Purpose:To describe the visual and anatomic outcomes after being lost to follow-up (LTFU) among patients with diabetic macular edema (DME) that treated by intravitreal anti-VEGF therapies, and to determine the risk factors of persistent vision loss. Design:A retrospective cohort study using national registry data. Participants:A total of 5660 patients who were LTFU >6 months after anti-VEGF treatments from April 2020 through July 2024. Methods:Visual and anatomic outcomes at the visit before being LTFU, the return visit, 3 months, 6 months, and 12 months after return, and the final visit were collected. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of risk factors for persistent vision loss. Main Outcome Measures:Visual acuity (VA) and central foveal thickness (CFT). Results:After a mean LTFU period of 11.3 months, 2712 (47.9%) patients had vision decline at return visit. Identified risk factors included increasing age (45-64 years vs. ≤44 years: OR, 1.30; 95% CI, 1.07-1.56; P = 0.007; ≥65 years vs. ≤44 years: OR, 1.41; 95% CI, 1.15-1.72; P = 0.001), being treated in less developed regions (OR, 1.20; 95% CI, 1.08-1.34; P = 0.001), better baseline VA (20/50-20/200 vs. worse than 20/200: OR, 3.20; 95% CI, 2.67-3.83; P < 0.001; 20/40 or better vs. worse than 20/200: OR, 5.89; 95% CI, 4.86-7.12; P < 0.001), and being LTFU for >12 months (OR, 1.22; 95% CI, 1.09-1.37; P = 0.001). A total of 792 patients returned with worsened vision and underwent ≥12 months of follow-up after resuming therapies. After a mean follow-up time of 17.3 months, 522 (65.9%) patients had persistent vision loss. Central foveal thickness presented paralleled changes with VA. Odds of persistent vision loss were greater among patients with VA of 20/40 or better before being LTFU (OR, 2.54; 95% CI, 1.25-5.15; P = 0.010) or having CFT of 350μm or more at return (OR, 1.57; 95% CI, 1.15-2.16; P = 0.005). In retreatment, odds of persistent vision loss were lower for patients who switched anti-VEGF agents (OR, 0.61; 95% CI, 0.45-0.84; P = 0.002) after return. Conclusions:Nearly half of the patients had vision decline after being LTFU, and after resuming therapies, vision loss still persisted in 2 of 3 patients. Clinical adherence should be strengthened for patients with baseline VA of 20/40 or better or having CFT of 350 μm or more at return. Multiple agents used were associated with vision recovery. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

ObjectivesThis meta-analysis aimed to compare the efficacy of botulinum toxin (BTX) injection versus surgery for acute acquired concomitant esotropia (AACE).MethodsPubMed, Embase, Web of Science, China Biomedical Sinomed, and the Cochrane Library were systematically searched for studies comparing BTX and surgery in AACE. The primary outcome was motor success rate, and secondary outcomes included stereopsis recovery and incidence of permanent exotropia. Random-effects models were applied. Sensitivity analyses, subgroup analyses, meta-regression, and publication bias assessment were performed.ResultsFourteen studies involving 1027 patients were included. At 6 months, motor success rates did not differ significantly between BTX and surgery (OR 0.45, 95% CI: 0.20–1.03, P = 0.06); however, this result was sensitive to the inclusion of a single study, and exclusion of this study favored surgery (OR 0.36, 95% CI: 0.17–0.77, P = 0.008). Subgroup analyses showed that comparable outcomes were observed between BTX and surgery in pediatric patients (OR 1.14, 95% CI: 0.45–2.89, P = 0.78) and in studies using bilateral medial rectus injection (OR 0.98, 95%CI: 0.35–2.70, P = 0.97), with stable sensitivity analyses in both subgroups. Stereopsis recovery at 6 months was similar between the two treatments (near: OR 0.61, 95% CI: 0.32–1.19, P = 0.15; distance: OR 1.05, 95%CI: 0.42–2.61, P = 0.92).ConclusionThe pooled short-term motor outcome showed substantial heterogeneity and sensitivity to individual studies. More consistent findings were observed in pediatric populations and in studies using bilateral medial rectus injections, where BTX may achieve short-term outcomes comparable to surgery. Stereopsis recovery at 6 months was also similar between the two treatments. However, given the limited number of available studies and the predominance of retrospective designs, adequately powered RCTs and prospective studies are needed to establish more definitive conclusions.Systematic Review RegistrationIdentifier: CRD420245127395.

BACKGROUND/AIMS:To identify sociodemographic and clinical factors associated with best-corrected visual acuity (BCVA) restoration at the visit after lost to follow-up (LTFU) in patients with myopic choroidal neovascularization (mCNV) treated with antivascular endothelial growth factor intravitreal injections (IVI). METHODS:A multicentre, retrospective cohort study was conducted in China of mCNV patients receiving injections who were LTFU >6 months. Data were collected from baseline visit, pre-LTFU, initial post-LTFU visit and 6 months post-LTFU, and the final visit. Logistic regression analyses assessed associations between sociodemographic/clinical factors and BCVA restoration. RESULTS:The study included 1155 LTFU patients with mCNV (mean (SD) age: 54 (16) years; 61.6% female), with 66.6% achieving BCVA restoration at the initial post-LTFU visit after LTFU (mean(SD) duration: 315 (154) days. Patients with BCVA restoration were younger (p=0.004), more often from eastern China (p=0.022), and had shorter LTFU duration (p=0.013). Stratification by pre-LTFU BCVA showed that patients with BCVA ≥20/40 had lower restoration odds (OR 0.65, 95% CI 0.44 to 0.96; p=0.032) compared with those with BCVA <20/200. BCVA decline was associated with increased central subfield thickness(CST) (OR 1.52, 95% CI 1.15 to 2.01; p=0.004). Among 223 patients with ≥6 months post-LTFU, those with initial post-LTFU CST >280 µm had higher BCVA restoration odds (OR 1.98, 95% CI 1.02 to 3.92; p=0.046). CONCLUSIONS:Better pre-LTFU BCVA (≥20/40) increased post-LTFU deterioration risk (associated with progressive CST thickening), while elevated post-LTFU CST (>280 µm) predicted higher BCVA restoration odds in patients with sustained follow-up, supporting CST-guided monitoring and early intervention for high-risk groups.

The pathogenesis of diabetic retinopathy (DR) is intricately associated with epigenetic regulation, and ferroptosis-mediated retinal vascular injury has been implicated as a potential key factor. However, the precise mechanism underlying epigenetic regulation by the long non-coding RNA taurine up-regulated gene 1 (TUG1) in DR-related vascular injury remains elusive. Initially, clinical samples, including serum and vitreous humor, were collected to examine the relationship between TUG1 and Krüppel-like factor 2 (KLF2). Next, the effects of TUG1 on vascular injury and ferroptosis markers were examined both in vitro and in vivo. Mechanistically, we elucidated the role of the specificity protein 1 (SP1)/TUG1/KLF2 axis. Clinical investigations revealed a negative correlation between TUG1 and KLF2 expression in DR. In a high-glucose environment, the transcription factor SP1 promoted the binding of TUG1 to PRC2, promoting H3K27me3 to suppress KLF2 transcription. This process ultimately led to cell death with the hallmarks of ferroptosis in human retinal microvascular endothelial cells. Functionally, silencing TUG1 or overexpressing KLF2 was shown to alleviate retinal vascular injury and ferroptosis markers in type 2 diabetic mice, and reduce pathological neovascularization in the retinas of OIR mice. Collectively, this study delineates an SP1/TUG1/KLF2 epigenetic axis through which hyperglycemia suppresses KLF2 expression and triggers ferroptosis-like process in retinal microvascular endothelial cells, providing a mechanistic basis for vascular injury in DR.

This study aims to identify potential biomarkers for retinal detachment secondary to choroidal melanoma (CM). Mendelian randomisation (MR) analysis, immunohistochemistry, cell proliferation and migration assays, co-culture experiments involving human microglial cells (HMC3) and CM cells, and tube formation assay were employed to validate the role of IL-8 in retinal detachment secondary to choroidal melanoma. Mendelian randomisation analysis identified four inflammatory mediators causally linked to malignant melanoma progression: CDCP1 concentration (P = 0.017, OR = 0.999, 95% CI [0.998–1.000]), CSF-1 concentration (P = 0.020, OR = 1.002, 95% CI [1.000–1.003]), IL-10Rβ concentration (P = 0.004, OR = 0.999, 95% CI [0.998–1.000]), IL-17C concentration (P = 0.002, OR = 1.003, 95% CI [1.001–1.005]); Four inflammatory factors exhibited a causal relationship with retinal detachment progression: IL-15Rα concentration (P = 0.029, OR = 1.001, 95% CI [1.000–1.001]), IL-2Rβ concentration (P = 0.007, OR = 1.003, 95% CI [1.001–1.004]), IL-8 concentration (P = 0.045, OR = 1.002, 95% CI [1.000–1.004]), TSLP concentration (P = 0.028, OR = 1.002, 95% CI [1.000–1.004]). MR analysis indicated that genetically predicted IL-8 levels are associated with an increased risk of retinal detachment. IL-8 is highly expressed in CM tissues and promotes the proliferation of CM and HMC3 cells. It partially relieves the inhibitory effects mediated by the supernatant of HMC3 cells and promotes angiogenesis. IL-8 may be involved in CM-related inflammatory microenvironments and secondary exudative retinal detachment. It is a potential biomarker and provides a new target for targeted anti-inflammatory therapy and improved patient prognosis.

To investigate whether protein kinase R-like ER kinase (PERK) inhibition mitigates hyperglycemia (HG)-induced multi-modal cell death, including ferroptosis, apoptosis, and pyroptosis, in human retinal endothelial cells (RECs) (HRECs) through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, thereby providing a unified therapeutic strategy for diabetic retinopathy. HRECs were cultured in normal glucose (NG, 5.5 mM, 48 h) and HG (HG, 25 mM, 48 h) DMEM media, with or without the PERK inhibitor ISRIB or the ferroptosis inhibitor Fer-1. Protein expression profiles from NG and HG-treated cells were compared using tandem mass tag (TMT)-LC-MS/MS and subjected to bioinformatic analysis. Cell viability was assessed via CCK-8 assay. Ferroptosis markers (Malondialdehyde (MDA), reactive oxygen species (ROS), Fe2+, GSH, glutathione peroxidase 4 (GPX4)), apoptosis mediators (caspase-3, caspase-7, Bcl-2), and pyroptosis markers (NLRP3, caspase-1, gasdermin D (GSDMD)) were quantified through biochemical assays and ELISA. Expression levels of PERK, Nrf2, and HO-1 were analyzed by real-time quantitative PCR (RT-qPCR) and Western blotting. Proteomic analysis identified 247 differentially expressed proteins (DEPs) significantly enriched in ferroptosis and peroxisome proliferator-activated receptor (PPAR) signaling pathways. HG conditions induced concurrent ferroptosis (increased MDA, ROS, Fe2+; decreased ↓GSH, GPX4), apoptosis (elevated caspase-3 and caspase-7; reduced ↓Bcl-2), and pyroptosis (upregulated NLRP3, caspase-1, and GSDMD; all p < 0.001). Treatment with ISRIB reversed these effects by normalizing ferroptosis markers, suppressing apoptosis (reduced caspase-3 and caspase-7; increased ↑Bcl-2), and inhibiting pyroptosis (decreased ↓NLRP3, caspase-1, GSDMD). Mechanistically, ISRIB activated the Nrf2/HO-1 pathway while downregulating PERK, with no significant effects observed under normoglycemic conditions. PERK inhibition simultaneously attenuates HG-induced ferroptosis, apoptosis, and pyroptosis in HRECs via activation of the Nrf2/HO-1 pathway. This coordinated blockade presents a promising therapeutic strategy to preserve retinal vasculature in diabetic retinopathy.

Purpose To describe the visual and anatomic outcomes after being lost to follow-up (LTFU) among patients with diabetic macular edema (DME) that treated by intravitreal anti-vascular endothelial growth factor (VEGF) therapies, and to determine the risk factors of persistent vision loss. Design A retrospective cohort study using national registry data. Participants A total of 5660 patients who were LTFU >6 months after anti-VEGF treatments from April 2020 through July 2024. Methods Visual and anatomic outcomes at the visit before being LTFU, the return visit, 3 month, 6 month, and 12 month after return, and the final visit were collected. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of risk factors for persistent vision loss. Main Outcome Measures Visual acuity (VA) and central foveal thickness (CFT). Results After a mean LTFU period of 11.3 months, 2712 (47.9%) patients had vision decline at return visit. Identified risk factors included increasing age (45-64 years vs ≤44 years: OR, 1.30; 95% CI, 1.07-1.56; p=0.007; ≥65 years vs ≤44 years: OR, 1.41; 95% CI, 1.15-1.72; p=0.001), being treated in less developed regions (OR, 1.20; 95% CI, 1.08-1.34; p=0.001), better baseline VA (20/50-20/200 vs worse than 20/200: OR, 3.20; 95% CI, 2.67-3.83; p<0.001; 20/40 or better vs worse than 20/200: OR, 5.89; 95% CI, 4.86-7.12; p<0.001), and being LTFU for >12 months (OR, 1.22; 95% CI, 1.09-1.37; p=0.001). A total of 792 patients returned with worsened vision and underwent ≥12 months of follow-up after resuming therapies. After a mean follow-up time of 17.3 months, 522 (65.9%) patients had persistent vision loss. CFT presented paralleled changes with VA. Odds of persistent vision loss were greater among patients with VA of 20/40 or better before being LTFU (OR, 2.54; 95% CI, 1.25-5.15; p=0.010) or having CFT of 350μm or more at return (OR, 1.57; 95% CI, 1.15-2.16; p=0.005). In retreatment, odds of persistent vision loss were lower for patients who switched anti-VEGF agents (OR, 0.61; 95% CI, 0.45-0.84; p=0.002) after return. Conclusion Nearly half of the patients had vision decline after being LTFU, and after resuming therapies, vision loss still persisted in 2 of 3 patients. Clinical adherence should be strengthened for patients with baseline VA of 20/40 or better or having CFT of 350μm or more at return. Multiple agents used were associated with vision recovery.

Objective To study the changes in vitreous humor proteins profile of proliferative diabetic retinopathy (PDR) and macular hole (MH) / epimacular membrane (EMM). Further, to identify potential biomarkers in PDR by screening differentially expressed proteins (DEPs). Methods The study used tandem mass tag (TMT) combined with LC-MS/MS for the identification of DEPs in vitreous samples of PDR and MH/EMM patients. The identified DEPs were analyzed bioinformatically to screen out candidate proteins for potential research potential. Using the parallel reaction monitoring (PRM) technique, 30 proteins with potential effects were targeted and validated. Results TMT combined with LC-MS/MS proteomic analysis isolated and identified a total of 4812 peptides and 877 proteins were identified, including a total of 59 DEPs (fold change > 1.2, P < 0.05). Bioinformatics analysis showed that DEPs were mainly involved in important biological processes such as cell transformation, stimulus-response, cellular processes, bioregulation, localization, and immune and metabolic processes. Validated by PRM, 23 proteins were quantified, the overall trends of the label-free quantification and PRM results were consistent. Among them, coagulation factor V (FV), profilin-1 (PFN1), thioredoxin (TXN), ferritin light chain (FTL) and Selenoprotein P (SeP) and not only showed consistent significant quantitative trends, but P < 0.05. Conclusion This study shows alterations in vitreous humor proteins profile of PDR. These five candidate proteins (FV, PFN1, TXN, FTL, SeP) can be used as biomarkers of PDR, providing new research directions and therapeutic targets for the pathogenesis of PDR.

Müller cell pyroptosis and immune inflammation-induced retinal ganglion cell (RGC) damage are the core pathological markers and potential therapeutic targets for neurodegeneration in early diabetic retinopathy (DR). Qiming Granules (QMG)—recommended by the traditional Chinese medicine guidelines for DR owing to their multi-target immunomodulatory, antioxidant, and microvascular protective effects. This study aimed to clarify the protective effect of QMG on early DR neurodegeneration, reveal their neuroprotective mechanism by regulating the P2X7R/NLRP3 pathway to inhibit Müller cell pyroptosis and immune inflammation, identify the chemical components of QMG and its absorbed components in rat plasma, study the effects of major absorbed components on inhibiting Müller cells pyroptosis and immune inflammatory response, and investigate the potential pharmacodynamic substances of QMG. An in vivo DR neurodegeneration model was established. HE staining, transmission electron microscopy, WB, and ELISA were used for detecting RGC apoptosis, histomorphological changes, P2X7R/NLRP3 expression, and pyroptosis pathway proteins. An in vitro high-glucose-induced Müller cell pyroptosis model was constructed. After activating or inhibiting P2X7R, lactate dehydrogenase levels were measured; moreover, ELISA, WB, and immunofluorescence were performed to examine cell membrane damage, inflammatory factor release, and pyroptosis pathway protein expression. UPLC-Q-Orbitrap HRMS was utilized to characterize the chemical and blood-entering profiles of QMG, aiming to evaluate the inhibitory effects of its main blood components on high glucose-induced Müller cell pyroptosis. QG inhibited RGC apoptosis, the P2X7R/NLRP3 pathway, and retinal cell pyroptosis in DR neurodegeneration model rats. In vitro, QMG reduced membrane rupture and pyroptosis pathway protein expression in Müller cells by suppressing the P2X7R/NLRP3 pathway, ultimately inhibiting Müller cell pyroptosis and immune-inflammatory responses. Nine of the 70 compounds identified in QMG were absorbed into the bloodstream. The main absorbed components, astragaloside IV and puerarin, effectively mitigated high glucose-induced Müller cell pyroptosis, with astragaloside IV exhibiting a more pronounced effect. QMG mitigated Müller cell pyroptosis and inflammatory responses by regulating the P2X7R/NLRP3 pathway, thereby inhibiting early neurodegeneration in DR. Astragaloside IV and puerarin absorbed into systemic circulation, significantly attenuated high glucose-induced pyroptosis, and suppressed immunoinflammatory responses in Müller cells.

PURPOSE:To describe the visual and anatomical changes after restarting anti-vascular endothelial growth factor (VEGF) therapy in patients with diabetic macular edema who returned with stabilized vision after being lost to follow-up (LTFU), and to explore the distinct predictors of clinical benefits upon retreatment. DESIGN:Retrospective clinical cohort study. METHODS:In this study, 976 patients who returned after being LTFU for ≥6 months were included. All participants had center-involved diabetic macular edema and presented with visual acuity (VA) <20/25 and central foveal thickness (CFT) ≥250 μm. VA and CFT were assessed before being LTFU, at return, and after retreatment. Patients were stratified into two groups: (1) Patients who returned with stabilized VA (the first VA upon returning ≥ the last recorded VA prior to being LTFU), and (2) patients who returned with vision decline (the first VA upon returning < the last recorded VA prior to being LTFU). RESULTS:After a median LTFU period of 259 days, 447 patients (45.8%) had stabilized VA, and 529 patients (54.2%) had vision decline. With similar follow-up periods (361 vs 356 days) after retreatment, visual gain was obtained in 32.7% of patients with stabilized VA, significantly lower than in those with vision decline (62.0%, P < .001). Consistently, CFT reduction by ≥10% was achieved in 56.4% of patients with stabilized vision and in 63.2% of those with decreased vision (P = .038) over similar follow-up periods (377 vs 361 days). Multivariate logistic regression analysis indicated that the odds of visual (odds ratio = 0.29, 95% CI:0.22-0.38, P < .001) and anatomical (odds ratio = 0.78, 95% CI: 0.59-1.02, P = .073) improvements were lower in patients who returned with stabilized VA, but increased with more anti-VEGF injections administered during retreatment (both P < .001). Notably, patients presenting with stabilized VA of 20/50 or better did not obtain vision gain after retreatment despite anatomical improvement. CONCLUSIONS:Patients who returned with stabilized vision exhibited suboptimal visual and anatomical responses to anti-VEGF retreatment. Those with VA of 20/50 or better did not improve sufficiently in vision despite anatomical improvements. The decision to readminister anti-VEGF therapy in patients returning with stabilized moderate-to-good vision should be weighed carefully, and alternative or combination therapies may be warranted.

Purpose:Some experimental reports have proposed an interaction between gut microbiota (GM) and uveitis. However, the exact association between GM and its metabolic pathways and uveitis remains unknown. This study was conducted to explore the bidirectional causal relationship between GM and its metabolic pathways and uveitis. Methods:Summary data of the GM and its metabolic pathways and uveitis were leveraged from the Dutch Microbiome Project and the Genome-Wide Association Studies (GWAS) Catalog, respectively. We then conducted Mendelian randomization (MR) analysis to explore whether the GM and its metabolic pathways have a corresponding causal relationship with uveitis. To confirm the credibility of the findings, we utilized MR Egger, the MR-PRESSO global test, and the Cochran Q test to detect pleiotropy and heterogeneity. Results:According to the inverse variance weighting method, the species Bacteroides faecis (odds ratio [OR] = 0.598, 95% confidence interval [CI] = 0.390–0.919, P = 0.019) and the superpathway of sulfate assimilation and cysteine biosynthesis (OR = 0.179, 95% CI = 0.038–0.843, P = 0.029) had beneficial effects on uveitis. In contrast, the genus Sutterellaceae (OR = 3.493, 95% CI = 1.121–10.879, P = 0.030); the species Parabacteroides distasonis (OR = 5.932, 95% CI = 1.321–26.635, P = 0.020), Faecalibacterium prausnitzii (OR = 4.838, 95% CI = 1.067–21.936, P = 0.040), and Bacteroides caccae (OR = 3.818, 95% CI = 1.010–14.437, P = 0.048); and the L1,2–propanediol degradation (OR = 2.084, 95% CI = 1.098–3.954, P = 0.024), galactose degradation I (Leloir pathway; OR = 3.815, 95% CI = 1.108–13.135, P = 0.033), TCA cycle VI (obligate autotrophs; OR = 2.955, 95% CI = 1.015–8.606, P = 0.046) and UMP biosynthesis (OR = 4.979, 95% CI = 1.000–24.782, P = 0.049) pathways had adverse effects on uveitis. No pleiotropy or heterogeneity was found. Leave-one-out analysis showed the reliability of the above findings. Conclusions:Our analysis revealed a causality between certain GM species and metabolic pathways and uveitis via genetic prediction, which may provide new perspectives into the etiology and therapies of uveitis. Translational Relevance:This study provides evidence that modulating the intestinal flora and its metabolic pathways is effective in treating uveitis.

PURPOSE:Diabetic retinopathy (DR) is the most common complication of diabetes mellitus. Stimulator of interferon genes (STING) plays an important regulatory role in the transcription of several genes. This study aimed to mine and identify hub genes relevant to STING in DR. METHODS:The STING-related genes (STING-RGs) were extracted from MSigDB database. Differentially expressed STING-RGs (DE-STING-RGs) were filtered by overlapping differentially expressed genes (DEGs) between DR and NC specimens and STING-RGs. A PPI network was established to mine hub genes. The ability of the hub genes to differentiate between DR and NC specimens was evaluated. Additionally, a ceRNA network was established to investigate the regulatory mechanisms of hub genes. Subsequently, the discrepancies in immune infiltration between DR and NC specimens were further explored. Additionally, we performed drug predictions. Finally, RT-qPCR of peripheral blood samples was used to validate the bioinformatics results. RESULTS:A grand total of four genes (IKBKG, STAT6, NFKBIA, and FCGR2A) related to STING were identified for DR. The AUC values of all four hub genes were greater than 0.7, which indicated that the diagnostic value was acceptable. The ceRNA network contained four hub genes, 170 miRNAs, and 135 lncRNAs. In addition, immunoinfiltration analysis demonstrated that the abundance of activated B cells was notably different between the DR and NC specimens. Moreover, 32 drugs were included in the drug-gene network, with twelve drugs targeting STAT6, nine drugs targeting NFKBIA, four drugs targeted IKBKG, and seven drugs targeted FCGR2A. The expression of the four hub genes in blood samples determined by RT-qPCR was consistent with our analysis. CONCLUSION:In conclusion, four hub genes (IKBKG, STAT6, NFKBIA, and FCGR2A) related to STING with a diagnostic value for DR were identified by bioinformatics analysis, which might provide new insights into the evaluation and treatment of DR.

To address the difficulty in comprehensive screening of fundus diseases, we develop three deep learning algorithms (DLAs) based on different algorithms (Swin Transformer and cross-domain collaborative learning [CdCL]) and imaging modalities (ultra-wide-field [UWF] images and the cropped posterior-pole-region [PPR] images) to identify 25 fundus conditions and provide referral suggestions: WARM (CdCL + UWF images), BASE (Swin Transformer + UWF images), and WARM-PPR (CdCL + PPR images). 59,475 UWF images are included to establish internal and external datasets. WARM shows the best performance on the internal test (area under the receiver operating characteristic curve [AUC] for screening = 0.915; AUC for referral = 0.911) and the external multi-center test (AUC for screening = 0.912; AUC for referral = 0.902). UWF images and the CdCL approach significantly enhance the DLA's ability to detect abnormalities in the peripheral retina. The WARM model shows promise as a reliable and accurate tool for comprehensive fundus screening on a large scale.

Diabetic retinopathy (DR) is a serious microvascular complication caused by dysregulated glucose metabolism and represents a primary cause of vision loss. Hyperglycemia-induced metabolic disturbances, oxidative stress, and inflammation are key drivers of DR progression. In this study, we developed a nanozyme cascade system by integrating gold nanozymes with glucose oxidase activity and platinum nanozymes exhibiting catalase and superoxide dismutase activities into a metal-organic framework. This composite, referred to as Pt-MOF/Au, was designed to remodel the pathological microenvironment associated with an aberrant glucose metabolism. The surface was modified with hyaluronic acid (Pt-MOF/Au@HA) to enhance the biocompatibility of Pt-MOF/Au. In vitro experiments demonstrated that Pt-MOF/Au@HA effectively decomposed glucose and scavenged excess reactive oxygen species. Cellular assays and studies in a streptozotocin-induced DR animal model revealed that Pt-MOF/Au@HA significantly alleviated retinal hypoxia; suppressed the expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, and pro-inflammatory factors; and reduced vascular leakage. Furthermore, in an oxygen-induced retinopathy mouse model, Pt-MOF/Au@HA inhibited pathological retinal neovascularization while promoting vascular remodeling and normalization. This comprehensive therapeutic strategy that combines glucose reduction, hypoxia alleviation, radical scavenging, and anti-inflammatory effects via a nanozyme cascade system demonstrates robust efficacy in the treatment of DR.

Background It is well-known that ultraviolet B (UVB) causes cataracts by inducing pyroptosis and the production of reactive oxygen species (ROS) in human lens epithelial cells (HLECs). The transcription factor E2F1 (E2F1) serves as a positive regulator of disrupted pathways involved in histone modification and cell cycle regulation. However, its function in UVB-treated HLECs remains unknown. Purpose: This study aims to investigate the function of E2F1 in UVB-treated HLECs, with a particular focus on its interaction with NLRP3 and its impact on oxidative stress and pyroptosis. Research Design: HLECs were irradiated with UVB, and cell damage was assessed using CCK-8, ROS, and pyroptosis detection. The interaction between E2F1 and NLRP3 was confirmed using Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays. Study Sample: The study was conducted using UVB-treated HLECs. Data Collection and/or Analysis Collected data were statistically analyzed using one-way analysis of variance (ANOVA). Results Our results show that HLECs were much more susceptible to oxidative stress, pyroptosis, and E2F1 in response to UVB-irradiation, but that E2F1 down-regulation effectively counteracted these effects. E2F1 was then suggested as a potential NLRP3 transcription factor by bioinformatics studies. At the same time, luciferase and CHIP assays showed that E2F1 could bind to the NLRP3 promoter and enhance NLRP3 transcription. In addition, the protective effects of si-E2F1 against oxidative stress and pyroptosis in HLECs are counteracted by overexpressing NLRP3. Conclusions All of the above provided the possibility to demonstrate that E2F1 plays a crucial role in regulating oxidative stress and pyroptosis in UVB-induced HLECs through inhibiting NLRP3, and it promotes oxidative stress-induced pyroptosis by suppressing NLRP3 expression.

To determine the correlations between six serological inflammatory markers, namely the systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), aggregate index of systemic inflammation (AISI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), and various stages of type 2 diabetic retinopathy (T2DR). Additionally, the diagnostic value of these markers in T2DR was evaluated. Clinical data were collected from a total of 397 patients with type 2 diabetes who visited the ophthalmology department at Mian Yang Central Hospital and the Affiliated Hospital of Southwest Medical University from January 2023 to December 2023. Based on the results of fundus photography, patients were categorized into a non-diabetic retinopathy group (NDR, n = 121), a non-proliferative diabetic retinopathy group (NPDR, n = 77), and a proliferative diabetic retinopathy group (PDR, n = 199). General patient information and systemic inflammatory markers, including the SII, SIRI, AIRI, NLR, PLR, and MLR, were compared among the groups, and their correlations with T2DR were analyzed. The SII values were found to be significantly higher in the PDR group compared to the NPDR group, which in turn were higher than those in the NDR group (P < 0.05). Similarly, the AISI values were significantly elevated in the PDR group compared to both the NPDR and NDR groups (P < 0.05). The SIRI and MLR values were significantly higher in the PDR group than in the NDR group (P < 0.05). Furthermore, the NLR and PLR values were significantly higher in the NPDR and PDR groups compared to the NDR group (P < 0.05). The Mantel‒Haenszel chi-square test revealed a significant linear trend between the SII and PLR and the incidence of PDR (P < 0.001), with the incidence of PDR increasing as the quartile levels of the SII and PLR increased. Multivariate logistic regression analysis indicated that, compared with NDR, a higher SII was found to be an independent risk factor for NPDR (ORSII = 1.002, p = 0.001) and PDR (ORSII = 1.002, P < 0.001). The ROC curve analysis suggested that the combined assessment of the six inflammatory indices had the highest accuracy in the evaluation of DR, with an area under the curve (AUC) of 0.69, a sensitivity of 54%, and a specificity of 75%. The results of this study indicate that the SII is an independent risk factor for T2DR. A close correlation was observed between the SII and PLR and the occurrence and progression of T2DR. The high accuracy of the combined diagnosis of T2DR via various serological inflammatory markers underscores their potential as early biological indicators for the diagnosis of T2DR.

Diabetic retinopathy (DR) is a common and severe microvascular complication of diabetes, leading to vision impairment and blindness, particularly in working-age adults. Oxidative stress plays a central role in the pathogenesis of DR, with excessive reactive oxygen species (ROS) damaging retinal tissues, including blood vessels and neurons. This oxidative damage is exacerbated through various metabolic pathways, such as the polyol pathway, protein kinase C(PKC) activation, and advanced glycation end-product(AGE) formation. Additionally, mitochondrial dysfunction, retinal cell apoptosis, inflammation, and lipid peroxidation are key pathological processes associated with oxidative stress in DR. Epigenetic modifications, including DNA methylation and histone alterations, further contribute to gene expression changes induced by oxidative stress. To mitigate oxidative damage, therapeutic strategies targeting ROS production, neutralizing free radicals, and enhancing antioxidant defenses hold promise. Various natural antioxidant compounds, such as polyphenols (e.g., epigallocatechin-3-gallate, quercetin, resveratrol) and carotenoids (e.g., lutein, zeaxanthin), have demonstrated potential in reducing oxidative stress and improving retinal health in DR models. Moreover, activation of the Nrf2 and SIRT1 pathways has emerged as a promising approach to enhance the antioxidant response. Although preclinical studies show promising results, further clinical trials are necessary to validate the efficacy and safety of these therapeutic strategies. In conclusion, a better understanding of the molecular mechanisms underlying oxidative stress in DR and the development of multi-target therapies could provide more effective treatment options for DR patients.