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To evaluate whether systemic interleukin-6 (IL-6) inhibitor use is associated with reduced risk of incident diabetic retinopathy (DR), DR progression, vision-threatening complications, and retinal interventions in adults with diabetes. Retrospective propensity score-matched cohort study. Adults with type 1 or type 2 diabetes were identified using the US TriNetX electronic health record network from January 1, 2004, through May 30, 2026. After 1:1 propensity score matching, the primary analysis included 2,605 diabetic patients receiving IL-6 inhibitors and 2,605 matched diabetic controls. The secondary analysis included 1,057 matched patients per group with known nonproliferative diabetic retinopathy (NPDR). Cohorts were matched on baseline characteristics, medication exposure, inflammatory disease burden, and ophthalmic history. The primary analysis assessed incident DR among patients without baseline retinopathy. Secondary analyses evaluated progression from NPDR to proliferative diabetic retinopathy (PDR) and compared IL-6 inhibitors with alternative immunosuppressants. Sensitivity analyses compared IL-6 inhibitors with intravitreal steroid injections among patients with severe NPDR or PDR and evaluated outcomes by IL-6 inhibitor occurrence frequency. Risk ratios for incident NPDR, PDR, vitreous hemorrhage (VH), diabetic macular edema (DME), neovascular glaucoma (NVG), and receipt of anti-vascular endothelial growth factor (anti-VEGF) injections, panretinal photocoagulation (PRP), and pars plana vitrectomy (PPV) at 1, 3, and 5 years. In the primary analysis, IL-6 inhibitor use was associated with significantly lower 5-year risks of NPDR (RR: 0.50; 95% CI: 0.42-0.60), PDR (RR: 0.47; 95% CI: 0.35-0.61), DME (RR: 0.37; 95% CI: 0.27-0.51), and VH (RR: 0.41; 95% CI: 0.28-0.61), with no significant difference in NVG. Anti-VEGF therapy, PRP, and PPV use were also significantly lower at 5 years. Among patients with baseline NPDR, IL-6 inhibitor use was associated with lower 5-year risks of progression to PDR, DME, VH, NVG, and retinal interventions. Findings were consistent in active comparator analyses. Systemic IL-6 inhibitor use was associated with lower risk of incident DR, DR progression, vision-threatening complications, and retinal interventions over 5 years, with findings persisting in active comparator and sensitivity analyses. Prospective studies are needed to evaluate whether IL-6 pathway modulation may have a therapeutic role in diabetic eye disease.

Data on sex-specific risk factors for type 1 diabetes microvascular complications are limited. We assessed sex-specific associations of longitudinal clinical risk factors and 30-year retinopathy and kidney end point incidence in the Pittsburgh Epidemiology of Diabetes Complications type 1 diabetes cohort. The cohort (n = 325 women and 333 men; mean baseline age 27 years; diabetes duration 19 years) was followed from 1986-1988 to 2016-2018 for the following: incident proliferative diabetic retinopathy (PDR) (Early Treatment of Diabetic Retinopathy Study grade ≥60 or laser photocoagulation); severely increased albuminuria (SIA) (albumin excretion rate ≥200 µg/min); and estimated glomerular filtration rate < 60 mL/min/1.73 m2 (chronic kidney disease [CKD] G3). Associations between longitudinal risk factors and time to each event were assessed by sex in multivariable joint models in those who were complication free at baseline. PDR incidence was similar by sex (57% in women vs. 59% in men; P = 0.54). SIA incidence was lower in women (18% vs. 25% in men; P = 0.10); and CKD G3 was higher in women (28% vs. 21% in men; P = 0.11). In both sexes, independent risk factors for PDR included HbA1c and blood pressure (BP) (women's systolic BP: hazard ratio [HR] 1.27 [95% CI 1.12, 1.45]; men's diastolic BP: HR 1.40 [95% CI 1.15, 1.70]). For SIA, HbA1c was associated in both sexes, but other factors differed, including triglyceride levels (HR 1.38 per log1.2; 95% CI 1.06, 1.78) and BMI (HR 0.87; 95% CI 0.76, 1.00) in women and smoking (HR 3.46; 95% CI 1.07, 11.24) in men. For CKD G3, HbA1c was a risk factor in both sexes; smoking was also associated in men. Although HbA1c and BP are important risk factors for retinopathy regardless of sex, sex-specific clinical targets warrant further research to optimize kidney protection in type 1 diabetes.

To develop a machine learning (ML)-driven polygenic risk score (PRS) for diabetic retinopathy (DR) and evaluate the extent to which lifestyle may mitigate genetic risk. Multicenter, multiethnic cohort study. 9 1691 participants with DR-free prediabetes/diabetes from the UK Biobank (UKB); and 1119 participants with DR-free diabetes from the Guangzhou Diabetic Eye Study (GDES). An ML-driven PRS for DR was constructed on an a priori basis by systematically integrating 182 literature-derived single nucleotide polymorphisms, which was subsequently applied to 2 multiethnic, prospective cohorts with genotyped data for unbiased stratification of genetic susceptibility. Lifestyle adherence was determined using a scoring system based on 4 behavioral factors (no smoking, optimal weight control, regular physical activity, and healthy sleep) that were categorized as favorable (3-4 factors), intermediate (2 factors), and unfavorable (0-1 factor). The independent and joint associations of genetic risk and lifestyle with incident DR were estimated using Cox proportional hazards models, with risk reduction analyses stratified by genetic risk category. Hazard ratios (HR) on incident DR. Participants at high genetic risk had a 37% higher risk of developing incident DR than those at low genetic risk, regardless of lifestyle (HR, 1.37, 95% confidence interval [CI], 1.18-1.60; P < 0.001). An unfavorable lifestyle was associated with a 49% higher risk than a favorable lifestyle, regardless of genetic risk (HR, 1.49, 95% CI, 1.34-1.65; P < 0.001). High genetic risk combined with an unfavorable lifestyle more than doubled the DR risk (HR, 2.09, 95% CI, 1.67-2.60; P < 0.001). Among participants at high genetic risk, a favorable lifestyle was associated with a 44% lower DR risk (HR, 0.56, 95% CI, 0.42-0.75; P < 0.001), corresponding to a reduction in the standardized DR rates from 7.5% (95% CI, 7.4-7.6) to 4.6% (95% CI, 4.5-4.7). The gene-lifestyle synergistic associations were confirmed by replication in the GDES: compared with participants at low genetic risk, those at intermediate (HR, 1.47, 95% CI, 1.13-1.93; P = 0.004) and high (HR, 1.68, 95% CI, 1.30-2.17; P < 0.001) genetic risk exhibited a significantly greater risk of incident DR. Adherence to a favorable lifestyle resulted in an relative risk reduction (RRR) of 47.4% and an absolute risk reduction (ARR) of 5380.0 standardized DR events for those at high genetic risk, and an RRR of 16.6% and an ARR of 988.3 standardized DR events for those at intermediate genetic risk, per 100,000 person‑years of follow‑up. Both genetic risk and modifiable lifestyles demonstrated independent and joint impacts on DR risk. Although risk reduction was greatest among those with high genetic risk, our findings support universal behavioral interventions for DR prevention, regardless of genetic background. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

To understand the associations between the topographic lesion distribution and vision-related quality of life (VR-QoL) in individuals with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Analysis of data from Chroma (NCT02247479) and Spectri (NCT02247531), which are identically designed Phase III clinical trials of lampalizumab. A total of 856 participants who were aged 50 years or more with bilateral GA who completed the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) at baseline. The NEI VFQ-25 was used to determine estimates of VR-QoL in the visual functioning (NEI VFQ-VF) domain, using calibrated item measures and rating category thresholds from the Rasch analysis. Geographic atrophy was automatically segmented on combined fundus autofluorescence and near-infrared reflectance images, and its extent in central regions across varying diameters (from 0.25 to 6.00 mm, in 0.25-mm intervals) relative to the fovea were then derived. Association between NEI VFQ-VF person measures and the minimum eye-level GA extent in the region evaluated within an individual (referred to as the "minimum GA extent"). Minimum GA extent within the central region across varying diameters between 0.25 and 6.00 mm were all significantly associated with the NEI VFQ-VF person measures (P ≤ 0.001 for all), but the highest proportion of variance explained was seen when evaluating the central 2.50-mm diameter region (R2 = 0.11). A multivariable analysis showed that only the minimum GA extent within the central 2.50-mm region (P < 0.001), but not the 2.50- to 6.00-mm annulus (P = 0.541), was independently associated with NEI VFQ-VF person measures. In this cohort, VR-QoL is most strongly associated with minimum eye-level GA extent within the central 2.50-mm region within an individual. These findings underscore the importance of evaluating GA extent in this region, beyond simply considering foveal GA involvement, when seeking to evaluate structural changes most closely associated with self-reported impairments in visual functioning. Proprietary or commercial disclosure may be found after the references.

Whether prior pars plana vitrectomy (PPV) independently increases the risk of cystoid macular edema (CME) following cataract surgery remains unknown. To evaluate associations between prior PPV and incidence of CME after cataract surgery. This retrospective cohort study was conducted using the TriNetX US Network, a multicenter federated electronic health record network from December 2005 to December 2025 including academic and community hospitals in the US. Adults aged 18 years or older who underwent cataract surgery were categorized into those with vs those without a history of PPV (≥6 months prior to cataract surgery), excluding those with preexisting CME or risk factors for CME. Data were analyzed from December 2025 through January 2026. History of PPV performed more than 6 months prior to cataract surgery. The primary outcome was the incidence of CME within 30 to 90 days postoperatively, identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. Risk ratios (RR) were used to compare outcomes. Propensity score matching was performed for demographic and clinical covariates (age, sex, race, hypertension, hyperlipidemia, diabetes, myopia, retinal detachment [RD] history). After propensity score matching with 615 983 patients undergoing cataract surgery, 7422 patients had a prior PPV. After propensity score matching, among patients with prior PPV, mean (SD) age was 62.0 (11.6) years, and 3623 patients (49.5%) were female; among the non-PPV group, mean (SD) age was 61.9 (12.2) years, and 3625 patients (49.5%) were female. Among 14 636 patients representing 7318 propensity score-matched pairs, CME occurred in 336 of 7318 patients with prior PPV (4.59%) compared with 90 of 7318 non-PPV controls (1.23%) (difference, 3.36%; 95% CI, 2.82%-3.90%; RR, 3.73; 95% CI, 2.97-4.70; P < .001). Elevated CME risk persisted in subgroup analyses evaluating prior PPV for RD (5.65% vs 1.22%; absolute difference, 4.43%; 95% CI, 3.48%-5.38%; RR, 4.62; 95% CI, 3.20-6.67; P < .001), as well as those for non-RD indications (3.99% vs 1.23%; absolute difference, 2.76%; 95% CI, 2.06%-3.48%; RR, 3.26; 95% CI, 2.36-4.50; P < .001). Furthermore, after excluding patients with intraoperative and postoperative complications of cataract surgery, the prior PPV group was still found to have a higher risk of CME (4.59% vs 1.26%; absolute difference, 3.32%; 95% CI, 2.77%-3.88%; RR, 3.63; 95% CI, 2.88-4.58; P < .001). Results of this cohort study suggest that eyes with vs without prior PPV have higher incidences of postoperative CME. However, numerous limitations, including dependence on coding-based diagnoses and lack of visual acuity outcomes, preclude determining the role of prophylaxis or monitoring for CME in vitrectomized eyes undergoing cataract extraction.

Substantial unexplained heritability remains for pathogenic inherited retinal disease (IRD) variants. Application of genome-wide association studies (GWAS) could help identify causal genes in rare diseases. To leverage a GWAS for the discovery of IRD-associated genes. This GWAS analysis was combined with replication of findings in 2 independent IRD cohorts. The study was conducted from January 2024 to December 2025 in a multicenter setting through FinnGen, 100 000 Genomes Project, and the National Health Service Genomic Medicine Service combined with clinical cohort from the Oulu University Hospital. Using IRD criteria from the International Classification of Diseases, 9th and 10th Revisions, 540 individuals with IRD and 473 945 control individuals were identified in the FinnGen study. For validation of FinnGen results, 49 patients were recruited from Oulu University Hospital. Results were further validated in 2 individuals identified from the UK cohort. The GWAS and proteomics analysis were performed in the FinnGen cohort. Sanger and whole-genome sequencing and RNA approaches were used in a clinical IRD cohort to validate pathogenicity of the identified XXYLT1 variant. This GWAS identified 13 recessive loci reaching genome-wide significance (defined as P < 5 × 10-8). Of these, 4 (near or within XXYLT1, ANKRD10, DYM, and CBLN4) had not been associated with IRD, including the XXYLT1 c.505-1G>C founder variant. This variant was further genotyped in the clinical replication cohort, leading to identification of 5 more homozygous individuals from 4 families. The phenotype was consistent with a cone-rod or macular dystrophy, with visual deterioration, cystoid macular edema and/or schisislike macular abnormalities. The effect of the XXYLT1 c.505-1G>C variant was further investigated using RNA sequencing and complementary DNA amplicon sequencing, demonstrating exon 2 skipping and a loss-of-function effect. These findings were replicated in an independent population identifying 2 patients from the UK harboring a homozygous XXYLT1 c.766G>A, p.(Glu256Lys) missense variant. This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels.

Current research on pathological retinal neovascularization primarily focuses on growth factors, inflammation, and endothelial signaling pathways. However, increasing attention is being directed toward disruptions in the retinal immune microenvironment. Therefore, deciphering the immune-angiogenic interplay could uncover therapeutic avenues for neovascular disorders. Through integrative analyses of single-cell RNA sequencing from human fibrovascular membranes and multicohort clinical datasets, we identified neutrophil infiltration as an independent risk factor for diabetic retinopathy progression. Mechanistically, activated microglia preceded and potentiated neutrophil infiltration by secreting galectin-3 (GAL3), establishing a self-amplifying feedback loop that sustained microglial activation and drove pathological angiogenesis in mice with oxygen-induced retinopathy (OIR). To therapeutically disrupt this loop, we engineered a photocurable hydrogel for the sustained intravitreal delivery of GAL3 and vascular endothelial growth factor (VEGF)-neutralizing antibodies, which effectively suppressed aberrant angiogenesis in mice with OIR. Together, these findings reinforce the concept of retinal neovascularization as an immunovascular disorder and underscore the therapeutic potential of microenvironment-modulating strategies using biomaterials.

Achieving the transition to net zero human greenhouse gas emissions requires a large increase in metal production by mining. Acid mine drainage (AMD) neutralization is a potentially important but poorly quantified source of mining industry CO2 emissions. Here, we show that AMD neutralization-related CO2 emissions can be a major component of metal production carbon footprints. Data from the rivers and estuarine system draining the central and eastern Iberian Pyrite Belt show that AMD neutralization emits 32 ± 11 kt CO2/yr. Normalized to historic copper production rates, AMD-associated emissions (0.3-4.2 t CO2 per t Cu) are of similar magnitude as conventional copper production carbon footprints (1-9 t CO2 per t Cu). However, continual oxidative weathering of waste sulfide minerals will increase AMD-related CO2 emission budgets into the future. Complete oxidative weathering of waste sulfide minerals extracted from this region will yield AMD-related CO2 emissions (7-165 t CO2 per t Cu) that exceed conventional Cu production carbon footprints by more than 1 order of magnitude. These findings highlight the need to account for AMD-related CO2 emissions from metal mining to support the transition toward net zero greenhouse gas emissions.

Posterior segment eye diseases are leading causes of vision impairment, yet current treatments such as intravitreal injections require frequent administration and carry risks of complications, including endophthalmitis and retinal detachment, highlighting the need for minimally invasive and controllable alternatives. Here, we present an improved hydrogel-forming microneedle (HFMN) platform composed of 20% poly(methyl vinyl ether-alt-maleic acid) and 7.5% poly(ethylene glycol) for minimally invasive, targeted drug delivery to the posterior segment via the suprachoroidal space. A dispensing-based drug-loading method reduced the required drug volume from 4 mL to 50 μL (∼80-fold), enabling precise dosing of expensive ophthalmic agents. We employed TOP-V122, a clinically relevant hydrophobic compound that releases nitric oxide and inhibits phosphodiesterase 5, addressing the limitations of prior hydrophilic model-drug studies. The platform exhibited sufficient mechanical strength for scleral penetration (2.49 N per needle) and biocompatibility (higher ARPE-19 cell viability than free drug). Validation included ex vivo drug permeation studies using Nile red as a fluorescent tracer, in vitro cytotoxicity assays, and a short-term in vivo rabbit feasibility study. The platform enabled rapid ex vivo V122 permeation across porcine scleral tissue, with 64.6 ± 10.5% of loaded drug detected within 30 min, and supported suprachoroidal space-associated fluorescence distribution after short-term ex vivo application. In the rabbit study, 15-min V122-HFMN application reduced intraocular pressure and increased ocular cyclic guanosine monophosphate levels, without overt acute histological damage at the insertion site. These findings support HFMNs as a promising platform for rapid, short-duration posterior segment therapy, potentially improving patient compliance and reducing healthcare burden. STATEMENT OF SIGNIFICANCE: Treating posterior segment eye diseases remains a significant clinical challenge. Repeated intravitreal injections, the standard of care, carry risks of serious complications and impose a substantial burden on patients. Here, we present a hydrogel-forming microneedle platform that penetrates the sclera, swells upon contact with ocular fluid, and transiently opens the suprachoroidal space to enable drug delivery to the posterior segment. A dispensing-based drug-loading method reduces the required drug volume by approximately 80-fold, enabling precise dosing of costly therapeutics. Using a clinically relevant hydrophobic compound with dual vascular activity, we demonstrate rapid, short-duration drug delivery and preliminary outcomes comparable to intravitreal injection, with reduced tissue disruption. This platform offers a practical, minimally invasive alternative for managing blinding posterior segment diseases.

Bioadhesive materials have been successfully applied across several ophthalmic fields, yet their translation into vitreoretinal surgery for the repair of retinal breaks and defects remains limited. Conventional strategies, including gas and silicone oil tamponade, continue to dominate retinal stabilization; however, they primarily provide temporary cavity-based support rather than direct interfacial closure of retinal defects and may require postoperative positioning, secondary interventions, or carry tamponade-related complications. Despite advances in biomaterial engineering, broader translation of vitreoretinal bioadhesives remains constrained by posterior-segment-specific barriers, including inadequate wet-surface bonding, residual adherent vitreous at retinal break margins, biomechanical mismatch with the compliant neural retina, unfavorable swelling or degradation behavior, inflammatory or proliferative responses, and challenges in precise intraoperative delivery. Importantly, the required adhesive profile differs by indication: peripheral retinal breaks require focal sealing and resistance to fluid ingress and tractional stress, whereas macular holes, optic disc pit maculopathy, and regenerative retinal repair may require different balances of scaffold support, controlled bioactivity, tissue bridging, fibrosis avoidance, and long-term safety. Hydrogel-based vitreous substitutes can reproduce key viscoelastic properties of the native vitreous but remain largely investigational and primarily provide temporary intraocular support rather than direct focal defect repair. Accordingly, next-generation platforms should be designed not simply for adhesion strength, but for indication-specific function, controlled persistence, intraoperative deliverability, secondary-surgery compatibility, and rigorous preclinical and clinical validation. Rather than serving as tamponade replacements, future bioadhesives may be better conceptualized as precision intraocular platforms that complement volumetric tamponade and retinopexy by adding interface-directed defect sealing, biological modulation, and controlled intraocular delivery. This review critically reappraises vitreoretinal bioadhesive strategies, with primary emphasis on retinal detachment and defect repair, through a problem-driven, retina-centered framework that integrates clinical vitreoretinal evidence with adhesion-engineering principles, providing a barrier-oriented translational perspective for interface-directed retinal repair. Building on this analysis, we outline an innovative perspective on the key functional and translational design principles for next-generation vitreoretinal bioadhesives and propose a mechanism-informed roadmap for scalable clinical translation.

Schwertmannite is an Fe(III) oxyhydroxysulfate that can host large amounts of As(V) in acid mine drainage (AMD) systems. However, schwertmannite is metastable and transforms over time to jarosite and/or goethite under strongly-acidic (pH < 3) AMD conditions. This study provides the first quantitative evaluation of schwertmannite transformation kinetics under these conditions, examining the combined effects of As(V) loading (As:Fe ratios spanning 0-0.0667) and temperature (20, 40 and 60 °C). Compositional analyses, X-ray diffraction (XRD) and extended X-ray absorption fine structure (EXAFS) spectroscopy, coupled with fitting of reaction progress data using the Avrami kinetic model, reveals that schwertmannite transformation responds systematically to As(V) loading in multiple ways that vary as a function of temperature. At 20°C and 40°C, schwertmannite transformed readily to jarosite at all As(V) loadings, with half transformation times (t50) spanning 47-164 days at 20°C and 12-33 days at 40°C. In contrast, schwertmannite transformation to goethite was inhibited by As(V) at 20°C and 40°C (with no goethite detected in any As(V)-bearing treatment). At 60°C, As(V) also retarded schwertmannite transformation to goethite, although goethite formation was not completely inhibited at this higher temperature until As:Fe ratios exceeded 0.025. Conversely, transformation of schwertmannite to jarosite at 60°C was accelerated by increases in As(V), with t50 dropping from ∼7 days under As(V)-free conditions to ∼4 days at the highest As(V) loading. Apparent activation energies for schwertmannite transformation to jarosite increased with As(V), indicating that this mineralogical transformation becomes more energy demanding at higher As(V) loadings.

Hydroclimatic extremes increasingly threaten groundwater quality, but storm-driven nitrate (NO3-) dynamics within highly permeable karst networks remain poorly constrained. Integrating high-frequency monitoring, artificial tracer tests and multi-isotope tracking (δD/δ18O-H2O, δ15N/δ18O-NO3- and δ13C-DIC), this study deciphered the coupled evolution of hydrological pathways, water quality and nitrogen transformations during an extreme storm event (116 mm within 2.9 h) in an acid mine drainage (AMD)-affected karst watershed in China. During flood recession, a rapid shift in NO3- source dominance was observed. The contribution of manure and sewage declined from 49 ± 14% to 16 ± 11%, whereas the AMD contribution increased from 44 ± 15% to 80 ± 12%, collectively accounting for > 88% of the total NO3- load. This dynamic provenance shift induced severe nitrogen pollution. NO3- concentrations surged from 19.67 mg L-1 to 44.37 mg L-1, and ammonium (NH4+) increased from below the detection limit to 1.92 mg L-1, approaching or exceeding WHO and Chinese drinking water thresholds. Mechanistically, whilst elevated NH4+ and persistently oxic conduit conditions favoured localised nitrification, directly driving rapid NO3- accumulation, the apparent denitrification signal captured at the conduit outlet was attributed to the flushing of residual NO3- that had undergone prior denitrification within the epikarst hydrologic network. Furthermore, the storm mobilised 1.69 × 104 kg of NO3- from the watershed, underscoring the disproportionate effect of extreme precipitation on mass nutrient export. These findings elucidate how hydraulically connected anthropogenic point sources can rapidly amplify groundwater nitrogen hazards and highlight the critical need for event-based monitoring and targeted AMD mitigation in vulnerable karst terrains.

The efficient, economical, and sustainable treatment of acid mine drainage (AMD) remains a major challenge. This study developed a low-cost biochar electrode for electrocoagulation (EC) that not only reduces material cost but also enables contaminant-specific control and resource recovery. Utilizing polyvinyl acetate (PVAC) as a binder, biochar as a catalyst, and Al mesh as a current collector, the optimized electrode (36 mg/cm2 biochar loading, 6 mA/cm2 current density) achieved high removal efficiency from field-collected AMD: 99% for Fe and Mn, 96.8% for Zn, and 91.4% for SO42--at substantially lower costs than conventional carbon electrodes. Beyond its performance, this system revealed element-specific behaviors and controllable Fe mineralogy. Mn predominantly accumulated on the electrode surface but largely redissolved (> 80%) upon polarity reversal, whereas Zn showed only partial release and Fe remained predominantly insoluble. X-ray absorption fine structure (XAFS) and complementary analyses revealed a sequential Fe phase transformation-from ferrihydrite through schwertmannite and lepidocrocite, ultimately to stable goethite, with polarity reversal capable of reversing this sequence and modulating Fe-SO₄ bonding, thereby enabling precise control over Fe speciation and laying the groundwork for understanding associated contaminant interactions. These insights establish a tunable platform for synchronizing heavy-metal removal, sludge stability, and selective metal recovery, transforming EC from a simple purification method into a predictive, resource-circular technology.

Vein occlusion (VO), including deep venous thrombosis (DVT) and retinal vein occlusion (RVO), is a common cause of multiple diseases that severely compromise the quality of life of affected individuals. Epidemiological evidence indicates that VO prevalence increases in cold seasons, yet the underlying mechanism remains unknown. Here, we show that cold exposure markedly elevates peripheral platelet counts, thereby aggravating VO in mouse models. Cold-augmented thrombocytopoiesis depends on the activation of adipose thermogenesis and subsequent increase in circulating free fatty acid (FFA) levels. Mechanistically, FFA-β-oxidation promotes acetyl-CoA production, which upregulates and stabilizes C/EBPα by shifting the balance between p300 acetyltransferase and SIRT1 deacetylase. Acetyl-C/EBPα transcriptionally upregulates GATA-1 and NF-E2 for megakaryocyte maturation and platelet production. Depletion of adipose triglyceride lipase PNPLA2, megakaryocyte-specific knockout of key β-oxidation enzyme CPT1α, or pharmacological inhibition of CPT1α and p300 abolishes cold-augmented thrombocytopoiesis and alleviates DVT and RVO in mouse models. In healthy volunteers, tolerable cold exposure activates adipose thermogenesis, increases circulating FFA levels, and increases platelet counts. Moreover, a retrospective cohort study of 425 patients reveals elevated platelet counts and higher DVT incidence during cold seasons. Similarly, increased platelet counts are observed in 448 patients with RVO at the time of diagnosis in cold seasons. Our study provides novel mechanistic insights into the increased VO risk induced by cold exposure and proposes a new therapeutic paradigm for VO by targeting megakaryocyte metabolism.

To review the current published literature on the utility of visual electrophysiology testing in the diagnosis of glaucoma. Literature searches of the PubMed database were last conducted in August 2025 and restricted to articles published on or after January 1, 2011. The search identified 738 articles that were reviewed in abstract form for relevancy, and 170 were selected for full-text review. After inclusion and exclusion criteria were applied, 37 articles were selected for data abstraction by panel members. A total of 20 studies were selected for inclusion, and the panel methodologist (J.A.R.) assigned each a level of evidence rating. None of these 20 articles were rated level I, 1 article was rated level II, and 19 articles were rated level III. Visual electrophysiology tests, including electroretinography (ERG) and visual evoked potentials (VEP), are objective measures that provide an assessment of visual function. Pattern electroretinography (PERG) may assist the clinician's ability to diagnose early glaucoma before visual field deficits are detected, especially in patients with retinal nerve fiber layer (RNFL) loss as measured by OCT. The photopic negative response (PhNR) of the cone-driven full-field ERG is sensitive to glaucoma damage and has a less strict requirement for lack of media opacity and steady fixation compared with PERG. Visual evoked potentials and multifocal VEP (mfVEP) can discriminate between glaucoma and control eyes, but they are technically challenging to perform, which may limit their adoption for glaucoma diagnosis. Although significant advances have been made in developing these objective visual electrophysiology tests to discriminate between glaucoma and control eyes, they are not yet recommended in routine clinical evaluation. They may have a role in select scenarios to augment currently accepted structural and functional assessments. Utility is limited because of barriers to widespread clinical implementation, including the lack of consensus on stimulation and analysis protocols with standardized reference ranges. Proprietary or commercial disclosure may be found after the references.

To evaluate the efficacy and safety of clobetasol propionate ophthalmic suspension (CPN) 0.05% to treat ocular inflammation and pain after cataract surgery. Two multicenter, randomized, double-masked, placebo-controlled phase 3 trials, identical in design except for a corneal endothelial cell (EC) safety substudy in the second trial. Patients who underwent uncomplicated cataract surgery. After surgery, participants were randomized 1:1 to CPN 0.05% or placebo 1 drop twice daily for 14 days instilled into the operated eye. Efficacy outcomes were: (1) the percentage of participants with anterior chamber cell (ACC) count of 0 at postoperative day (POD) 8, maintained through POD 15; (2) the percentage of participants with ocular pain (OP) grade of 0 at POD 4, maintained through POD 15; and (3) inflammation, OP grade, and visual acuity at PODs 4, 8, 15, and 22. Safety outcomes were adverse event reports, ophthalmoscopy, intraocular pressure (IOP), and EC assessments. Seven hundred forty-eight participants were randomized to receive CPN 0.05% (n = 366) or placebo (n = 382). The demographic and baseline characteristics were well balanced between the 2 groups. CPN 0.05% met the primary end points, producing rapid and sustained clearance of inflammation and absence of OP that was statistically significantly greater than placebo. At POD 15, 58.2% of participants receiving CPN 0.05% and 17.3% of participants receiving placebo had an ACC count of 0 (P < 0.001), and 88.5% of participants receiving CPN 0.05% and 45.8% of participants receiving placebo had an OP grade of 0 (P < 0.001). By POD 4, visual acuity had improved more rapidly in the CPN 0.05% group than in the placebo group (P < 0.001). No rebound of the efficacy parameters was noted on POD 22 after CPN 0.05% was stopped for 1 week. More participants receiving placebo than receiving CPN 0.05% required rescue medications (P < 0.001). CPN 0.05% was well tolerated, with a safety profile similar to that of the placebo. No meaningful IOP increases or corneal EC changes occurred in the group receiving CPN 0.05%. CPN 0.05% twice daily for 14 days was safe and rapidly improved inflammation, OP, and visual acuity after cataract surgery. Disclosures are in the Footnotes and Disclosures.

To investigate the characteristics, surgery incidence, and outcomes of pigmentary glaucoma (PG) compared with primary open-angle glaucoma (POAG). Retrospective cohort study. Eyes with PG and POAG defined by diagnosis codes (2013-2025) in the IRIS® Registry (Intelligent Research in Sight). Cumulative incidence of procedures (trabeculectomy, tube shunt surgery, minimally invasive glaucoma surgery [MIGS], laser trabeculoplasty [LTP], and cyclophotocoagulation) was estimated using the Kaplan-Meier method. Cumulative failure probability was estimated for matched eyes. Cumulative incidence of procedures in each diagnosis group. We identified 49 171 eyes with PG and 2 546 775 eyes with POAG. Compared with the POAG group, the PG group had more non-Hispanic White patients (89.2% vs. 69.0%, P < 0.001). In the PG group, the percentage of severe stage was the highest in non-Hispanic Black patients (25.1%), followed by Asian (20.2%), Hispanic (19.7%), and non-Hispanic White patients (14.6%). The 4-year cumulative incidence of procedures, including LTP, was 22.2% (95% confidence interval [CI], 21.8-22.6) in PG and 19.5% (95% CI, 19.4-19.5) in POAG (log-rank test, P < 0.001), with the highest incidence observed in the severe stage. Filtering or cyclodestructive procedures accounted for 12.8% and 10.3% of procedures in PG and POAG, respectively (P < 0.001). The cumulative probability of failure after LTP and MIGS was statistically higher in PG than in POAG (60.7% vs. 58.2% and 66.7% vs. 60.8% at 1 year, respectively, both P < 0.001). Combined trabeculectomy-cataract surgery had higher 1-year failure rates than stand-alone trabeculectomy in both PG (56.4% vs. 33.5%) and POAG (49.1% vs. 34.9%, both P < 0.001). Eyes with PG underwent glaucoma-related procedures more frequently than those with POAG, including filtering and cyclodestructive procedures. Although the proportion of Asian or Black patients among those with PG is relatively small compared with White patients, they are more frequently categorized as having severe disease, underscoring the need for closer monitoring and tailored management in these populations. Surgical failure was more frequent after LTP and MIGS in PG than in POAG. Combined trabeculectomy and cataract surgery had higher failure probability than stand-alone trabeculectomy in both the PG and POAG groups. Proprietary or commercial disclosure may be found after the references.

Progressive visual field (VF) loss resulting from glaucoma affects quality of life (QoL). Although treatments aim to preserve vision, the extent to which slowing VF loss translates into QoL changes in advanced disease is not understood fully. We compare the 5-year rate of VF and QoL change and examined their correlation in the Treatment for Advanced Glaucoma Study. Multicenter randomized clinical trial (27 secondary care glaucoma departments in the UK). Adults (n = 453) with newly diagnosed advanced open-angle glaucoma in at least 1 eye were randomized to trabeculectomy (n = 227) or medical management (n = 226) as initial treatment. One eligible index eye was identified per participant. Mean difference in rate of change in monocular index eye VF (24-2 SITA Standard), binocular integrated (BI) VF, and the 25-item Visual Function Questionnaire (VFQ-25) composite score over 5 years (intention to treat) using a Bayesian longitudinal hierarchical model. Data from 442 patients with reliable VF (false-positive rate ≤15%) or VFQ-25 data from >2 time points were included (221 patients in the trabeculectomy-first arm). Baseline characteristics were similar between arms. The rate of index eye VF loss was faster in the medications-first arm (-0.75 [95% credible interval (CrI), -0.90 to -0.59] dB/year) compared with the trabeculectomy-first arm (-0.37 [95% CrI, -0.53 to -0.22] dB/year; P = 0.002). Differences between groups were not statistically significant for BI VF decline (P = 0.062) or VFQ-25 change (P = 0.392). Correlations between VF and QoL were stronger for BI VF for baseline (0.41 [95% CrI, 0.32-0.49]; P < 0.001) and rate of change (0.56 [95% CrI, 0.41-0.70]; P < 0.001) than for index eye VF (0.22 [95% CrI, 0.12-0.32]; P < 0.001 and 0.43 [95% CrI, 0.26-0.58]; P < 0.001, respectively). Trabeculectomy more effectively reduced the rate of VF loss compared with medical treatment in advanced glaucoma. Despite a moderately strong correlation with the BI VF, no difference was found in the measured QoL, suggesting that the VFQ-25 might not be reactive or sensitive enough to monocular glaucoma interventions. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

To investigate the incidence of perimetric glaucoma and the effectiveness of interventions in eyes with pseudoexfoliation syndrome (PXF) with and without ocular hypertension (OHTN). Retrospective cohort study. Eyes with documented PXF between 2016 and 2023 at a tertiary referral hospital. We applied 2 natural-language processing models to identify patients with pseudoexfoliation and confirmed PXF status through chart review. Glaucoma incidence was defined using consecutive Humphrey visual field (HVF) tests with positive results for glaucoma labelled by PyGlaucoMetrics (https://github.com/Mousamoradi/PyGlaucoMetrics), which use validated algorithms to estimate glaucoma probability from reproducible HVF data. We estimated the cumulative incidence of perimetric glaucoma using the Kaplan-Meier method and a multivariable Cox regression model to identify factors associated with glaucoma incidence. Outcomes of procedural interventions were evaluated. Glaucoma incidence rates. Among 485 eyes from 369 patients, the 4-year cumulative incidence of perimetric glaucoma was 26.5% (95% confidence interval [CI], 20.7%-32.0%) in eyes without OHTN and 37.5% (95% CI, 24.3%-48.4%) in those with OHTN (P = 0.005, log-rank test). Factors associated with incident glaucoma were older age (hazard ratio [HR], 1.39 per 5 years [95% CI, 1.19-1.62]), OHTN (HR, 2.18 [95% CI, 1.39-3.42]), higher cup-to-disc ratio (CDR; HR, 1.17 per 0.1-higher CDR [95% CI, 1.04-1.31]), and phakia (HR, 1.94 [95% CI, 1.13-3.34]). During follow-up, incident OHTN was observed in 14.6% of eyes with PXF without baseline OHTN. However, 87.3% of eyes that demonstrated glaucoma had no documented OHTN, based on measured intraocular pressure (IOP) at any office visit. Standalone lens extraction reduced the mean ± standard deviation (SD) IOP from 15.8 ± 2.5 mmHg with 0.40 ± 0.78 medications before surgery to 12.9 ± 2.7 mmHg with 0.28 ± 0.57 medications at 1 year postoperatively. More than one-fourth of eyes with documented PXF without OHTN and more than one-third of those with OHTN demonstrated perimetric glaucoma within 4 years. Older age, OHTN, higher CDR, and phakia were associated with incident glaucoma. Nearly 90% of eyes with normal baseline IOP that later demonstrated glaucoma had no documented OHTN at any office visit. Standalone lens extraction reduced IOP by 3 mmHg at 1 year postopertively. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Nanoparticulate drug delivery systems represent a promising platform for sustained intraocular drug release following intravitreal administration, leveraging low metabolic turnover of the vitreous to maintain therapeutic drug levels over extended periods. Despite this potential, nanoparticle diffusion toward the visual axis can induce light scattering and visual disturbance. Given the negative charge of the vitreous, surface-engineered nanoparticles provide a strategy to modulate particle mobility and restrict off-target migration. Here, we performed a 6-week in vivo evaluation in pigs of an intravitreally applied, positively charged, cyclic-arginine surface-functionalized liposomal nanocarrier designed to reduce intravitreal mobility. Three formulations containing 0.1%, 0.5%, or 1% cyclic-arginine-modified phospholipid were compared with unmodified control liposomes in a large animal pig model. A multimodal biocompatibility and performance assessment was conducted, including intraocular pressure monitoring, fundus imaging, structural and angiographic OCT, dye-based angiography, and post-mortem retinal immunostainings. Cyclic-arginine surface functionalization of the liposomes resulted in a concentration-dependent reduction in intravitreal mobility, quantified by vitreous haze and fundus-based distribution analyses. All surface-engineered nanoparticles demonstrated excellent ocular biocompatibility without structural or vascular adverse effects. These data establish cyclic-arginine surface modification as a robust design principle to modulate intravitreal mobility and support the development of next-generation nanoparticle biomaterials for long-acting ophthalmic drug delivery.

Fixation approaches for secondary intraocular lenses (IOLs) in the absence of capsular support are varied and technically challenging and can lead to high rates of complications. A scleral-fixated prosthetic capsular bag (PCB) was developed to provide secure, sutureless fixation of posterior chamber IOLs, and this study reports the first-in-human results of the PCB in eyes without capsular or zonular support. This was a multicenter, prospective, open-label, single-arm, exploratory, first-in-human investigation. Patients with insufficient capsular or zonular integrity, or both, to support an IOL were recruited from 3 retina practices in Sydney, Australia. Patients underwent pars plana vitrectomy with removal of dislocated crystalline lens or IOL as needed. The PCB was inserted using a standard IOL injector with or without a preloaded IOL. The PCB was secured transsclerally via 3 fixation arms without the use of sutures or scleral pockets. The primary end points included the incidence and characterization of adverse events related to the PCB through 12 months after surgery. Fifteen patients underwent PCB fixation with secondary IOL placement. One device-related serious adverse event occurred: a patient with Marfan's syndrome experienced reinternalization of a single footplate requiring secondary surgical intervention to refixate the footplate. No cases of conjunctival erosion over the footplates occurred, nor were there any cases of IOL dislocation from the PCB. Ninety-three percent of patients showed best-corrected visual acuity (BCVA) within 1 line of the screening BCVA. On average, uncorrected visual acuity (UCVA) improved 12 lines and 71% of patients showed UCVA within 2 lines of the screening BCVA. The PCB provided reliable refractive outcomes with a mean spherical equivalent of 0.12 diopters (D; standard deviation, 0.39 D). These first-in-human results suggest that this PCB is a viable platform for secure posterior scleral fixation of an IOL in eyes without capsular support. Additional studies are planned to confirm these findings. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Corneal alkali burns frequently lead to severe pathological manifestations (including oxidative stress and inflammatory response) and dysregulated matrix remodeling-associated stromal fibrosis. Current treatments mainly target inflammation but remain insufficient for preventing fibrotic scarring and enhancing corneal clarity. To address this limitation, a natural anti-fibrotic proteoglycan i.e., decorin (DCN) was conjugated to quaternary ammonium (QA)-modified nanoceria (Ce) as multifunctional metallic therapeutics (Ce-QA/DCN). The biofunctionalized nanomaterials exhibited favorable physicochemical stability and good ocular biocompatibility. Our results demonstrated that the conjugated DCN can preserve its ability to inhibit collagen fibrillogenesis and downregulate fibrosis-associated signaling pathways. In a rat model of alkali burns, topical administration of Ce-QA/DCN markedly improved corneal tissue transparency and promoted stromal architectural restoration as compared with conventional pharmacological treatment (dexamethasone). The combination of ceria-mediated redox regulation and DCN-mediated fibrotic inhibition enables simultaneous alleviation of pathological manifestations and enhancement of matrix remodeling during corneal wound healing. In summary, the biomaterial-based nanomedicine may provide a promising therapeutic strategy for managing severe corneal injuries and fibrosis-related ocular surface disorders. STATEMENT OF SIGNIFICANCE: Owing to their tunable surface properties and intrinsic biological activities, metallic nanomaterials have been considered promising platforms for ocular delivery and therapy; however, achieving effective corneal epithelial penetration while simultaneously regulating complex ocular pathological process remains a major challenge. This work presents the first report on rational design of ceria-based (quaternary ammonium/decorin-functionalized) nanotherapeutics for tailoring the structure-function relationships toward effective treatment of corneal alkali burn. Integrating cationic interface engineering with antagonist conjugation is demonstrated to critically govern permeability and biocompatibility of nanoparticles, indicating that the optimized formulations can enhance epithelial barrier penetration and inhibit stromal oxidation/inflammation/fibrosis. In vivo, such a biomaterial design achieves ∼92% reduction in corneal haze, highlighting its potential for treating eye injuries and promoting tissue remodeling.

The clinical translation of gene therapies using non-viral delivery vectors remains constrained by challenges to reconcile high cargo capacity, biological stability, and safe intracellular release, particularly for large genetic constructs and barrier-protected tissues such as the retina in the eye. Here, we report a peptide-based complex coacervate platform that leverages liquid-liquid phase separation to overcome these limitations through a minimalistic, yet programmable molecular design. By integrating sequence-encoded peptide interactions with the biologically derived amphiphilic modulator sodium deoxycholate, we engineer coacervates that are stabilized by a combination of electrostatic, aromatic, and hydrophobic interactions. These hybrid peptide coacervates form spontaneously under physiological conditions and are compatible with a broad range of cargos, including small dyes, peptides, and multi-kilobase plasmid DNAs. Critically, the coacervates display a balance between extracellular stability and intracellular responsiveness: they remain structurally robust across wide ionic, thermal, and pH conditions, as well as serum protein environments, yet undergo controlled disassembly in response to intracellular cues, enabling efficient cytosolic release of cargo without reliance on endosomal acidification or disruptive escape agents. In biologically stringent models, including human retinal pigment epithelial monolayers, the platform preserves epithelial barrier integrity, exhibits negligible hemolysis, and achieves effective transgene expression for plasmid DNA cargos up to 9.3 kb. Beyond ocular applications, these hybrid complex coacervates provide a generalizable framework for next-generation non-viral vectors capable of bridging the translational gap between small-RNA therapeutics and emerging large-gene modalities. STATEMENT OF SIGNIFICANCE: This work presents a designed peptide-based complex coacervate platform that advances liquid-liquid phase separation (LLPS) materials from conceptual soft matter to functionally validated intracellular delivery systems. In the current work, coacervates were engineered with tailored peptide sequences and amphiphilic modulators to enhance extracellular stability, cellular uptake, and controlled cytosolic release of gene cargo, including multi-kilobase plasmid DNA, in both permissive and challenging cellular models. The system demonstrates functionality under physiologically relevant ionic strengths, serum exposure, and epithelial barriers, and enables proof-of-function expression of target genes, establishing a clear application intent beyond fundamental materials behavior.

The mesenchymal stromal/stem cell (MSC) secretome is emerging as a cell-free pharmacological agent with multitarget activity in regenerative and inflammatory diseases. Rather than durable engraftment or differentiation, most therapeutic effects of MSC-based therapies are mediated by a complex mixture of soluble factors and extracellular vesicles (EVs) that can, in principle, be formulated as standardized biological drugs. This review appraises current evidence on MSC secretome composition, mechanisms of action, and pharmacological profile, emphasizing its potential as a scalable off-the-shelf platform. We first characterize the source-dependent architecture of the MSC secretome derived from bone marrow, adipose tissue, and umbilical cord, identifying a conserved core of 894 shared proteins alongside tissue-specific signatures that determine differential bioactivity. Pharmacologically active components are classified by mechanism, encompassing anti-inflammatory, pro-angiogenic, neuroprotective, antifibrotic, and regenerative mediators. We then critically examine preclinical evidence for secretome- and EV-based interventions across cardiovascular, neurological, ocular, inflammatory, musculoskeletal, and dermatological diseases, comparing mechanistic profiles, delivery routes, and potential advantages over current standard-of-care therapies. Finally, we address key translational challenges, including conditioning strategies to modulate secretome potency, biomaterial-assisted encapsulation and controlled-release technologies to improve stability and bioavailability, and the European regulatory framework, in which MSC secretome products are classified as biological medicinal products rather than Advanced Therapy Medicinal Products (ATMPs), with implications for Good Manufacturing Practice (GMP)-compliant production. We propose a research agenda centered on multiparametric potency assays linked to defined mechanisms of action, predictive pharmacokinetic/pharmacodynamic (PK/PD) biomarkers, rational combination with conventional therapies, and adaptive clinical trial designs aligned with regulatory expectations for complex biologics. Overall, MSC secretomes represent a promising class of cell-free pharmacological agents whose clinical implementation will depend on integrated drug-development strategies that combine pharmacology, biomaterials engineering, manufacturing science, and regulatory science.

Glioblastoma harbors frequent alterations in the retinoblastoma pathway, providing a genetic rationale for therapeutic targeting with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The NOA-20 trial did not reveal a progression-free survival benefit of CDK4/6 inhibition plus radiation therapy in newly diagnosed, O6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma. In fact, CDK4/6 inhibitor monotherapy has not demonstrated efficacy in solid tumors. We aimed at discovering response modulators to CDK4/6 inhibition, paving the way for rational combination therapies. We conducted genome-wide CRISPR-Cas9 screens in human glioma cell lines and stem-like cells (LN229, LN18, LNZ308, T98G, and GS-9) under CDK4/6 inhibition, employing knockout (Brunello library) and activation strategies (Calabrese library), followed by genetic and pharmacological validation of selected candidate genes in vitro and ex vivo (primary cultures) as well as the investigation of 1 functionally instructed combination therapy in vivo. Loss of AMBRA1 and gain of function of CCNE1 reduced sensitivity to CDK4/6 inhibition in glioma cells, whereas disruption of checkpoint kinase 1 (CHEK1) or FAM122A resulted in synthetic lethality in combination with CDK4/6 inhibition. AMBRA1-deficient glioma cells exhibited increased sensitivity to CHK1 inhibition, revealing a context-specific vulnerability. Combined inhibition of CHK1 and CDK4/6 led to synergistic antiglioma activity in vitro, ex vivo, and in vivo. Our data identify AMBRA1, CCNE1, CHEK1, and FAM122A as potential molecular modifiers of CDK4/6 inhibition response in experimental glioma and provide a biological rationale for combinatorial targeting with CDK4/6 inhibition in glioblastoma.

Fungal keratitis is a highly blinding ocular infection that demands innovative treatment strategies, moving beyond conventional antifungal therapies. In this study, we explore the potential of MoS2 nanodots engineered with sulfur vacancies, small sizes, hydrophilicity and surface positive charge as eye drops for effective fungal keratitis management. The tailored MoS2 nanodot-based hybrid nanomaterials (HNAF) exhibit remarkable antifungal efficacy through a synergistic interaction of their abundant sulfur vacancies and positive surface charges. The ultrasmall size and positive surface charge of HNAF allow the nanodots to pass through corneal epithelial barriers and electrostatically bind to the negatively charged cell membranes of Fusarium solani. The rich sulfur vacancies act as active catalytic centers that decompose local H2O2 into toxic hydroxyl radicals (•OH) and deplete intracellular GSH under dark physiological conditions, without requiring external stimuli in fungal cells. This cooperation between barrier penetration and targeted catalytic oxidation leads to significant antifungal activity in vitro and in vivo with excellent biosafety. This research underscores the potential of MoS2 nanodot-based hybrid nanomaterials as a step forward in managing fungal keratitis, offering an antibiotic-free, safe, and potent alternative to current therapeutic modalities.

Comparative evaluations of commercially available artificial intelligence (AI) systems for use in diabetic retinopathy (DR) screening, particularly studies that identify systems by name, are limited, constraining procurement and implementation. This study aimed to identify commercially available AI systems potentially suitable for DR screening in a low-resource Tanzanian setting and compare their accuracy in detecting referable DR. Through a scoping review and expert consultation, we identified AI systems potentially suitable for implementation. Systems confirmed as suitable, and whose developers agreed to participate, were evaluated. Performance was assessed on a data set of retinal images collected from a Tanzanian DR screening program. The primary outcomes were sensitivity and specificity in detecting referable DR. Additional implementation data, including regulatory approval, referral thresholds, and additional product features, were also collected. Four commercially available AI systems (Medios AI/Remidio, MONA, Ophtai, and SELENA+) were evaluated. Among 689 people included in the test data set, 379 (55.0%) had referable DR and 93 (13.5%) had proliferative DR. Sensitivity in detecting referable DR ranged from 83.9% to 93.7%, with lower specificity ranging from 70.3% to 79.0%. Sensitivity in detecting proliferative DR exceeded 98% in all four AI systems. All the evaluated AI systems were Conformité Européenne-marked medical devices; one system (Medios AI/Remidio) functions offline as standard. Several commercially available AI systems demonstrated high sensitivity in detecting referable and proliferative DR, supporting their potential implementation. Consensus on minimum performance thresholds and consideration of implementation factors such as regulatory approval and offline functionality are needed.

Machine vision serves as the essential sensorial interface for intelligent systems, yet conventional vision systems based on the von Neumann architecture suffer from significant latency and high power consumption due to the physical separation of sensing and processing units. To address these bottlenecks, neuromorphic vision systems inspired by the efficient, localized processing of the human retina have emerged. As a core paradigm of in-sensor computing, reconfigurable nonvolatile photodetectors (RNVPs) that integrate photodetection, nonvolatile memory, and processing into a single device represent a promising frontier for energy-efficient, real-time artificial intelligence. This review provides a comprehensive overview of RNVPs. It begins by introducing the human visual perception system and the paradigm of bioinspired in-sensor computing architectures. Subsequently, we overview the core concepts of RNVPs and establish the key performance metrics. Recent advances in RNVPs are then discussed in detail according to their working mechanisms, followed by a summary of their potential applications in image processing. To conclude, we highlight current challenges and offer perspectives on the future trajectory of RNVPs for next-generation in-sensor computing.

Perfluoroalkyl and polyfluoroalkyl substances are closely associated with visual impairment; however, the pathogenic mechanisms through which they cause optic nerve damage and their relationships with the onset of ocular diseases remain poorly defined. In this study, a mouse model of perfluorooctanoic acid (PFOA) exposure was established by oral administration of PFOA (1 mg/kg/day) for 60 consecutive days to investigate the effects of PFOA on retinal ganglion cells (RGCs), the primary constituents of the optic nerve, and retinal microglia, the immune sentinels of the optic nerve. Retinal ischemia‒reperfusion (IR) is a key common pathological process of multiple vision-threatening ocular diseases. Comparisons of changes in visual function, retinal structure and key cellular biological processes between PFOA-exposed mice and IR-injured mice revealed that PFOA contributed to visual impairment by inducing microglia-mediated neuroinflammation and RGC apoptosis. Experiments using an in vitro coculture system further demonstrated that PFOA directly impaired RGCs by affecting mitochondrial function and indirectly caused RGC damage by triggering microglial activation and subsequent inflammatory cascades. Moreover, we observed that PFOA exposure increased retinal susceptibility and exacerbated neuroinflammation and RGC injury under pathological conditions, thereby accelerating disease progression and vision loss. This study reveals the mechanisms underlying PFOA-induced optic nerve damage and its potential role in promoting retinal disease progression, suggesting that PFOA may represent an environmental risk factor for visual impairment.

The increasing amount of multi-walled carbon nanotubes (MWCNTs) released into the environment due to extensive production and application has raised great concerns for public health. However, there is scarce knowledge of their detrimental effects on eyes, one organ directly exposed to the environment. To mine the mechanisms underlying the toxic effects of MWCNT exposure on ocular cells from the aspects of metabolomics and transcriptomics. Two ocular cell lines (ARPE-19 and HCE-T) were exposed to 0 or 100 μg/mL MWCNTs for 24 h and then untargeted metabolomics (n = 6) or RNA-sequencing (n = 3) were performed. Totally, 290 differential metabolites (DMs) were identified for ARPE-19 and they were enriched in 68 KEGG pathways, while 74 DMs were obtained for HCE-T and they were annotated in 31 KEGG pathways. Venn diagrams showed 37 DMs and 20 KEGG pathways were overlapped between two cells, which comprised bile acids [e.g. chenodeoxycholic acid (CDCA)] and amino acids [e.g. leucine (Leu), glutamine (Gln)] metabolism. Totally, 3,539 and 2,005 differentially expressed genes (DEGs) were respectively screened for ARPE-19 and HCE-T, from which 70 DEGs were shared, including bile acids (CYP7B1, ABCG2)-, Gln metabolism (SLC1A5)- and inflammation (IL11, CXCL8)-related genes. Targeted metabolomics or ELISA assay confirmed CDCA, Leu and Gln were elevated in two ocular cells after MWCNT exposure, while qRT-PCR or ELISA verified MWCNT exposure up-regulated CYP7A1 and ABCG2 at protein levels, CYP7B1, BCAT1 (a hydrolytic enzyme for Leu) and SLC1A5 at mRNA and protein levels in both cells. CCK-8 assays only validated the addition of CDCA at MWCNT-induced dose reduced the cell viability and induced the expression of pro-apoptotic CASP3 as well as pro-inflammatory CXCL8 or IL11. CDCA and its related genes may represent potential targets for the diagnosis and treatment of ocular damages for populations exposed to MWCNTs.

Chronic overlapping pain conditions (COPCs) comprise a cluster of ten chronic pain disorders that frequently co-occur and are conceptualized as sharing centrally mediated or nociplastic mechanisms. Chronic ocular surface pain (COSP), defined as ocular surface pain lasting more than three months, has traditionally been classified under "dry eye disease." However, emerging evidence suggests that in a subset of individuals, COSP shares important clinical and mechanistic features with COPCs, supporting the need for an updated synthesis as increasing data implicate central contributions to pain. This narrative review examines COSP within the broader COPC framework across epidemiology, risk factors, pathophysiology, diagnosis, and treatment, and proposes that in select cases, COSP may warrant conceptual consideration as an additional COPC. Across the literature, COSP shares several similarities with COPCs, including high prevalence, female predominance, and increasing frequency with age. Chronic ocular surface pain also commonly clusters with COPCs and, when nociplastic features are present, is associated with psychosocial comorbidity. Mechanistically, COSP in some individuals demonstrates characteristics of nociplastic pain, including symptom-sign discordance, persistent pain despite topical anesthesia, multisite hyperalgesia, and altered functional connectivity within central pain and sensory processing networks. Collectively, current evidence supports substantial overlap between COSP and COPCs within a nociplastic framework, suggesting that COSP may be best understood, in part, within this broader construct. Recognizing COSP in the context of COPCs has important implications for mechanism-based approaches to diagnosis, treatment, and future research aimed at improving outcomes.

Dry eye disease (DED) is a multifactorial ocular surface disorder driven by tear film instability, excessive evaporation, frictional damage, oxidative stress, and epithelial injury. Current artificial tears mainly replenish aqueous volume and provide lubrication, but they may not adequately reproduce the coordinated interfacial functions of the native tear film that contribute to ocular surface stability. Here, we reported a tear film-inspired biomimetic strategy based on two complementary hyaluronic acid (HA) derivatives for the treatment of DED. HP was engineered by grafting zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) side chains onto HA to generate a highly hydrated, anti-evaporative, and low-friction interface, whereas HD was constructed by conjugating dopamine to HA to enhance ocular surface anchoring and provide intrinsic antioxidant activity. The integrated HP/HD system exhibited enhanced water retention, favorable shear-thinning behavior, and superior lubrication performance. Transverse relaxation (T2) NMR analysis further supported the key role of the zwitterionic hydration layer in interfacial lubrication. Quartz crystal microbalance with dissipation monitoring, fluorescence quenching, FTIR, in vitro and in vivo retention studies showed that HD strengthened mucin interaction and prolonged ocular surface residence. In addition, the catechol-containing component endowed the system with effective free-radical-scavenging capacity and intracellular reactive oxygen species suppression. In a benzalkonium chloride-induced guinea pig model of DED, topical administration of HP/HD significantly improved tear secretion, accelerated corneal epithelial repair, promoted goblet cell recovery, and reduced corneal oxidative stress compared with the commercial lubricant control. Collectively, this work establishes a tear film-inspired biomimetic strategy that integrates anti-evaporation, hydration lubrication, surface anchoring, and antioxidation within a system, offering a promising material approach for DED therapy. STATEMENT OF SIGNIFICANCE: Dry eye disease (DED) causes severe discomfort and surface damage. Current treatments for DED primarily rely on transient aqueous supplementation, which fails to reconstruct the hierarchical architecture of the native tear film and is limited by rapid precorneal clearance. To overcome this fundamental limitation, we proposed a tear film inspired biomimetic strategy. By integrating zwitterionic hydration lubrication (via PMPC-grafted hyaluronic acid) with catechol-mediated mucoadhesion and active antioxidant defense, our system synergistically reconstructs the physiological "mucin-aqueous-lipid" interface. Functionally, this system integrates anti-evaporation, moisturizing lubrication, surface anchoring, and antioxidant protection, effectively breaking the vicious cycle of DED self-reinforcement. This work provides a physiologically informed biomaterial strategy that shifts the paradigm of DED management from passive moisture supplementation to overall tear film reconstruction.

Bacterial keratitis is a major contributor to preventable blindness worldwide, with infections caused by Pseudomonas aeruginosa posing significant challenges due to the formation of biofilms and insufficient tissue regeneration following antimicrobial therapy. Conventional treatments predominantly target the infection while neglecting the promotion of healing processes, often resulting in corneal scarring and subsequent vision impairment. Therefore, therapeutic approaches for condition should extend beyond antibacterial measures to include strategies that facilitate early limbal stem cell participation in tissue regeneration. In this study, we present a dual-functional hydrogel system that integrates quaternized ultra-highly deacetylated chitosan (QUDCS) with oxidized dextran (OD) and stromal cell-derived factor-1 (SDF-1). This system effectively eradicates bacterial biofilms while simultaneously promoting the recruitment of endogenous stem cells for corneal regeneration. The hydrogel exhibits rapid gelation and mechanical properties similar to corneal tissue, along with significant antimicrobial activity mediated by electrostatic membrane disruption. The sustained release of SDF-1 establishes chemotactic gradients that attract limbal stem cells, thereby activating Wnt/β-catenin signaling pathways and enhancing cellular proliferation and regenerative potential. This integrated therapeutic platform represents a paradigm shift from traditional monotherapy to advanced biomaterial systems that simultaneously address infection and facilitate molecular-level tissue regeneration. It offers transformative potential for the treatment of infectious ocular diseases and other biofilm-associated infections that necessitate concurrent antimicrobial intervention and tissue repair.

Meibomian glands (MGs) are holocrine glands that secrete lipids to maintain the homeostasis of the ocular surface, and their dysfunction leads to dry eye disease. Herein, we established long-term 3D organoid culture for murine and human MGs, which retained the cell lineages and lipid-producing ability. The organoids mimicked the drug treatment responses and generated functional MGs after orthotopic transplantation. Inspired by organoid cultures, we found FGF10 eye drops could rescue all-trans retinoic acid-induced MG dysfunction in mice. Besides, nicotinamide uniquely hampered the human MG organoid expansion by inhibiting FGF10 signaling. Single-cell atlas and lipidome not only aligned the delineated cell types and featured lipids between human MGs and organoids, but also highlighted MAPK signaling inhibition enhanced acinar cell differentiation and functional maturation of MG organoids. In summary, this study established an organoid platform to explore epithelial homeostasis and dysfunction of MGs, facilitating drug development and regenerative medicine for dry eye disease.

Drug-device combinations (DDCs) have evolved from simple drug-coated implants into sophisticated intelligent platforms capable of real-time sensing, adaptive drug delivery, and closed-loop therapeutic control. This transformation is driven by converging advances in nanotechnology, biomaterials, controlled release mechanisms, wireless communication, artificial intelligence, and additive manufacturing. This review first systematically compares the divergent regulatory frameworks governing DDCs in the United States, European Union, and China. It then examines key enabling technologies and their integration into implantable, wearable, oral, and next-generation DDC platforms, emphasizing how functional convergence enables transition from passive delivery to feedback-controlled, patient-adaptive systems. Clinical applications are evaluated across therapeutic areas including ophthalmology, orthopedics, cardiovascular diseases, diabetes, oncology, and neurology, with attention to mechanistic distinctions and translational status. Finally, the review analyzes persistent technical, regulatory, and translational barriers. By connecting regulatory considerations, technological foundations, and clinical applications, this review offers a coherent roadmap for the next generation of intelligent DDCs.

Melanocytes reside in diverse microenvironments that influence their susceptibility to oncogenic transformation; however, investigation of rare melanoma subsets has been limited by the lack of suitable preclinical animal models. In this study, we developed a primary, immunocompetent zebrafish model to study uveal melanoma using choroidal melanocyte-targeted injection and electroporation of plasmids encoding human GNAQQ209L together with CRISPR/Cas9 cassettes for somatic tumor-suppressor gene deletion. Single-cell transcriptional profiling of primary melanocytes and melanoma derived from the eye and skin revealed distinct transcriptional programs, with epithelial-to-mesenchymal transition pathways enriched in ocular tumors. In addition, choroidal fibroblasts from tumor-bearing eyes exhibited marked transcriptional changes, including increased fibronectin and collagen expression, consistent with stromal remodeling. Given prior associations between mitfa loss and accelerated GNAQQ209L tumor onset, the model was applied to determine whether melanocyte differentiation state contributes to the emergence of GNAQ-driven tumors. The increased susceptibility resulted from expansion of Mitfa-independent melanocyte progenitor populations in germline mitfa-mutant zebrafish, rather than somatic mitfa loss in differentiated melanocytes, as conditional, melanocyte-specific mitfa deletion in adult zebrafish did not accelerate tumor growth. Furthermore, pax3a-positive melanocyte progenitor cells in mitfa-deficient zebrafish embryos and adult eyes and skin were highly susceptible to transformation induced by GNAQQ209L but not BRAFV600E. Analogous PAX3 positive populations were also identified in mouse and human single-cell transcriptomic datasets. Collectively, these findings establish a critical role for Mitfa-independent melanocyte progenitors in uveal melanoma pathogenesis. Choroid-targeted GNAQQ209L expression induces anatomically correct uveal melanoma in adult zebrafish, with germline mitfa deletion expanding mitfa-independent melanocyte progenitors with enhanced susceptibility that are transcriptionally distinct from the subpopulation transformed by BRAFV600E.

Recent studies have reported a possible association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and non-arteritic anterior ischemic optic neuropathy (NAION). The North American Neuro-Ophthalmology Society and the American Academy of Ophthalmology provide consensus expert opinion and clinical guidance about this association. Currently available evidence primarily includes retrospective observational studies, many of which rely on analysis of electronic health record and administrative claims data and are subject to limitations. Although many report a small possible increased risk of NAION in patients taking GLP-1 RAs such as semaglutide, some studies report no correlation, and the overall magnitude of the risk of NAION remains low. Shared decision-making between each patient and their care team is warranted to decide whether to start, continue, or discontinue GLP-1 RAs. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

High myopia (HM), characterized by significant ocular axial length elongation, affects hundreds of millions of people and is often inherited, particularly in cases that develop during childhood or adolescence. Although numerous myopia loci (MYP) have been identified, most causative genes remain undefined. Here, we analyzed two large HM pedigrees and refined the critical region through haplotype linkage analysis to a 3.9-Mb interval on 2q37.1, which was previously reported as MYP12 with an unknown pathogenic gene. Whole-genome sequencing identified the noncoding promoter variants c.-187G>T and c.-187G>C in PRSS56, encoding a trypsin-like serine protease, which exclusively co-segregated with all affected members in both pedigrees. Compared with matched controls, increased PRSS56 expression was observed in both patient-derived iPSCs carrying c.-187G>T and knock-in mice (c.-155G>T, corresponding to human c.-187G>T) that faithfully recapitulate myopia phenotypes. Noncoding PRSS56 variants promote self-expression via enhanced binding to the transcription factor EGR1, as confirmed by dual-luciferase assays. Notably, we demonstrated that higher PRSS56 levels directly increase ocular axial length in a dose- and activity-dependent manner in multiple transgenic mouse models. Guinea pig myopia models consistently exhibited high Prss56 expression, and short-wave light exposure reduced Prss56 mRNA levels and attenuated further axial elongation. Mechanistically, higher PRSS56 expression was associated with reduced abundance of myosin-4 in the sclera and with molecular signatures of scleral remodeling, which were in turn correlated with axial elongation. In conclusion, our findings provide strong genetic and functional evidence for the pathogenic role of noncoding PRSS56 variants in HM and highlight PRSS56 as a promising therapeutic target for juvenile HM.

The human visual system is inherently blind to infrared radiation due to the insufficient energy of infrared photons to trigger the photoisomerization of the retinal chromophore, resulting in the loss of over half of the solar spectrum. Here, we report a colloidal quantum dot (CQD)-based infrared-to-visible upconverter that enables ultrasensitive upconversion of multispectral infrared light radiation as full-color visible vision. The photon-energy-selective excitonic transitions in quantum-confined states and the photon flux, respectively, enable infrared wavelength- and intensity-dependent number of photogenerated carriers. A dual-emissive-layer organic architecture with the strategically engineered hole-injection barrier could route these carriers into distinct color emission channels, resulting in correlated wavelength/intensity-to-color/luminance mapping. This paradigm shift yields a discrimination sensitivity for subtle infrared variations exceeding more than two orders of magnitude higher than conventional single-color modes, capitalizing on the human eye's intrinsic superiority in chromatic differentiation over only brightness contrast. The resulting upconverter exhibits broadband detection extending beyond 2 μm, luminance exceeding 700 cd m-2, and a photon-to-photon conversion efficiency of 3.85%. The upconverter could be applied as a lightweight, semi-transparent wearable eyeglass that projects multispectral infrared as full-color vision directly onto the retina. Besides, upconverters bound to light-sensitive proteins, potentially as an implantable retinal photoreceptor, confer innate infrared vision. By surpassing the evolutionary constraints of natural vision, this work establishes a versatile foundation for next-generation visual prosthetics and human-integrated sensory expansion.