Slowing of Greater Axial Length Elongation Stemming from the Coronavirus Disease 2019 Pandemic with Increasing Time Outdoors: The Tokyo Myopia Study.

Purpose: To investigate the changes in axial length (AL) elongation and other ocular parameters before and during the coronavirus disease 2019 pandemic. Design: A longitudinal school-based study. Participants: Public elementary schoolchildren in Tokyo (grades 1-6; age, 6-12 years) participated in this study from 2018 to 2021. Methods: All participants underwent eye examinations and provided written consent to measurements of the noncycloplegic refraction and ocular biometry including AL, among others. The students' parents also completed a questionnaire about the students' lifestyles. We included the right eye in our analysis and compared the changes in the ocular parameters among the periods using a linear mixed-effects model for repeated measures and examined the univariate and step-wise multiple regression analyses to evaluate the associations between myopia and other covariates. Main Outcome Measures: Changes in AL elongation and other ocular parameters from 2018 to 2019 (prepandemic), that of 2019 to 2020 (immediately after the pandemic onset), and that of 2020 to 2021 (during the pandemic). Results: A total of 578 students before the pandemic period, 432 immediately after the pandemic onset, and 457 during the pandemic period were evaluated. The changes in the ALs and spherical equivalents (SEs) a year before, immediately after onset, and during the pandemic were 0.31 mm/-0.20 diopter, 0.38 mm/-0.27 diopter, and 0.28 mm/-0.47 diopter, respectively (ALs, P < 0.001; SEs, P = 0.014). The results of the questionnaire showed that time spent outdoors daily had changed during the 3 years to 79, 63, and 77 minutes/day, respectively (P < 0.001). Time spent using smartphones or tablets increased year by year to 41, 52, and 62 minutes/day (P < 0.001). The greatest AL elongation occurred during the period when the shortest amount of time was spent outdoors during the 3 years. Conclusions: These results suggested that the school closures and decreasing time spent outdoors might have caused greater AL elongation among schoolchildren in Tokyo; however, it is possible that, although the time spent in near work still increased, the return to the time spent outdoors to the prepandemic levels may have affected the slowing of AL elongation after lockdown. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Short-Term Exposure to Violet Light Emitted from Eyeglass Frames in Myopic Children: A Randomized Pilot Clinical Trial.

Violet light (VL), 360−400 nm wavelength, is contained in the sunlight and is an effective element for myopia suppression. This study is to investigate the safety and efficacy of novel eyeglasses that emit VL from the frames. This is a double-masked, randomized, pilot clinical trial conducted in a clinic in Japan. Forty-three children with myopia were enrolled. Participants were randomly assigned to two groups, wearing VL-emitting eyeglass frames (VLf) that emitted VL of 310 µW/cm2 (VLf group, n = 22) or pseudo-placebo eyeglass frames with a minimal emission of VL (<10 µW/cm2) (control group, n = 21). The exposure time was 3 h per day. The primary outcomes were visual acuity, tear film break-up time, corneal endothelial cell density, and the slit-lamp/fundus examinations. The secondary outcome was the 6-month changes in the axial lengths and cycloplegic refractions. Forty-one (95%) participants were included; twenty-one in the VLf group and twenty in the control group. No significant differences were seen in any safety evaluation. Significant changes were seen in axial elongation, choroidal thickness, and cycloplegic refractions in the subgroup analysis of 8- to 10-year-old children (p < 0.05), but otherwise no significant differences were seen. The VLf showed short-term safety and effectiveness against myopia progression.

Multicenter prospective validation study for international chronic ocular graft-versus-host disease consensus diagnostic criteria.

PURPOSE: To validate the international chronic ocular graft-versus-host disease (GVHD) diagnostic criteria (ICCGVHD) compared to the National Institute of Health diagnostic criteria 2014 (NIH2014) for chronic ocular GVHD. METHODS: Between 2013 and 2019, the study enrolled 233 patients with or without chronic ocular GVHD combined with the presence or absence of systemic chronic GVHD in an internationally prospective multicenter and observational cohort from 9 institutions. All patients were evaluated for four clinical parameters of ICCGVHD. RESULTS: The relation between the ICCGVHD score (0-11) and NIH2014 eye score (0-4) was relatively high (r = 0.708, 95% CI: 0.637-0.767, p < 0.001). The sensitivity and specificity of ICCGVHD for NIH 2014 for 233 patients were 94.3% (95% CI: 89.6%-98.1%) and 71.7% (95% CI: 63.0-79.5%), respectively (cutoff value of the ICCGVHD score = 6). The positive predictive value was 77.1% (95% CI: 71.1%-82.1%), and the negative predictive value was 87.0% (95% CI:81.6-92.5%). For the patients with systemic GVHD (n = 171), the sensitivity and specificity were 94.2% and 67.2%, respectively (ICCGVHD-score cutoff value = 6). By receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.903 (95% CI: 0.859-0.948). For patients without systemic GVHD (n = 62), the sensitivity and specificity were 100% and 76.7%, respectively (ICCGVHD-score cutoff value = 6). The AUC was 0.891 (95% CI 0.673-1.000). CONCLUSIONS: Good sensitivity, specificity, predictive value and correlation were found between ICCGVHD and NIH2014. ICCGVHD scores ≥6 can be useful to diagnose ocular GVHD with or without systemic GVHD for clinical research.

Children in Tokyo Have a Long Sustained Axial Length from Age 3 Years: The Tokyo Myopia Study.

Background: myopia prevalence is high among Japanese schoolchildren, but the underlying causes are unclear. Objective: To examine the distributions of ocular biometry and refraction and their associations with lifestyle variables among Japanese schoolchildren. Methods: This cross-sectional school-based study included 2140 children aged 3−14 years in Tokyo, Japan, and evaluated the distributions under non-cycloplegic conditions and the associated environmental factors. Results: The prevalence of spherical equivalent (SE) ≤−0.75 diopter among preschoolers (aged 3−6 years), elementary school students (aged 6−11 years), and junior high school students (aged 12−14 years) was 49.7%, 72.4%, and 87.7%, respectively. Multiple linear regression analyses showed that the time spent using digital devices was associated positively with lens thickness (ß = 0.010; p < 0.050) but not SE, axial length, or vitreous chamber depth. The time spent reading was associated negatively with lens thickness (ß = −0.012; p < 0.050), SE (ß = −0.152; p < 0.010), axial length (ß = 0.110; p < 0.001), and vitreous chamber depth (ß = 0.110; p < 0.001). Conclusions: The data indicated that almost half of preschoolers may be myopic. The association with the lens thickness differed depending on the type of near work performed.

Relation between dry eye and myopia based on tear film breakup time, higher order aberration, choroidal thickness, and axial length.

The purpose of this study was to investigate the association between dry eye disease (DED) and myopia by evaluating higher order aberrations (HOAs) and choroidal thickness (CT). We recruited 72 myopic children with DED symptoms (mean age 12.8 years), measured the tear film breakup time (TBUT), corneal/intraocular/total ocular HOAs, CT, and axial length (AL), administered lifestyle questionnaires, and evaluated the relationships among TBUT, HOAs, CT, and AL. The TBUT was correlated significantly with the corneal HOAs and intraocular HOAs but not with the total ocular HOAs. Multiple regression analyses showed that the AL was associated significantly with the TBUT (ß = - 0.067, P = 0.004), the intraocular HOAs, and total ocular HOAs but not with the corneal HOAs. The CT was associated significantly with the TBUT and AL (ß = 9.15 and - 7.85, respectively; P < 0.001 and = 0.01, respectively). Our data suggested the association between DED and myopia might be independent of the HOAs. We showed that the TBUT was associated with the CT, which is related to the AL. Because the parasympathetic nervous system affects the lacrimal glands and CT, the parasympathetic nervous system might be a common upstream factor in the association between DED and myopia.

Lipidomic analysis revealed n-3 polyunsaturated fatty acids suppressed choroidal thinning and myopia progression in mice.

Myopia is increasing worldwide and its preventable measure should urgently be pursued. N-3 polyunsaturated fatty acids (PUFAs) have been reported to have various effects such as vasodilative and anti-inflammatory, which myopia may be involved in. This study is to investigate the inhibitory effect of PUFAs on myopia progression. A lens-induced myopia (LIM) model was prepared using C57B L6/J 3-week-old mice, which were equipped with a -30 diopter lens to the right eye. Chows containing two different ratios of n-3/n-6 PUFA were administered to the mice, and myopic shifts were confirmed in choroidal thickness, refraction, and axial length in the n-3 PUFA-enriched chow group after 5 weeks. To exclude the possibility that the other ingredients in the chow may have taken the suppressive effect, fat-1 transgenic mice, which can produce n-3 PUFAs endogenously, demonstrated significant suppression of myopia. To identify what elements in n-3 PUFAs took effects on myopia suppression, enucleated eyes were used for targeted lipidomic analysis, and eicosapentaenoic acid (EPA) were characteristically distributed. Administration of EPA to the LIM model confirmed the inhibitory effect on choroidal thinning and myopia progression. Subsequently, to identify the elements and the metabolites of fatty acids effective on myopia suppression, targeted lipidomic analysis was performed and it demonstrated that metabolites of EPA were involved in myopia suppression, whereas prostaglandin E2 and 14,15-dihydrotestosterone were associated with progression of myopia. In conclusion, EPA and its metabolites are related to myopia suppression and inhibition of choroidal thinning.

Relationship of choroidal thickness and axial length with posterior vitreous detachment in patients with high myopia.

Although accumulating evidence suggests a higher prevalence of posterior vitreous detachment (PVD) in highly myopic eyes, the relation between ocular biometric features and PVD stages in such eyes remains unclear. Therefore, we enrolled 170 patients with high myopia (axial length ≥ 26.0 mm) to investigate the status of PVD regarding subfoveal choroidal thickness and axial length. Utilising swept-source optical coherence tomography, we classified the PVD status into five stages. The distribution of PVD grades increased as the choroidal thickness decreased and axial length increased (P < 0.01). On adjusting for age and sex, decreased choroidal thickness and increased axial length were associated with more advanced PVD stages: odds ratios with the highest vs. lowest groups were 0.31 (95% confidence interval [CI] 0.09-1.01; Ptrend = 0.009) for choroidal thickness and 5.16 (95% CI 1.34-19.80; Ptrend = 0.002) for axial length. The inverse association between choroidal thickness and PVD status seemed stronger in women than in men (Pinteraction = 0.05). In conclusion, we firstly observed a significant trend of decreased choroidal thickness, along with increased axial length, with increased grade of PVD, particularly among women with highly myopic eyes, suggesting that advanced morphological myopic changes contribute to PVD in middle-aged adults.

Eyelid blood vessel and meibomian gland changes in a sclerodermatous chronic GVHD mouse model.

PURPOSE: To investigate pathological changes in blood vessels and meibomian glands (MGs) in the eyelids of sclerodermatous chronic graft-versus-host disease (cGVHD) model mice. METHODS: We used an established major histocompatibility complex compatible, multiple minor histocompatibility antigen-mismatched sclerodermatous cGVHD mouse model. Blood vessels and MGs of eyelids from allogeneic bone marrow transplantation (allo-BMT) recipient mice and syngeneic bone marrow transplantation (syn-BMT) recipient mice were assessed by histopathology, immunohistochemistry and transmission electron microscopy. Peripheral blood samples from the recipients were examined by flow cytometry. RESULTS: Allo-BMT samples showed dilating, tortuous and branching vessels and shrunk MGs in the eyelids; showed significantly higher expression of VEGFR2 (p = 0.029), CD133 (p = 0.016), GFP (p = 0.006), and α-SMA (p = 0.029) in the peripheral MG area; showed endothelial damage and activation, fibrotic change, and immune cell infiltration into MGs compared with syn-BMT samples. Fewer Ki-67+ cells were observed in allo- and syn-BMT samples than in wild-type samples (p = 0.030). Ultrastructural changes including endothelial injury and activation, fibroblast activation, granulocyte degranulation, immune cell infiltration into MGs, and necrosis, apoptosis of MG basal cells were found in allo-BMT samples compared with syn-BMT samples. CONCLUSION: A series of our studies indicated that cGVHD can cause eyelid vessel and MGs changes, including endothelial injury and activation, neovascularization, early fibrotic changes, immune cell infiltration, MG basal cell necrosis and apoptosis, and resultant MG atrophy.

ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss.

Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. At 3 weeks of age, visual function impairment, specifically photoreceptor dysfunction, as recorded by electroretinography (ERG), was evident in homozygous, but not heterozygous, Adipor1 KO mice. However, although photoreceptor loss was evident at 3 weeks of age and progressed until 10 weeks, the level of visual dysfunction was already substantial by 3 weeks, after which it was retained until 10 weeks of age. The rhodopsin mRNA levels had already decreased at 3 weeks, suggesting that reduced rhodopsin may have contributed to early visual loss. Moreover, inflammation and oxidative stress were induced in homozygous KO retinas. Prior to observation of photoreceptor loss via optical microscopy, electron microscopy revealed that POSs were present; however, they were misaligned and their lipid composition, including docosahexaenoic acid (DHA), which is critical in forming POSs, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids expressed in the PIS, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in homozygous KO mice. The causal relationship between ADIPOR1 deficiency and Elovl2 repression, together with upregulation of lipogenic genes, was confirmed in vitro. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required to supply sufficient DHA for appropriate photoreceptor function and survival.

Positive Effects of Oral Antibiotic Administration in Murine Chronic Graft-Versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is one of the most frequent complications experienced after allogeneic hematopoietic stem cell transplantation. Reportedly, dysbiosis and severe damage to the microbiome are also closely associated with GVHD. Herein, we aimed to elucidate the positive and negative effects of the administration of various antibiotics in a murine model of cGVHD. For allogeneic bone marrow transplantation (allo-BMT), bone marrow from B10.D2 mice were transplanted in BALB/c mice to induce cGVHD. The cGVHD mice were orally administered ampicillin, gentamicin (GM), fradiomycin, vancomycin, or the solvent vehicle (control group). Among the antibiotic-treated mice, the systemic cGVHD phenotypes and ocular cGVHD manifestations were suppressed significantly in GM-treated mice compared to that in control mice. Inflammatory cell infiltration and fibrosis in cGVHD-targeted organs were significantly attenuated in GM-treated mice. Although regulatory T cells were retained at greater levels in GM-treated mice, there were significantly fewer Th17 cells and interleukin (IL)-6-producing macrophages in cGVHD-targeted organs in these mice. Collectively, our results revealed that orally administered GM may exert positive effects in a cGVHD mouse model.

Eosinophils promote corneal wound healing via the 12/15-lipoxygenase pathway.

Lipid mediators play important roles in regulating inflammatory responses and tissue homeostasis. Since 12/15-lipoxygenase (12/15-LOX)-derived lipid mediators such as lipoxin A4 (LXA4 ) and protectin D1 (PD1) protect against corneal epithelial cell damage, the major cell types that express 12/15-LOX and contribute to the corneal wound healing process are of particular interest. Here, we found that eosinophils were the major cell type expressing 12/15-LOX during the corneal wound healing process. Eosinophils were recruited into the conjunctiva after corneal epithelium wounding, and eosinophil-deficient and/or eosinophil-specific 12/15-LOX knockout mice showed delayed corneal wound healing compared with wild-type mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based mediator lipidomics revealed that a series of 12/15-LOX-derived mediators were significantly decreased in eosinophil-deficient mice and topical application of 17-hydroxydocosahexaenoic acid (17-HDoHE), a major 12/15-LOX-derived product, restored the phenotype. These results indicate that 12/15-LOX-expressing eosinophils, by locally producing pro-resolving mediators, significantly contribute to the corneal wound healing process in the eye.

Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans.

Chronic graft-vs-host disease (cGVHD) is a multifactorial inflammatory disease that affects patients undergoing hematopoietic stem cell transplantation. Multiple organs, including the lacrimal glands (LGs), are negatively affected by cGVHD and lose function due to the resultant fibrosis. An abnormal immune response is thought to be a major factor in the development of chronic ocular GVHD, which is currently treated primarily with immunosuppressive therapies. However, all the treatments yield unsatisfactory outcomes, and additional treatment strategies are needed. To meet this unmet medical need, we aimed to elucidate an additional pathway of chronic ocular GVHD. Our findings suggest a potential association between chronic ocular GVHD pathogenesis and stress-induced cellular senescence through the senescence-associated secretory phenotype (SASP). Senescent cells produce cytokines and chemokines, such as IL-6 and CXCL9. Indeed, senescent cell accumulation was presumably associated with cGVHD development in LGs, as evidenced by the improvement in LGs after the selective elimination of senescent cells (senolysis) with ABT-263. Results in the sclerodermatous cGVHD mouse model suggest that inhibiting the major components of the SASP, including IL-6 and CXCL9, with senolytics is a potential novel strategy for treating cGVHD-affected LGs. Taken together, our results indicate a potential association between the SASP and cGVHD development in LGs and suggest that targeted senolytic treatment may be a new therapeutic option for this disease.

The Effect of Rebamipide Ophthalmic Solution on Cytokine and Mucin Secretion in Culture of Conjunctival Epithelial Cells From the Cu, Zn-Superoxide Dismutase-1 (SOD-1) Knock-Down Mouse.

OBJECTIVES: To evaluate the in vitro effects of 1-mM rebamipide ophthalmic solution on the expression of inflammatory cytokines and MUC5AC in Cu, Zn-superoxide dismutase-1 (SOD-1) knock-down conjunctival epithelium. METHODS: Conjunctival epithelium from C57BL/6 wild-type mice was cultured and treated with rebamipide ophthalmic solution. Using cytometric bead array, we examined the levels of interleukin-(IL)-6, IL-10, IL-17, monocyte chemoattractant protein-1, interferon-γ (INF-γ), tumor necrosis factor, and IL-12p70 in the culture supernatants. The culture supernatants were obtained from the culture medium of nontreated or SOD-1 knock-down conjunctival epithelium using small interfering RNA (siRNA). In addition, ELISA was performed to ascertain the MUC5AC concentration in the culture medium. RESULTS: After rebamipide ophthalmic solution was applied, IL-6 concentration in the supernatants of conjunctival epithelial cells treated with and without siRNA showed a significant timewise decrease from 0 to 24 hr (963±42 to 0.07±0.05 pg/mL and 932±168 to 2.2±0.05 pg/mL, respectively) (P<0.001). Compared with baseline values, MUC5AC concentrations significantly increased 24 hr after rebamipide application to the conjunctival cultures-both with and without SOD-1 siRNA treatment (P<0.05 in both cases). CONCLUSIONS: Rebamipide seems to increase MUC5AC levels and suppress inflammation by decreasing IL-6 levels in mouse conjunctival epithelial cell cultures. SOD-1 siRNA-treated mouse conjunctival epithelial cell culture is a practical method for investigating changes in mucosa-associated mucins and proinflammatory cytokines in response to therapeutic interventions.

Method for selective quantification of immune and inflammatory cells in the cornea using flow cytometry.

The cornea serves as a protective surface against the environment (i.e., allergens, pollutants, desiccation and microorganisms) and promotes vision, made possible by corneal transparency. This protocol describes corneal preparation for flow cytometry to assess cells localized in the cornea. Our model details the process, from determining how many corneas are needed in the experiment to corneal excision to digestion and staining of the cornea cells. The simplicity of the model allows for systematic analysis of different corneal mechanisms of immunity, inflammation, angiogenesis and wound healing. In corneal transplantation, residential immune and inflammatory cells are key to the mechanisms that underlie angiogenesis, opacity, and graft rejection. In addition, this model can also elucidate cellular mechanisms mediating corneal graft outcomes and wound healing. Lastly, this model can be used to analyze the efficacy of new medications such as instillation and subconjunctival injections and assess the potential of therapeutic molecules to enhance graft survival and wound healing in vivo.

Evaluation of the Effect of Moist Chamber Spectacles in Patients With Dry Eye Exposed to Adverse Environment Conditions.

PURPOSE: To evaluate the effect of moist chamber spectacle wear on the ocular surface and tear functions in a controlled wind exposure environment. METHODS: Twenty-eight eyes of 14 probable dry eye subjects (4 men, 10 women; mean age: 34.5 years) underwent constant wind exposure for 10 min without spectacle, with conventional spectacle wear, and with moist chamber spectacle wear. Dryness Visual Analog Scale (VAS) scores, tear evaporation, blink rate, tear film breakup testing, and fluorescein staining were performed before and after wind exposure. RESULTS: The mean dryness VAS score after wind exposure was significantly higher when no spectacles were worn or when conventional spectacles with no moist chambers were worn compared with after exposure scores when moist chamber spectacles were worn (P=0.02). The mean of tear evaporation rate from the ocular surface and blink rate increased significantly with wind exposure when no spectacles were worn or when conventional spectacles with no moist chambers were worn (P=0.04). There were no significant changes before and after wind exposure when the moist chamber spectacles were worn (P=0.1). CONCLUSION: Moist chamber spectacles appear to have favorable effects on dry eye symptomatology, tear stability, and blink rates in adverse environment conditions such as wind exposure.

Caruncular and Pericaruncular Sebaceous Gland Hyperplasia: A Report of 2 Cases and Literature Review.

PURPOSE: To report the clinical and histopathological features of two patients with caruncular and pericaruncular sebaceous gland hyperplasia (SGH) with a literature review. METHODS: We performed a retrospective pathology database search of 1195 ophthalmic specimens receiving the clinical diagnosis of SGH for caruncular/pericaruncular lesions during 2004 to 2014 at Tokyo Dental College, Ichikawa General Hospital. Paraffin sections were stained with hematoxylin and eosin. A retrospective patient record and literature review was also performed. RESULTS: Database search disclosed 2 male patients with SGH of 1195 specimens (0.15%). Pathological specimens revealed neither any cellular/nuclear atypia nor any mitotic figures and invasive features. No recurrences were observed in these 2 cases 12 to 18 months after excision. CONCLUSIONS: Caruncle and pericaruncular SGH is an uncommon lesion which needs careful histopathological evaluation for differentiation especially from caruncular neoplasias.