PURPOSE: To compare the clinical characteristics and in vivo confocal microscopy (IVCM) findings of patients with neuropathic corneal pain (NCP) due to refractive surgery (RS-NCP) and herpetic eye disease (H-NCP) to controls. METHODS: Sixteen patients with RS-NCP and 7 patients with H-NCP, and 37 healthy reference age- and sex-matched healthy controls were included to the study. The medical records were reviewed for demographic features, detailed disease history, ocular surface disease index (OSDI), ocular pain assessment survey (OPAS) scores. IVCM images of patients were analyzed and compared to reference controls by two masked observers. RESULTS: The mean pain intensity score for the last 24 h (5.1 ± 2.4 vs. 3.9 ± 1.2; p = 0.27), last 2 weeks (6.1 ± 2.5 vs. 4.8 ± 2.3; p = 0.13) for RS-NCP vs. H-NCP respectively, and quality of life scores (p = 0.23) were similar in both groups. Quality of life, especially mood (p = 0.06) and enjoying life/relations to others (p = 0.10) were affected in both groups, but were not statistically significant between groups. The mean total nerve density was lower in RS-NCP (5702.4 ± 4599.0 μm/mm) compared to their respective controls (26,422.8 ± 4491.0; p < 0.001) and in the H-NCP group (2149.5 ± 2985.9) compared to their respective controls (22,948.8 ± 3169.0; p < 0.001). Alterations in DC density were similar between all groups (38.3 ± 48.0 cells/mm in RS-NCP, 61.0 ± 76.9 in H-NCP, p = 0.95). CONCLUSION: Neuropathic corneal pain patients due to refractive surgery show similar clinical characteristics, pain levels, quality of life impact, and IVCM findings as patients with NCP due to herpetic eye disease.

Disruption of retinal pigment epithelial (RPE) barrier integrity and RPE migration are hallmark features in neovascular age-related macular degeneration (nAMD), but the underlying causes and pathophysiology are not completely well-defined. Herein, we aimed to evaluate the effect of bone morphogenetic proteins (BMPs) on the barrier function and migration of RPE. In particular, we investigated the role of BMP2 and BMP4 in these processes as our analysis of RNA-sequencing (seq) data from human donor eyes demonstrated that they are highly differentially expressed BMP members in macular RPE/choroid versus macular retina. We used electrical cell-substrate impedance sensing (ECIS) system to monitor precisely in real time the barrier integrity and migration of ARPE-19 after treatment with various concentrations of BMP2 or BMP4. Immunofluorescence was also used to assess the changes in the expression and the organization of the key tight junction protein, zona occludens (ZO)-1, in ARPE-19 cells under BMP2 or BMP4 treatment. This was followed by measuring the activity of matrix metalloproteinases (MMPs). Finally, RNA-seq and ELISA were used to determine the local and circulating levels of BMP2 and BMP4 in retinas and serum samples from nAMD donors. Our ECIS results showed that BMP4 but not BMP2 decreased the transcellular electrical resistance (TER) of ARPE-19 and increased their migration in comparison with control (vehicle-treated cells). Furthermore, immunofluorescence showed a disorganization of ZO-1 in BMP4-treated ARPE-19 not in BMP2-treated cells or vehicle-treated controls. This effect of BMP4 was associated with significant increases in the activity of MMPs, specifically MMP2. Lastly, these results were corroborated by additional findings that circulating but not local BMP4 levels were significantly higher in nAMD donor samples compared to controls. Collectively, our results demonstrated unreported effects of BMP4 on inducing RPE dysfunction and suggest that BMP4 but not BMP2 may represent a potential therapeutic target in nAMD.

Telemedicine is the provision of healthcare-related services from a distance and is poised to move healthcare from the physician's office back into the patient's home. The field of ophthalmology is often at the forefront of technological advances in medicine including telemedicine and the use of artificial intelligence. Multiple studies have demonstrated the reliability of tele-ophthalmology for use in screening and diagnostics and have demonstrated benefits to patients, physicians, as well as payors. There remain obstacles to widespread implementation, but recent legislation and regulation passed due to the devastating COVID-19 pandemic have helped to reduce some of these barriers. This review describes the current status of tele-ophthalmology in the United States including benefits, hurdles, current programs, technology, and developments in artificial intelligence. With ongoing advances patients may benefit from improved detection and earlier treatment of eye diseases, resulting in better care and improved visual outcomes.

PURPOSE: To evaluate the association between Medicaid expansion and diabetic dilated eye examinations. DESIGN: A retrospective difference in differences (DiD) analysis using individual-level survey response data from January 1, 2009, to December 31, 2017. PARTICIPANTS: A total of 52 392 survey responses from 50 states and the District of Columbia between 2009 and 2017. Responders were adults aged 18 to 64 years reporting a previous diagnosis of diabetes and a household income below 138% of the US federal poverty line (FPL). METHODS: The Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System data were used to identify survey responders who were asked about the presence of dilated eye examinations from years before and after Medicaid expansion implementation. MAIN OUTCOME MEASURES: The DiD in proportion of dilated eye examinations among diabetic persons aged 18 to 64 years with household incomes below 138% of the FPL between states that did and did not implement Medicaid expansion. RESULTS: Implementation of Medicaid expansion policies was associated with a 1.3% (95% confidence interval [CI], -3.8 to 6.4; P = 0.61), 6.3% (95% CI, 1.3-11.3; P = 0.016), 4.1% (95% CI, -0.8 to 9.0; P = 0.11), and 2.3% (95% CI, -1.6 to 6.2; P = 0.23) increase in the proportion of diabetic persons aged 18 to 64 years with incomes below 138% of the FPL receiving a dilated eye examination within the past year due to Medicaid expansion 1, 2, 3, and 4 cumulative years after expansion, respectively. CONCLUSIONS: Medicaid expansion policies were significantly associated with an increase in dilated eye examination rates within the first 2 years after implementation. However, this increase did not persist beyond this period, with nonsignificant increases 3 and 4 cumulative years after implementation. Healthcare policymakers should be aware that additional measures beyond expanding insurance coverage may be necessary to increase and sustain the rate of dilated eye examinations among diabetic populations.

OBJECTIVES: Understanding trends of marijuana use in the USA throughout a period of particularly high adoption of marijuana-legalisation, and understanding demographics most at risk of use, is important in evolving healthcare policy and intervention. This study analyses the demographic-specific changes in the prevalence of marijuana use in the USA between 2005 and 2018. DESIGN, SETTING AND PARTICIPANTS: A 14-year retrospective cross-sectional analysis of the National Health and Nutrition Examination Survey database, a publicly available biennially collected national survey, weighted to represent the entire US population. A total of 35 212 adults between 18 and 69 years old participated in the seven-cycles of surveys analysed (2005-2018). PRIMARY OUTCOME MEASURED: Lifetime use, first use before 18 years old, and past-year use of marijuana. RESULTS: The majority of adults reported ever using marijuana. While the overall prevalence of lifetime marijuana use remained stable (p=0.53), past-year use increased significantly between 2005 and 2018 (p<0.001) with highest rate of past-year use among younger age groups (p<0.001), males (p<0.001) and those with income below poverty level (p<0.001). Past-year use was the most common among non-Hispanic blacks, and less common among Hispanic/Mexican populations (p<0.002). Trends in past-year use increased among all age categories, males/females, all ethnicities, those with high school education/above, and those at all income levels (p<0.01 for all). CONCLUSIONS: While lifetime marijuana use remained stable, past-year use significantly increased between 2005 and 2018. While past-year use remained the most common in younger age groups, males, non-Hispanic blacks and those with lower income; increasing trends in past-year use were significant for all age, sex, race and income categories, and for those with high school education/above. With high adoption of marijuana-legalisation laws during this period, our results suggest an associated increase in past-year marijuana use.An accurate understanding of those most at risk can help to inform decisions of healthcare policy-makers and professionals, and facilitate a safe transition of changing marijuana legalisation and use in the USA.

PURPOSE: To determine the efficacy and safety of sentinel lymph node biopsy (SLNB) in the management of eyelid and conjunctival malignancy. METHODS: A literature search was performed in August 2019 and January 2020 for articles published in English in the PubMed and Cochrane Library databases. This search yielded 151 articles that were reviewed for relevancy, of which 27 were deemed to have met the inclusion criteria for this assessment. The data from these articles were abstracted and the articles were rated for strength of evidence by the panel methodologist. RESULTS: All 27 studies were rated level III, and a total of 197 SLNBs were reported. Diagnoses included conjunctival and eyelid cutaneous melanoma (85 and 42 patients, respectively), sebaceous gland carcinoma (35 patients), squamous cell carcinoma (26 patients), Merkel cell carcinoma (6 patients), pigmented epithelioid melanocytoid tumor (1 patient), mucoepidermoid carcinoma (1 patient), and signet ring carcinoma (1 patient). Tracer was found in regional lymph nodes in 100% of patients in 21 of 27 articles and in 191 of 197 patients overall. The number of lymph nodes removed ranged from 1 to 16, with most ranging from 1 to 5. Tumor-positive lymph nodes were found in 33 of 197 patients (16.8%), prompting recommendations for adjuvant treatments. Survival data were reported for 16 of these patients, with follow-up periods ranging from 3 to 36 months (average, 12.7 months). Fourteen of 16 patients received adjuvant treatments. Nine were alive and well, 1 was alive with metastases, and 6 had died of metastatic disease (including 2 patients who declined additional treatment). False-negative SLNB results were reported in 5 articles involving 9 of 197 procedures (4.6%). Complications were documented in 7 of 27 articles and included transient facial nerve weakness, persistent blue dye staining of the conjunctiva, neck hematoma, and suture abscess. CONCLUSIONS: Sentinel lymph node biopsy is a promising procedure in patients with eyelid and conjunctival malignancy, and it is useful in identifying sentinel lymph nodes. However, at present, insufficient evidence exists showing that SLNB improves patient outcomes and survival. Recognition of microscopic metastatic disease may prove beneficial in staging and guiding adjuvant therapy.

PURPOSE: In recent decades, the medical and surgical treatment of limbal stem cell deficiency (LSCD) has evolved significantly through the incorporation of innovative pharmacological strategies, surgical techniques, bioengineering, and cell therapy. With such a wide variety of options, there is a need to establish a global consensus on the preferred approaches for the medical and surgical treatment of LSCD. METHODS: An international LSCD Working Group was established by the Cornea Society in 2012 and divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to reach agreement on a strategic plan and methods after a comprehensive literature search. A writing group drafted the current study. RESULTS: A consensus in the medical and surgical management of LSCD was reached by the Working Group. Optimization of the ocular surface by eyelid and conjunctival reconstruction, antiinflammatory therapy, dry eye and meibomian gland dysfunction treatment, minimization of ocular surface toxicity from medications, topical medications that promote epithelialization, and use of a scleral lens is considered essential before surgical treatment of LSCD. Depending on the laterality, cause, and stage of LSCD, surgical strategies including conjunctival epitheliectomy, amniotic membrane transplantation, transplantation of limbal stem cells using different techniques and sources (allogeneic vs. autologous vs. ex vivo-cultivated), transplantation of oral mucosal epithelium, and keratoprosthesis can be performed as treatment. A stepwise flowchart for use in treatment decision-making was established. CONCLUSIONS: This global consensus provides an up-to-date and comprehensive framework for the management of LSCD.

PURPOSE: To examine IOP measurement disagreement between technicians and physicians and the impact of an educational intervention on the short and long-term disagreement in IOP measurement using Goldmann applanation tonometry. DESIGN: Prospective study designed to enhance measurement reliability. SETTING: A glaucoma clinic at a university hospital. StudyPopulation: 6 technicians and 2 physicians. INTERVENTION: An educational intervention was implemented for the technicians to improve IOP measurement agreement with physicians. MainOutcomeMeasures: Frequency of IOP measurement disagreement between physicians and technicians, defined as a difference in IOP of >2 or >3 mm Hg and assessed at baseline and immediately and 6 months postintervention. RESULTS: IOP was evaluated for a total of 529 eyes (physician measured mean IOP = 16.4 mm Hg [SD = 5.9]), 30 per technician-physician pair for each data collection period: baseline, immediately postintervention and 6 months postintervention. At baseline, physicians disagreed 17% and 7% of the time when measuring IOP using >2 and >3 mm Hg to define disagreement, respectively, whereas the average disagreement between technicians and physicians was 25% and 13%. Disagreement was greater at IOPs greater than 20 mm Hg. No significant changes were noted in the frequency of disagreement between technicians and physicians immediately or 6 months postintervention. CONCLUSIONS: Two physicians measuring the same patient in the same room disagreed by >2 mm Hg in 17% of patients' eyes, and this amount of disagreement was even higher when comparing physicians to certified technicians. An educational intervention did not improve agreement in IOP measurements between technicians and physicians. This highlights an important limitation of Goldmann tonometry.

PURPOSE: Specialized pro-resolving lipid mediator resolvin (Rv) E1 stimulates secretion including mucins from conjunctival goblet cells. RvE1 can use both its ChemR23 receptor and the LTB receptor BLT1 to increase [Ca]. The purpose of this study was to determine the expression of ChemR23 and BLT1 and receptors on conjunctival goblet cells and the respective roles these two receptors play in goblet cell responses to RvE1. METHODS: Goblet cells were cultured from male rat or human conjunctiva from both sexes. Western blotting analysis, reverse transcription PCR and immunofluorescence microscopy were used to demonstrate the expression of ChemR23 and BLT1 in conjunctival goblet cells. High molecular weight glycoprotein secretion was determined using an enzyme-linked lectin assay. Signaling pathways were studied by measuring the increase in [Ca] using fura 2/AM. RESULTS: ChemR23 and BLT1 and receptors were present on both rat and human conjunctival goblet cells. The BLT1 inhibitors LY293111 and U75302 significantly blocked RvE1-and LTB-stimulated [Ca] increase. RvE1-and LTB-stimulated [Ca] and secretion increases were blocked by BLT1-targeted siRNA. RvE1-stimulated [Ca] and secretion increases were also blocked by ChemR23-targeted siRNA. Addition of RvE1 2 min before or simultaneously with LTB desensitized the LTB [Ca] response. Addition of RvE1 and LTB simultaneously caused secretion that was decreased compared to either response alone. CONCLUSION: RvE1, in addition to the ChemR23 receptor, uses the BLT1 receptor to increase [Ca] and stimulate secretion in both rat and human cultured conjunctival goblet cells.

Transcription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is necessary. We analyzed how the expression of the homeobox TF, orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during development in the mouse retina. We identified seven -regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs, respectively. The chromatin status of these three CRMs was found to be distinct in different retinal cell types and at different stages. We conclude that retinal cells use a cohort of TFs with different expression patterns and multiple CRMs with different chromatin configurations to regulate the expression of Otx2 precisely.