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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.)

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: 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 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: 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.

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: 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: To report a case of bilateral herpetic epithelial keratitis after bilateral intravitreal bevacizumab injections for the treatment of exudative age-related macular degeneration., Methods: A 66-year-old man with diabetes and an extensive history of bilateral anti-vascular endothelial growth factor treatments for exudative age-related macular degeneration received an intravitreal bevacizumab injection in the right eye and triple therapy (bevacizumab, photodynamic therapy, and triamcinolone acetonide) in the left eye. After 4 days, he presented with pain, photophobia, tearing, and decreased vision in both eyes. Slit-lamp examination revealed bilateral dendritic epithelial lesions with terminal bulbs, and he was diagnosed with bilateral herpes simplex epithelial keratitis., Results: The patient was treated with ganciclovir ophthalmic ointment and oral acyclovir with resolution of signs and symptoms., Conclusions: To our knowledge, this is the first documented account of bilateral herpetic epithelial keratitis after bilateral intravitreal bevacizumab injections.

Purpose: To describe imaging of the external eye with Crossed Polarizers to enhance clinically important features in digital photographs of the eyelids., Methods: External photographs with and without crossed polarizing filters were taken of patients with blepharitis and controls with no clinical eye pathology., Results: Photographing eyelid skin through Crossed Polarizers decreased reflections on the skin surface and improved visualization of eyelid telangiectasias and blood vessels in patients with a broad range of skin pigmentation and ethnicities., Conclusions: The use of Crossed Polarizers in imaging the external eye reduces reflections and glare from the eyelid skin and margins, thereby allowing for a more detailed evaluation of underlying structures and analysis of images. These findings suggest that including Crossed Polarizers in clinical photography has informative applications for assessing eyelid disease.

Purpose: To describe a standardized technique for acquiring and viewing photographic images of eyelids, assess the reproducibility and validity of a grading protocol for signs of anterior blepharitis, and to explore whether the signs depend on the eyelid or the area of the eyelid assessed., Methods: Subjects with anterior blepharitis ranging from none to severe were examined by ophthalmologists at clinical sites. Digital images of the eyelids of subjects were acquired using a protocol that allowed for the calibration of color and luminance. Three ophthalmologists at a centralized reading center applied a novel protocol for grading features of anterior blepharitis from the digital images viewed on color-calibrated monitors. The agreement among graders was assessed using percent agreement and weighted kappa statistics (Kw), and the correlation of photographic and clinical gradings was assessed using Spearman correlation coefficients., Results: Agreement among graders was excellent (Kw > 0.80) on the number of eyelid margin vessels and was substantial (Kw between 0.61 and 0.80) for erythema, collarettes, number of engorged vessels, and number of lashes. Grading of the photographic images and the clinical assessments of erythema and lid debris were moderately correlated (r = 0.27-0.45). The grades for different features depended on whether the upper or lower eyelid, eyelid skin or lid margin, and central or lateral lid were assessed., Conclusions: The application of a protocol to obtain and display calibrated digital images of eyelids supports the standardized assessment of anterior blepharitis in clinical care and research studies.

Purpose: The Schirmer test is one of the 2 ocular surface tests included in the current classification criteria for Sjögren syndrome (SS). Tear osmolarity may also be a useful test for the diagnosis of dry eye disease. The purpose of this study was to examine the relationship between tear osmolarity, the Schirmer test I, and dry eye symptoms in SS., Methods: Patients with a diagnosis of SS were assessed for tear osmolarity with the TearLab Osmolarity System, tear production with Schirmer testing, symptoms with the Ocular Surface Disease Index (OSDI), and discomfort associated with each test., Results: Forty-nine patients with a mean age of 53.7 years and a female (92%) predominance were enrolled. The majority of patients (86%) were receiving systemic therapy for severe SS. Higher tear osmolarity was moderately associated with lower scores on the Schirmer test I (ρ = -0.39, P < 0.01) and OSDI (ρ = -0.45, P < 0.01). Schirmer test I results and lower OSDI scores were not correlated significantly (ρ = 0.20, P = 0.17). Tear osmolarity testing was significantly less painful than Schirmer testing (P < 0.01)., Conclusions: Signs and symptoms of dry eye in SS patients were not strongly correlated. An unexpected finding was that higher tear osmolarity was associated with lower symptom severity. Tear osmolarity testing in the clinical setting was feasible and was associated with significantly less discomfort than Schirmer testing in patients with severe SS.

Purpose: The aim of this study was to examine the relationship among oral contraceptive pill (OCP) use, contact lens wear, and dry eye signs and symptoms in healthy young women., Methods: Fifty-two women using OCPs and 45 women not using any form of hormonal contraception were enrolled. Medical, menstrual, and contact lens histories were obtained and dry eye symptoms assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment iN Dry Eye (SANDE) questionnaires. Tear osmolarity testing was performed using the TearLab Osmolarity System., Results: The mean age of all subjects was 26.0 ± 3.7 years. There were no significant differences in any of the measurements between the follicular and luteal phases. Although SANDE scores were significantly higher in subjects with OCP and recent contact lens use (P < 0.01), there were no significant differences in OSDI and tear osmolarity among the same subject groups. Subjects who reported both OCP and recent contact lens use had significantly higher OSDI and SANDE scores (P = 0.015 and P < 0.001, respectively)., Conclusions: There were no differences between the phases of the menstrual cycle. Tear osmolarity was not affected by OCP or contact lens use in young women. However, the combination of OCP use and contact lens wear may increase the severity of dry eye symptoms.

Purpose: To describe a patient with resolution of cornea verticillata while still using amiodarone as a result of a drug interaction lowering serum levels of amiodarone., Methods: An 83-year-old retired physician with long-standing cornea verticillata was noted to have complete resolution of cornea verticillata on a routine follow-up eye examination. The patient reported complete compliance with using amiodarone daily, with no recent changes in dosage or formulation. Despite this, he reported a recent increase in the frequency of palpitations. He had recently started rifampin for treatment of tuberculosis., Results: Serum amiodarone and desethylamiodarone levels were obtained and found to be below therapeutic range. After rifampin was discontinued, serum amiodarone and desethylamiodarone levels increased to a therapeutic range and cornea verticillata returned after 4 months., Conclusions: In patients currently using amiodarone, clearing of cornea verticillata should alert the ophthalmologists to the possibility of decreased serum amiodarone levels.

Elevated intraocular pressure-induced interlamellar stromal keratitis (PISK) is an entity of interface haze usually occurring weeks to months after laser in situ keratomileusis (LASIK) that is associated with elevated intraocular pressures and worsening with steroid treatment. There is evidence that this interface haze is the result of abnormal fluid dynamics that occur in the cornea after LASIK. We present a case of pressure-induced interlamellar stromal keratitis occurring 9 years after LASIK in the setting of anterior uveitis. This case emphasizes the importance of considering such diagnoses as pressure-induced interlamellar stromal keratitis in the differential diagnosis when presented with a patient with corneal haze and a history of LASIK.

Purpose: To report a case of presumed bilateral corneal copper deposition secondary to oral contraceptive use., Methods: A 23-year-old woman was referred for evaluation of bilateral corneal opacities. The location of the deposits deep in Descemet's membrane and appearance made copper deposition a likely consideration., Results: Subsequent laboratory results revealed an elevated serum copper level (189 μg/dL). Other causes of cupremia were subsequently ruled out, and the patient's corneal copper deposition was attributed to her oral contraceptive use. With cessation of the oral contraceptive, her serum copper levels normalized, but the corneal deposits remained after 5 months of follow up., Conclusion: To our knowledge, we report the first case in the ophthalmic literature of presumed corneal copper deposition in the setting of oral contraceptive use. It is important to recognize the corneal findings associated with copper deposition, because it may lead to the diagnosis and treatment of other serious systemic conditions causing elevated serum copper levels.

Purpose: The objective of this study was to undertake a systematic review of the literature reporting on clinical registries in dry eye disease (DED)., Methods: Electronic searches were conducted using systematic review methodology to provide an overview of clinical registries in ophthalmology and to identify clinical registries reporting on dry eye parameters. Two reviewers independently assessed titles and abstracts, then full-texts for eligibility., Results: A total of 129 clinical registries in ophthalmology were identified. The most common conditions captured were blindness or low vision, followed by glaucoma and corneal transplantation. Most of the registries originated in Europe (n = 56), followed by North America (n = 28). Of the registries identified, 12 were multinational, 59 were national, and 17 were regional. The second search identified 27 eligible articles, from which 8 clinical registries reporting on dry eye parameters were identified. One registry included patients with a diagnosis of dry eye. The remaining 7 registries included patients from a nationwide administrative ophthalmic database (n = 1), Sjögren syndrome (n = 4), glaucoma (n = 1), or were monozygotic and dizygotic twins (n = 1), who were evaluated for DED. Five of the registries were actively collecting data., Conclusions: Most of the registries identified in this review evaluated aqueous deficient dry eye; however, the most common type of dry eye in the general population is evaporative. Few registries also collected recommended dry eye clinical assessment. A well-designed clinical registry for DED that engages international eye care clinicians has the potential to vastly contribute to addressing pivotal gaps in understanding this highly prevalent disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to estimate the longitudinal trend in the incidence of diagnosed dry eye disease (DED) from 2001 to 2015 in Taiwan., Methods: We obtained data from the Taiwan National Health Insurance Research Database that covers 99.9% of Taiwanese residents. The incident DED cases were identified according to diagnoses, drug codes, and procedure codes. We estimated age-specific and sex-specific incidence rates (IRs) between 2001 and 2015., Results: The annual age-adjusted IRs of DED increased from 0.97 per 1000 in 2001 to 2.52 per 1000 in 2015 among male population and from 2.06 in 2001 per 1000 to 4.91 in 2015 per 1000 among female population. From 2001 to 2015, the annual IRs increased starting from age 20 to 39 years to age 70 to 79 years in both the male and female population. The men in both 20 to 39 and 50 to 59 age groups showed 3-fold higher IRs in 2015 than in 2001. However, the IRs were consistently lower in men than in women from 2001 to 2015. Overall, the IR was highest, between 10.3 (95% confidence interval, 10.1-10.5) and 13.8 (13.5-14.1) per 1000 population, in the population with the highest socioeconomic status., Conclusions: The IRs of DED increased from 2001 to 2015 for all demographics, particularly in the 20 to 39 and 50 to 59 years aged male population. These findings highlight the disease burden of DED and are expected to grow substantially., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To determine risk factors for meibomian gland disease and associated structural abnormalities in meibography among young medical trainees., Methods: This study included 84 medical students and residents younger than 45 years. All participants completed an ocular history and lifestyle questionnaire and the standardized patient evaluation of eye dryness (SPEED) II questionnaire. Meibomian gland (MG) dropout and structural changes were evaluated using meibography and scored by 2 graders using meiboscores. Statistical analysis aimed to identify MG loss risk factors., Results: Eighty-four individuals participated, and 168 meibography images were reviewed. Previous contact lens (CL) use (n = 88) demonstrated increased MG loss (P = 0.007). Correlation analysis revealed positive associations between MG loss and both frequency (Spearman r = 0.212, P = 0.003) and duration (Spearman r = 0.271, P <0.001) of CL use. Eye makeup users (n = 112) showed greater MG loss than nonusers (n = 56, P = 0.030), particularly eyeliner (n = 102) and eyeshadow (n = 100) users showing increased meiboscores (P = 0.020 and P = 0.040, respectively). Self-reported screen time and SPEED II scores did not correlate with meiboscores (P >0.05)., Conclusions: In a young trainee population, where age-related factors are reduced, previous CL use and eye makeup use are significant risk factors for MG loss. Frequency and length of CL wear affect MG dropout severity. Eye makeup usage also affected MG loss. Highlighting the incongruence of symptoms to signs, SPEED II scores showed no relationship with MG structural integrity., Competing Interests: M. Farid is a consultant for Johnson & Johnson Vision. The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of this study was to investigate the impact of demographic characteristics and psychiatric comorbidity on the prevalence of dry eye disease in the American geriatric population., Methods: Data were collected from a 2011 nationwide sample of Medicare beneficiaries aged 65 years and older (N = 1,321,000). Age, sex, race/ethnicity, residential area, climate region, and income, along with psychiatric comorbidities including depression and anxiety, were collected. Multivariable logistic regression models were used to assess the relationship between demographic and psychiatric factors and the prevalence of dry eye disease., Results: Among 21,059 patients with clinically significant dry eye, women had higher odds of having dry eye compared with men [odds ratio (OR) 2.03, 95% confidence interval (1.97-2.10)]. Asian and Native American patients had increased odds of having dry eye compared with White patients [OR 1.85 (1.69-2.02) and OR 1.51 (1.19-1.93)], while Black patients were less likely to have dry eye [OR 0.83 (0.79-0.87)]. Patients aged 75 to 84 years and 85+ were more likely to have dry eye compared with those aged 65 to 74 years [OR 1.49 (0.45-1.53) and OR 1.54 (1.48-1.60)]. Having both depression and anxiety were associated with higher odds of having dry eye [OR 2.38 (2.22-2.55)] compared with having depression alone [OR 1.95 (1.86-2.04)] or anxiety alone [OR 2.22 (2.10-2.35)]., Conclusions: Significant racial and regional disparities in dry eye prevalence were found. Psychiatric association with dry eye varied with age, sex, race, and residence region. Further research is needed to comprehend the underlying mechanisms, implications, and to address disparities in the diagnosis and management of dry eye., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to examine Tear Film Imager (TFI, AdOM, Israel) generated parameters across controls and dry eye (DE) subgroups and examine the changes in TFI parameters with contact lens (CL) placement., Methods: The retrospective study (n = 48) was conducted at the Miami Veterans Hospital. Symptoms were assessed through validated questionnaires and signs of tear function by tear break-up time and Schirmer scores. Participants were grouped as 1) healthy, 2) evaporative, 3) aqueous deficient, and 4) mixed DE based on tear function. Seventeen individuals had a baseline scan and a repeat scan following CL placement. Descriptives were compared across groups and over time., Results: The median age was 27 years, 74% self-identified as White, 45% as male, and 51% as Hispanic. Subjects in the aqueous deficiency category had lower muco-aqueous layer thickness (MALT) (2672 vs. 3084 nm) but higher lipid layer thickness (47.5 vs. 38.3 nm), lipid break-up time (4.4 vs. 2 seconds), and interblink interval (13.9 vs. 5.4 seconds) compared with the evaporative group. Subjects in the evaporative group had the highest MALT values (3084 vs. 2988, 2672, 3053 nm) compared with healthy, aqueous-deficient, and mixed groups. Symptoms were not significantly correlated with TFI parameters. CL placement significantly decreased MALT values (2869 → 2175 nm, P = 0.001)., Conclusions: The TFI provides unique information regarding the dynamic function of the tear film not captured by clinical examination. TFI generated metrics demonstrate a thinner aqueous layer in individuals with aqueous deficiency but highlight a thicker aqueous layer in those with evaporative DE., Competing Interests: Professor Alon Harris would like to disclose that he received remuneration from AdOM, Qlaris, and Cipla for serving as a consultant, and he serves on the board of AdOM, Qlaris and SlitLed. Professor Alon Harris holds an ownership interest in AdOM, Oxymap, Qlaris, and SlitLed. All relationships listed above are pursuant to Icahn School of Medicine's policy on outside activities. If you have questions regarding paid relationships that your physician/researcher may have with industry, you are encouraged to talk with your physician/researcher, or check for industry relationships posted on individual faculty pages on our website at http://icahn.mssm.edu/ . The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Neuropathic corneal pain (NCP) has been recognized as a distinct disease, yet treatment options remain limited. The aim of this pilot study was to explore the effectiveness of extranasal neurostimulation (EXNS) as a potential pain relief strategy for individuals with the peripheral component of NCP., Methods: A retrospective study was performed to identify patients who were diagnosed with refractory peripheral or mixed NCP and subsequently underwent a single session of EXNS. Visual analog scale (VAS) was used to evaluate pain intensities in the office before and after 60 seconds of EXNS. Demographic information, changes in pain scores, and comorbidities were recorded, and their correlations with pain score changes were analyzed., Results: Twenty-two patients with a mean age of 48.91 ± 3.32 years were included. The average VAS score before EXNS was 5.59 ± 0.41, which was reduced to 2.59 ± 0.43 after EXNS, indicating a 54.88% reduction (P < 0.001). EXNS reduced VAS scores from 4.90 ± 0.72 to 1.60 ± 0.42 (68.40%) for 10 patients with peripheral NCP and from 6.17 ± 0.42 to 3.42 ± 0.62 (43.61%) for 12 patients with mixed (peripheral and central) NCP (P = 0.005 for both groups). Fourteen patients (63.63%) experienced an improvement of at least 50% in their pain scores, 2 patients (9.09%) showed an improvement between 30% and 49.9%, while 6 patients (27.27%) experienced an improvement of less than 30%. No correlations between the change in pain scores and patient demographics, as well as comorbidities were detected., Conclusions: EXNS may be used as an adjuvant therapy to ameliorate pain among patients with NCP with the peripheral pain component., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate the effects of artificial tears (AT) on the sublayers of the tear film assessed by a novel tear film imaging (TFI) device., Methods: The mucoaqueous layer thickness (MALT) and lipid layer thickness (LLT) of 198 images from 11 healthy participants, 9 of whom had meibomian gland disease, were prospectively measured before and after exposure to 3 different AT preparations (Refresh Plus; Retaine [RTA]; Systane Complete PF [SYS]), using a novel nanometer resolution TFI device (AdOM, Israel). Participants were assessed at baseline and at 1, 5, 10, 30, and 60 minutes after instilling 1 drop of AT during 3 sessions on separate days. Repeated-measures analysis of variances were used for comparisons with P < 0.05 considered significant., Results: For all ATs, the mean MALT was greatest 1 minute after drop instillation, with an increase of 67%, 55%, and 11% above the baseline for SYS, Refresh Plus, and RTA, respectively. The SYS formulation demonstrated the highest percentage increases in mean MALT and LLT at most postdrop time points. The MALT differences were significantly higher in the SYS than in the RTA ( P = 0.014). After 60 minutes, no AT group demonstrated statistically significant changes in MALT or LLT compared with baseline., Conclusions: We report, for the first time, the effects of AT on MALT and LLT using a high-resolution TFI. A substantial acute mean MALT increase occurs 1 minute after AT instillation with all agents tested, but there were clear differences in response and durability, suggesting the benefits of choosing specific AT according to the needs of each patient., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Clinical diagnosis of dry eye disease is based on a subjective Ocular Surface Disease Index questionnaire or various objective tests, however, these diagnostic methods have several limitations., Methods: We conducted a comprehensive review of articles discussing various applications of artificial intelligence (AI) models in the diagnosis of the dry eye disease by searching PubMed, Web of Science, Scopus, and Google Scholar databases up to December 2022. We initially extracted 2838 articles, and after removing duplicates and applying inclusion and exclusion criteria based on title and abstract, we selected 47 eligible full-text articles. We ultimately selected 17 articles for the meta-analysis after applying inclusion and exclusion criteria on the full-text articles. We used the Standards for Reporting of Diagnostic Accuracy Studies to evaluate the quality of the methodologies used in the included studies. The performance criteria for measuring the effectiveness of AI models included area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy. We calculated the pooled estimate of accuracy using the random-effects model., Results: The meta-analysis showed that pooled estimate of accuracy was 91.91% (95% confidence interval: 87.46-95.49) for all studies. The mean (±SD) of area under the receiver operating characteristic curve, sensitivity, and specificity were 94.1 (±5.14), 89.58 (±6.13), and 92.62 (±6.61), respectively., Conclusions: This study revealed that AI models are more accurate in diagnosing dry eye disease based on some imaging modalities and suggested that AI models are promising in augmenting dry eye clinics to assist physicians in diagnosis of this ocular surface condition., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the pharmacogenomics of response to topical ocular tumor necrosis factor α (TNFα) inhibitor licaminlimab in patients with DED., Methods: Three single-nucleotide polymorphisms (SNPs) associated with Sjögren syndrome, 3 in the TNFα gene and 1 in the TNF receptor 1 (TNFR1) gene, were assessed for association with response to licaminlimab in participants from a randomized, vehicle-controlled, Phase 2 study in which adults with DED and severe ocular discomfort persisting despite treatment with artificial tears received licaminlimab or vehicle for 6 weeks. Response was assessed for change from baseline in Global Ocular Discomfort score at Day 29 of treatment. The pharmacogenomic analysis was a prospectively specified exploratory objective of the study. mRNA expression for TNFα, interleukin (IL) 1β, and IL8 in conjunctival epithelium cells was determined. The relationship between SNPs and response to licaminlimab was assessed using a mixed model repeated measures analysis., Results: SNP rs1800693 in the TNFR1 gene showed a significant effect on response to licaminlimab ( P < 0.0001, initial association test); no effect was seen for any of the other SNPs tested. The CC genotype of rs1800693 was associated with much greater response to licaminlimab than the CT or TT genotypes: LS mean changes from baseline to Day 29 in Global Ocular Discomfort score were -29.5, -0.09, and -3.90, in patients with the CC, CT, and TT genotypes, respectively ( P < 0.0001). No significant effect was observed in vehicle-treated patients. Improvements from baseline were seen in 3/4 licaminlimab-treated participants with the CC genotype. Conjunctival epithelium cell levels of mRNA for TNFα, IL1β, and IL8 decreased from baseline in participants with the CC genotype, but not with the CT or TT genotypes. Between-genotype differences in mRNA levels were not observed in participants receiving vehicle., Conclusions: The CC genotype of rs1800693, relatively common in patients with DED, was strongly associated with response to licaminlimab and decreased inflammatory cytokine gene expression in ocular surface cells during treatment. This study is one of the first to our knowledge to investigate pharmacogenomics in the treatment of DED., Competing Interests: Y. He and G. Weissgerber were employees and equity holders of the original study sponsor (Alcon/Novartis). C. Baudouin is a consultant for Abbvie, Alcon, Horus Pharma, Oculis, Santen, and Thea and is the coinventor of the EyePrim device used in this study and receives royalties from OPIA technologies. V.L. Perez is a consultant for Brill, Dompe, Kioria, Novartis, RegenTree, Santen, and Trefoil and has research support from Alcon, Evolve by Nature, and NIH/NEI. A. Galor is a consultant to Novartis, Oculis, EyeCool Therapeutics, Dompe, AstraZeneca, Tarsus, Oyster Point, Ocular Therapeutics, Ocular Therapeutix, Horizon Therapeutics, Daiichi Sankyo Inc, Heidelberg Engineering, Allergan, Inc., Alcon, Johnson & Johnson, and SUN and has received research support from the US department of Veterans affairs, Department of Defense and NEI. E. Donnenfeld reports no conflicts of interest relating to the work described here., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Recent advancements in infrared sensing technology have made it possible to visualize tear film dynamics in real time, enabling evaluation of tear film quality during blinking. A retrospective clinical evaluation was conducted to explore this by grading videos of the tear film and comparing grading data with dry eye diagnostic results using the OCULUS keratograph (K5M)., Methods: Videos were used to grade patients' tear film perturbations as compared with healthy control subjects. The grading was then correlated with the ocular surface disease index (OSDI) scores, tear film breakup time (TFBUT), tear meniscus height (TMH), corneal staining, redness, and meibography data., Results: Infrared imaging of the ocular surface revealed instantaneous and recurring dynamic characteristics of the tear film, allowing for the differentiation between normal and abnormal tear films. Abnormal features included a complete absence of a spreading tear film, hindered spreading of the tear film after blinking, areas of tear film instability, or a combination of the latter 2. Some of these features show a resemblance to the tear film appearance after fluorescein staining. The grading of these features correlated with TFBUT and, to a lesser extent, with TMH but did not show significant correlation with any other diagnostic data from the K5M. Furthermore, the speed of tear film spreading after blinking showed a positive correlation with TMH., Conclusions: Direct visualization of the tear film across the entire palpebral aperture using infrared sensing offers a noninvasive, reproducible, and rapid method for assessing the health and quality of the tear film., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study addresses the growing concern of Dry Eye Disease (DED), which has become increasingly prevalent due to modern lifestyles characterized by prolonged screen usage, global warming, polypharmacy, and extended life expectancy., Methods: Grounded in the Dry Eye Workshop II (DEWSII) diagnosis framework, the study focuses on DED as a multifactorial condition affecting the ocular surface's tear film homeostasis. The study evaluates the short-term impact of 5 commercially available ocular lubricants on disrupting the hyperosmolar environment and determine whether these lubricants can offer potential treatment benefits for DED., Results: Conducted on 300 eyes (from 150 patients) with 5 preservative-free lubricants compared to a control group, the study reveals that all lubricants effectively reduced tear film osmolarity within 15 minutes of application. Notably, the control group exhibited an increase in average osmolarity (+0.98 mOsm/L) without lubricant use. Siccafluid demonstrated the most substantial osmolarity reduction after 15 minutes, with an average decrease of 11.54 mOsm/L. Statistical significance was observed for Siccafluid, Optive Fusion unique dose (UD), and Systane Ultra UD, while Hyabak and Freegen preservative free (PF) showed lower significance., Conclusions: Emphasizing the importance of disrupting the hyperosmolar environment to break the cycle of inflammation, the study concludes that ocular lubricants, at least as an immediate post-application effect, can interrupt this cycle and improve the hyperosmolar environment of the ocular surface., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To analyze the short-term (up to 1 month) clinical outcomes in patients undergoing corneal laser refractive surgery and the impact on dry eye disease (DED) metrics and corneal nerves using in vivo confocal microscopy (IVCM)., Methods: The unaided distance visual acuity, corrected distance visual acuity, and spherical equivalent refraction (SEQ) were determined in 16 and 13 patients undergoing FS-LASIK and SMILE, respectively. DED metrics assessed were Ocular Surface Disease Index, Dry Eye Questionnaire 5-items (DEQ-5), tear film osmolarity, tear meniscus height, noninvasive keratograph breakup time (NIKBUT), ocular staining, and meibomian gland atrophy. An automated analysis of corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length (CNFL), and corneal nerve fiber fractal dimension were obtained from the IVCM scans using ACCMetrics software (University of Manchester)., Results: Both surgical techniques provided good refractive and visual outcomes. DED symptoms were found to be higher after FS-LASIK compared with SMILE (P < 0.05). A decrease in tear meniscus height (∼31%) and NIKBUT (∼40%) was reported after FS-LASIK (P = 0.005 and P = 0.001, respectively) but not after SMILE. Both procedures affected corneal nerve fiber density, corneal nerve branch density, CNFL, and corneal nerve fiber fractal dimension, but the impact was significantly greater with FS-LASIK (P = 0.001). Only CNFL correlated with the reported symptoms (DEQ-5) after FS-LASIK (r = -0.545, P = 0.029)., Conclusions: FS-LASIK and SMILE provided good refractive and visual outcomes. There was an increased impact on DED symptoms after FS-LASIK compared with SMILE, although there were no significant differences between the procedures for most of the other ocular surface metrics assessed. The IVCM findings showed that SMILE had less impact on corneal nerves compared with FS-LASIK.

Purpose: To investigate intereye agreement in dry-eye disease (DED) signs in the Dry Eye Assessment and Management study., Methods: Tear break-up time (TBUT), Schirmer test, conjunctival staining, corneal staining, meibomian gland dysfunction (MGD), and tear osmolarity were measured at baseline, 3, 6, and 12 months. Intereye agreement was assessed by intraclass correlation coefficient, weighted kappa, and percentage of participants with absolute intereye difference (AID) exceeding a clinically significant threshold (2 points for conjunctival staining and MGD, 2 seconds for TBUT, 3 points for corneal staining, 5 mm/5 minutes for Schirmer test, and 8 mOsms/L for osmolarity). The worse eye at each visit for each DED sign was determined as the eye with a sign worse than the contralateral eye by at least the clinically significant threshold., Results: DED signs had moderate-to-good intereye agreement with intraclass correlation coefficient ranging from 0.45 (tear osmolarity) to 0.81 (corneal staining and Schirmer test) and weighted kappa from 0.58 (plugging) to 0.69 (lid secretion). Percentage of participants exceeding threshold AID was 15% to 20% for conjunctival staining, 11% to 15% for TBUT, 17% to 21% for MGD, 13% to 18% for corneal staining, 21% to 23% for Schirmer test, and 44% to 47% for osmolarity. The eye with a worse DED sign ranged between 36% (TBUT) and 80% (osmolarity) of participants., Conclusions: Participants demonstrated moderate-to-good intereye agreement, yet a substantial portion showed clinically significant intereye differences in each sign. The worse eye was not the same eye in the majority during follow-up. These findings suggest considering signs from both eyes in future DED trials., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: In this cross-sectional survey, we assessed the prevalence of dry eye disease (DED) in a representative German population sample. In addition, we examined the associations between DED, health-related quality of life (HRQoL), and level of fatigue. Finally, we further validated the German version of the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire and present norm data of the German population., Methods: A random sample of German residents aged 16 years and older was recruited between October and December 2021. All participants completed the SPEED, Short Form 36, and Multidimensional Fatigue Inventory 20 questionnaires., Results: Of the 2495 participants who completed the survey, 450 (21.6%; 95% confidence intervals 20.0-23.1) reported a SPEED total score of ≥4, indicating a positive screening for DED. DED was significantly more common in women and older age. Participants who screened positive for DED reported significantly higher levels of fatigue and lower values in all domains of HRQoL. A receiver operating characteristic curve of the SPEED was generated using an ophthalmologist's diagnosis. The area under the curve was estimated to be 0.886 (95% confidence intervals 0.858-0.913). A cutoff score ≥4 seemed to be appropriate as an indicator of DED. Cronbach's α was excellent (0.95)., Conclusions: DED is common in the German population. We confirmed associations with sex, age, HRQoL, and fatigue level, indicating a high burden of DED. The German version of the SPEED is a valid instrument for the assessment of DED symptoms., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of this study was to investigate the effects of artificial tears (AT) on the sublayers of the tear film assessed by a novel tear film imaging (TFI) device., Methods: The mucoaqueous layer thickness (MALT) and lipid layer thickness (LLT) of 198 images from 11 healthy participants, 9 of whom had meibomian gland disease, were prospectively measured before and after exposure to 3 different AT preparations (Refresh Plus; Retaine [RTA]; Systane Complete PF [SYS]), using a novel nanometer resolution TFI device (AdOM, Israel). Participants were assessed at baseline and at 1, 5, 10, 30, and 60 minutes after instilling 1 drop of AT during 3 sessions on separate days. Repeated-measures analysis of variances were used for comparisons with P < 0.05 considered significant., Results: For all ATs, the mean MALT was greatest 1 minute after drop instillation, with an increase of 67%, 55%, and 11% above the baseline for SYS, Refresh Plus, and RTA, respectively. The SYS formulation demonstrated the highest percentage increases in mean MALT and LLT at most postdrop time points. The MALT differences were significantly higher in the SYS than in the RTA (P = 0.014). After 60 minutes, no AT group demonstrated statistically significant changes in MALT or LLT compared with baseline., Conclusions: We report, for the first time, the effects of AT on MALT and LLT using a high-resolution TFI. A substantial acute mean MALT increase occurs 1 minute after AT instillation with all agents tested, but there were clear differences in response and durability, suggesting the benefits of choosing specific AT according to the needs of each patient., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The aim of the study was to examine subjective responses to cyclosporine A (CsA) 0.05% versus lifitegrast 5% in individuals with dry eye disease., Methods: This study was a retrospective review of individuals with clinically diagnosed dry eye disease treated with both CsA 0.05% and lifitegrast 5% over the course of their disease. Information collected included demographics, comorbidities, and dry eye disease signs. Treatment preferences were noted as mild or strong for a particular medication, no preference, or unable to tolerate either medication. The primary outcome measure was patient-reported medication preference. The secondary outcome measure was an examination of individual and eye factors that related to medication preference., Results: Sixty-four individuals (mean age 66.73 ± 13.17 years; 82.8% male, 71.9% White, 29.7% Hispanic) used both CsA and lifitegrast over the course of their disease. Of those, 33 preferred CsA (12.5% mildly and 39.1% strongly), 14 preferred lifitegrast (3.1% mildly and 18.8% strongly), 12 had no preference (18.8%), and 5 could not tolerate either medication (7.8%) due to side effects. No demographic characteristics, comorbidities, or ocular surface findings correlated with medication preference., Conclusions: In individuals who used both CsA 0.05% and lifitegrast 5% over the course of their disease, a higher frequency of individuals preferred CsA. No clinical factors correlated with medication preference., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to assess the safety, tolerability, dosing, and efficacy of the active 19 amino acid fragment of lacritin (Lacripep), a broad regulator of ocular surface homeostasis, in the treatment of ocular surface disease associated with primary Sjögren syndrome., Methods: Two hundred four subjects were randomized to receive vehicle, 22 μM Lacripep, or 44 μM Lacripep 3 times daily for 28 days, preceded by a 14-day run-in and followed by 14-day washout. Outcome measures were corneal fluorescein staining (CFS), lissamine conjunctival staining, Schirmer with anesthesia, tear break-up time, SANDE scoring, and visual analog scale assessment of symptoms., Results: This study established the safety and tolerability of topical treatment with Lacripep in patients with primary Sjögren syndrome. There were few adverse events: Only mild irritation was found in less than 3 percent of patients dosed with Lacripep. Total CFS and Eye Dryness Score were not significantly changed at day 28. Post hoc analysis of patients with Eye Dryness Severity scores of 60 or greater at baseline revealed significant improvements in inferior CFS at 14 and 28 days and complaints of burning and stinging at 14 days. Significant improvement in regional lissamine conjunctival staining was seen at 14 and 28 days., Conclusions: This first-in-human study of Lacripep in patients with primary Sjögren syndrome demonstrated clinically significant improvements in specific signs and symptoms on which to base future studies. This study established safety and tolerability and potential metrics of efficacy in patients with moderate to severe disease. Further work on appropriate dosing and concentration is ongoing., Competing Interests: G. W. Laurie: Cofounder and CSO of TearSolutions, Inc; Financial interest in TearSolutions, Inc. E. C. Parsons: Consultant to TearSolutions, Inc. MGO: CMO of Tear Solutions, Inc; Financial interest in TearSolutions, Inc. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of this study was to assess the diagnostic performance of measurements from a new noninvasive, automated ocular surface analyzer (IDRA) in the diagnosis of dry eye disease (DED)., Methods: We prospectively identified patients with and without DED using best practice methods. Subsequently, all participants underwent IDRA analysis, consisting of 5 components: noninvasive tear film break-up time, tear meniscus height, lipid layer interferometry, eye blink quality, and infrared meibography. The manufacturer provides cutoff values for a pathologic result for each of these components. Using a stepwise augmentation multivariate logistic regression model, we identified the components with the strongest association for the presence of DED. For the 3 components with the strongest association (interferometry, tear meniscus, and infrared meibography), we calculated the probability of DED., Results: We enrolled 40 patients (80 eyes) with DED (mean age 60.5 years; women 78.3%) and 35 healthy subjects (70 eyes, mean age 31.1 years; women 21.7%). The IDRA had an area under the curve of 0.868 (95% confidence interval: 0.809-0.927) to detect DED. A normal (≥80) interferometry combined with a normal (>0.22) tear meniscus and a normal (≤40) infrared meibography was associated with an estimated probability of 18% for the presence of DED, whereas the estimated probability of DED was as high as 96% when all 3 findings were pathologic., Conclusions: The results of IDRA showed a positive concordance with routine clinical diagnostic tests. The new analyzer is an easy-to-access diagnostic tool to rule out the presence of DED in the extramural setting and to guide a timely DED treatment., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate and compare the safety and efficacy of low-level light therapy (LLLT) and intense pulsed light (IPL) for the treatment of meibomian gland dysfunction (MGD)., Methods: Forty eyes of 40 patients with MGD were randomized to receive either LLLT or IPL. Four weekly sessions of LLLT (MY MASK-E, Espansione Marketing S.p.A., Bologna, Italy) and IPL (Eye-light device, Espansione Marketing S.p.A., Bologna, Italy) were performed. The following parameters were evaluated before and 2 weeks after the last session for each treatment: Standard Patient Evaluation of Eye Dryness questionnaire, noninvasive break-up time, tear meniscus height, redness score, meiboscore, and meibomian gland loss., Results: All patients completed regularly all the scheduled sessions, and no adverse events were reported in any of the groups. The Standard Patient Evaluation of Eye Dryness score significantly decreased after both LLLT and IPL (P < 0.001) although the improvement was significantly greater in the LLLT compared with the IPL group (-9.9 ± 3.2 vs. -6.75 ± 4.5; P = 0.014). Patients in the LLLT group showed a significantly higher increase in tear meniscus height compared with those in the IPL group (0.06 ± 0.10 mm vs. -0.01 ± 0.014; P = 0.040). In both groups, the noninvasive break-up time, redness score, meiboscore, and meibomian gland loss did not vary significantly after treatment (all P > 0.05)., Conclusions: Both LLLT and IPL were safe and effective in improving ocular discomfort symptoms in patients with MGD; however, the former determined a greater improvement in symptoms and an improvement of tear volume., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The aim of this study was to determine the association between caffeine intake and dry eye disease (DED) in the large, population-based LifeLines cohort in the Netherlands., Methods: DED was cross-sectionally assessed in 85,302 participants (59% female participants) using the Women's Health Study dry eye questionnaire. Dietary caffeine was calculated from the intake of coffee, tea, cola, and energy drinks. Logistic regression was used to investigate the relationship between DED and caffeine, correcting for demographic variables, smoking status, alcohol intake, and 48 comorbidities of DED., Results: The mean (SD; range) age of participants was 50.7 years (12.4; 18-96), and 50,339 (59%) were female. The mean (SD) caffeine intake was 285 (182) mg/d. After correcting for demographics, body mass index, smoking status, and alcohol intake, higher caffeine intake was associated with a decreased risk of Women's Health Study-defined DED [odds ratio (OR) 0.971 per 100 mg/d, 95% CI, 0.956-0.986, P < 0.0005]. When additionally adjusting for medical comorbidities, no significant effect was observed (OR 0.985, 95% CI, 0.969-1.001, P = 0.06). Caffeine's effect on DED was similar in male and female participants and independent of sleep quality and stress at work. Decaffeinated coffee intake was significantly associated with an increased risk of DED, when adjusted for caffeinated coffee, demographics, alcohol intake, smoking status, and comorbidities (OR 1.046 per cup/d, 95% CI, 1.010-1.084, P = 0.01). None of the beverages were significantly associated with the risk of DED, when correcting for intake of the other caffeinated beverages, demographics, smoking status, alcohol intake, and all comorbidities., Conclusions: Dietary caffeine intake does not seem to be a risk factor for DED in the general population., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of this study was to assess short-term efficacy and safety of tear promotion eye drops (biological tear substitutes and topical secretagogues) for treating dry eye disease., Methods: Randomized controlled trials comparing short-term effects of biological tear substitutes or topical secretagogues versus placebo or other topical dry eye treatments in adults with dry eye disease were identified from the MEDLINE, Embase, Scopus, ClinicalTrials.gov , and World Health Organization International Clinical Trials Registry Platform databases. Pairwise meta-analysis and network meta-analysis were performed. Outcomes were ocular symptoms, ocular surface staining, tear break-up time, Schirmer test, and adverse events. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations approach., Results: Thirty-nine randomized controlled trials (3693 patients) were eligible. Using artificial tears as a reference, autologous platelet lysate was the most effective treatment for lowering ocular surface disease index (unstandardized mean difference [USMD] -31.85; 95% confidence interval [CI]: -43.19 to -20.51) and platelet rich plasma showed the most reduction in corneal fluorescein staining scores (standardized mean difference -2.52; 95% CI: -3.23 to -1.82). Cord blood serum was the most effective treatment for increasing tear break-up time (USMD 2.67; 95% CI: 0.53-4.82), and eledoisin was superior to others in improving Schirmer scores (USMD 2.28; 95% CI: 0.14-4.42). Most interventions did not significantly increase ocular adverse events compared with artificial tears., Conclusions: Biological tear substitutes, including autologous serum, autologous platelet lysate, platelet rich plasma, and cord blood serum, might be the most effective treatment among tear promotion eye drops in relieving dry eye symptoms without increasing adverse events. However, there remains uncertainty around these findings because of low/very low certainty of evidence., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The aim of this study was to evaluate the demographic features, quality, and reliability of YouTube videos addressing dry eye disease (DED)., Methods: The term "dry eye disease" has been searched on YouTube. The first 500 videos that emerged using the defined search term were evaluated. Duplicated-split videos, videos shorter than 60 seconds, videos with a language other than English or videos with an unintelligible English accent, and videos unrelated to DED were excluded. Video uploaders, types, origins, durations, and viewer interactions of the videos were noted. DISCERN, the Global Quality Score, and the Video Quality Score (created by the authors) were used to evaluate the video quality., Results: Of the 500 videos, 262 videos were excluded, and the remaining 238 videos were evaluated. Videos were of moderate quality on all 3 scoring systems. The medical institute and academic society videos had the highest quality ( P < 0.05). The quality of videos uploaded by physicians was significantly lower than medical institute and academic society videos and was higher than the others ( P < 0.05). User interactions and video duration were weakly positively correlated with the video quality ( P < 0.05)., Conclusions: Among YouTube videos on DED, only a minority are of good or excellent quality. Videos uploaded by medical institutes or academic societies scored higher in quality than those uploaded by physicians, which, in turn, scored higher than those uploaded by all others. User interactions were weakly correlated with quality values, suggesting user interactions are not good indicators of the quality of YouTube videos on DED., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to characterize rates of opioid prescription for different ulcerative keratitis types., Methods: This cohort study included patients diagnosed with ulcerative keratitis according to the University of Michigan electronic health record data between September 1, 2014 and December 22, 2020. Ulcerative keratitis was categorized by etiologic type (bacterial, fungal, viral, acanthamoeba, inflammatory, polymicrobial, or unspecified) using rule-based data classification that accounted for billing diagnosis code, antimicrobial or antiinflammatory medications prescribed, laboratory results, and manual chart review. Opioid prescriptions were converted to morphine milligram equivalent and summed over 90 days from diagnosis. Opioid prescription rate and amount were compared between ulcerative keratitis types., Results: Of 3322 patients with ulcerative keratitis, 173 (5.2%) were prescribed at least 1 opioid for pain management within 90 days of diagnosis. More patients with acanthamoeba (32.4%), fungal (21.1%), and polymicrobial (25.0%) keratitis were treated with opioids compared with bacterial (6.7%), unspecified (2.9%), or viral (1.8%) keratitis (all Bonferroni adjusted P < 0.05). For the 173 patients who were prescribed opioids, a total of 353 prescriptions were given within 90 days of diagnosis, with half given within the first week after diagnosis. The quantity of opioid prescribed within 90 days from diagnosis was not significantly different between ulcerative keratitis types (P = 0.6559). Morphine milligram equivalent units prescribed ranged from 97.5 for acanthamoeba keratitis to 112.5 for fungal keratitis., Conclusions: The type of ulcerative keratitis may influence the opioid prescription rate. Providers can better serve patients needing opioids for pain management through improved characterization of pain and development of more tailored pain management regimens., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The unifying characteristic of dry eye is the loss of tear film homeostasis, and the tear lipid layer is a key component for maintaining film stability. The detection of tear lipid is of great significance for the diagnosis of dry eye. In this study, we explored a new test strip for the detection of tear lipid., Methods: The tear lipid test strip was prepared by coating the strip material with hydrophobic nano-silica. We tested its physical properties with iodine vapor chromogenic and cobalt chloride test methods. Its biosafety was evaluated by an ocular irritation test in rabbits. Finally, we established a rabbit meibomian gland dysfunction model and measured both eyes with the tear lipid test strip at the first, third, seventh, 14th, 16th, and 21st day after surgery., Results: The tear lipid test strip had fine lipophilicity and hydrophobicity. It can extract lipid from tear, and the tear lipid can be quantified by measuring the length of lipid infiltration. In the ocular irritation test, the test strip had no obvious eye irritation. The length of lipid infiltration between experimental and control rabbit eyes began to show statistical difference since the third day after surgery., Conclusions: The novel tear lipid test strip has great lipophilicity, hydrophobicity, and biological safety. It might be effectively applied in diagnosis of dry eye., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To assess the efficacy, safety, and tolerability of a topical water-free cyclosporine A formulation (CyclASol 0.1% ophthalmic solution) in comparison with vehicle for the treatment of dry eye disease (DED)., Methods: Three hundred twenty-eight patients were enrolled in this prospective, 12-week, multicenter, randomized, double-masked, confirmatory, vehicle-controlled clinical study. After a 2-week run-in period, eligible DED patients were randomized 1:1 to either CyclASol 0.1% or vehicle twice daily. The primary efficacy endpoint was change from baseline in total corneal fluorescein staining (National Eye Institute scale), and the second hierarchical primary efficacy endpoint was change from baseline in the Ocular Surface Disease Index score, both at 4 weeks. Secondary efficacy and safety assessments included conjunctival lissamine green staining (Oxford scale), visual analog scales for dry eye symptoms, and adverse event., Results: Treatment with CyclASol 0.1% was superior to vehicle in the primary endpoint: total corneal fluorescein staining at week 4 (Δ -0.8; 95% confidence interval, -1.3 to -0.4; P = 0.0002, analysis of covariance). This difference had already reached statistical significance after 2 weeks and was maintained throughout the study. The study did not statistically meet its second hierarchically tested primary endpoint: Ocular Surface Disease Index score (P = 0.2634). However, CyclASol 0.1% treatment showed statistically significant improvement compared with that of vehicle in the eye dryness score at week 4 (Δ -4.783; 95% confidence interval, -9.129 to -0.438; P = 0.0311)., Conclusions: CyclASol 0.1% was effective in treating signs and symptoms of DED. It significantly reduced corneal and conjunctival staining and improved ocular dryness compared with vehicle. CyclASol 0.1% was safe and showed excellent tolerability., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To assess the association of severity of ocular discomfort with measures of quality of life among patients with moderate to severe dry eye disease (DED)., Methods: This is a prospective, observational, cohort study within a randomized clinical trial. Patients (N = 535) in the Dry Eye Assessment and Management study with moderate to severe DED completed the Ocular Surface Disease Index on DED symptoms, the SF-36 on quality of life, and the Brief Ocular Discomfort Inventory questionnaire and had a comprehensive ophthalmic assessment by a study-certified clinician. The ocular discomfort on average over the past week was scored on an 11-point scale (0 for no discomfort and 10 for discomfort as bad as you can imagine)., Results: The average ocular discomfort scores for patients ranged from 0 to 10, with a mean of 4.28. Discomfort scores did not vary with demographic characteristics, signs of DED, self-reported depression, or self-reported nonocular pain conditions. Ocular discomfort scores did correlate moderately to strongly with total Ocular Surface Disease Index scores (Spearman correlation coefficient, rs, 0.47-0.67) and with measures of interference with activities of daily living [general activity level, mood, walking ability, ability for normal work, relations with other people, sleep, and enjoyment of life (rs = 0.39-0.65)]., Conclusions: Among patients in the Dry Eye Assessment and Management study, worse ocular discomfort was associated with worse overall DED symptoms and interfered to a greater degree with activities of daily living. Ocular discomfort is an important part of the assessment of patients with DED., Competing Interests: R. R. Sayegh has received personal fees from Allergan and Novartis. P. A. Asbell has received research grants from the National Eye Institute, MC2 Therapeutics, Miotech, and Regeneron; personal fees from Shire, Medscape, MC2 Therapeutics, Miotech, Bausch & Lomb, ECLA, Astra Zeneca, Topovert, Regeneron, Blephex, Senju, Axero, Eyepoint, Novaliq, Kala, Dompe, Alcon, Allados, Motive, and Sun; and nonfinancial support from ECLA and Regeneron. J. T. Farrar has received research grants and contracts from the US Food and Drug Administration and National Institutes of Health and consulting fees from Analgesic Solutions, Aptinyx, Biogen, Opioid Post-Marketing Consortium, Daiichi Sankyo, DepoMed, Evadera, Jansen, Lilly, Novartis, Vertex, and Pfizer; payment for or data and safety monitoring committee services from NIH-NIA and Cara Therapeutics. M. G. Maguire has received grants from the National Eye Institute and Foundation Fighting Blindness; personal fees from Genentech and Regenera for data and safety monitoring committee services. The remaining authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Lissamine green (LG) is often used in addition to fluorescein to assess the severity of conjunctival damage in dry eye syndrome, which is graded manually. Our purpose was to describe an algorithm designed for image analysis of LG conjunctival staining., Methods: Twenty pictures of patients suffering from dry eye with visible LG conjunctival staining were selected. The images were taken by 2 different digital slit lamps with a white light source and a red filter transmitting over the wavelengths absorbed by LG. Conjunctival staining appeared in black on a red background. The red channel was extracted from the original image. Stained areas were then detected using a Laplacian of Gaussian filter and applying a threshold whose value was determined manually on a subset of images. The same algorithm parameters remained constant thereafter. LG-stained areas were also drawn manually by 2 experts as a reference., Results: The delineation obtained by the algorithm closely matched the actual contours of the punctate dots. In 19 cases of 20 (95%), the algorithm found the same Oxford grade as the experts, even for confluent staining that was detected as a multitude of dots by the algorithm but not by the experts, resulting in a high overestimation of the total number of dots (without mismatching the Oxford grade estimated by the experts). The results were similar for the 2 slit-lamp imaging systems., Conclusions: This efficient new image-analysis algorithm yields results consistent with subjective grading and may offer advantages of automation and scalability in clinical trials., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Dry eye disease (DED) is a chronic, multifactorial ocular surface disorder with multiple etiologies that results in tear film instability. Globally, the prevalence of DED is expected to increase with an aging society and daily use of digital devices. Unfortunately, the medical field is currently unprepared to meet the medical needs of patients with DED. Noninvasive, reliable, and readily reproducible biomarkers have not yet been identified, and the current mainstay treatment for DED relies on symptom alleviation using eye drops with no effective preventative therapies available. Medical big data analyses, mining information from multiomics studies and mobile health applications, may offer a solution for managing chronic conditions such as DED. Omics-based data on individual physiologic status may be leveraged to prevent high-risk diseases, accurately diagnose illness, and improve patient prognosis. Mobile health applications enable the portable collection of real-world medical data and biosignals through personal devices. Together, these data lay a robust foundation for personalized treatments for various ocular surface diseases and other pathologies that currently lack the components of precision medicine. To fully implement personalized and precision medicine, traditional aggregate medical data should not be applied directly to individuals without adjustments for personal etiology, phenotype, presentation, and symptoms.

Purpose: Systemic implications necessitate the identification of dry eye patients with Sjögren syndrome (SS). This study aims to explore the utility of tear MUC5AC and inflammatory cytokine levels in the differential diagnosis of SS-related dry eye., Methods: A prospective, observational, case-control study was conducted on 62 patients (those with a definitive diagnosis of SS dry eye, non-SS dry eye, and age-matched healthy controls with no dry eye). Clinical evaluations included the following tests in the order listed here: noninvasive tear break-up time, osmolarity, tear sampling, Schirmer test without anesthesia, and ocular surface staining (lissamine green for conjunctiva and fluorescein for cornea). Tear MUC5AC levels were assessed with enzyme-linked immunosorbent assay, and cytokines [interferon-gamma, tumor necrosis factor alpha, interleukin (IL)-6, IL-17a, IL-1β, IL-8, IL-10, and IL-12p70] were measured using a Luminex assay in a masked fashion., Results: The Bulbar conjunctival lissamine green staining score was significantly greater in patients or controls with SS versus non-SS dry eye. This greater conjunctival staining was associated with a reduction in tear MUC5AC (B = -17.8 ng/mL, 95% confidence interval = -31.8 to -3.9, P = 0.01). Among the tear cytokines, a significant association was found between IL-8 levels (hazard ratio [HR] = 1.002, 95% confidence interval = 1.000-1.003, P = 0.03) and SS diagnosis. When patients were stratified based on tear MUC5AC levels, significantly increased tear IL-8 levels were detected in patients with SS dry eye but not with non-SS dry eye, in comparison with healthy controls., Conclusions: Tear levels of goblet cell-specific MUC5AC combined with IL-8 can potentially serve as a useful biomarker for differential diagnosis of SS dry eye from non-SS dry eye.

Purpose: The present study aimed to compare the prevalence of dry eye disease (DED) among visual display terminal users using the revised and previous DED criteria., Methods: This cross-sectional study included 561 participants (187 women)., Results: The distribution of diagnostic status according to the previous DED criteria was as follows: definite DED (n = 65, 11.6%), probable DED (n = 303, 54.0%), and non-DED (n = 193, 34.4%). According to the revised criteria, 329 participants (58.6%) were classified as DED and 232 participants (41.4%) were classified as non-DED., Conclusions: The prevalence of DED among visual display terminal users has increased to 58.6% from 11.6%, according to the revised DED diagnostic criteria of the Asia Dry Eye Society.