduPurpose: Platelet rich plasma (PRP) is an autologous preparation that concentrates platelets in a small volume of plasma. The purpose of this study was to determine if PRP eye drops improved the symptoms and signs of ocular surface disease.Patients and Methods: A retrospective case series was conducted of patients who were prescribed PRP eye drops. Subjects were excluded if they did not have follow-up, underwent intraocular surgery prior to follow-up, received nerve growth factor treatments, or did not have a baseline examination with photography. Symptoms were assessed using the Ocular Surface Disease Index (OSDI). Patients also underwent a slit lamp exam, ocular surface staining with fluorescein and lissamine green, and Schirmer testing.Results: The charts of 47 patients treated with PRP drops for ocular surface disease were reviewed. Sixty-four eyes of 32 patients were included in the study who had photographs of lissamine green staining taken at baseline and at follow-up. Thirteen patients (28%) had ocular graft-versus-host disease, 16 patients (34%) had Sjögren’s syndrome, and 4 patients (8.5%) had rheumatoid arthritis. There was a statistically significant decrease in OSDI score from baseline to follow-up (39.5 vs 30.8 points, p = 0.02). Among the 64 eyes included, 9 (14%) had an improvement in conjunctival lissamine green staining, while 6 (9%) had an increase in staining at follow-up. Among the 20 eyes with Schirmer testing, there was a borderline significant increase in score from baseline to follow-up (5.9 vs 9.7, p = 0.06). Among the 44 eyes that had corneal fluorescein staining (CFS) reported, 8 (18.2%) had decreased staining and 2 (4.5%) had increased staining at follow-up.Conclusion: Treatment with PRP drops was associated with a significant improvement in symptoms in patients with ocular surface disease. Future larger prospective studies are needed to further evaluate the efficacy of PRP drops for treating ocular surface disease.Keywords: ocular surface disease, cornea, lissamine green, Ocular Surface Disease Index, platelet-rich plasma

Zujaja Tauqeer,1 Stephanie E Jinno,1,2 Caroline W Chung,1 Mina Massaro-Giordano,1 Vatinee Y Bunya1 1Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Drexel University School of Medicine, Philadelphia, PA, USACorrespondence: Vatinee Y Bunya, Tel +1-215-662-8100, Email Vatinee.Bunya@pennmedicine.upenn.eduPurpose: Ocular adverse events have been reported in association with dupilumab, a monoclonal antibody to treat allergic diseases including atopic dermatitis (AD). We describe clinical findings and treatment of dupilumab-related ocular complications.Patients and Methods: Retrospective study of 19 dupilumab-treated AD patients seen for a new ocular complaint. Primary outcomes were specific ocular exam findings (conjunctival injection, corneal fluorescein staining, blepharitis, meibomian gland dysfunction (MGD)), treatments, and follow-up.Results: Nineteen dupilumab-treated AD patients were included. Median age was 47 years (range 18– 73). Over half were women (11/19) and majority were Caucasian (13/19). Symptom onset occurred at a mean of 99 days (range 23– 520 days) from first dupilumab dose. The most common symptoms were redness (63%), tearing (47%), and pruritus (37%). Most common ocular findings were conjunctival injection (75%) and corneal staining (60%). Blepharitis was seen in about a third (30%), and 25% had MGD. Initially, 10% were observed without treatment, while 15% were treated with artificial tears alone. Other treatments included antihistamine drops (20%) and steroid drops alone (15%). In 40% of patients, a combination of steroids and various other topical eye drops were prescribed. Eighty-four percent (16/19) of patients were seen for follow-up. Steroid drops were required at follow-up in 3 out of 4 patients initially treated with antihistamines alone and in two-thirds of patients initially treated with artificial tears only. Mean follow-up period was 88 days (range 5– 369). Dupilumab was discontinued in 31.5% (6/19) of patients; of those who discontinued, 3 restarted it later.Conclusion: Conjunctival injection was the most frequent dupilumab-related ocular symptom and most common exam finding followed by corneal staining. Most patients initially treated with antihistamine drops or artificial tears alone subsequently required steroid drops to control symptoms. Some patients who discontinued dupilumab restarted the medication after achieving adequate control of ocular symptoms.Keywords: dupilumab, atopic dermatitis, conjunctivitis, cornea, dry eye

Jonathan Lilley,1 Erin C O’Neil,1 Vatinee Y Bunya,1 Kennedy Johnson,1 Gui-Shuang Ying,2 Peiying Hua,2 Mina Massaro-Giordano1 1Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 2Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Mina Massaro-GiordanoDepartment of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA, 19104, USATel +1 215-662-9393Email mina@pennmedicine.upenn.eduPurpose: To assess the efficacy and safety of an intranasal tear neurostimulator (ITN) device in Sjögren syndrome (SS) patients.Methods: This was a two-visit prospective, randomized, controlled, same-day crossover study in participants with SS. Inclusion criteria were assessed at a baseline screening visit and included an Ocular Surface Disease Index (OSDI) score ≥ 13, and a Schirmer with anesthesia ≤ 10 mm/5 min (in at least one eye), with a cotton swab stimulation induced increase of ≥ 4 mm in the same eye. Participants returned for the application visit, where they received intranasal and extranasal applications of the ITN in random sequence, separated by at least 60 min. Schirmer scores were measured in both eyes after each application and compared to baseline values. Generalized linear models were performed to compare the change in Schirmer scores from baseline, and generalized estimating equations were used to account for correlations from repeated measurements in the same eye and measurements from two eyes of the same patient.Results: Fifty-five participants were screened and 35 were enrolled (all female), ranging in age from 31 to 72 years (mean, 57 years). The baseline OSDI score ranged from 14 to 91 (mean, 50.5), and the baseline Schirmer score had a mean (SD) of 6.4 (3.5) ranging from 0 to 20 (mm/5min). Improvement in Schirmer scores was significantly greater for intranasal device application (13.5 mm/5min, 95% CI: 10.4, 16.5) compared to extranasal device application (0.8mm/5min, 95% CI: − 0.9, 2.4) (p< 0.0001). The effects of the intranasal device application were significant regardless of the participant’s baseline Schirmer score and systemic SS medication usage (p< 0.05).Conclusion: Intranasal application of the ITN device significantly increased tear production in a subset of SS patients compared to baseline and was more effective than extranasal application. While production of the ITN device was recently discontinued, our findings suggest that other therapies that neurostimulate the lacrimal function unit may be effective in a subset of SS patients.Keywords: Sjögren syndrome, intranasal tear neurostimulation, tear production

Purpose: To report the design of FLuorometholone as Adjunctive MEdical therapy for TT surgery (FLAME) trial., Design: Parallel design, double-masked, placebo-controlled clinical trial with 1:1 randomization to fluorometholone 0.1% eye drops twice daily or placebo twice daily for 4 weeks in eyes undergoing trachomatous trichiasis (TT) surgery for assessing the efficacy, safety, and cost-effectiveness of fluorometholone 0.1% in preventing recurrent postoperative trichiasis (PTT)., Methods: Up to 2500 eligible persons with trachomatous trichiasis undergoing lid rotation surgery were enrolled in the Jimma zone, Ethiopia. Participants, surgeons, study field staff, and study supervisors leading operational aspects of the trial are masked to treatment assignment. Randomization is stratified by the surgeon and is simultaneously stratified by the district. Study visits (in addition to programmatic follow-ups) are at the baseline/enrollment, at four-week post-enrollment, and after 6 months and 1 year. The primary outcome is cumulative one-year PTT incidence, defined as: ≥1 lashes touching the globe, evidence of epilation, and/or repeat TT surgery. Secondary postoperative outcomes include the number of trichiatic lashes, location (touching the cornea or not), evidence of post-operative epilation, entropion, changes in corneal opacity, IOP elevation, need for cataract surgery, visual acuity change from the baseline, eyelid contour abnormality, granuloma, eyelid closure defect, and the occurrence of adverse events. Health economic analyses center on calculating the incremental cost per case of PTT avoided by fluorometholone treatment., Conclusion: The FLAME Trial is designed to provide evidence of the efficacy, safety, and cost-effectiveness of adjunctive topical peri-/postoperative fluorometholone 0.1% therapy with trichiasis surgery, which is hypothesized to reduce the risk of recurrent trichiasis while being acceptably safe., Clinical Trial Registration: https://www.clinicaltrials.gov/study/NCT04149210.

Purpose of Review: Meibomian gland dysfunction (MGD) is one of the most common disorders encountered by ophthalmologists, and its management can prove challenging for both clinicians and patients. Intense pulsed light (IPL), which has been historically used in the field of dermatology, has emerged as a tool to help improve meibomian gland function. The goal of this review is to assess the clinical efficacy, utility, and safety of IPL for the treatment of MGD., Recent Findings: In recent randomized controlled trials, IPL has been shown to improve meibomian gland function, and subsequently tear film quality and dry eye symptoms. The mechanism of action still remains unclear. Recent literature suggests that IPL may also be used in conjunction with other therapies, such as meibomian gland expression, low-level light therapy, and thermal pulsation. Careful attention should be placed on each patient's Fitzpatrick skin type, as well as protecting the ocular structures to reduce the risk of adverse effects. Cost, accessibility, as well as a limited duration of efficacy may be drawbacks., Summary: There is significant evidence supporting that IPL may be used as a potential well tolerated and effective treatment for MGD, though there are certain caveats regarding its long-term efficacy, accessibility, and cost., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the progression of dry eye disease (DED) symptoms and signs over 2 years through a secondary analysis of data collected from the Dry Eye Assessment and Management study., Methods: Participants who were assigned to omega-3 fatty acid in the first year were rerandomized in the second year to either continue with omega-3 fatty acid or switch to placebo. At baseline, 3, 6, 12, 18, and 24 months, DED symptoms were evaluated by using the Ocular Surface Disease Index and the Brief Ocular Discomfort Index (BODI). DED signs were assessed using conjunctival staining, corneal staining, tear break-up time, Schirmer testing, and keratography measures. Medication usage was documented at each visit. Because the treatment and placebo groups displayed no statistical differences in both signs and symptoms, data from the 43 participants were combined to assess longitudinal changes in symptoms and signs., Results: At 3 months after omega-3 fatty acid treatment, there were significant improvements from baseline in Ocular Surface Disease Index and Brief Ocular Discomfort Index scores (all P ≤ 0.002) and less use of artificial tears or gel ( P = 0.02), but between 3 and 24 months, no significant changes in symptoms and treatments were observed ( P ≥ 0.06). Except for a significant improvement in conjunctival staining score over 2 years ( P = 0.001), there were no significant sign changes in corneal staining ( P = 0.32), tear break-up time ( P = 0.43), Schirmer test ( P = 0.09), and additional measures (all P ≥ 0.07)., Conclusions: We did not observe a progression of DED signs or symptoms over a 2-year period, except for a probable placebo response in symptoms in the first 3 months and an improvement in conjunctival staining score., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The primary goal of this study was to develop a parametric model that relates variation in stimulation of the trigeminal nerve to properties of the blink response. We measured blink responses in 17 healthy, adult participants to air puffs directed at the lateral canthus of the eye at five different, log-spaced intensities (3.5-60 PSI). Lid position over time was decomposed into amplitude and velocity components. We found that blink amplitude was systematically related to log stimulus intensity, with the relationship well described by a sigmoidal function. The parameters of the model fit correspond to the slope of the function and the stimulus intensity required to produce half of a maximal blink response (the half-response threshold). There was a reliable increase in the half-response threshold for the contralateral as compared to the ipsilateral blink response. This increase was consistent across participants despite substantial individual differences in the half-response threshold and slope parameters of the overall sensitivity function, suggesting that the laterality effect arises in the neural circuit subsequent to individual differences in sensitivity. Overall, we find that graded mechanical stimulation of the somatosensory trigeminal afferents elicits a graded response that is well described by a simple parametric model. We discuss the application of parametric measurements of the blink response to the detection of group differences in trigeminal sensitivity., (© 2024 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Nicole Fuerst,1 Nicole Langelier,1 Mina Massaro-Giordano,1 Maxwell Pistilli,1 Kalliopi Stasi,1 Carrie Burns,2 Serena Cardillo,2 Vatinee Y Bunya1 1Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Purpose: To assess the relationship between tear osmolarity and dry eye symptoms in patients with diabetes. Patients and methods: Fifty patients with diabetes were enrolled. Demographic information and past medical history were recorded. Symptoms were assessed using the ocular surface disease index (OSDI). Tear osmolarity of each eye was measured with the TearLab® Osmolarity System. Results: The majority of the subjects were female (76%), African American (56%), and/or had a diagnosis of type 2 diabetes (82%). The mean ± standard deviation (SD) for age was 54.6±13.4, and maximum tear osmolarity was 304.6±12.7 mOsm/L. Men had higher osmolarity than women (mean ± standard error (SE) 311.8±4.0 mOsm/L versus 302.3±1.9 mOsm/L, P=0.02). Age, race, use of artificial tears, years of diabetes, and hemoglobin A1c did not have a statistically significant association with tear osmolarity. Longer duration of diabetes was associated with lower (less severe) OSDI scores (r=-0.35, P=0.01). Higher tear osmolarity was associated with lower (less severe) OSDI scores (r=-0.29, P=0.04). Conclusion: Approximately half of the diabetic subjects in our study had elevated tear osmolarity, and half of our population also reported symptoms consistent with dry eye disease. However, the two were slightly inversely related in that those with higher osmolarity reported fewer symptoms. Subjects with a longer duration of diabetes also reported fewer dry eye symptoms. Therefore, health care providers should be aware that patients who are most likely to have ocular surface disease, including those with long-standing diabetes, may not experience symptoms and seek care in a timely manner. Keywords: dry eye, osmolarity, diabetes

Purpose: To examine the ocular signs and symptoms in participants of the Sjögren's International Collaborative Clinical Alliance cohort, and to compare them across Sjögren's disease (SjD) status., Methods: Our study population comprised 3380 Sjögren's International Collaborative Clinical Alliance participants who had no missing data relevant to this study. Participants' SjD status was assessed using the updated 2016 American College of Rheumatism/European League Against Rheumatism SjD classification criteria. Participants completed baseline questionnaires of ocular symptoms and underwent ocular examinations. Differences in the ocular signs and symptoms between SjD and non-SjD groups were assessed. We used multivariable linear and linear mixed-effects models to investigate the impact of SjD on Ocular Surface Disease Index-6 and OSS., Results: Among 1532 participants classified as SjD, their Ocular Surface Disease Index-6 did not clinically differ from those classified as non-SjD (adjusted difference, -0.97; 95% confidence interval, -1.52 to -0.41). However, SjD participants exhibited an elevated ocular staining score (adjusted difference, 3.47; 95% confidence interval, 3.36-3.57; P < 0.001) compared with non-SjD participants. In addition, SjD was associated with increased odds of ocular signs, such as reduced tear break-up time, abnormal Schirmer I test, and corneal abnormalities, and was strongly related to more intense corneal and conjunctival staining, as well as additional corneal staining points., Conclusions: SjD is associated with a higher risk of ocular signs and pathology compared with non-SjD, whereas ocular symptoms remain similar. In addition, corneal abnormalities and corneal staining patterns could serve as a potential biomarker in identifying SjD-related dry eye.

Background/aims: To compare dry eye disease (DED) signs and symptoms between men and women, as well as between premenopausal and postmenopausal women, in the Dry Eye Assessment and Management (DREAM) study., Methods: 434 women and 101 men self-reported prior medical history and underwent a standardised DED assessment using the Ocular Surface Disease Index, Brief Pain Inventory, Tear Break-Up Time (TBUT)(s), Schirmer's test 2 (mm/5 min), National Eye Institute-graded lissamine conjunctival staining, corneal staining, meibomian gland dysfunction evaluation and tear osmolarity (mOsms/L) at baseline, 6 months and 12 months. Multivariable linear regression models were used to compare these scores., Results: Women experienced significantly worse DED signs than men with lower Schirmer's test scores (9.27 vs 12.16; p<0.001), higher corneal staining scores (3.59 vs 2.70; p=0.006) and worse composite DED sign scores (0.52 vs 0.40; p<0.001). Postmenopausal women experienced significantly worse DED signs than premenopausal women with higher corneal staining scores (3.74 vs 2.58, p<0.001), higher conjunctival staining scores (2.80 vs 2.22, p<0.001), higher tear osmolarity (304 vs 299, p=0.004), lower TBUT (3.37 vs 3.93, p=0.047), worse meibomian gland dysfunction (3.05 vs 2.62, p=0.04) and worse composite DED sign scores (0.54 vs 0.42, p<0.001). There were no significant differences in DED symptoms between sex and between premenopausal and postmenopausal women (all p≥0.08)., Conclusion: In the DREAM study, women experienced more severe DED signs than men. Further, postmenopausal women presented with more severe DED signs than premenopausal women. Elucidating these differences may improve DED diagnosis and provide future direction in understanding sex-related differences in DED., Trial Registration Number: NCT02128763., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To develop a screening questionnaire to identify patients with dry eye with a high likelihood of having underlying Sjögren syndrome (SS)., Methods: This was a cross-sectional study of participants with dry eye complaints who were self-referred or referred by an ophthalmologist to the Sjögren's International Collaborative Clinical Alliance study. Symptoms and ocular surface examination findings were candidate predictors. Univariable and multivariable logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of a symptom and/or ocular sign with SS. Area under the receiver operating characteristic curve (AUC) was used to summarize the predictive ability of different regression models and the derived likelihood score., Results: Four questions were statistically significant in the final multivariable model: 1) Is your mouth dry when eating a meal? [Yes = OR 1.63 (1.18-2.26)]; 2) Can you eat a cracker without drinking a fluid or liquid? [No = OR 1.46 (1.06-2.01)]; 3) How often do you have excessive tearing? [None of the time = OR 4.06 (1.81-9.10)]; and 4) Are you able to produce tears? [No = OR 2.24 (1.62-3.09)]. The SS likelihood score had an AUC of 0.70 (95% CI, 0.66-0.73), and when including tear break-up time and conjunctival staining, it yielded an AUC of 0.79 (95% CI, 0.77-0.82)., Conclusions: This questionnaire can be used to identify patients with dry eye with a high likelihood of having SS. With future refinement and validation, this screening tool could be used alone or in combination with examination findings to identify patients with SS earlier, thereby facilitating better clinical outcomes., Competing Interests: V. Y. Bunya: Bausch & Lomb (funding for research study); Celularity (consultant); Verily (consultant). E. K. Akpek: Allergan Inc. (institutional support), Novalique Gmb. (consultant), Regeneron (consultant), Sjogren's Syndrome Foundation (unpaid board member). M. Massaro-Giordano: Celularity (consultant); PRN (personal financial interest); Verily (consultant). F. B. Vivino: Novartis (consultant), Biogen-Idec (consultant), Celularity (consultant), Boston Pharmaceuticals (consultant) Bristol-Myers Squibb (consultant), Immco Diagnostics (consultant). A. N. Baer: Bristol-Myers Squibb (consultant), Abbvie (consultant), Sanofi (consultant). The remaining authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to compare objective, noninvasive assessments of tear function using the OCULUS Keratograph with the corresponding clinical assessments [tear break-up time (TBUT), Schirmer test, and bulbar erythema] among patients with moderate-to-severe dry eye disease., Methods: Participants in the Dry Eye Assessment and Management study at centers having an OCULUS Keratograph were assessed using standardized procedures. Associations between the assessments from the Keratograph [noninvasive keratograph break-up time (NIKBUT), tear meniscus height (TMH), and bulbar redness (BR)] and clinical examination (TBUT, Schirmer test, and bulbar erythema) and between these test results and Ocular Surface Disease Index (OSDI) scores were summarized with Spearman correlation coefficients (r s ); 95% confidence intervals (95% CI) accounted for intereye correlation., Results: Among 288 patients (576 eyes), the mean (standard deviation) age was 56.6 (13.8) years, 78.1% were female, and the mean baseline OSDI score was 44.3 (14.0). The mean was 2.9 (1.5) seconds for TBUT and 8.2 (5.7) seconds for NIKBUT (their correlation r s = 0.18, 95% CI = 0.09-0.28). The mean was 10.6 (7.6) mm for the Schirmer test and 0.3 (0.2) mm for TMH (r s = 0.15, 95% CI = 0.04-0.25). The median clinical grade redness was mild, and the mean BR score was 1.1 (0.5) (r s = 0.25, 95% CI = 0.15-0.35). Correlation between results of each of the 6 tests and OSDI scores was low (r s from -0.07 to 0.05)., Conclusions: In the Dry Eye Assessment and Management study, NIKBUT, TMH, and BR were weakly correlated with their clinical counterparts. No measurements were correlated with the OSDI score., Competing Interests: P. A. Asbell has received research funding from MC2 Therapeutics and Novartis; consultant fees from Novartis, ScientiaCME, Shire, and WebMD; and travel/financial compensation from Novartis, Santen, ScientiaCME, and Shire. V. Y. Bunya has received research funding from Bausch & Lomb/Immco Diagnostics and support from the National Eye Institute R01 EY026972. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Sjögren disease (SjD) cohorts represent rich resources to study associations between dry eye/mouth (sicca) signs/symptoms and depression. Because SjD affects mainly women, little is known about men with sicca signs/symptoms and associations with depression. The Sjögren's International Collaborative Clinical Alliance contained many men allowing for studying associations between sicca signs/symptoms and depression. We hypothesized that sicca symptoms would be positively associated with depression in males., Design: Cross-sectional study., Methods: At baseline, participants completed questionnaires and underwent ocular and oral examinations. Depression was assessed using the Patient Health Questionnaire-9. Logistic regression models were used to identify associations between depression and SjD diagnostic criteria and sicca symptoms., Results: Of 309 males, 98 were classified as SjD, whereas 198 were classified as non-SjD. We found that having a labial salivary gland biopsy with focus score ≥1 foci/mm 2 was associated with a lower odds of being classified as depressed (odds ratio [OR]: 0.36, 95% CI: 0.18-0.73, P = .01). Having positive anti-Sjögren syndrome antigen A antibody was associated with lower odds of being classified as depressed (OR: 0.44, 95% CI: 0.23-0.88, P = .02). Higher odds of depression were found with ocular burning (OR: 3.16, 95% CI: 1.74-5.73, P < .001), light sensitivity (OR: 2.59, 95% CI: 1.48-4.55, P = .001), and complaints of dry mouth (OR: 4.58, 95% CI: 1.54-13.63, P = .006)., Conclusion: Ophthalmologists should be specific when inquiring about ocular discomfort (focusing on burning and light sensitivity) and consider querying about depression and/or providing mental health resources to those who endorse such qualities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To evaluate how increasing age is associated with dry eye disease (DED) signs and symptoms in the Dry Eye Assessment and Management (DREAM) study. This study was undertaken to better understand how DED signs and symptoms differ across decades of life with goals to help assess detection and treatment of DED., Design: Secondary analysis of the DREAM study., Subjects: One hundred twenty, 140, 185, and 90 participants aged < 50, 50 to 59, 60 to 69, and ≥ 70 years, respectively., Methods: We performed a secondary analysis of data from the DREAM study, a multicenter randomized clinical trial, to evaluate the effect of omega-3 fatty acid supplementation for the treatment of DED. At baseline, 6 months, and 12 months follow-up, participants underwent an assessment of DED symptoms and signs using Ocular Surface Disease Index, Brief Pain Inventory, tear break-up time (TBUT) (in seconds), Schirmer test with anesthesia (mm/5 minutes), conjunctival staining, corneal staining, meibomian gland dysfunction evaluation, and tear osmolarity (mOsm/l). Multivariable generalized linear regression models were used to compare DED symptoms and signs across the 4 age groups among all participants and by sex., Main Outcome Measures: Scores of DED symptoms, individual signs, and composite scores of DED signs., Results: Among 535 patients with DED, increasing age was significantly associated with worse TBUT ( P  = 0.01), corneal staining ( P < 0.001), a composite severity score of DED signs ( P  = 0.007), and tear osmolarity ( P  = 0.001). Similar significant differences were found across 4 age groups of 334 women in TBUT, corneal staining score, composite severity score of DED signs, and tear osmolarity (all P < 0.05) but not in men., Conclusion: We found that corneal staining, TBUT, tear osmolarity, and a composite severity score of DED signs were significantly more severe with increasing age in women but not in men; worsening symptoms did not increase with increasing age., Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article., (© 2023 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Objective: Although symptom relief is a critical aspect for successful drug development in Sjögren's disease, patient experiences with Sjögren's-related symptoms are understudied. Our objective was to determine how pain, dryness, and fatigue, the cardinal symptoms of Sjögren's disease, drive cluster phenotypes., Methods: We used data from the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry and a Sjögren's Foundation survey. We performed hierarchical clustering of symptoms by levels of dryness, fatigue, and pain. Using international and US cohorts, we performed multiple logistic regression analysis to compare the clusters, which included comparisons of differences in symptoms, quality of life (QoL), medication use, and systemic manifestations., Results: Four similar clusters were identified among 1,454 SICCA registrants and 2,920 Sjögren's Foundation survey participants: 1) low symptom burden in all categories (LSB); 2) dry with low pain and low fatigue (DLP); 3) dry with high pain and low to moderate fatigue (DHP); and 4) high symptom burden in all categories (HSB). Distribution of SICCA registrants matching the symptom profile for each cluster was 10% in the LSB cluster, 30% in the DLP cluster, 23% in the DHP cluster, and 37% in the HSB cluster. Distribution of survey participants matching the symptom profile for each cluster was 23% in the LSB cluster, 14% in the DLP cluster, 21% in the DHP cluster, and 42% in the HSB cluster. Individuals in the HSB cluster had more total symptoms and lower QoL but lower disease severity than those in the other clusters. Despite having milder disease as measured by laboratory tests and organ involvement, individuals in the HSB cluster received immunomodulatory treatment most often., Conclusion: We identified 4 symptom-based Sjögren's clusters and showed that symptom burden and immunomodulatory medication use do not correlate with Sjögren's end-organ or laboratory abnormalities. Findings highlight a discordance between objective measures and treatments and offer updates to proposed symptom-based clustering approaches., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

To gain insight into the Sjögren's disease (SjD) patient experience using a survey generated by patients and providers. We evaluated the results of the 2016 Sjögren's Foundation survey, with 25 questions designed in a collaborative effort between the Foundation, patients with SjD, SjD provider experts, and a marketing research company. We used descriptive statistics to provide a thorough understanding of SjD demographics, symptoms, quality of life (QoL), cost, and treatments. Analyses revealed high symptoms, QoL, and financial burdens in SjD. Dry mouth and eye were the most commonly reported symptoms (94 and 93%, respectively). The most frequent extra-glandular symptoms included fatigue, dry or itchy skin, and morning stiffness. The top three aspects of QoL most impaired included (i) sex life (53%), (ii) participating in hobbies/social activities/extracurricular activities (52%), and (iii) job/career or ability to work (49%). SjD respondents commonly reported taking health food supplements/remedies, vitamin D, and exercising, in addition to taking treatments for symptomatic dryness. SjD costs were high, including a total yearly cost, on average, of $2026 for dental care. SjD respondents reported that dryness and risk factors for lymphoma and fatigue are essential to address with new therapies. In this comprehensive overview of the SjD experience, we demonstrated a high burden of disease to SjD respondents, including symptoms, QoL, and financial burden. We also identify the top goals of therapy for new systemic SjD therapies. Key Points • The top three symptoms or signs that patients with Sjögren's hope new treatments will address are dryness, fatigue, and reduction in lymphoma or blood cancer risk • The top aspects of quality of life reported to be impaired by Sjögren's are sex life, hobbies, social activities and extracurricular activities, job/career or ability to work, and finding the correct word during conversations • Patients with Sjögren's have a yearly mean dental cost of $2026 but also have high costs associated with prescription medications, healthcare appointments, over-the-counter medications, alternative therapies, and medical equipment., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: The objective of this study was to examine the association of smoking with Primary Sjögren syndrome (pSS) classification and pSS diagnostic test results. We hypothesized that past and current smokers would have lower odds of being classified as having Sjögren syndrome (SS) and lower odds of having abnormal individual SS diagnostic test results compared with nonsmokers., Methods: Participants with suspected or established pSS were enrolled into the Sjögren's International Collaborative Clinical Alliance (SICCA) registry and had oral, ocular, and rheumatologic examinations performed; blood and saliva samples collected; and labial salivary gland biopsy examinations performed; they also completed questionnaires at baseline. Logistic regression was used to determine whether smoking status was associated with pSS classification and individual pSS diagnostic test results., Results: A total of 3514 participants were enrolled in SICCA. A total of 1541 (52.9%) met classification criteria for pSS. Compared with never smokers, current smokers had reduced odds of being classified as having pSS, reduced odds of having a focus score ≥ 1 and serologic positivity for anti-SSA/anti-SSB antibodies, and lower odds of having abnormal signs or test results of dry eye disease. Compared with never smokers, past smokers did not have a statistically significant reduction in odds of being classified as having pSS and of having abnormal individual pSS diagnostic test results., Conclusion: Compared with never smokers, current smokers in the SICCA cohort had lower odds of being classified as having pSS, lower odds of exhibiting abnormal signs and test results for dry eye disease, and lower odds of having a labial salivary gland biopsy supportive of pSS classification. Such negative associations, however, do not suggest that current smoking is of any benefit with respect to pSS., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Sjögren's syndrome (SS) is frequently undetected or misdiagnosed as other rheumatologic diseases. We aimed to develop an SS screening questionnaire for the rheumatology practice., Methods: We developed the Sjögren's Syndrome Screening Questionnaire (SSSQ) via secondary analysis of data from 974 participants referred by rheumatologists to the Sjögren's International Collaborative Clinical Alliance (SICCA) study. Participants answered 88 questions regarding symptoms, medical history, and demographics. They underwent ocular, dental, and serologic tests and were classified as SS or non-SS using the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria. We conducted univariate and multivariate logistic regression to identify questions most discriminative of SS, from which we derived an individual's likelihood of SS ("SSSQ score")., Results: Five questions were significantly discriminative of SS in the multivariate analysis (p < 0.05): (1) Can you eat a cracker without drinking a fluid/liquid? (no: odds ratio [OR], 1.39; 95% confidence interval [CI], 1.06-1.82]); (2) How would you describe your dental and oral health in general? (fair/poor: OR, 1.68; 95% CI, 1.04-2.75); (3) During the last week, have you experienced tearing? (none of the time: OR, 2.26; 95% CI, 1.23-4.34); (4) Are you able to produce tears? (no: OR, 1.62; 95% CI, 1.12-2.37); and (5) Do you currently smoke cigarettes? (no: OR, 2.83; 95% CI, 1.69-4.91). SSSQ score ≥7 (possible range, 0-11) distinguishes SS from non-SS patients with 64% sensitivity and 58% specificity (area under receiver operating characteristic curve, 0.65)., Conclusions: The SSSQ is a simple 5-item questionnaire designed to screen for SS in clinical practice, with a potential impact to reduce delays in diagnosis., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To define the association between oral and systemic manifestations of Sjögren syndrome (SS) and quality of life (QOL)., Methods: We analyzed a cross-sectional survey conducted by the Sjögren's Foundation in 2016, with 2961 eligible responses. We defined oral symptom and sign exposures as parotid gland swelling, dry mouth, mouth ulcers/sores, oral candidiasis, trouble speaking, choking or dysphagia, sialolithiasis or gland infection, and dental caries. Systemic exposures included interstitial lung disease, purpura/petechiae/cryoglobulinemia, vasculitis, neuropathy, leukopenia, interstitial nephritis, renal tubular acidosis, autoimmune hepatitis, primary biliary cholangitis, or lymphoma. Outcomes included SS-specific QOL questions generated by SS experts and patients., Results: Using multivariable regression models adjusted for age, sex, race, and employment, we observed that mouth ulcers or sores, trouble speaking, and dysphagia were associated with poor quality of life. The following oral aspects had the greatest effect on the following QOL areas: (1) mouth ulcers/sores on the challenge and burden of living with SS (OR 4.26, 95% CI 2.89-6.28); (2) trouble speaking on memory and concentration (OR 4.24, 95% CI 3.28-5.48); and (3) dysphagia on functional interference (OR 4.25, 95% CI 3.13-5.79). In contrast, systemic manifestations were associated with QOL to a lesser extent or not at all., Conclusion: Oral manifestations of SS, particularly mouth ulcers or sores, trouble speaking, and dysphagia, were strongly associated with worse QOL. Further study and targeted treatment of these oral manifestations provides the opportunity to improve quality of life in patients with SS., (Copyright © 2021 by the Journal of Rheumatology.)

Objective: To evaluate how ocular, oral, and bodily neuropathic pain symptoms, which characterize small fiber neuropathies, are associated with Sjögren's syndrome (SS) classification based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria., Methods: Participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry had ocular, rheumatologic, oral, and labial salivary gland (LSG) biopsy examinations, blood and saliva samples collected, and completed questionnaires at baseline. We used mixed effects modeling with age, country, gender, and depression being fixed effects and study site, a random effect, to determine if neuropathic pain indicators (assessed via questionnaires) were associated with being classified as SS., Results: A total of 3,514 participants were enrolled into SICCA, with 1,541 (52.9%) meeting the 2016 ACR/EULAR classification criteria for SS. There was a negative association between being classified as SS and experiencing bodily neuropathic pain features of needle-like pain, prickling/tingling sensation, ocular neuropathic pain of constant burning, and constant light sensitivity, and having a presumptive diagnosis of neuropathic oral pain., Conclusions: We found that those classified as SS had lower scores/reports of painful neuropathies compared with those classified as non-SS. Non-SS patients with dry eye disease or symptoms could benefit from pain assessment as they may experience painful small-fiber neuropathies (SFNs). Pain questionnaires may help identify pain associated with SFNs in patients with SS and non-SS dry eye. Future studies would be helpful to correlate self-reports of pain to objective measures of SFNs in those with SS, non-SS dry eye, and healthy controls., (© 2021 World Institute of Pain.)

The purpose of this review is to delve into the clinical and research understanding of the pathophysiology and presentation of Sjögren's-related keratoconjunctivitis sicca in order address the diagnostic and management challenge that it represents, as well as to provide a basis for appreciating the pharmacotherapies designed to treat the ophthalmic symptoms of Sjögren's disease.

Background: Although dupilumab has been associated with the development of conjunctivitis, little is known about other ocular surface disorders such as dry eye and how these side effects are managed., Objective: To evaluate the incidence and management of ocular surface disorders, including dry eye and conjunctivitis, among patients treated with dupilumab., Methods: Using US claims data, we evaluated the incidence of encounters for ocular surface disorders among patients treated with dupilumab. Secondary outcomes included ophthalmic medication use. A propensity score matched, active-comparator, new-user cohort design was used to compare the incidence of ocular surface disorders between those starting dupilumab versus methotrexate., Results: Among those with a history of atopic dermatitis, encounters for ocular surface disorders were more common in the 6 months after starting dupilumab than in the 6 months prior (11.7% versus 8.7%, P  < .001); 59.7% of those with a new ocular surface disorder diagnosis filled a prescription for an ophthalmic medication. The incidence of ocular surface disorders was higher among those treated with dupilumab than that in those treated with methotrexate (odds ratio 1.64; 95% confidence interval 1.17-2.30)., Limitations: Observational design., Conclusions: Dupilumab use for atopic dermatitis was associated with an increased risk of ocular surface disorders. Most patients who developed an ocular surface disorder received a prescription for an ophthalmic medication., Competing Interests: Dr Margolis was a member of joint Sanofi/Regeneron Data Safety and Monitoring Board for studies of dupilumab; he left the Data Safety and Monitoring Board about 2 years ago. He receives research funding to the Trustees of the University of Pennsylvania from the NIH-NIAMS and Valiant for unrelated studies of atopic dermatitis. He was on an advisory board sponsored by Leo, which disbanded about 2 years ago, and is currently a consultant for Leo both with respect to atopic dermatitis. Dr Bunya has served as a consultant for Verily and receives grant funding from 10.13039/100007489Bausch and Lomb for an unrelated study. Dr Massaro-Giordano has served as a consultant for Verily and was on advisory boards sponsored by Dompe and Lynthera. Author Barbieri has no conflicts of interest to declare. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (© 2021 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Purpose: This systematic review examines the specific effects of pingueculum and pterygium on the ocular surface and evaluates the efficacy of surgical excision in reversing those effects., Methods: A systematic review was performed according to the Preferred Reporting Items for the Systematic Review and Meta-Analyses statement and included 59 articles studying the effects of pterygium and pingueculum on the ocular surface as measured by tear break-up time (TBUT), Schirmer testing, tear osmolarity, Ocular Surface Disease Index (OSDI), and the effects of surgical removal on these ocular surface parameters., Results: In most studies, eyes with pterygium or pingueculum when compared with control eyes had a statistically significantly lower TBUT (average 3.72 s), lower Schirmer I without anesthesia (average 3.01 mm), lower Schirmer II (average 4.10 mm), higher tear osmolarity (average 12.33 mOsm/L), and higher OSDI (average 6.82 points). Moreover, excision of pterygium and pingueculum led to a statistically significantly higher TBUT (average 3.15 s higher at 1 mo postexcision), lower tear osmolarity (average 3.10 mOsm/L lower at 3 mo postexcision), and lower OSDI score (average 2.86 points lower 1 mo postexcision) in most of the studies. The effect of excision on Schirmer test scores was equivocal because most studies did not reach significance., Conclusions: Our data confirm the relationship between pterygium and pingueculum and abnormal tear function and symptoms of dry eye disease. Furthermore, the data suggest that tear film parameters might improve after surgical removal of pterygium or pingueculum. Future studies would be helpful in exploring the potential role of pterygium and pingueculum excision in the management of dry eye disease., Competing Interests: V. Y. Bunya is a consultant for Verily and has received funding from the National Eye Institute (R01 EY026972), Research to Prevent Blindness, and Bausch & Lomb. M. M.-Giordano is a consultant for Dompe, Lynthera, and PRN. The remaining authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To compare the burden related to dry eye with systemic symptoms of Sjögren syndrome; to estimate the burden related to ocular treatments; and to compare the impact of dry eye and extraocular manifestations of Sjögren syndrome on various aspects of patient life., Design: Cross-sectional study., Methods: We conducted a postal survey of adult patients with a history of physician-diagnosed Sjögren syndrome., Results: The survey was completed by 2,961 patients (mean age 65.1 years, standard deviation 11.7 years), most of whom were women (96%) and white (94%). Forty-one patients younger than 18 years of age were excluded. More than half (53%) experienced severe dry eye (ie, dry eye daily/almost daily with major impact on their life). Corresponding proportions for dry mouth and fatigue were 48% and 45%, respectively. Almost all patients (97%) had used nonprescription eye drops/artificial tears/ointments. Compared with patients who did not experience dry eye, those who experienced significant dry eye (ie, daily/almost daily dry eye) more often agreed that living with Sjögren syndrome made every day a challenge (adjusted odds ratio [OR] 3.81, 95% confidence interval [CI] 2.49 to 5.86) and added a significant emotional burden (adjusted OR 2.22, 95% CI 1.49 to 3.31). Adjusted ORs for the impact of dry eye were generally lower than those for fatigue, but were similar to dry mouth and considerably higher than use of systemic treatments for serious manifestations of the disease and diagnosis of lymphoma., Conclusions: Sjögren-related dry eye is more burdensome than systemic manifestations of the disease. While fatigue has the greatest impact on patient life, the impact of dry eye is comparable to that of other systemic manifestations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To describe associations between symptoms and signs of dry eye disease (DED) and meibomian gland (MG) morphology., Methods: Cross-sectional study utilizing data from the Dry Eye Assessment and Management (DREAM) Study. Readers graded MG features in the middle third of upper and lower lids on infrared meibography images. Associations with signs and symptoms of DED were evaluated with adjustment for age and sex., Results: Among 268 patients, no MG features were associated with symptom scores (p > 0.08). Among 394 upper eyelids, better tear break-up times (<2, >2- <3.2and ≥ 3.2 s) were associated with more tortuous glands (mean (SD) 0.58(0.95), 0.83(1.2) and 1.14 (1.4), p = 0.01) and with higher scores on a composite score of MG features (21.90 (9.76), 23.29 (9.50), 26.26 (10.27); p = 0.02). Longer Schirmer test wetting lengths (0-5, >5-10, and >10 mm) were associated with increasing composite scores (22.02 (9.29), 23.80 (10.34), 24.96 (9.96), p = 0.03). Patients with Sjogren syndrome compared to other patients had fewer distorted MGs (mean 3.4 (2.3) vs 4.3 (2.3), p = 0.03) and fewer ghost glands (mean 0.33 (0.88) vs 0.89 (1.8), p = 0.006) in the upper lid., Conclusion: In the DREAM study, most MG morphologic features were not associated with the severity of DED symptoms or signs. Tortuous glands and a higher composite score for MG features were associated with longer tear break-up times and longer Schirmer test length in the upper eyelid only. Patients with Sjogren syndrome had fewer distorted and ghost glands., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: To evaluate the ocular signs and tests for keratoconjunctivitis sicca (KCS) in the absence of a gold standard., Methods: Cross-sectional study of participants from the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Participants had oral/ocular/rheumatologic examinations, blood/saliva samples collected, and salivary gland biopsy. Latent class analysis (LCA) identified clusters of patients based on 3 to 4 predictor variables relating to signs or tests of KCS. The resulting model-based "gold standard" classification formed the basis for estimated sensitivity and specificity associated with these predictors., Results: A total of 3514 participants were enrolled into SICCA, with 52.9% classified as SS. LCA revealed a best-fit model with 2 groups. For the gold standard-positive group, an abnormal tear breakup time, ocular staining score (OSS), and Schirmer I had a sensitivity of 99.5%, 91.0%, and 47.4%, respectively. For the gold standard-negative group, an abnormal tear breakup time, OSS, and Schirmer I had a specificity of 32.0%, 84.0%, and 88.5%, respectively. OSS components (fluorescein and lissamine staining), exhibited a sensitivity of 82.6% and 90.5%, respectively, in the gold standard-positive group, whereas these signs in the gold standard-negative group had a specificity of 88.8% and 73.0%, respectively., Conclusions: OSS and its components (fluorescein and lissamine staining) differentiated 2 groups from each other better than other KCS parameters and had relatively high sensitivity and specificity.

Purpose: Reliable assessment is critical for diagnosing and managing meibomian gland dysfunction. Multi-functional diagnostic devices, such as meibographers, streamline clinical workflows by integrating multiple ocular assessments. Ensuring reproducibility across examiners is vital for accurate diagnosis and monitoring of treatment. This prospective study determined the inter-examiner reproducibility (IER), inter-rater reproducibility (IRR) and within-subject variability (WSV) of the Huvitz HRK-9000A meibographer., Methods: Meibomian glands (MGs) of both eyelids of healthy participants were captured during the same session by Examiner 1 (E1) and Examiner 2 (E2) in a counter-balanced design. The images were rated offline by E1, E2 and an Independent rater (R1). The inter-examiner reproducibility (IER between E1 vs. E2) and inter-rater reproducibility (IRR between E1 vs. R1 and E2 vs. R1) were determined based on non-parametric Bland-Altman plots, intraclass correlation coefficients (ICCs) and weighted Kappa (κ) values. Within-subject variability (WSV) was determined using ICCs., Results: Mean MG loss of the upper (E1: 1.0 ± 0.8 vs. R1: 0.9 ± 0.8, E2: 1.2 ± 0.8 vs. R1: 0.9 ± 0.7) and lower eyelids (E1: 1.9 ± 0.9 vs. R1: 2.1 ± 1.1, E2: 1.5 ± 1.0 vs. R1: 1.8 ± 1.0) of 35 participants (mean age 22 ± 3 years, range 19-30) was significantly correlated (p < 0.001) for all pairs of examiners (E1-E2, E1-R1 and E2-R1), but was significantly different for the upper eyelids of E2 vs. E1 (p < 0.002) and E2 vs. R1 (p < 0.003). Median differences between pairs of raters for both eyelids were close to zero, with >74% of comparisons falling within the interquartile range, except for the upper eyelids of E2 vs. E1 and E2 vs. R1 (63% and 66%, respectively). IRR demonstrated moderate agreement (0.43-0.57) with good reliability (ICC range 0.76-0.86) for the upper eyelids and good agreement (0.60-0.65) with good reliability (ICC range 0.85-0.88) for the lower eyelids. The WSV was excellent (ICCs for repeated measurements > 0.90)., Conclusions: The HRK-9000A meibographer demonstrated excellent reliability, with good inter-examiner and inter-rater reproducibility. It is suitable for meibographic assessment, follow-up or treatment., (© 2025 College of Optometrists.)

Purpose: To evaluate the prevalence of novel candidate autoantibodies associated with Sjögren syndrome (SS) and their ability to identify those with SS among participants with dry eye enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) study at the University of Pennsylvania (Penn)., Methods: All participants previously underwent a full ocular and systemic evaluation for possible SS as part of the SICCA study. An enzyme-linked immunosorbent assay was used to detect IgG, IgA, and IgM autoantibodies to salivary protein 1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase 6 from previously banked baseline serum samples from SICCA study participants enrolled at Penn. The prevalence rate of each autoantibody, calculated by considering the presence of any isotype as antibody positive, was compared between participants with dry eye with SS (n = 81) or without SS (n = 129) using the Fisher exact test., Results: The prevalence of SP-1 IgM autoantibodies was higher in those with SS compared with those without SS (14% vs. 5%; P = 0.03). Similarly, the prevalence of PSP IgA autoantibodies was higher in those with SS compared with non-SS dry eye participants (21% vs. 11%; P = 0.048). There was no statistically significant difference in the prevalence of carbonic anhydrase 6 autoantibodies between those with or without SS (15% vs. 20%; P = 0.36)., Conclusions: In the Penn SICCA cohort, SP-1 IgM and PSP IgA autoantibodies were more prevalent in the serum of SS-related dry eye participants compared with those without SS. Further longitudinal studies are needed to determine the clinical significance of these findings.

Here we present a miniaturized analog of a blinking human eye to reverse engineer the complexity of the interface between the ocular system and the external environment. Our model comprises human cells and provides unique capabilities to replicate multiscale structural organization, biological phenotypes and dynamically regulated environmental homeostasis of the human ocular surface. Using this biomimetic system, we discovered new biological effects of blink-induced mechanical forces. Furthermore, we developed a specialized in vitro model of evaporative dry-eye disease for high-content drug screening. This work advances our ability to emulate how human physiological systems interface with the external world, and may contribute to the future development of novel screening platforms for biopharmaceutical and environmental applications.

Purpose: To describe and evaluate a comprehensive grading system for meibomian gland (MG) digital infrared images developed for the Dry Eye Assessment and Management (DREAM) Study., Methods: Cross-sectional study. Reading Center (RC) certified readers independently evaluated MG features of both lids from meibography images of dry eye disease subjects. Dropout areas were measured using planimetry software. Inter-reader and grade-regrade agreement and comparison of meiboscale scores (Meiboscale © ; Pult) from clinical centers to RC percent dropout and of MG features with clinical parameters were evaluated., Results: Among 551 eyes of 277 patients at baseline, 62 (11%) upper lid and 5 (1%) lower lid images were missing. Lid eversion was poor in 63 (13%) of upper lids compared to 15 (3%) of lower lids. Intraclass correlation for inter-reader and grade-regrade agreement was moderate to substantial for most MG features. MG features were more frequent in the upper lid (p < 0.001), except for dropout glands, gaps, fluffy gland areas and dropout areas. Clinic meiboscale score was associated with RC percent dropout (p < 0.001), a clinic score of 0% having a mean RC score of 19%, and a clinic score of >75% having a mean RC score of 66%. MG plugging was associated with ghost glands (p = 0.009), dropout glands (p < 0.001) and a composite severity score (p = 0.02); turbid and absent secretions were associated with ghost glands (p = 0.046)., Conclusion: RC readers identified MG features with good reproducibility. Upper lids had more MG features. RC dropout areas correlated well with clinic meiboscale scores. Ghost glands were associated with paste like and absent meibomian secretions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To determine whether signs and symptoms of ocular surface disease improve after placement of a self-retained, cryopreserved amniotic membrane (CAM) in patients with Sjögren syndrome (SS)., Methods: The medical records of SS patients who received a self-retained CAM implant (Prokera or Prokera Slim; TissueTech Inc, Doral, FL) for the treatment of ocular surface disease between August 2012 and August 2016 at a single, large academic institution were reviewed retrospectively. Visual acuity, results of slit-lamp examination of the cornea and conjunctiva, and dry eye symptoms, were evaluated before and after CAM insertion., Results: A total of 6 eyes of 6 patients (all female; mean age, 62.5 ± 13.0 years [range, 49-86 years]) were included. All patients were on topical medications at the time of the study and had signs of ocular surface dryness. There were reductions in corneal and/or conjunctival staining in 5 eyes (83%) after the CAM dissolved. All patients who completed therapy (5/5) experienced a relapse in their signs and symptoms within 1 month of removal of the CAM, with an average time to relapse of 24.6 days. Mean follow-up time was 54.5 days. Foreign body sensation and blurred vision were the most common complaints associated with the CAM implant., Conclusions: In this small case series, self-retained CAM implantation was found to be beneficial in SS patients with ocular surface disease that is refractory to standard therapies; however, we found that the effects were temporary. Future larger studies are needed to confirm these benefits.

Significance: Identification of the association of specific signs of dry eye disease with specific visual function deficits may allow for more targeted approaches to treatment., Purpose: The purpose of this study was to explore the association of dry eye signs and symptoms with visual acuity (VA) and contrast sensitivity in the Dry Eye Assessment and Management study., Methods: Baseline data from participants in the Dry Eye Assessment and Management study were used in this secondary cross-sectional analysis. Standardized procedures were used to obtain results on the Ocular Surface Disease Index (OSDI), high-contrast logMAR VA, contrast sensitivity, tear film debris, tear breakup time (TBUT), corneal fluorescein staining, meibomian gland evaluation, conjunctival lissamine green staining, and Schirmer test scores. Generalized linear models that included age, refractive error status, and cataract status were used to assess the association between VA and contrast sensitivity with OSDI score and each dry eye sign. The Hochberg procedure was used to account for multiple comparisons., Results: Among 487 participants (974 eyes), worse VA was associated with worse mean score on the OSDI vision subscale (39.4 for VA 20/32 or worse vs. 32.4 for VA 20/16 or better; adjusted linear trend, P = .02); scores were not associated with contrast sensitivity. Severe meibomian gland plugging and abnormal secretions were associated with worse mean log contrast sensitivity (1.48 for severe vs. 1.54 for not plugged [P = .04] and 1.49 for obstructed vs. 1.57 for clear [P = .002], respectively). Longer TBUT was associated with better mean log contrast sensitivity (1.57 for TBUT >5 seconds and 1.51 for TBUT ≤2 seconds, P < .0001)., Conclusions: Worse VA rather than worse contrast sensitivity drives vision-related symptoms in dry eye. Greater tear film instability was associated with worse contrast sensitivity.

Purpose: Sjögren's syndrome (SS) is a common autoimmune disease affecting about four million Americans. Although approximately 1 in 10 patients with clinically-significant aqueous deficient dry eye has underlying SS, widespread underappreciation of SS leads to significant underdiagnosis, delays in diagnosis, and consequent morbidity and mortality. The purpose of this article is to illustrate that in addition to dry eye, SS can cause serious, vision-threatening extraglandular ocular manifestations., Methods: We conducted a narrative review of studies that have examined the dry eye and extraglandular ocular complications of SS., Results: SS-related dry eye is a progressive condition with major negative impact on the quality-of-life of afflicted patients, not only due to symptoms of ocular discomfort but also visual dysfunction. In addition, SS can lead to corneal melt/perforation, uveitis, scleritis, retinal vasculitis, and optic neuritis. A major problem with currently-available SS disease activity measurement instruments is the lack of domains evaluating dry eye-related visual dysfunction. For example, one of the most commonly-used instruments for assessing patient symptoms in SS (the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]) only includes one item (out of three) that addresses the severity of overall dryness, without mention of dry eye symptoms or vision-related quality-of-life. Similarly, no extraglandular ocular complications are included in currently-available SS disease activity instruments (e.g., the EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI])., Conclusions: There needs to be a paradigm shift in which eye care providers and rheumatologists become more familiar with various SS-related extraglandular ocular manifestations. Existing disease activity measurement instruments must incorporate dry eye symptoms, particularly those related to visual dysfunction. An evidence-based screening algorithm for determining which patients with dry eye should be tested for underlying SS may be particularly helpful in preventing delays in diagnosis.

Purpose of Review: The prevalence and burden of dry eye disease continues to grow at a rapid pace, creating an increased need for new therapies. In a sector once limited to only a handful of treatments, clinicians now have multiple options available for patients who fail traditional therapies. This review summarizes the various treatment options available to clinicians treating complex dry eye disease patients., Recent Findings: As we better understand the multifactorial mechanisms leading to dry eye disease, treatments increasingly focus on the amelioration of the underlying deficiencies and inflammation, rather than on transient symptomatic relief alone. Most topical medications seek to replace deficient growth factors and/or decrease inflammation on the ocular surface. The majority of new devices and procedures seek to treat meibomian gland dysfunction, with one new device stimulating tear production through utilizing the nasolacrimal reflex pathway., Summary: Clinicians have more options at their disposal in the treatment of dry eye disease than ever before, including topical medications and devices.

Background: The Primary Sjögren's Syndrome Quality of Life questionnaire (PSS-QoL) is the first specific instrument to assess health-related quality of life (HRQoL) in Sjögren's disease (SjD). The aim is to translate and cross-culturally adapt the PSS-QoL into Brazilian Portuguese and to evaluate its psychometric properties., Methods: The original English version was translated into Brazilian Portuguese by two native Brazilians who were proficient in the English language. The retranslation was conducted by two native Americans proficient in Brazilian Portuguese. A committee undertook an analysis of the translated and retranslated versions, resulting in the generation of the first Brazilian version, which was submitted to the cross-cultural adaptation phase. In this phase, 50 participants with SjD responded to the instrument in Stages I and II, resulting in the generation of the second and final Brazilian version. To assess the psychometric properties, demographic and clinical data were collected from 75 patients. The HRQoL questionnaires (final Brazilian version of the PSS-QoL, Short Form-36 Health Survey (SF-36) and EuroQoL-5 dimension (EQ-5D)) were completed. Construct validity was analyzed using the Pearson or Spearman correlation coefficient. Reliability was analyzed using Cronbach's alpha and the intraclass correlation coefficient (ICC)., Results: Eight questions and one response item were revised due to an incomprehension rate of greater than 15% among the participants in the cross-cultural adaptation phase. The final Brazilian version of the PSS-QoL was validated, revealing a high correlation between the total score and functional capacity (r= -0.713, p < 0.001), and vitality (r= -0.770, p < 0. 001) and mental health (r= -0.742, p < 0.001) domains of the SF-36 and a moderate correlation with the other domains of the SF-36 and a moderate correlation with the EQ-5D-tto (r= -0.573, p < 0.001), and EQ-5D-VAS (r= -0.559, p < 0.001). The intraobserver (ICC = 0.939; Cronbach's alpha = 0.964) and interobserver (ICC = 0.965; Cronbach's alpha = 0.964) reliability of the total score showed very high consistency., Conclusion: The Brazilian version of the PSS-QoL has been demonstrated to be a valid and reproducible instrument for the assessment of HRQoL in patients with SjD., (© 2024. The Author(s).)

Purpose: To compare the effects of 2% rebamipide clear solution and 0.1% sodium hyaluronate eye drops in patients with visual display terminal (VDT)-related dry eye disease (DED)., Design: Prospective, randomized, double-blinded Study., Methods: This was a prospective, double-blind, and randomized controlled study. Patients with VDT-related DED were randomly allocated to a 2% rebamipide (REB) group or a 0.1% sodium hyaluronate (HYA) group (4 times/day for 4 weeks). The ocular surface disease index (OSDI), dry eye questionnaire-5 (DEQ-5), Placido disk-tear film analyzer, fluorescein-stained tear break-up time (FBUT), ocular surface staining score, and Schirmer 1 test were examined before and after the instillation of drug., Results: A total of 56 eyes of 28 patients (28 eyes of 14 patients in each group) were included. There were no significant differences in the baseline data. The OSDI, DEQ-5, FBUT, and conjunctival erosion scores improved significantly in both groups after treatment. In the REB group, corneal staining and bulbar nasal redness scores also improved significantly after treatment ( P <0.001 and 0.036, respectively), whereas no significant differences were found in these parameters in the HYA group ( P =0.326 and 0.118, respectively). The REB group showed a significantly larger decrease in the corneal staining score than the HYA group ( P =0.016). No adverse reactions were observed., Conclusions: A 2% rebamipide clear solution effectively improved the symptoms and signs in patients with VDT-related DED and was superior to 0.1% sodium hyaluronate ophthalmic solution in improving corneal epithelial damage, making it a safe and effective treatment option for VDT-related DED., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Contact Lens Association of Ophthalmologists.)

Objective: To survey ophthalmologists about current practice patterns regarding the evaluation of dry eye patients and referrals for a Sjogren syndrome (SS) workup., Methods: An online survey was sent to ophthalmologists affiliated with the Scheie Eye Institute or Wills Eye Hospital using REDCap in August 2015. Descriptive statistics were used to summarize the data., Results: Four hundred seventy-four survey invitations were sent out and 101 (21%) ophthalmologists completed the survey. The common traditional dry eye test performed was corneal fluorescein staining (62%) and the most common newer dry eye test performed was tear osmolarity (18%). Half of respondents (51%) refer fewer than 5% of their dry eye patients for SS workups, with 18% reporting that they never refer any patients. The most common reasons for referrals included positive review of systems (60%), severe dry eye symptoms (51%) or ocular signs (47%), or dry eye that is refractory to treatment (42%). The majority (83%) felt that there is a need for an evidence-based standardized screening tool for dry eye patients to decide who should be referred for evaluation for SS., Conclusions: Ophthalmologists continue to prefer the use of traditional dry eye tests in practice, with the most common test being corneal fluorescein staining. There is an underreferral of dry eye patients for SS workups, which is contributing to the continued underdiagnosis of the disease. Most respondents felt that there was a need for an evidence-based standardized screening tool to decide which dry eye patients should be referred for SS evaluations.

Purpose: To evaluate the prevalence of novel candidate Sjogren syndrome (SS) autoantibodies [salivary protein-1 (SP-1), parotid secretory protein, carbonic anhydrase 6] in the DRy Eye Assessment and Management (DREAM) cohort, a study evaluating the effectiveness of omega-3 fatty acid supplements for the treatment of dry eye., Methods: Participants underwent ocular surface examinations and serological testing for traditional and novel SS autoantibodies. Dry eye assessment and management participants were categorized into the following 3 groups: 1) no history of SS or other autoimmune diseases and negative traditional SS autoantibodies (n = 352); 2) no history of SS but a history of other autoimmune diseases (n = 66); and 3) those who met the 2012 American College of Rheumatology SS classification criteria (n = 52)., Results: Eleven percent had a history of SS, and 6% of those without a history of SS most likely had undiagnosed SS. The SS group had a higher prevalence of SP-1 autoantibodies than the group without SS or other autoimmune diseases (33% vs. 19%; P = 0.02) but had no difference in carbonic anhydrase 6 (P = 0.31) or parotid secretory protein autoantibodies (P = 0.33). Participants who were positive for the traditional autoantibodies alone or positive for both traditional and novel autoantibodies had the highest scores for corneal (P = 0.002) and conjunctival staining (P < 0.001)., Conclusions: Data from this multicenter, prospective study demonstrated that one of the novel candidate autoantibodies, SP-1, is associated with underlying SS and that novel autoantibodies may be associated with worse ocular surface disease. Future longitudinal studies are needed to evaluate their utility in screening patients with dry eye for SS.

Purpose: Current scales for assessment of bulbar conjunctival redness have limitations for evaluating digital images. We developed a scale suited for evaluating digital images and compared it to the Validated Bulbar Redness (VBR) scale., Methods: From a digital image database of 4889 color corrected bulbar conjunctival images, we identified 20 images with varied degrees of redness. These images, ten each of nasal and temporal views, constitute the Digital Bulbar Redness (DBR) scale. The chromaticity of these images was assessed with an established image processing algorithm. Using 100 unique, randomly selected images from the database, three trained, non-physician graders applied the DBR scale and printed VBR scale. Agreement was assessed with weighted Kappa statistics (K w )., Results: The DBR scale scores provide linear increments of 10 from 10-100 when redness is measured objectively with an established image processing algorithm. Exact agreement of all graders was 38% and agreement with no more than a difference of ten units between graders was 91%. K w for agreement between any two graders ranged from 0.57 to 0.73 for the DBR scale and from 0.38 to 0.66 for the VBR scale. The DBR scale allowed direct comparison of digital to digital images, could be used in dim lighting, had both temporal and nasal conjunctival reference images, and permitted viewing reference and test images at the same magnification., Conclusion: The novel DBR scale, with its objective linear chromatic steps, demonstrated improved reproducibility, fewer visualization artifacts and improved ease of use over the VBR scale for assessing conjunctival redness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Describe trial design and baseline characteristics of participants in the DRy Eye Assessment and Management (DREAM©) Study., Design: Prospective, multi-center, randomized, double-masked "real-world" clinical trial assessing efficacy and safety of oral omega-3 (ω3) supplementation for the treatment of dry eye disease (DED)., Methods: RESULTS: Mean age of participants was 58.0 ± 13.2 years. Mean OSDI score at baseline was 44.4 ± 14.2. Mean conjunctival staining score (scale 0-6) was 3.0 ± 1.4, corneal staining score (scale 0-15) was 3.9 ± 2.7, tear break-up time was 3.1 ± 1.5 s, and Schirmer test was 9.6 ± 6.5 mm/5 min., Conclusions: DREAM© participants mirror real world patients who seek intervention for their DED-related symptoms despite their current treatments. Results regarding the efficacy of omega-3 supplementation will be helpful to clinicians and patients with moderate to severe DED who are considering omega-3 as a treatment. This trial design may be a model for future RCT's on nutritional supplements and DED treatments seeking to provide useful information for clinical practice., Trial Registration: ClinicalTrials.gov number NCT02128763., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Currently available treatment options for non-infectious scleritis, including non-steroidal anti-inflammatory drugs, systemic corticosteroids and immunosuppressive therapies, have both efficacy and side effect limitations. Iontophoretic delivery of corticosteroids has been demonstrated to be effective for anterior uveitis and represents a potential new approach to scleritis therapy. We hypothesised that iontophoretic delivery would provide effective and precise medication delivery to the sclera, while limiting systemic exposure and side effects. This first-in-human randomised, double-masked, dose-escalating study of iontophoretic administration of dexamethasone phosphate for scleritis suggests the treatment to be well tolerated and safe (within the limitations of the 18 patients sample size). There was a suggestion of efficacy in the lowest (1.2 mA/min at 0.4 mA) dose group (corresponding to the superficial location of scleritis compared with anterior uveitis), with 5/7 eyes meeting the primary efficacy outcome within 28 days. Our results suggest iontophoretic delivery of corticosteroids is a promising potential treatment for scleritis, with favourable safety and preliminary efficacy results in this phase 1 trial., Trial Registration Number: NCT01059955., Competing Interests: Competing interests: The study was secondarily funded and the study treatment was provided by EyeGate Pharma. JHK and JPD have served as consultants in the last 12 months for AbbVie., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: To determine whether ocular phenotypic features of keratoconjunctivitis sicca (KCS) and/or participant-reported symptoms of dry eye disease are associated with depression in women participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA)., Design: Cross-sectional study., Methods: Women enrolled in the SICCA registry from 9 international research sites. Participants met at least 1 of 5 inclusion criteria for registry enrollment (including complaints of dry eyes or dry mouth, a previous diagnosis of Sjögren syndrome (SS), abnormal serology (positive anti-Sjögren syndrome antigen A and/or B [anti-SSA and/or anti-SSB]), or elevated antinuclear antibody and rheumatoid factor), bilateral parotid gland enlargement, or multiple dental caries). At baseline, participants had oral, ocular, and rheumatologic examination; blood and saliva collection; and a labial salivary gland biopsy (LSGB). They also completed an interview and questionnaires including assessment of depression with the Patient Health Questionnaire 9 (PHQ-9). Univariate logistic regression was used to assess the association between depression and demographic characteristics, participant-reported health, phenotypic features of Sjögren syndrome, and participant-reported symptoms. Mixed-effects modeling was performed to determine if phenotypic features of KCS and/or participant-reported symptoms of dry eye disease were associated with depression, controlling for health, age, country or residence, and sex and allowing for nonindependence within geographic site., Results: Dry eye complaints produced a 1.82-fold (95% confidence interval [CI] 1.38-2.40) higher odds of having depression compared to being symptom-free (P < .001). Additionally, complaints of specific ocular sensations were associated with a higher odds of depression including burning sensation (odds ratio 2.25, 95% CI 1.87-2.72, P < .001) compared to those without complaints. In both women with and without SS, the presence of symptoms of dry eyes and/or dry mouth rather than SS itself resulted in higher odds of depression. One particular ocular phenotypic feature of SS, a positive ocular staining score, was inversely correlated with depression., Conclusions: Participant-reported eye symptoms, particularly specific ocular sensations such as burning, were found to be positively associated with individual American College of Rheumatology/EUropean League Against Rheumatism (ACR/EULAR) SS criteria items., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Lissamine green (LG) staining of the conjunctiva is a key biomarker in evaluating ocular surface disease. The disease currently is assessed using relatively coarse subjective scales. Objective assessment would standardize comparisons over time and between clinicians., Objective: To develop a semiautomated, quantitative system to assess lissamine green staining of the bulbar conjunctiva on digital images., Design, Setting, and Participants: Using a standard photography protocol, 35 digital images of the conjunctiva of 11 patients with a diagnosis of dry eye disease based on characteristic signs and symptoms were obtained after topical administration of preservative-free LG, 1%, solution. Images were scored independently by 2 masked ophthalmologists in an academic medical center using the van Bijsterveld and National Eye Institute (NEI) scales. The region of interest was identified by manually marking 7 anatomic landmarks on the images. An objective measure was developed by segmenting the images, forming a vector of key attributes, and then performing a random forest regression. Subjective scores were correlated with the output from a computer algorithm using a cross-validation technique. The ranking of images from least to most staining was compared between the algorithm and the ophthalmologists. The study was conducted from April 26, 2012, through June 2, 2016., Main Outcomes and Measures: Correlation and level of agreement among computerized algorithm scores, van Bijsterveld scale clinical scores, and NEI scale clinical scores., Results: The scores from the automated algorithm correlated well with the mean scores obtained from the gradings of 2 ophthalmologists for the 35 images using the van Bijsterveld scale (Spearman correlation coefficient, rs = 0.79), and moderately with the NEI scale (rs = 0.61) scores. For qualitative ranking of staining, the correlation between the automated algorithm and the 2 ophthalmologists was rs = 0.78 and rs = 0.83., Conclusions and Relevance: The algorithm performed well when evaluating LG staining of the conjunctiva, as evidenced by good correlation with subjective gradings using 2 different grading scales. Future longitudinal studies are needed to assess the responsiveness of the algorithm to change of conjunctival staining over time.