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Purpose: The purpose of this study was to assess the immediate ocular immune response to soft contact lens (CL) wear by examining presumed epithelial immune cell (EIC) density and morphology at the central, peripheral, limbal cornea, and conjunctiva., Methods: Fifty-four participants naïve to CL wear (mean age = 24.8 ± 9.8 years, 44% female participants), were examined using in vivo confocal microscopy at baseline and after 2 hours of CL wear (1-Day ACUVUE MOIST). Images were captured at the central, temporal far peripheral and limbal cornea, and bulbar conjunctiva. EIC density was counted manually and morphology was graded. Differences in EIC parameters pre- and post-CL wear were examined using a generalized estimating equation model with appropriate post hoc analyses., Results: After 2 hours of soft CL wear, there was a significant increase in EIC density in all regions other than the central cornea (all P < 0.001). Cell body size was significantly larger, and a higher proportion of participants exhibited EIC with long dendrites after lens wear at the central and peripheral cornea (both P < 0.001). There was a significant increase in the number of participants displaying EIC with thick dendrites at the peripheral (P = 0.04) and limbal cornea (P < 0.001) after lens wear., Conclusions: EICs were primarily recruited to the peripheral regions, whereas the central cornea shows no significant recruitment after short-term CL wear. Both central and peripheral corneas exhibited an enhanced antigen capture capacity, whereas migratory capacity was increased in the peripheral corneal regions suggesting EIC activation following a short period of CL wear.

Background: Corneal and conjunctival epithelial dendritic cells (DC) have an established role in vernal keratoconjunctivitis, however, their role in more prevalent forms of allergic eye disease remains unclear. This study evaluated corneal and conjunctival epithelial DC density, morphology, and distribution observed using in vivo confocal microscopy (IVCM) in allergic conjunctivitis., Methods: In this prospective, observational study, 66 participants (mean age 36.6 ± 12.0 years, 56% female): 33 with allergic conjunctivitis and 33 controls were recruited. IVCM was performed at the corneal centre, inferior whorl, corneal periphery, corneal limbus, and temporal bulbar conjunctiva. DC were counted and their morphology was assessed as follows: largest cell body size, presence of dendrites, and presence of long and thick dendrites. Mixed model analysis (DC density) and non-parametric tests (DC morphology) were used., Results: DC density was higher in allergic participants at all locations (p ≤ 0.01), (corneal centre median (IQR) 21.9 (8.7-50.9) cells/mm 2 vs 13.1 (2.8-22.8) cells/mm 2 ; periphery 37.5 (15.6-67.2) cells/mm 2 vs 20 (9.4-32.5) cells/mm 2 ; limbus 75 (60-120) cells/mm 2 vs 58.1 (44.4-66.2) cells/mm 2 ; conjunctiva 10 (0-54.4) cells/mm 2 vs 0.6 (0-5.6) cells/mm 2 , but not at the inferior whorl 21.9 (6.2-34.4) cells/mm 2 vs 12.5 (1.9-37.5) cells/mm 2 , p = 0.20. At the corneal centre, allergic participants had larger DC bodies (p = 0.02), a higher proportion of DC with dendrites (p = 0.02) and long dendrites (p = 0.003) compared to controls., Conclusions: Corneal and conjunctival DC density was increased, and morphology altered in allergic conjunctivitis. These findings imply that the ocular surface immune response was upregulated and support an increased antigen-capture capacity of DC in allergic conjunctivitis., (© 2023. The Author(s).)

The aim of the study was to compare the distribution of corneal and conjunctival epithelial dendritic cells (DCs) in vernal keratoconjunctivitis (VKC), allergic conjunctivitis (AC), and non-allergic controls to examine if the allergy type causes differences in immune cell activation. The prospective study included 60 participants: 20 with VKC, 20 with AC, and 20 non-allergic controls. In vivo confocal microscopy was performed on the right eye. The locations scanned included the corneal centre, inferior whorl, corneal periphery, corneal limbus, and bulbar conjunctiva. The DCs were counted manually, and their morphology was assessed for the largest cell body size, the presence of dendrites, and the presence of long and thick dendrites. The DC density was higher in VKC and AC compared to non-allergic group at all locations ( p ≤ 0.01) except at the inferior whorl. The DC density in VKC participants was significantly higher than in AC at the limbus ( p < 0.001) but not at other locations. Both the AC and the VKC group had larger DC bodies at the corneal periphery and limbus compared to the non-allergic group ( p ≤ 0.03). The study found a higher proportion of participants with DCs exhibiting long dendrites at both the corneal periphery in AC ( p = 0.01) and at the corneal centre, periphery, and limbus in VKC, compared to the non-allergic group ( p ≤ 0.001). In conclusion, a higher DC density at the limbus may be a marker of more severe VKC. DCs with larger cell bodies and a greater proportion of participants with DCs displaying long dendrites can be potential markers to differentiate allergy from non-allergy, and more severe forms of allergy from milder forms.

Background: Increased density and altered morphology of dendritic cells (DC) in the cornea and conjunctiva occur during active allergic conjunctivitis. This study investigated whether inflammation (characterised by altered DC density and morphology) persists during the symptom-free phase of allergic conjunctivitis., Methods: Twenty participants (age 43.3 ± 14.3 years, 55% female) assessed during their active (symptomatic) phase of allergic conjunctivitis were re-examined during the asymptomatic phase. Ocular allergy symptoms and signs were evaluated during both phases, and five ocular surface locations (corneal centre, inferior whorl, corneal periphery, corneal limbus, and bulbar conjunctiva) were examined using in vivo confocal microscopy (HRT III). DC were counted manually, and their morphology was assessed for cell body size, presence of dendrites, presence of long dendrites and presence of thick dendrites using a grading system. Mixed model analysis (DC density) and non-parametric tests (DC morphology) were used to examine differences between phases., Results: DC density at corneal locations did not change between the active and asymptomatic phases (p ≥ 0.22). However, corneal DC body size was smaller and fewer DC presented with long dendrites during the asymptomatic phase (p ≤ 0.02). In contrast, at the bulbar conjunctiva, DC density was reduced during the asymptomatic phase compared to the active phase (p = 0.01), but there were no changes in DC morphology., Conclusions: Dendritiform immune cell numbers persist in the cornea during the symptom-free phase of allergic conjunctivitis, whereas conjunctival DC appear to return to a baseline state. The morphology of these persisting corneal DC suggests their antigen-capture capacity is reduced during the asymptomatic phase., (© 2023. The Author(s).)

Purpose: LASIK causes corneal nerve damage and may affect the neuro-immune crosstalk. This study examined the effects of LASIK on corneal epithelial dendritic cells (CEDC) density and morphology and explored their relationships with corneal nerves and tear neuropeptides. A grading system was developed to assess CEDC morphology., Methods: Intra- and inter-observer repeatability of the CEDC morphology grading system was established using kappa (κ). In vivo confocal microscope images of the central cornea were captured from 20 participants who had undergone LASIK 12-16 months earlier and 20 controls (age 18-32 years, 55%F). CEDC density was counted manually, and CEDC morphology was assessed using a new grading system. CEDC sub-types (contacting nerves [CEDCc] and not contacting nerves [CEDCnc]) were also assessed. Differences in CEDC density and morphology were examined using mixed models and chi-squared test. Relationships between CEDC and corneal nerve parameters and tear substance P were explored using Spearman's correlation., Results: Excellent intra- and inter-observer repeatability was demonstrated for the grading system (κ = 0.82-0.97). In post-LASIK participants, CEDC density was lower compared with controls (5 [0-34] vs. 21 [7-77] cells/mm 2 ; p = 0.01), and the proportion of CEDC with thick dendrites was higher (55%-73% vs. 11%-21%, p < 0.003). Higher tear substance P levels were associated with higher CEDC density (rho = 0.48, p = 0.003). Fewer nerve interconnections were observed in participants in whom CEDC had dendrites (p = 0.03). CEDC sub-types followed a similar pattern to CEDC., Conclusions: The findings suggest that CEDC may remain altered more than 12 months post-LASIK. The association with substance P suggests a role for CEDC in corneal neurogenic inflammation., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Smartphone use by children is rising rapidly, but its ocular surface impact is unknown. This study examined the effect of smartphone use on blinking, symptoms, and tear function in children., Methods: Prospective intervention study where 36 children aged 6-15years (14 M:22 F) played games on a smartphone continuously for one hour. Symptoms (SANDE, IOSS, NRS) and tear film (lipid layer thickness, tear secretion, stability) were assessed before and after gaming. Blink rate and interblink interval were measured in situ using an eye tracking headset, before (during conversation) and continuously throughout gaming. Symptoms and tear film changes were examined using paired t-tests. Changes in blinking throughout one hour were examined using repeated measures ANOVA, post-hoc comparisons with Bonferroni correction. Associations examined using Pearson bivariate correlation. Significance level was 0.05., Results: Symptoms worsened following one hour smartphone gaming (SANDE + 8.2units, p = 0.01; IOSS + 1.3units, p < 0.001; NRS-average +6.3units, p = 0.03; NRS-comfort +7.6units, p = 0.04; NRS-tiredness +10.1units, p = 0.01), but tear film remained unchanged. Blink rate reduced from 20.8 blinks/min to 8.9 blinks/min (p < 0.001) and interblink interval increased from 2.9 s to 8.7 s (p = 0.002) within the first minute of gaming relative to baseline conversation, and this effect remained unchanged throughout one hour of gaming., Conclusions: Smartphone use in children results in dry eye symptoms and immediate and sustained slowing of blinking, with no change in tear function evident up to one hour. Given the ubiquitous use of smartphones by children, future work should examine whether effects reported herein persist or get worse over a longer term causing cumulative damage to the ocular surface., (© 2022. The Author(s).)

Purpose: To compare blinking measured in situ during various tasks and examine relationships with ocular surface symptoms. The day-to-day repeatability of the blink rate and interblink interval was assessed., Methods: Twenty-four students (28.6 ± 6.3 years; 8 male and 16 female) completed six reading tasks (printed text, laptop, TV, smartphone, smartphone at 50% brightness, smartphone with complex text), and two nonreading tasks (conversation, walking) in a randomized cross-over study. Ocular surface symptoms and clinical signs were assessed. The blink rate and interblink interval were measured using a wearable eye tracking headset. Blink parameters were compared across tasks and time (linear mixed model and post hoc comparisons with Bonferroni correction). Associations between blinking, symptoms, ocular surface, and clinical signs were assessed (Spearman's correlation). The smartphone reading task was completed twice to determine the coefficient of repeatability., Results: The blink rate was lower (mean 10.7 ± 9.7 blinks/min) and the interblink interval longer (mean 9.6 ± 8.7 seconds) during all reading tasks compared with conversation (mean 32.4 ± 12.4 blinks/min; 1.5 ± 0.6 seconds) and walking (mean 31.3 ± 15.5 blinks/min; 1.9 ± 1.3s) (P < 0.001). There were no significant differences in blink parameters between any of the reading tasks or between conversation and walking. Changes in blinking occurred within 1 minute of starting the task. No associations were evident between blink rate or interblink interval and ocular surface symptoms or signs. The coefficient of repeatability was ±12.4 blinks/min for blink rate and ±18.8 seconds for interblink interval., Conclusions: Spontaneous blinking can be measured reliably in situ. The blink rate was decreased and the interblink interval increased during reading compared with conversation and walking. Changes in blinking were immediate, sustained, and not associated with ocular surface symptoms or signs.

Wildfires are occurring worldwide with greater frequency and intensity. Wildfires, as well as other sources of air pollution including environmental tobacco smoke, household biomass combustion, agricultural burning, and vehicular emissions, release large amounts of toxic substances into the atmosphere. The ocular surface is constantly exposed to the ambient air and is hence vulnerable to damage from air pollutants. This review describes the detrimental effects of wildfire smoke and air pollution on the ocular surface and resultant signs and symptoms. The latest relevant evidence is synthesised and critically evaluated. A mechanism for the pathophysiology of ocular surface damage will be proposed considering the existing literature on respiratory effects of air pollution. Current strategies to reduce human exposure to air pollutants are discussed and specific possible approaches to protect the ocular surface and manage air pollution induced ocular surface damage are suggested. Further avenues of research are suggested to understand how acute and chronic air pollution exposure affects the ocular surface including the short and long-term implications., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Accurate measurement of very low circulating estradiol (E 2 ) (<5 pg/ml) in postmenopausal women and in mice is essential to investigating sex steroid action in target tissues. However, direct immunoassays are too inaccurate and conventional mass spectrometry-based measurement too insensitive at these serum E 2 levels. We report application of an ultrasensitive method using a novel estrogen-selective derivatization in liquid chromatography-mass spectrometry to measure serum E 2 , with a detection limit of 0.25 pg/ml in small (0.2 ml) serum volumes that can quantify serum E 2 in 98% and serum E 1 in 100% of healthy postmenopausal women. Aromatase inhibitor (AI) treatment of postmenopausal women with breast cancer further reduces serum E 2 by 85% and serum estrone (E 1 ) by 80%. The wide scatter of circulating E 2 in AI-treated women suggests that the degree of sustained E 2 depletion, now quantifiable, may be an efficacy or safety biomarker of adjuvant AI treatment. This ultrasensitive method can also measure serum E 2 in most (65%) female but not in any male mice. Further studies are warranted using this and comparable ultrasensitive liquid chromatography-mass spectrometry estrogen measurements to investigate the relationship of circulating E 2 (and E 1 ) in male, postmenopausal female, and childhood health where accurate quantification of serum estrogens was not previously feasible. This will focus on the direct impact of estrogens as well as the indirect effects of androgen aromatization on reproductive, bone, and brain tissues and, notably, the efficacy and safety of AIs in adjuvant breast cancer treatment., (© Commonwealth of Australia, 2020.)

Purpose: We examined agreement among experts in the assessment of corneal subbasal nerve tortuosity., Methods: Images of corneal subbasal nerves were obtained from investigators at seven sites (Auckland, Boston, Linköping, Manchester, Oslo, Rostock, and Sydney) using laser-scanning in vivo confocal microscopy. A set of 30 images was assembled and ordered by increasing tortuosity by 10 expert graders from the seven sites. In a first experiment, graders assessed tortuosity without a specific definition and performed grading three times, with at least 1 week between sessions. In a second experiment, graders assessed the same image set using four focused tortuosity definitions. Intersession and intergrader repeatability for the experiments were determined using the Spearman rank correlation., Results: Expert graders without a specific tortuosity definition had high intersession (Spearman correlation coefficient 0.80), but poor intergrader (0.62) repeatability. Specific definitions improved intergrader repeatability to 0.79. In particular, tortuosity defined by frequent small-amplitude directional changes (short range tortuosity) or by infrequent large-amplitude directional changes (long range tortuosity), indicated largely independent measures and resulted in improved repeatability across the graders. A further refinement, grading only the most tortuous nerve in a given image, improved the average correlation of a given grader's ordering of images with the group average to 0.86 to 0.90., Conclusions: Definitions of tortuosity specifying short or long-range tortuosity and considering only the most tortuous nerve in an image improved the agreement in tortuosity grading among a group of expert observers. These definitions could improve accuracy and consistency in quantifying subbasal nerve tortuosity in clinical studies.

Purpose: Dry eye is common in Asian populations, but there are limited validated instruments available to assess ocular symptoms within these populations. This study aimed to develop and assess the psychometric properties of a Chinese version of the ocular comfort index (OCI-C)., Methods: The OCI was translated and back translated by 32 bilingual volunteers and a preliminary OCI-C was produced for analysis; 165 bilingual volunteers completed both the OCI and the preliminary OCI-C. The item scores for preliminary OCI-C were compared with the OCI using Cronbach's α. Repeatability of the total score of OCI-C was evaluated in a subgroup of 20 participants after a week by calculating the coefficient of repeatability (CoR) and intraclass correlation coefficient (ICC) for the OCI-C score; 322 subjects, including 81 dry eye subjects, completed the OCI-C to verify the sensitivity in dry eye diagnosis. Rasch analysis was used to estimate interval measures from ordinal Likert score and assess psychometric property of item-fit, category function, targeting of items to subjects, and person separation reliability., Results: Cronbach's α for all items was above 0.85. The CoR was ± 5.84 and the ICC was 0.96 (95% confidence interval 0.91-0.98). The total score of OCI-C was able to differentiate dry eye (40.0) with non-dry eye (30.2) (P < 0.0001). In the Rasch analysis model, the OCI-C showed robust psychometric properties for item-fit and category calibration: person-separation reliability: 2.47 and item reliability: 8.42., Conclusions: The psychometric properties of the OCI-C are comparable with the OCI and the instrument is appropriate as a diagnostic tool and to determine the severity of dry eye in this population., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

This report characterizes the neurobiology of the ocular surface and highlights relevant mechanisms that may underpin contact lens-related discomfort. While there is limited evidence for the mechanisms involved in contact lens-related discomfort, neurobiological mechanisms in dry eye disease, the inflammatory pathway, the effect of hyperosmolarity on ocular surface nociceptors, and subsequent sensory processing of ocular pain and discomfort have been at least partly elucidated and are presented herein to provide insight in this new arena. The stimulus to the ocular surface from a contact lens is likely to be complex and multifactorial, including components of osmolarity, solution effects, desiccation, thermal effects, inflammation, friction, and mechanical stimulation. Sensory input will arise from stimulation of the lid margin, palpebral and bulbar conjunctiva, and the cornea.

Purpose: This study was designed to map the sub-basal nerve plexus (SBNP) in the cornea of orthokeratology (OK) lens wearers., Methods: Laser scanning confocal microscopy (LSCM) was performed in vivo on three subjects: a non-lens wearer and two OK lens wearers. Scans were performed on the right eye while the left eye fixated a moving target. A total of 575, 430, and 676 contiguous images of the SBNP were taken from the non-lens wearing and the OK lens wearing subjects, respectively, and used to construct maps of the central to mid-peripheral SBNP., Results: In the non-lens wearing eye, nerves radiated towards a whorl-like complex centered nasally and inferiorly in an overall pattern consistent with previously reported studies. In the OK lens wearing eyes, this whorl pattern was absent, replaced by a tortuous network of nerve fibers centrally, and thicker curvilinear fibers mid-peripherally, particularly in the nasal, inferior, and temporal regions., Conclusions: This study maps the corneal SBNP in OK lens wearers and provides compelling evidence that OK lens wear alters the normal SBNP distribution observed in healthy, non-lens wearing eyes.

Purpose: Deprivation of oxygen to the ocular surface during contact lens wear has been implicated in the alteration of sensory function. This study investigates whether increasing oxygen availability through discontinuation of contact lens wear or transfer into highly oxygen transmissible (high Dk/t) lenses leads to a change in corneal or conjunctival sensitivity., Methods: Twenty-seven long-term extended wearers of low Dk/t soft contact lenses ceased lens wear for 1 week and were refitted with high Dk/t silicone hydrogel lenses. A control group of 25 nonwearers matched for age and sex was also recruited. Central corneal and inferior conjunctival sensitivity were measured using an air-jet aesthesiometer. Threshold was determined using a staircase technique. Measurements were taken during low Dk/t lens wear; after 1 week of no wear; and after 1, 3, 6, and 12 months of high Dk/t lens wear. Measurements were carried out on one occasion on the nonwearers., Results: Corneal sensitivity decreased 1 week after discontinuation of low Dk/t lenses and no further change in sensitivity occurred with high Dk/t lens wear. Conjunctival sensitivity did not change over the same time frame. Ocular surface sensitivity in long-term low Dk/t soft lens wearers was similar to that of nonwearers. Sensitivity was higher in females than males in the nonwearers, but not in the lens-wearing group. An interaction of sex on change in conjunctival threshold was found in the lens wearers., Conclusions: These findings indicate that factors other than oxygen availability alone determine sensitivity of the ocular surface. Silicone hydrogel contact lenses appear to have only a minor impact on ocular surface sensitivity in previous lens wearers.

Purpose: To estimate the just-noticeable difference (JND) in ocular comfort rating by human, contact lens-wearing subjects using 1 to 100 numerical scales., Methods: Ostensibly identical, new contact lenses were worn simultaneously in both eyes by 40 subjects who made individual comfort ratings for each eye using a 100-point numerical ratings scale (NRS). Concurrently, interocular preference was indicated on a five-point Likert scale (1 to 5: strongly prefer right, slightly prefer right, no preference, slightly prefer left, strongly prefer left, respectively). Differences in NRS comfort score (ΔC) between the right and left eyes were determined for each Likert scale preference criteria. The distribution of group ΔC scores was examined relative to alternative definitions of JND as a means of estimating its value., Results: For Likert scores indicating the presence of a slight interocular preference, absolute ΔC ranged from 1 to 30 units with a mean of 7.4 ± 1.3 (95% confidence interval) across all lenses and trials. When there was no Likert scale preference expressed between the eyes, absolute ΔC did not exceed 5 units., Conclusions: For ratings of comfort using a 100-point numerical rating scale, the inter-ocular JND is unlikely to be less than 5 units. The estimate for the average value in the population was approximately 7 to 8 units. These numbers indicate the lowest level at which changes in comfort measured with such scales are likely to be clinically significant.