We aim to summarize the current evidence of Vascular endothelial growth factors (VEGF)s in external eye diseases and determine whether serum and plasma VEGF levels are associated with tear and ocular surface tissues. A systematic search of PUBMED and EMBASE was conducted using PRISMA guidelines between October 2022 and November 2023, with no restriction on language or publication date. Search terms included relevant MESH terms. These studies were evaluated for quality, and an assessment of the risk of bias was also carried out. Extracted data were then visually represented through relevant tables or figures. The initial literature search yielded 777 studies from PUBMED, 944 studies from EMBASE, and 10 studies from manual searches. Fourteen eligible studies were identified from 289 articles published from 2000 to 2023 in the English language or with English translations, including rabbit models, murine models, and human-derived samples. Most studies were retrospective in nature and case–control studies. Various common external eye diseases, such as dry eye disease (DED) and allergic eye disease were investigated. Despite limitations and small sample sizes, researchers have found elevated tissue levels of the VEGF in the vascularized cornea, especially in animal models, but there is no evidence of clear changes in the tear concentrations of VEGF in DED and allergic eye disease. Tear VEGF is associated with corneal vascularization. Anti-VEGF therapies may have the potential to manage such conditions.

Purpose Noninvasive keratograph break up times (NIKBUTs) are preferred to dye-based methods to evaluate tear stability in translational medicine. We analyzed the NIKBUTs in different regions of the precorneal tear by using a common imaging technology and explored potential correlations with clinical parameters. Methods We tested NIKBUTs of 120 participants (62.5% females, aged 61.0 ± 13.8 years) with the Keratograph 5M, with standardized symptoms, ocular surface evaluation, and tear lipid layer interferometry. NIKBUTs were obtained from color maps in up to 165 spatial zones corresponding to 7 concentric rings. Results The lowest NIKBUT of tested zones averaged 7.8 ± 7.4 seconds (median, 4.5; range, 1.5–24 seconds), with the lowest NIKBUT measuring <2 seconds in many inferior zones. A mean of 5 zones had broken up by 2 seconds compared to a mean of about 50 zones by 10 seconds. NIKBUTs in specific inferior peripheral zones were significantly directly correlated to tear lipid thicknesses. The receiver operating characteristics for detecting reduced tear lipid thickness were better than overall NIKBUTs for participants with readings in these zones. Weaker correlations of NIKBUTs with symptoms were observed in two other zones. Overall, the NIKBUT displayed by keratograph was not significantly associated with any clinical parameters. Conclusions Decreased NIKBUTs in specific peripheral locations may be associated with lower lipid thicknesses. Future measurements of NIKBUTs should ideally be determined in smaller defined zones than current maps. Translational Relevance An understanding of how to evaluate tear stability allows a more robust clinical evaluation of new drugs and medical devices for dry eye.

Purpose: Assessment of tear film and conjunctiva is critical to define presence and severity of ocular surface disease. We aimed to characterize tear meniscus area (TMA) and conjunctivochalasis by anterior segment optical coherence tomography (ASOCT) in population-based patients and identify potential factors associated with low TMA and severe conjunctivochalasis. Methods: Study subjects were enrolled from The Singapore Indian Eye Study, a population-based study of Asian Indian in Singapore. Imaging with ASOCT was performed on three ocular regions (nasal, central and temporal). TMA was obtained by measuring the cross-sectional area of the inferior tear meniscus. Severity of conjunctivochalasis was quantified by measuring the conjunctivochalasis ratio (CCR), the ratio of area of redundant conjunctiva to the TMA. Ocular symptoms and demographic factors were assessed by standardized questionnaires. Results: A total of 403 participants (52.9% women) 40 years of age and older were included. TMA centrally was 2818 +/- 5308 pixel(2). Female sex and the presence of meibomian gland dysfunction (MGD), but not older age, were associated with a lower TMA (p = 0.031, p = 0.031 and p = 0.956 respectively). In this population, 9.2% had severe conjunctivochalasis (CCR>0.7) whereas 39.0% had mild to no conjunctivochalasis (CCR <= 0.3). Conjunctivochalasis was more severe in temporal, followed by nasal and central sections. Older age was associated with severe conjunctivochalasis (p < 0.001). Conclusion: MGD and female gender were associated with lower TMA, while older age was associated with increased severity of conjunctivochalasis. Objective measurement of TMA and CCR using ASOCT imaging may be useful in the assessment of tear volume and ocular surface tear function.

Diabetic retinopathy is a leading cause of vision impairment and blindness. We systematically reviewed studies published from Jan 1, 1980, to Jan 7, 2018, assessed the methodological quality, and described variations in incidence of diabetic retinopathy by region with a focus on population-based studies that were conducted after 2000 (n=8, including two unpublished studies). Of these eight studies, five were from Asia, and one each from the North America, Caribbean, and sub-Saharan Africa. The annual incidence of diabetic retinopathy ranged from 2·2% to 12·7% and progression from 3·4% to 12·3%. Progression to proliferative diabetic retinopathy was higher in individuals with mild disease compared with those with no disease at baseline. Our Review suggests that more high-quality population-based studies capturing data on the incidence and progression of diabetic retinopathy with stratification by age and sex are needed to consolidate the evidence base. Our data is useful for conceptualisation and development of major public health strategies such as screening programmes for diabetic retinopathy.

Non-recirculating resident memory (T RM ) and recirculating T cells mount vigorous immune responses to both self and foreign antigens in barrier tissues like the skin, lung and gastrointestinal tract. Using impression cytology followed by flow cytometry we identified two T RM subsets and four recirculating T-subsets in the healthy human ocular surface. In dry eye disease, principal component analysis (PCA) revealed two clusters of patients with distinct T-cell signatures. Increased conjunctival central memory and naïve T cells characterized Cluster-1 patients, and increased CD8 + T RM s and CD4 + recirculating memory T cells characterized Cluster-2 patients. Interestingly these T-cell signatures are associated with different clinical features: the first signature correlated with increased ocular redness, and the second with reduced tear break up times. These findings open the door to immune-based characterization of dry eye disease and T-subset specific immunotherapies to suppress T-subsets involved in disease. They may also help with patient stratification during clinical trials of immunomodulators.

We introduced a new method for detecting iris surface furrows and identify its associations with dynamic changes in iris volume in healthy eyes. Swept-source optical coherence tomography was performed on 65 subjects with open angle under light and dark conditions. Iris boundaries were identified and a reconstruction of the anterior iris surface was obtained. Furrows were detected by identifying locally deep (minima) points on the iris surface and reported as furrow length in millimetres. Iris volume was quantified. Associations between furrow length and dynamic changes in iris volume were assessed using linear regression model. With pupil dilation, furrow length increased (15.84 mm) whereas iris volume decreased (−1.19 ± 0.66 mm 3 ). Longer furrow length was associated with larger static iris volume, as well as smaller loss of iris volume with pupil dilation (β = −0.10, representing 0.1 mm 3 less loss in iris volume per 10 mm increase in iris furrow length; P = 0.002, adjusted for age, gender and changes in pupil size). Our iris furrow length measurements are robust and intuitive. Eyes with longer furrows have larger iris volume and lose less volume during physiological pupil dilation. These findings highlight the potential for iris surface features as indicators of iris morphological behavior.

PURPOSE:To identify ocular factors that affect signal strength in spectral-domain optical coherence tomography (SD-OCT).METHODS:Data from 1312 participants of the population-based Singapore Malay Eye Study-2 (SiMES-2) were included in the analysis. All participants underwent standardized ophthalmic examination, including measurements of best-corrected visual acuity (BCVA), refractive error, axial length, corneal curvature and presence of cataracts. Optic disc and macular cube scans were acquired using the Cirrus HD-OCT (software version 6.0, Carl Zeiss Meditec, Dublin, CA, USA). Signal strength of the optical coherence tomography (OCT) scan was recorded for each study eye. Multivariable linear regression analyses were performed to evaluate the associations between ocular factors and signal strength of the OCT scans.RESULTS:The mean (±SD) age of our study participants was 61 ± 9 years, and 44.6% were male. Mean optic disc scan signal strength was 7.90 ± 1.25, range = 0-10, while mean macular scan signal strength was 8.80 ± 1.27, range = 0-10. In multivariable regression analyses, poorer signal strength in optic disc and macular cube scans was each associated with older age (per decade, β = -0.373, p < 0.001; β = -0.373, p < 0.001, respectively), poorer BCVA (per logMAR line; β = -0.123, p < 0.001; β = -0.156, p < 0.001, respectively), greater degree of myopia (per negative dioptre of spherical equivalent; β = -0.112, p < 0.001; β = -0.117, p < 0.001, respectively), presence of cortical cataracts (β = -0.331, p < 0.001; β = -0.314, p < 0.001, respectively) and presence of posterior subcapsular cataracts (β = -0.910, p < 0.001; β = -0.797, p < 0.001, respectively).CONCLUSION:We found that older age, poorer BCVA, greater degree of myopia and presence of cortical and posterior subcapsular cataracts were associated with reduced signal strength in Cirrus SD-OCT. Our findings provide information on the barriers to obtaining good image quality when using SD-OCT, and allow clinicians to potentially identify individuals who are more likely to have unreliable OCT measurements.

Traditionally, ocular surface cytology is studied with techniques such as spatula technology and brush technology. The problem with these techniques is that they may induce traumatic lesions on the surface of the eye, which can progress to scarring, eyelid deformity, limbal stem cell deficiency and in some cases, cause great discomfort to the subject. To avoid these clinical problems, impression cytology (IC) was developed to diagnose dry eye disease and later neoplasia, atopic disease, vernal keratoconjunctivitis and keratoconjunctivitis sicca. Typically, clinicians manually cut filter papers into required shapes and apply these to the ocular surface. Here, we describe how to perform IC using a commercially available medical device. This technique is explained here followed by immunophenotyping by flow cytometry. This technique requires less manual handling and causes less injury to the ocular surface.

PURPOSE:To determine the relationship between iris surface features and acute primary angle closure (APAC) in eyes with angle closure.DESIGN:Case-control study involving Asian patients diagnosed with previous APAC, primary angle closure suspect (PACS), primary angle closure (PAC) and primary angle closure glaucoma (PACG) at an eye centre in Singapore between August 2012 and January 2015.METHODS:Participants underwent ophthalmic examination and digital slit-lamp iris photography. Iris surface features were graded based on crypts, furrows and colour. Fellow eyes of APAC were compared with PACS and PAC/PACG eyes with regard to their iris surface features.MAIN OUTCOME MEASURE:Occurrence of APAC.RESULTS:A total of 309 patients (71 APAC, 139 PACS, 47 PAC and 52 PACG) were included (mean age: 67.7±7.2 years and 36.6% male). Compared with PACS, higher crypt grade was significantly associated with lower odds of APAC (OR=0.58 for one grade higher in crypt grade; p=0.027, adjusted for age, gender, ethnicity and pupil diameter). The results remained similar when compared with PAC/PACG group (OR=0.58 for one grade higher in crypt grade; p=0.043). We did not observe any significant associations between iris furrows or colour with presence of APAC.CONCLUSIONS:Our study comprising Asian eyes with angle closure suggests that the presence of a higher crypt grading may be protective for APAC. As such, assessing iris surface architecture for crypts could be a new measure for risk stratification of developing APAC in eyes with angle closure.

Background It is difficult to standardize assessment of dry eye in different clinical settings. Increasingly, tear stability is recognized to be important for the definition and assessment of patients with dry eye. Recently, two commercially available instruments have been made available for objectively measuring noninvasive tear break-up time (NIBUT), as an indicator of tear stability: the Tomey RT-7000 Auto Refractor-Keratometer and Oculus Keratograph (K)5M. We aim to assess the agreement of NIBUT measurements using these modalities. Methods This prospective cross-sectional study was carried out in a tertiary referral eye center and involved 126 consecutive dry eye patients. NIBUT assessment was performed on the right eyes of participants with both the RT-7000 and the K5M techniques, with the order of assessment randomized. The Standardized Patient Evaluation of Eye Dryness (SPEED) questionnaires were administered to assess dry eye symptoms in the 2 weeks before assessment. Results The age of the participants was 56.0±14.3 years (69.84% females). Measurements for both modalities were non-normally distributed (right-skewed). The median RT-7000 and K5M readings were 4.2 (range 0.1–10.0) and 6.4 (0.1–24.9) seconds, respectively. RT-7000 and K5M readings were poorly correlated (ρ=0.061, P=0.495). Intraclass correlation coefficient between the modalities was 0.187 (95% confidence interval −0.097 to 0.406). The Bland–Altman plot showed no systematic differences between the readings with these machines. The agreement between machines was not different in different SPEED categories. Conclusion While there are theoretical and practical benefits of NIBUT for assessment of tear stability over dye-based methods, the agreement between the two modalities was poor. Hence, studies and trials assessing NIBUT should avoid using these modalities interchangeably for NIBUT assessment. More research is needed to improve consensus on how to determine NIBUT.

Diabetic retinopathy (DR) is a leading cause of vision-loss globally. Of an estimated 285 million people with diabetes mellitus worldwide, approximately one third have signs of DR and of these, a further one third of DR is vision-threatening DR, including diabetic macular edema (DME). The identification of established modifiable risk factors for DR such as hyperglycemia and hypertension has provided the basis for risk factor control in preventing onset and progression of DR. Additional research investigating novel risk factors has improved our understanding of multiple biological pathways involved in the pathogenesis of DR and DME, especially those involved in inflammation and oxidative stress. Variations in DR prevalence between populations have also sparked interest in genetic studies to identify loci associated with disease susceptibility. In this review, major trends in the prevalence, incidence, progression and regression of DR and DME are explored, and gaps in literature identified. Established and novel risk factors are also extensively reviewed with a focus on landmark studies and updates from the recent literature.

Dry eye is the most common post-operative complication in patients who undergo laserassisted in situ keratomileusis and other photorefractive procedures. Epidemiological studies have found that almost all patients experience some form of dry-eye-related discomfort in the post-operative period. This review seeks primarily to identify patient factors, which predispose to this complication, as well as outline the possible interventions clinicians can consider to avoid, prevent and treat this complication. Numerous pre-,intra-and postoperative guidelines are provided. The ideal method of post-laser-assisted in situ keratomileusis dry eye prevention is a meticulous peri-operative management plan, as opposed to post-operative management alone. Newer modalities of photorefractive surgery may have differing effects on the ocular surface.

PurposeEpithelial cell migration is required for regeneration of tissues and can be defective in a number of ocular surface diseases. This study aimed to determine the expression pattern of Rho family small G-proteins in human corneal epithelial cells to test their requirement in directional cell migration. MethodsRho family small G-protein expression was assessed by reverse transcription-polymerase chain reaction. Dominant-inhibitory constructs encoding Rho proteins or Rho protein targeting small interfering RNA were transfected into human corneal epithelial large T antigen cells, and wound closure rate were evaluated by scratch wounding assay, and a complementary non-traumatic cell migration assay. Immunofluorescence staining was performed to study cell polarization and to assess Cdc42 downstream effector. ResultsCdc42, Chp, Rac1, RhoA, TC10 and TCL were expressed in human corneal epithelial cells. Among them, Cdc42 and TCL were found to significantly affect cell migration in monolayer scratch assays. These results were confirmed through the use of validated siRNAs directed to Cdc42 and TCL. Scramble siRNA transfected cells had high percentage of polarized cells than Cdc42 or TCL siRNA transfected cells at the wound edge. We showed that the Cdc42-specific effector p21-activated kinase 4 localized predominantly to cell-cell junctions in cell monolayers, but failed to translocate to the leading edge in Cdc42 siRNA transfected cells after monolayer wounding. ConclusionRho proteins expressed in cultured human corneal epithelial cells, and Cdc42, TCL facilitate two-dimensional cell migration in-vitro. Although silencing of Cdc42 and TCL did not noticeably affect the appearance of cell adhesions at the leading edge, the slower migration of these cells indicates both GTP-binding proteins play important roles in promoting cell movement of human corneal epithelial cells.