Form-deprivation myopia promotes sclera M2-type macrophages polarization in mice.

PURPOSE: To explore the phenotype of sclera macrophages in form-deprivation (FD) myopia mice and the effects of M2 macrophage in FD myopia development. METHODS: C57BL/6 mice were under 2 weeks of unilateral FD treatment. and they were separated into two groups, including an intraperitoneally injected(IP) vehicle group and Panobinostat (LBH589) (10 mg/kg per body weight) treatment group. All biometric parameters were measured before and after treatments, and the type and density of sclera macrophages were identified by immunofluorescence and RT-qPCR. In vitro, we analyzed the M2 macrophage and primary human sclera fibroblast (HSF) co-culture system by using the transcriptome sequencing method. Gene ontology (GO) and KEGG enrichment analyses were used to pinpoint the biological functions and pathways associated with the identified Differentially Expressed Genes (DEGs). The hub genes were investigated using the STRING database and Cytoscape software and were confirmed using RT-qPCR. RESULTS: We found that the M2-type sclera macrophage density and expression increased in FD-treated eyes. The results showed that LBH589 inhibited the M2 macrophage polarization, and reduced FDM development. GO and KEGG analyses revealed that the DEGs were predominantly involved in the synthesis and breakdown of the extracellular matrix (ECM), as well as in pathways related to ECM-receptor interaction and the PI3K-Akt signaling pathway. Five hub genes (FN-1, MMP-2, COL1A1, CD44, and IL6) were identified, and RT-qPCR validated the variation in expression levels among these genes. CONCLUSION: M2 macrophage polarization occurred in the sclera in FDM mice. Panobinostat-mediated inhibition of M2 macrophage polarization may decrease FDM progression, as M2 macrophages are crucial in controlling ECM remodeling by HSFs.

Causal relationship between central corneal thickness and open-angle glaucoma: Evidence from Mendelian randomization.

Glaucoma is the leading cause of irreversible blindness worldwide. Previous observational studies have suggested a relationship between central corneal thickness (CCT) and glaucoma; however, the results are inconsistent. This study aimed to investigate whether CCT is associated with a risk for developing open-angle glaucoma (OAG). We employed two-sample Mendelian randomization to assess the relationship between CCT and OAG, namely, primary open-angle glaucoma (POAG) and suspected glaucoma. Genetic instruments composed of variants associated with CCT at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies from Iglesias et al. for discovery and Bonnemaijer et al. for replication. Summary-level statistics for these instruments for the OAG were obtained from the FinnGen Project (Release 10). Inverse-variance-weighted regression of genetic susceptibility predicted that increased CCT was positively associated with an increased risk for POAG (odds ratio [OR], 1.005; 95% confidence interval [CI], 1.002-1.008; P = 0.001) and suspected glaucoma (OR, 1.006; 95% CI, 1.003-1.009; P < 0.001). In the replication sample of CCT, increased CCT was also positively associated with an increased risk for POAG (OR, 1.004; 95% CI, 1.000-1.008; P = 0.029) and suspected glaucoma (OR, 1.005; 95% CI, 1.001-1.008; P = 0.013). We found genetic evidence supporting a potential causal association between increased CCT and the risk of POAG and suspected glaucoma in the European population. This findings indicates the clinical significance of CCT in the diagnosis and treatment of glaucoma. Further studies are needed to elucidate the underlying mechanisms of this causal relationship.

Visual impairment burden in retinopathy of prematurity: trends, inequalities, and improvement gaps.

Retinopathy of prematurity (ROP) is an important cause of avoidable childhood visual impairment, and the increase in number and survival of premature infants may inflate its burden globally. We aimed to comprehensively assess the trends and inequalities in the burden of ROP-related visual impairment and to identify improvement gaps to facilitate appropriate actions in neonatal care systems. We obtained ROP data from the Global Burden of Disease 2019 study. We employed joinpoint regression analysis to assess the trends of the burden of ROP-related visual impairment, measured by age-standardised prevalence rates, health equity analysis methods to evaluate cross-country burden inequalities, and data envelopment and stochastic frontier analyses to identify improvement gaps based on the development status, i.e., sociodemographic index (SDI). Between 1990 and 2019, the age-standardised prevalence rates of ROP-related visual impairment significantly increased worldwide (average annual percentage change: 0.23 [95% confidence interval, 0.21-0.26] among males and 0.26 [0.25-0.27] among females), primarily in developed regions. Although significant SDI-related cross-country inequalities were identified, these reduced over time (slope index of inequality: -57.74 [-66.22 to -49.25] in 1990 to -29.68 [-38.39 to -20.97] in 2019; health concentration index: -0.11 [-0.13 to -0.09] in 1990 to -0.07 [-0.09 to -0.06] in 2019). Notably, some less-developed countries exhibited superior performance despite limited resources, whereas others with a higher SDI delivered lagging performance.  Conclusion: The global burden of ROP-related visual impairment has steadily increased between 1990 and 2019, with disproportionate burden concentration among less-developed countries, requiring appropriate preventive and intervention measures. What is Known: • Retinopathy of prematurity (ROP) is an important cause of avoidable childhood visual impairment. • The prevalence of ROP is anticipated to increase due to the growing number of extremely premature infants. What is New: • The prevalence of ROP-related visual impairment has increased worldwide, primarily in developed regions, with declining but persisting cross-country inequalities. • The increasing burden of ROP-related visual impairment should be considered as part of global and national health agendas, requiring interventions with proven efficacy.

Empagliflozin targets Mfn1 and Opa1 to attenuate microglia-mediated neuroinflammation in retinal ischemia and reperfusion injury.

BACKGROUND: Neuroinflammation and mitochondrial dysfunction play crucial roles in retinal ischemia and reperfusion (IR) injury. Recent studies have identified mitochondrial function as a promising target for immunomodulation. Empagliflozin (EMPA), an anti-diabetic drug, has exhibited great potential as both an anti-inflammatory agent and a protector of mitochondrial health. This study aimed to assess the therapeutic efficacy of EMPA in retinal IR injury. METHODS: To evaluate the protective effects of EMPA, the drug was injected into the vitreous body of mice post-retinal IR. Single-cell RNA sequencing (scRNA-seq) analysis was conducted to uncover the underlying mechanisms, and the results were further validated through in vivo and in vitro experiments. RESULTS: EMPA effectively protected retinal ganglion cells (RGCs) from IR injury by attenuating local retinal inflammation. The scRNA-seq analysis revealed that EMPA downregulated the nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) signaling pathway and restored mitochondrial dynamics by upregulating the expression of mitochondrial fusion-related genes, Mitofusin 1 (Mfn1) and optic atrophy 1 (Opa1). These findings were further corroborated by Western blotting. In vitro experiments provided additional insights, demonstrating that EMPA suppressed lipopolysaccharide (LPS)-induced cell inflammation and NLRP3 inflammasome activation. Moreover, EMPA enhanced mitochondrial fusion, neutralized mitochondrial reactive oxygen species (mtROS), and restored mitochondrial membrane potential (MMP) in BV2 microglia. Notably, genetic ablation of Mfn1 or Opa1 abolished the anti-inflammatory effects of EMPA. CONCLUSIONS: Our findings highlight the positive contribution of Mfn1 and Opa1 to the anti-inflammatory therapeutic effect of EMPA. By restoring mitochondrial dynamics, EMPA effectively mitigates microglia-mediated neuroinflammation and prevents RGC loss in retinal IR injury.

Temporal trends and projection of blindness and vision loss prevalence in older adults in BRICS countries.

BACKGROUND: Blindness and vision loss (BVL) is a major global health issue affecting older adults, but its burden in transition countries has received limited attention. Therefore, we aimed to assess the trends in the burden of BVL among older adults between 1990 and 2019 across Brazil, Russia, India, China, and South Africa (BRICS), and predict the burden by 2040. METHODS: Data on BVL and its related causes were obtained from the Global Burden of Disease 2019 study. We investigated the temporal trends by calculating the average annual percentage change using joinpoint regression analysis. Subsequently, we performed Bayesian age-period-cohort modeling to estimate the burden of BVL and its related causes by 2040. RESULTS: Most BRICS countries experienced a significant decline (p < 0.05) in age-standardized prevalence rates, and the decreasing trends tend to continue. However, by 2040, the number of BVL cases is expected to increase by approximately 50% across BRICS, with an estimated approximately 192, 170, 25, 17, and 7 million cases in China, India, Russia, Brazil, and South Africa, respectively. The related ranks of BVL causes are also estimated to change in the future, particularly in India. CONCLUSIONS: The different burdens and trends of BVL across BRICS reflected the different stages of population health transition. Effective eye disease prevention requires appropriate public health interventions. Developing effective health policies and services for older adults is urgently needed in BRICS countries.

Lens Power and Associated Factors in Nonhuman Primate Subjects: A Cross-sectional Study.

Purpose: We aimed to examine the normative profile of crystalline lens power (LP) and its associations with ocular biometric parameters including age, axial length (AL), spherical equivalent refraction (SE), corneal radius (CR), lens thickness, anterior chamber depth, and AL/CR ratio among a cynomolgus monkey colony. Methods: This population-based cross-sectional Non-human Primate Eye Study recruited middle-aged subjects in South China. All included macaques underwent a detailed ophthalmic examination. LP was calculated using the modified Bennett's formula, with biometry data from an autorefractometer and A-scan. SPSS version 25.0 was used for statistical analysis. Results: A total of 301 macaques with an average age of 18.75 ± 2.95 years were collected in this study. The mean LP was 25.40 ± 2.96 D. Greater LP was independently associated with younger age, longer AL, and lower SE (P = 0.028, P = 0.025, and P = 0.034, respectively). LP showed a positive correlation with age, SE, CR, AL, lens thickness, and anterior chamber depth, whereas no correlation was observed between LP and AL/CR ratio. Conclusions: Our results suggested the LP distribution in the nonhuman primate colony and indicated that AL and SE strongly influenced the rate of LP. Therefore, this study contributed to a deeper understanding of the relative significance of the LP on the optics of the crystalline lens study.

Relationships between Frailty and the Risk of Glaucoma in Middle-aged and Older Adults.

PURPOSE: Increased frailty in older individuals increases health risks, but its relationship with glaucoma, the leading cause of irreversible blindness in middle-aged and older adults, is unclear. We investigated the association between frailty and glaucoma in a large-scale representative sample and explored possible causal relationships. DESIGN: Combined cross-sectional and Mendelian randomization (MR) study. PARTICIPANTS: In the cross-sectional analysis, we included 5744 participants of the US National Health and Nutrition Examination Surveys 2005-2008 aged ≥40. For the MR analysis, frailty genome-wide association study (GWAS) data were sourced from a UK Biobank and TwinGen meta-analysis, and GWAS data on glaucoma subtypes were derived from FinnGen. METHODS: According to the 49-item frailty index, we classified participants into nonfrail (≤0.10), prefrail (0.10-0.21), and frail (>0.21) groups. Using survey-weighted logistic regression models adjusted for multiple covariates, we explored the association between frailty and glaucoma. We further assessed causation using MR. MAIN OUTCOME MEASURES: The associations between different levels of frailty (nonfrail, prefrail, and frail) and glaucoma, as well as causal relationships between genetically predicted frailty and various subtypes of glaucoma (primary open-angle glaucoma, primary angle-closure glaucoma, normotensive glaucoma, exfoliation glaucoma, and suspected glaucoma). RESULTS: After adjusting for covariates, higher frailty levels were significantly associated with glaucoma in frail individuals (odds ratio [OR]=1.83, 95% confidence interval [CI]=1.05-3.19, P=0.036) but not prefrail (OR=1.90, 95% CI=0.99-3.64, P=0.052). The association was significantly stronger among male participants (P interaction=0.042). The variation in the association between frailty and glaucoma did not reach statistical significance across age groups (P interaction=0.575) or race groups (P interaction=0.092). MR revealed that genetically predicted frailty was linked to greater risks for primary open-angle glaucoma (OR=1.67, 95% CI=1.24-2.25, P=0.001), primary angle-closure glaucoma (OR=2.78, 95% CI=1.48-5.20, P=0.001), exfoliation glaucoma (OR=1.70, 95% CI=1.18-2.43, P=0.004), and suspected glaucoma (OR=1.74, 95% CI=1.30-2.34, P<0.001), but not for normotensive glaucoma (OR=1.01, 95% CI=0.61-1.68, P=0.956). CONCLUSIONS: Our study revealed an association between frailty and increased glaucoma risk and emphasized the significance of glaucoma screening in frail individuals. Targeted healthcare strategies can help prevent or delay irreversible blindness among middle-aged and older adults.

Quantitative assessment of colour fundus photography in hyperopia children based on artificial intelligence.

OBJECTIVES: This study aimed to quantitatively evaluate optic nerve head and retinal vascular parameters in children with hyperopia in relation to age and spherical equivalent refraction (SER) using artificial intelligence (AI)-based analysis of colour fundus photographs (CFP). METHODS AND ANALYSIS: This cross-sectional study included 324 children with hyperopia aged 3-12 years. Participants were divided into low hyperopia (SER+0.5 D to+2.0 D) and moderate-to-high hyperopia (SER≥+2.0 D) groups. Fundus parameters, such as optic disc area and mean vessel diameter, were automatically and quantitatively detected using AI. Significant variables (p<0.05) in the univariate analysis were included in a stepwise multiple linear regression. RESULTS: Overall, 324 children were included, 172 with low and 152 with moderate-to-high hyperopia. The median optic disc area and vessel diameter were 1.42 mm2 and 65.09 µm, respectively. Children with high hyperopia had larger superior neuroretinal rim (NRR) width and larger vessel diameter than those with low and moderate hyperopia. In the univariate analysis, axial length was significantly associated with smaller superior NRR width (ß=-3.030, p<0.001), smaller temporal NRR width (ß=-1.469, p=0.020) and smaller vessel diameter (ß=-0.076, p<0.001). A mild inverse correlation was observed between the optic disc area and vertical disc diameter with age. CONCLUSION: AI-based CFP analysis showed that children with high hyperopia had larger mean vessel diameter but smaller vertical cup-to-disc ratio than those with low hyperopia. This suggests that AI can provide quantitative data on fundus parameters in children with hyperopia.

Global, Regional, and National Epidemiology of Visual Impairment in Working-Age Individuals, 1990-2019.

Importance: Visual impairment in working-age individuals can affect their general health and employment prospects, leading to decreased social and economic productivity and increased poverty rates. Nonetheless, investigations in this population appear to be limited. Objective: To investigate the trends of visual impairment prevalence and disability-adjusted life-years (DALYs) in working-age individuals from 1990 to 2019. Design, Setting, and Participants: This cross-sectional, population-based study used data for individuals of working age (15-64 years) from 204 countries and territories obtained from the Global Burden of Disease 2019 study. The data analysis was performed between May 1 and 10, 2023. Exposure: Visual impairment, defined as visual acuity of less than 6/18 (20/60) or near visual acuity of less than 6/12 (20/40) distance equivalent as determined by Snellen chart. Main Outcomes and Measures: Trends of visual impairment prevalence, DALYs, and corresponding estimated annual percent changes (EAPCs) from 1990 to 2019 were stratified according to region, nation, and sociodemographic index (SDI). Results: There were 437 539 484 (95% uncertainty interval [UI], 325 463 851-575 573 588) prevalent cases of visual impairment globally (53.12% female and 46.88% male) in 2019, representing an increase of 91.46% from 1990 (prevalent cases, 228 530 964; 95% UI, 172 515 833-297 118 596). Over 3 decades, visual impairment-associated DALYs increased from 7 601 852 (95% UI, 5 047 030-11 107 897) to 12 563 276 (95% UI, 8 278 866-18 961 723). Among the 5 SDI groups, the low-SDI group had the largest increase in DALYs (898 167 [95% UI, 597 161-1 301 931] in 1990 to 1 634 122 [95% UI, 1 079 102-2 444 381] in 2019). Regionally, the greatest increase in prevalence was observed in Eastern Europe (EAPC, 0.10; 95% CI, 0.02-0.19). Among all countries and territories, Nepal had the highest national prevalence of visual impairment per 100 000 population in 2019 (26 008.45; 95% UI, 19 987.35-32 482.09), while South Sudan had the highest DALY rate per 100 000 population (480.59; 95% UI, 316.06-697.06). Conclusions and Relevance: Despite the mild decrease in visual impairment prevalence rates in less-developed countries, these findings suggest that the number of prevalent cases globally has increased substantially, with discernible unfavorable patterns in developed regions. The findings support the notion that visual impairment in working-age individuals is a growing global health challenge. A better understanding of its epidemiology may facilitate the development of appropriate measures for prevention and treatment from both medical and social perspectives.

Peripapillary Retinal Nerve Fiber Layer and Macular Ganglion Cell-Inner Plexiform Layer Parameters and Their Associated Factors in Cynomolgus Macaques.

Purpose: The purpose of this study was to define the normal range of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer (mGCL), and macular inner plexiform layer (mIPL) thickness in cynomolgus macaques, and explore their inter-relationship and correlation with age, refractive errors, and axial length (AL). Methods: In this cross-sectional study, we measured biometric and refractive parameters, and pRNFL/mGCL/mIPL thickness in 357 healthy cynomolgus macaques. Monkeys were divided into groups by age and spherical equivalent (SE). Correlation and regression analyses were used to explore the relationship between pRNFL and mGCL/mIPL thickness, and their correlation with the above parameters. Results: The mean age, SE, and AL were 14.46 ± 6.70 years, -0.96 ± 3.23 diopters (D), and 18.39 ± 1.02 mm, respectively. The mean global pRNFL thickness was 95.06 ± 9.42 µm (range = 54-116 µm), with highest values in the inferior quadrant, followed by the superior, temporal, and nasal quadrants (P < 0.001). Temporal pRNFL thickness correlated positively with age (r = 0.218, P < 0.001) and AL (r = 0.364, P < 0.001), and negatively with SE (r = -0.270, P < 0.001). In other quadrants, pRNFL thickness correlated negatively with age and AL, but positively with SE. In the multivariable linear regression model, adjusted for sex and AL, age (ß = -0.350, P < 0.001), and SE (ß = 0.206, P < 0.001) showed significant associations with global pRNFL thickness. After adjusting for age, sex, SE, and AL, pRNFL thickness positively correlated with mGCL (ß = 0.433, P < 0.001) and mIPL thickness (ß = 0.465, P < 0.001). Conclusions: The pRNFL/mGCL/mIPL thickness distribution and relationship with age, AL, and SE in cynomolgus macaques were highly comparable to those in humans, suggesting that cynomolgus monkeys are valuable animal models in ophthalmic research.

Temporal trends in the visual impairment burden attributable to high fasting plasma glucose levels: a population-based study.

AIMS: Elevated fasting plasma glucose (FPG) levels have been associated with visual impairment. Recognising global patterns of high FPG level exposure can facilitate the prevention and treatment of related visual impairment. We aimed to assess the trends of the visual impairment burden attributable to high FPG levels globally, regionally, nationally, and by income level. METHODS: We obtained data on the visual impairment burden attributable to high FPG levels from the Global Burden of Disease Study 2019. We evaluated the trends of related disability-adjusted life-years (DALYs) from 1990 to 2019 through joinpoint regression analysis and calculated the annual percentage change (APC) and average APC (AAPC). Countries/territories were categorised into high-, upper-middle-, lower-middle-, and low-income groups based on the 2019 World Bank criteria. RESULTS: The age-standardised rate of DALYs due to visual impairment attributable to high FPG levels significantly increased globally, from 6.75 (95% uncertainty interval [UI], 1.55-15.79) in 1990 to 8.44 per 100,000 population (95% UI, 2.00-19.63) in 2019 (AAPC, 0.79; 95% confidence interval [CI], 0.69-0.89; p < 0.001). The largest increases were observed in high-income (AAPC, 0.73; 95% CI, 0.60-0.85) and lower-middle-income countries/territories (AAPC, 0.68; 95% CI, 0.62-0.73). In 2019, lower-middle-income countries/territories had the highest age-standardised DALY rate (18.94 per 100,000 population; 95% UI, 4.39-43.98), whereas high-income countries/territories had the lowest (2.97 per 100,000 population; 95% UI, 0.75-6.74). CONCLUSIONS: The visual impairment burden associated with elevated FPG levels has increased significantly, necessitating enhanced public health prevention measures, clinical management, and treatment to mitigate adverse outcomes.

Effect of atropine, orthokeratology and combined treatments for myopia control: a 2-year stratified randomised clinical trial.

PURPOSE: To investigate the 2-year efficacy of atropine, orthokeratology (ortho-k) and combined treatment on myopia. To explore the factors influencing the efficacy. METHODS: An age-stratified randomised controlled trial. Children (n=164) aged 8-12 years with spherical equivalent refraction of -1.00 to -6.00 D were stratified into two age subgroups and randomly assigned to receive placebo drops+spectacles (control), 0.01% atropine+spectacles (atropine), ortho-k+placebo (ortho-k) or combined treatment. Axial length was measured at baseline and visits at 6, 12, 18 and 24 months. The primary analysis was done following the criteria of intention to treat, which included all randomised subjects. RESULTS: All interventions can significantly reduce axial elongation at all visits (all p<0.05). Overall, the 2-year axial elongation was significantly reduced in combined treatment than in monotherapies (all p<0.05). After stratification by age, in the subgroup aged 8-10, the difference between combined treatment and ortho-k became insignificant (p=0.106), while in the subgroup aged 10-12, the difference between combined treatment and atropine became insignificant (p=0.121). A significant age-dependent effect existed in the ortho-k group versus the control group (p for interaction=0.013), and a significant age-dependent effect existed in the ortho-k group versus the atropine group (p for interaction=0.035), which indicated that ortho-k can achieve better efficacy in younger children. CONCLUSIONS: Atropine combined with ortho-k treatment can improve the efficacy of myopia control compared with monotherapy in children aged 8-12. Younger children might benefit more from ortho-k. TRIAL REGISTRATION NUMBER: ChiCTR1800015541.

Trends in prevalence rates of blindness among patients with diabetic retinopathy in high-income countries from 1990 to 2019: A joinpoint regression analysis.

AIMS: Diabetic retinopathy (DR) is the leading cause of blindness in patients with diabetes mellitus (DM). We investigated its trends in high-income countries to gain insights into preventing DR-related blindness in diabetes-epidemic areas. METHODS: For joinpoint regression analysis, we extracted data from the Global Burden of Disease 2019 study and analysed the prevalence trends of DR-related blindness according to DM type, patients' sex and age, region, and nation. RESULTS: Overall, the age-standardised prevalence rate (ASPR) of DR-related blindness has decreased. The prevalence rates of blindness decreased more sharply for Type 1 DM than for Type 2 DM. The ASPR was higher and the decreasing trend was less pronounced in women than in men. Southern Latin America had the highest ASPR, whereas Australasia had the lowest ASPR. Singapore experienced the greatest decline, whereas unfavourable trends were observed in the USA. CONCLUSIONS: Despite decrease in the overall ASPR of DR-related blindness during the study period, large improvement opportunities were identified. As DM prevalence increases and the population ages rapidly in high-income countries, novel effective screening, treatment, and prevention strategies are urgently needed to improve the visual outcomes of individuals with DM or at risk of DM.