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Gestational age at birth plays a critical part in childhood neurodevelopment, especially for individuals born preterm (<37 weeks' gestation). To investigate the association between gestational age and educational outcomes at primary and high school age, controlling for unmeasured confounding by family-level factors. This population-based cohort study conducted in Australia included all individuals born at 23 to 42 weeks' gestation in New South Wales (NSW) between 2001 and 2011 and in Victoria between 2005 and 2012 who had school outcomes assessed by standardized assessments in grade 3 (age 8-9 years) and/or grade 9 (age 14-15 years). Analyses were conducted between June 2024 and February 2026. Gestational age at birth. Standardized numeracy and reading assessment z-scores were calculated in grade 3 and grade 9 and compared across gestational age groups using multivariable general linear mixed models. A clinically meaningful difference was considered an adjusted mean difference (AMD) in z-score of 0.2 or greater. The study included 1 095 816 children in grade 3 (772 589 NSW-born [50.7% male] and 323 227 Victoria-born [50.5% male]) and 292 027 NSW-born adolescents in grade 9 (50.7% male). Among children assessed at grade 3, 6.4% in NSW and 7.0% in Victoria were born before 37 weeks' gestation and 54.1% in NSW and 41.1% in Victoria were born at 39 to 40 weeks' gestation; 6.3% of NSW adolescents assessed at grade 9 were born before 37 weeks' gestation and 53.8% at 39 to 40 weeks' gestation. Compared with children born at 39 to 40 weeks, children born at 38 weeks had lower numeracy (AMD, -0.02; 95% CI, -0.03 to -0.02) and reading (AMD, -0.02; 95% CI, -0.02 to -0.01) z-scores in grade 3. z-Scores decreased in a stepwise manner for each gestational age group, with the greatest difference for those born at 23 to 27 weeks vs 39 to 40 weeks (numeracy: AMD, -0.54 [95% CI, -0.58 to -0.49]; reading: AMD, -0.29 [95% CI, -0.34 to -0.25]). However, among siblings at grade 3, these differences were attenuated, and clinically meaningful differences compared with birth at 39 to 40 weeks were only seen for numeracy in children born at 28 to 31 weeks (AMD, -0.23; 95% CI, -0.27 to -0.19) and 23 to 27 weeks (AMD, -0.45; 95% CI, -0.53 to -0.38) and for reading, only for children born at 23 to 27 weeks (AMD, -0.28; 95% CI, -0.36 to -0.21). Results were similar in grade 9, with clinically meaningful differences for numeracy (AMD, -0.53; 95% CI, -0.62 to -0.45) and reading (AMD, -0.39; 95% CI, -0.48 to -0.30) only seen for adolescents born at 23 to 27 vs 39 to 40 weeks' gestation in the full-cohort analysis. In this cohort study of over 1 million Australian children, the independent association of gestational age at birth with educational performance was most pronounced for children born at less than 28 weeks' gestation; for children born from 28 to 38 weeks' gestation, differences were not clinically meaningful and were likely primarily attributable to unmeasured confounding by shared familial factors. These findings support prioritizing prevention of the earliest preterm births and suggest that children born before 28 weeks' gestation may benefit from early identification of learning difficulties and targeted educational support.

Radon (222Rn, Rn) and thoron (220Rn, Tn) progeny are the primary contributors to natural radiation exposure. Accurate assessment of the radiological hazard from radon/thoron depends heavily on the characteristic parameters of these progeny, with particle size distribution identified as the most critical factor. However, systematic measurements of radon/thoron progeny size distributions remain very limited, mainly due to the insufficient attention given to thoron and the constraints of measurement sensitivity. Extensive field surveys were conducted in diverse environments in China with an 8-stage screen diffusion battery (SDB) system and a newly developed graded screen array (GSA) system. The results show that the activity median diameter (AMD) of attached radon progeny is 209 ± 16 nm (AMD¯±σAMD¯) indoors, 277 ± 26 nm in coal mines, 218 ± 20 nm in the investigated NORM (Naturally occurring radioactive material) environments and 189 ± 16 nm outdoors, with similar values observed for thoron progeny. Analysis of environmental factors indicated that ambient temperature, seasonal variation, and aerosol number concentration had minor effects on the AMD of attached progeny, while carrier aerosol size and sampling location exerted significant influences. The AMD of unattached progeny is 1.10 ± 0.15 nm for radon and 2.20 ± 0.20 nm for thoron. The results are expected to improve the accuracy of inhalation dose assessment and provide important input parameters for radiation protection models.

To investigate the effect of nonsteroidal anti-inflammatory drug (NSAID) use and the risk of age-related macular degeneration (AMD). Retrospective cohort study using a de-identified multicenter electronic medical records database. This study included patients who received prescriptions for NSAIDs and individuals who did not to assess for the effects of NSAID prescriptions on future AMD risk. Data from the TriNetX database between January 1, 2015, and December 31, 2024, were used to identify patients who were prescribed NSAIDs with no prior history of AMD. The NSAID patient cohort was propensity score-matched in a 1:1 ratio with a control group of randomly selected patients without a history of NSAID use, based on age, sex, race, and selected comorbidities of interest, including smoking and other common adult comorbidities that potentially could affect future AMD risk. Cumulative incidence and hazard ratio (HR) of AMD. Six hundred thirty-four thousand seven hundred ninety-four patients who were prescribed NSAIDs (mean ± standard deviation age, 59.93 ± 11.95 years) and 634 794 patients who were not prescribed NSAIDs (mean ± standard deviation age, 59.68 ± 12.15 years) were recruited. Among NSAID users, decreased risk of AMD development was seen at 6 months (HR, 0.31; 95% confidence interval [CI], 0.27-0.36), 1 year (HR, 0.36; 95% CI, 0.33-0.39), 3 years (HR, 0.42; 95% CI, 0.40-0.44), and 5 years (HR, 0.48; 95% CI, 0.47-0.50) after the index date compared with nonusers. A protective effect against AMD development was observed (HR, 0.58; 95% CI, 0.56-0.59) among NSAID users compared with nonusers. A protective effect against AMD development was observed among patients who were prescribed aspirin (HR, 0.72; 95% CI, 0.69-0.75) and those prescribed nonselective cyclooxygenase-2 inhibitors (HR, 0.41; 95% CI, 0.36-0.46) compared with their respective nonusers. A decreased risk of AMD was observed for both nonexudative (HR, 0.56; 95% CI, 0.55-0.58) and exudative (HR, 0.62; 95% CI, 0.59-0.65) AMD subtypes after index NSAID prescription compared with nonusers. A protective effect against future AMD development was suggested among patients prescribed NSAIDs compared with nonusers. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Retinal diseases driven by pathological angiogenesis and vascular leakage, including neovascular age-related macular degeneration and diabetic retinopathy, impose substantial visual and treatment burdens because current anti-vascular endothelial growth factor (anti-VEGF) therapy requires repeated intravitreal administration. Ocular gene therapy can provide durable intraocular expression of therapeutic proteins and sustained pathway-level disease control. This systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, Scopus, Web of Science, ScienceDirect, and the Cochrane Library were searched from inception to April 21, 2026. Eligible studies included preclinical, in vitro, and clinical investigations of gene-based interventions targeting retinal angiogenesis, vascular permeability, or related anatomical and treatment-burden outcomes. Random-effects meta-analyses were performed using standardized mean differences (SMDs), mean differences (MDs), and logit event rates. Twenty-five studies were included. Preclinical gene therapy significantly reduced pathological neovascularization, with a pooled standardized mean difference (SMD) of -1.16 (95% confidence interval [CI], -1.48 to -0.84; p < 0.001) and negligible heterogeneity (I² = 0%). Vascular leakage was also significantly reduced across preclinical experimental studies, with a pooled mean difference (MD) of 0.215 (95% CI, 0.178-0.251; p < 0.001; I2 = 0%) after directional harmonization. In clinical cohorts, ocular gene therapy significantly reduced central subfield thickness (CST) by -55.30 μm (95% CI, -72.58 to -38.03; p < 0.001) and was associated with reduced anti-vascular endothelial growth factor (anti-VEGF) treatment burden, with a pooled logit event rate of 0.62 (95% CI, 0.20-1.04; p = 0.0039), corresponding to a pooled proportion of approximately 65% of participants meeting study-specific criteria for reduced supplemental anti-VEGF use. Ocular gene therapy shows strong preclinical anti-angiogenic and anti-permeability effects, with emerging clinical evidence of anatomical improvement and reduced anti-VEGF treatment burden in neovascular retinal disease cohorts. Larger disease-specific randomized trials are required to confirm long-term efficacy, safety, and patient selection.

Diabetic vascular complications are a major determinant of poor prognosis in diabetic patients, with their development closely linked to persistent low-grade inflammation. Macrophages, as key regulatory cells in the immune system, undergo significant metabolic reprogramming in the diabetic hyperglycemic microenvironment. This reprogramming involves a coordinated remodeling of key metabolic pathways, including carbohydrate metabolism, lipid metabolism, and amino acid metabolism. This review systematically discusses the classical theories of macrophage polarization and provides an in-depth analysis of how key molecules drive the M1/M2 imbalance. Additionally, it explores the intricate regulatory interactions between the three major metabolic pathways. The metabolic reprogramming-polarization axis is further examined in the context of four typical diabetic vascular complications-diabetic atherosclerosis, diabetic kidney disease, diabetic retinopathy, and diabetic cardiomyopathy-highlighting their specific pathological roles. This work aims to elucidate the theoretical value of this regulatory axis as a central mechanism in diabetic vascular complications and explores its clinical translational potential as a precise therapeutic target. It provides a systematic theoretical foundation and proposes new directions for future research.

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.

The type and quantity of lesions are critical determinants in the assessment of diabetic retinopathy (DR) grading. Since multi-view fundus images provide a broader field of view and capture more lesions, multi-view DR grading has garnered increasing attention in recent years. However, existing multi-view methods either only focus on fundus feature extraction, or only take the lesion map as a part of the input, failing to fully leverage the comprehensive lesion information. Moreover, the significant variation in lesion size and their scattered distribution present substantial challenges for effective information learning. To address these issues, this paper proposes a CNN-injected transformer network with Lesion Reconstruction for Multi-View DR grading (LRMVDR), which utilizes lesion maps twice to fully exploit lesion information. Specifically, to tackle the large-scale variations and widespread distribution of lesions, the lesion maps are concatenated with the fundus images and then input into the local and global branches for extracting hierarchical global-local features. Adapters are designed to inject CNN features into the Transformer between the two branches, significantly enhancing the integration of multi-scale global and local features. Additionally, a dedicated lesion reconstruction branch is employed to explicitly extract lesion features. These features are subsequently fused with those from the local branch via a wavelet enhancement module, enabling Interactive fusion of frequency domain information and spatial domain information. Extensive experiments on large public datasets demonstrate the effectiveness and competitiveness of the proposed method. Our code is available at https://github.com/HuYongting/LRMVDR.

Photoreceptor (PR) loss causes vision loss in many blinding diseases and effective therapies to prevent this cell loss are lacking. Aspartate aminotransferases (GOTs), located in the cytosol (GOT1) and mitochondria (GOT2), are key components of the malate-aspartate shuttle, which transfers reducing equivalents from cytosol to mitochondria. Previous work has implicated the GOTs as potential modulators of blinding retinal disease. To determine the roles of GOT1 and GOT2 in rod PRs, we generated rod PR-specific Got1 or Got2 conditional knockout mice (Got1 or Got2 cKO). We previously showed that Got1 cKO causes PR degeneration and is accompanied by NADH accumulation and a decreased retinal NAD+/NADH ratio. Here, we show that NADH oxidation via metabolic or genetic means prolongs PR survival in Got1 cKO animals, implicating NADH accumulation, or reductive stress, as a key driver of PR degeneration. In contrast, Got2 cKO causes minimal PR degeneration and alterations in retinal NADH and the NAD+/NADH ratio that oppose reductive stress. Interestingly, GOT2, but not GOT1, is decreased in multiple models of PR degeneration, including retinal detachment (RD) where the NAD+/NADH ratio favors a reductive state. Notably, loss of Got2 in PRs demonstrates a neuroprotective effect after experimental RD suggesting decreased GOT2 expression may be part of a stress response to promote PR survival. Overall, this study illustrates the differential dependence on the GOTs for PR health, provides evidence that an overly reductive environment is detrimental to PR survival, and identifies GOT2 as a novel therapeutic target with potentially broad application in blinding diseases.

Age-related macular degeneration (AMD) involves sub-retinal pigment epithelium (sub-RPE) lipid deposition in the early stage, with dysregulated lipid metabolism and impaired macroautophagy/autophagy implicated, yet the molecular mechanisms underlying their interaction remain unclear. In this study, transcriptomic analysis of human macular tissues identified FASN (fatty acid synthase), a regulator of lipid metabolism and lysosomal function, as a significantly upregulated key hub gene in early AMD. In apoe-/- mice fed a high-fat diet (HFD), retina-RPE-choroid complexes revealed elevated FASN alongside autophagy suppression, lysosomal dysfunction, and lipid accumulation. In vitro, FASN protein levels increased in RPE cells treated with the autophagy inhibitor 3-methyladenine (3-MA), but decreased with the autophagy activator rapamycin (RAPA), without transcriptional changes; lysosomal blockade with chloroquine (CQ) induced FASN accumulation, which was significantly delayed following autophagy inhibition. These findings indicate that FASN accumulation results from insufficient autophagic degradation. Conversely, FASN knockdown or pharmacological inhibition enhanced autophagic flux and promoted lysosomal lipid clearance in RPE cells. Mechanistically, FASN inhibition increased AMPK phosphorylation and decreased MTOR activity, thereby facilitating autophagy and lipophagy. Collectively, our findings reveal a self-amplifying pathological circuit in early AMD: autophagy impairment drives FASN accumulation, which in turn exacerbates lysosomal dysfunction and lipid accumulation. Targeting the FASN-AMPK-MTOR axis may offer a promising therapeutic strategy for early AMD.

Surface acoustic waves (SAWs) are an optimal method for manipulating small biomolecules because of their non-contact, tunable, and buffer-compatible characteristics. Numerous prior studies have demonstrated various manipulative strategies for inorganic particles by SAWs, yet little has focused on biosensing so far. To address this gap in the scientific community, we employed a powerful SAW tool, known as omnidirectional spiral SAWs (OSSAWs), as the principal driving mechanism to realize enhanced particle manipulation. The manipulation was performed in a 3D-printed well with a thin elastomeric film on the reverse side of an OSSAW substrate to reduce cross-contamination, surface wear, and electrode fouling. Instead of solid microparticles, porous hydrogel microparticles (PHMs) composed of gelatin methacryloyl were used as probes to detect target biomolecules associated with diseases. In the presence of biomarker proteins, sandwich immunocomplexes (capture antibody-antigen-probe antibody) conjugated with fluorescent polystyrene particles were immobilized within the PHMs. Subsequently, the immunocomplexed PHMs were concentrated in the center of the well by OSSAWs, enhancing immunofluorescence. Experimental results showed that the immunofluorescence of 5 μL of suspension was enhanced within 3 min, surpassing the conventional 2 h immunoassay in a tube. The specificity for lipocalin 1 (LCN1) surpassed that of other unrelated proteins, whereas a limit of detection of 31.1 pg/μL was achieved. Practical use was verified through preliminary clinical tests using human tear samples from diabetic retinopathy (DR) patients and healthy individuals. Results successfully showed elevated LCN1 concentrations in DR samples compared to healthy controls, confirming LCN1 as a biomarker for DR. This study marks the first attempt of an OSSAW-based biosensor integrated with PHMs and a disposable well for rapid disease diagnosis. Therefore, the successful demonstration provides insight into future point-of-care testing.

Bile acids, as cholesterol metabolites, orchestrate a regulatory network with mitochondrial quality control through nuclear receptor FXR, membrane receptor TGR5, and other signaling molecules, modulating mitochondrial biogenesis, dynamic equilibrium, selective autophagy, and redox homeostasis. TGR5 promotes PGC-1α-mediated mitochondrial biogenesis via the cAMP-PKA-CREB pathway, while concurrently regulating mitochondrial fission and calcium homeostasis through the PKCδ/Drp1 and GRP75-MAMs pathways. FXR, acting through transcriptional reprogramming and epigenetic mechanisms, governs fatty acid oxidation, antioxidant defense, and apoptotic pathways, and has been shown to restore PINK1/Parkin-dependent autophagy and suppress NLRP3 inflammasome activation in alcoholic liver disease. Noncanonical receptors, including S1PR2, VDR, and PXR, also participate in the regulation of mitochondrial dynamics and autophagy. Dysregulation of this network is closely associated with metabolic dysfunction-associated fatty liver disease, diabetic retinopathy, pancreatic β-cells injury, alcoholic liver disease, and sepsis-induced immunoparalysis. Agonists targeting the aforementioned receptors, such as INT-777, INT-767, and Fexaramine, have demonstrated the capacity to restore mitochondrial function and alleviate tissue damage in animal models. Future investigations should employ multi-omics and structural biology approaches to elucidate receptor crosstalk and concentration-dependent bidirectional effects, and to develop tissue-selective modulators, thereby facilitating clinical translation.

(1) To determine whether intraocular pressure (IOP) fluctuations while playing musical instruments is specific to the instrument type; (2) to investigate the role of the Valsalva maneuver as an underlying mechanism; and (3) to evaluate relationships between IOP values and demographic and environmental factors. Cross-sectional study. Sixty-five musicians were enrolled. Of these, 2 were excluded due to glaucoma history and intolerance to IOP measurements. The final sample consisted of 63 young professional musicians (34 wind instrumentalists and 29 nonwind instrumentalists). Participants underwent tonometry (iCare IC100) and otoscopy (Dino-Lite Basic EarScope) and completed a self-administered questionnaire on demographic and environmental factors. Tonometry and otoscopy procedures were performed simultaneously at 4 time points: before playing, while playing a low-pitched note and a high-pitched note, and after playing. Intraocular pressure and tympanic membrane movement. No differences in IOP were observed between wind and nonwind instrumentalists at baseline, during low-pitch playing, or after playing (Mann-Whitney U test, all P ≥ 0.052). However, IOP differed while high-pitch playing (Mann-Whitney U test, P = 0.007), with both high- and low-resistance wind instrumentalists showing higher IOP than nonwind instrumentalists (Mann-Whitney U test, both P ≤ 0.041). Intraocular pressure change relative to baseline (ΔIOP) similarly revealed differences during high-pitch playing and additionally detected differences during low-pitch playing (Mann-Whitney U test, both P ≤ 0.025). Within the wind category, no differences in IOP were found between high- and low-resistance (Mann-Whitney U test, all P ≥ 0.323), and the same pattern was observed for ΔIOP (Mann-Whitney U test, all P ≥ 0.112). The Valsalva maneuver was not detected for any instrument or under any measurement conditions. In addition, no relationships were found with demographic or environmental factors and IOP fluctuations (Pearson's or Spearman's correlation, all P ≥ 0.273), although baseline IOP positively correlated with age at which wind instrumentalists began playing their instrument (Pearson's correlation, r = 0.348, P = 0.048). Intraocular pressure fluctuations during musical instrument performance occur specifically in wind instrumentalists (both low- and high-resistance), and are not due to involuntary Valsalva maneuvers during playing. Moreover, basal IOP correlated with age of instrument debut in wind instrumentalists, whereas no other demographic or environmental factors related to IOP measurements or its fluctuations. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

To evaluate the incidence of endophthalmitis after ophthalmic surgery using a national ophthalmic registry. Retrospective clinical cohort study. Patients in the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) who underwent ophthalmic surgeries were included in this analysis. Incidence of endophthalmitis during the first 30 days after surgery. Pediatric and adult patients in the IRIS® Registry with a diagnosis of acute endophthalmitis within 30 days after surgery from 2016 through 2024. The study analyzed 17 457 881 procedures. Rates of endophthalmitis varied by procedure. Among adults, the highest incidence occurred after open-globe repair (0.94%; 1 case per 106 procedures). The incidence of endophthalmitis was 0.097% (1 case per 1031 procedures) after vitrectomy for retinal detachment, 0.1% for trabeculectomy (1 case per 1000 procedures), 0.075% for tube shunts (1 case per 1333 procedures), and 0.068% for scleral buckle surgery (1 case per 1459 procedures). The incidence after cataract surgery was 0.038% (1 case per 2652 procedures), 0.039% (1 case per 2551 procedures) after standalone minimally invasive glaucoma surgery, 0.02% (1 case per 5013 procedures) after goniotomy, and 0.011% for strabismus surgery (1 case per 9091 procedures). Among pediatric patients, the incidence of endophthalmitis after open-globe repair was 0.87% (1 case per 115 procedures). The incidence of endophthalmitis was 0.415% (1 case per 675 procedures) after scleral buckle surgery, 0.11% (1 case per 871 procedures) after cataract surgery, 0.084% (1 case per 1190 procedures) after vitrectomy for retinal detachment, and 0.0072% (1 case per 13 884 procedures) after strabismus surgery. The risk of endophthalmitis was significantly higher for pediatric vs. adult patients after cataract surgery (P = 0.014). Endophthalmitis rates after same-date cataract and glaucoma surgery vs. glaucoma surgery alone did not differ significantly. Rates of endophthalmitis after ophthalmic surgical procedures are variable, with the highest incidence being open-globe repair. Minimally invasive glaucoma surgery procedures showed comparable infection rates as standard cataract surgery. A higher rate of infection after cataract surgery occurred in pediatric patients when compared with adults. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinoblastoma (RB) represents the most common primary intraocular malignancy in childhood and stands as a paradigm for translating molecular oncology into precision clinical management. This review synthesizes the comprehensive evolution in the understanding and treatment of RB. First, we deconstruct the intricate oncogenic circuitry that extends far beyond Knudson's classic "two-hit" RB1 inactivation model, describing non-classical MYCN-driven pathogenesis, multi-layered epigenetic reprogramming (including chromatin, RNA and histone changes), and distinct histological subtypes with defined clinical correlates, such as the favorable-prognosis cavitary RB. Single-cell genomics has elucidated the cellular origin from cone precursor cells and intratumoral heterogeneity. Risk stratification has been refined through well-defined classification systems, from the therapy-guiding International Intraocular Retinoblastoma Classification (IIRC) to the comprehensive American Joint Committee on Cancer Tumor-Node-metastasis (AJCC TNM) staging.Furthermore, the diagnostic paradigm has advanced from conventional anatomical imaging to liquid biopsies, enabling non-invasive molecular staging and monitoring via tumor-derived cell-free DNA analysis. Concurrently, the therapeutic landscape has undergone a radical shift, moving from enucleation and external-beam radiotherapy to an era dominated by local sight-preserving strategies. We provide a critical synthesis of the evidence for intravenous chemotherapy and the transformative role of super-selective intra-arterial chemotherapy (IAC), and describe essential randomized controlled trials, technical innovations, and optimized drug regimens. Finally, we explore emerging targeted molecular therapies and future directions. By integrating cutting-edge molecular insights with robust, high-level clinical evidence, this review offers the framework for achieving patient and eye survival as well as vision preservation in children with Retinoblastoma.

Smartphone-based fundus imaging (SBFI) is an emerging approach with potential relevance for global ophthalmic care, including in low- and middle-income countries and other resource-constrained settings. This scoping review, based on a structured literature search, synthesises current SBFI technology, clinical and teaching applications, implementation challenges and future directions. Analysing 30 hardware solutions (based on three principal technical designs) and 274 scientific publications and other relevant sources, we found that some SBFI devices can provide fields of view and image quality sufficient to support screening or triage for referable diabetic retinopathy, glaucoma-related optic nerve head changes, and selected retinopathy of prematurity applications. Reported sensitivity, specificity and gradability varied by disease, device, protocol, operator, and reference standard; no universal performance threshold could be inferred. After brief training, allied healthcare workers can acquire usable images in selected settings, suggesting that SBFI may support task-shifted screening and referral pathways. Artificial intelligence may further support scalability by assisting image-quality and protocol compliance assessment, frame selection, montage generation and disease classification. However, costs, maintenance requirements, data governance and domain shift remain important implementation considerations. Key challenges include variable image quality and fields of view, heterogeneous reporting, smartphone compatibility, regulatory compliance, photobiological safety verification, data security, and patient privacy. We therefore suggest minimum reporting standards to increase comparability across studies. Large-scale implementation and cost-effectiveness studies are needed to determine whether improved access to ophthalmic imaging can translate into sustainable and equitable eye-care services.

Neurons actively shape immune responses that maintain central nervous system integrity. We identify SPP1 (secreted phosphoprotein 1) as a neuron-derived signal that reprograms microglia into a neuroprotective, homeostatic state after injury and during neurodegeneration. In mouse models of glaucoma and optic nerve damage, neuronal SPP1 enhances microglial autophagy, debris clearance, and anti-inflammatory activity, preserving neuronal survival and visual function. SPP1 is elevated in neurons of human and primate glaucomatous retinas, where SPP1+ cells show increased resilience. In Alzheimer's disease brain, neuronal SPP1 correlates with neuronal survival, while microglia around Aβ plaques display defective autophagy. In human iPSC co-cultures, SPP1 enhances microglial Aβ clearance and prevents neurodegeneration. Thus, SPP1 defines a protective neuron-microglia axis in glaucoma and possibly other neurodegenerative diseases.

Patient-centric Biologics-Device Combination Products (BDCP) improve patient experience and compliance, while enhancing therapeutic outcomes by enabling novel routes of delivery, tackling frequent dosing and large-volume delivery requirements, and/or by simplifying administration in a healthcare setting as well as in out-patient dosing (e.g. self-administration). They also present promising solutions to overcome vaccine immunization challenges, particularly in developing nations. The BDCP opportunities, however, are often tempered by intrinsic properties of biologics (e.g. stability, viscosity etc.) and devices (e.g. design control, human factor engineering etc.) which can be further compounded by regulatory complexity across multiple jurisdictions. This comprehensive review examines the current landscape of combination product spanning across the complexities of modality (e.g. proteins, vaccines, oligonucleotide, mRNA/lipid nanoparticle (LNP) and to a limited extent cell & gene therapy) and delivery (parenteral, oral, ocular etc.) through the lens of business drivers, phase-appropriate technical development, regulatory frameworks, and patient-centric design principles. Selected case studies and commercially approved products for each modality are also presented here. Continued investments in new and improved devices such as prefilled syringes, wearable pumps, pen devices, jet devices and autoinjectors for liquid and lyophilized products highlight the recent paradigm shift for integration of delivery devices from self-administration to personalized medicine. Persistent innovation in the field, for example, has enabled device integration beyond chronic conditions such as diabetes and autoimmune diseases and prophylactic vaccination such as flu to cancer immunotherapy. Furthermore, technical, clinical and regulatory successes in achieving novel routes of delivery (e.g. oral biologics, inhaled insulin, inhaled vaccines, intradermal vaccination etc.), smart delivery systems and digital technologies have further advanced the boundaries of BDCP to not only increase market penetration but create new markets. This not only benefits patients worldwide but also paves the way for precision medicine in the future.

Ocular toxoplasmosis is a common infectious eye disease caused by the ubiquitous parasite, Toxoplasma gondii, and the leading cause of posterior uveitis in most populations worldwide. For the growing number of individuals living with some form of immunocompromise, T. gondii often represents an aggressive ocular pathogen. To demonstrate how an impaired immune system may impact the course and outcomes of ocular toxoplasmosis, the clinical descriptions of 276 immunocompromised patients, published across 109 reports in the medical literature, were compiled, and relevant epidemiological and immunological studies were summarised. The diverse phenotypes of ocular toxoplasmosis associated with congenital or acquired immunodeficiency or immunosuppression are described; diagnostic methods and their interpretation are outlined; and management approaches that may limit infectious ocular and systemic complications are highlighted. The visual outcome of ocular toxoplasmosis is often poor in immunocompromised individuals. Atypical presentations occur frequently in this patient group, and in over one-half of those whose clinical information has been reported, the diagnosis was initially missed. By synthesising the published literature, this review offers a perspective that may support improved outcomes of ocular toxoplasmosis in people living with systemic immunocompromise.

The key characteristics of the cornea, its transparency and avascularity, emerge from spatial organization of cell populations, extracellular matrix layers, biomechanical properties, and morphogenic cues. This review translates these organizing principles into contextual considerations for advancements in corneal regeneration therapies. We begin by outlining the development of the cornea, followed by how layer-specific microenvironments underpin homeostasis, and provide an outlook on current and future therapies. While full-thickness corneal transplantation remains the gold standard for global corneal blindness, definitive care is transitioning toward layer-specific procedures. These surgeries improve safety and recovery, yet remain limited by critical vulnerabilities such as donor supply scarcity and tissue rejection. Regenerative strategies are explored through full-thickness and layer-specific therapies with an ultimate goal to recapitulate native tissue by rebuilding the way it is patterned in vivo. Across the layers, successful corneal regeneration depends on reproducing where signals are presented, in what mechanical context, and with what architectural alignment. Cell-based therapies, from limbal epithelial stem cell transplantation to intrastromal keratocyte injection, require precise spatial control over the cellular microenvironment to ensure stemness, survival, and proper tissue integration. Scaffold-based therapies, by encapsulating these spatial rules into advanced fabrication platforms (such as additive manufacturing), biomaterials, and delivery schemes offers a path to long-term clarity, avascularity, and physiologic function, and exemplifies how spatial patterning drives the next generation of truly biomimetic corneal repair. Despite these advancements, achieving widespread clinical translation will require addressing key challenges, including standardizing safe cell therapies and overcoming technical limitations in the high-resolution, moderate-scale scaffold manufacturing.

Atopic dermatitis (AD) is a heterogeneous inflammatory skin disorder characterized by recurrent eczematous lesions and persistent pruritus. Its pathogenesis involves epidermal barrier dysfunction, immune dysregulation, microbial dysbiosis, and altered neuroimmune signaling. Genetic defects in structural proteins, particularly filaggrin, and altered epidermal lipids increase allergen and microbial penetration, perpetuating itch, scratching, tissue injury, and inflammation. Molecular evidence further reveals AD endotypes beyond conventional clinical phenotypes, with heterogeneity in immune polarization, barrier dysfunction, microbial colonization, and pruritic pathways. This heterogeneity may underlie differences in clinical presentation and treatment response. Conventional treatments, including skin hydration, antihistamines, and topical anti-inflammatory agents, often provide incomplete or transient control. Mechanism-based therapies targeting IL-4/IL-13, OX40/OX40L, JAK, and PDE4, together with AhR agonists, have broadened treatment options. However, efficacy must be balanced against treatment-specific risks. Biologics require monitoring for ocular and injection-site reactions, whereas systemic JAK inhibitors require monitoring for infections and laboratory abnormalities and carry regulatory class warnings regarding major adverse cardiovascular events, venous thromboembolism, and malignancy; however, these warnings are largely extrapolated from studies in older patients with rheumatoid arthritis, and the magnitude of these risks in patients with AD remains uncertain. Long-term safety and real-world evidence remain limited for several emerging therapies. This review synthesizes current knowledge of barrier dysfunction, immune heterogeneity, molecular endotypes, microbiome imbalance, neuroimmune signaling, and mechanism-based therapies. Integrating clinical phenotypes with molecular endotypes, predictive biomarkers, efficacy, and individualized safety assessment may enable more precise treatment selection and durable disease control.

To review the evidence on neurodevelopmental outcomes after intravitreal anti-VEGF compared with laser photocoagulation surgery (LPC) for primary treatment of retinopathy of prematurity (ROP). A literature search was last conducted in the PubMed database in December 2025 without date restrictions and limited to articles published in English. The search yielded 52 articles, 26 of which met criteria for inclusion. The panel methodologist assigned ratings to the articles according to the level of evidence. Of the 26 articles included, 4 articles on 3 randomized controlled trials (RCTs) were rated level II evidence and 22 comparative cohort studies were rated level III evidence. The studies included infants who were treated and followed over a 17-year period from 2006 through 2022 in 39 countries. The most common neurodevelopmental test used was the Bayley Scales of Infant and Toddler Development, used in 13 studies (50%). The age at assessment ranged from 0 months corrected age to 12 years, where most studies (n = 14 [54%]) included testing of infants younger than 24 months of age. Most studies (n = 20 [77%]), including all RCTs, did not detect a statistically significant difference in neurodevelopmental outcomes after anti-VEGF compared with LPC for primary treatment of ROP. Neurodevelopmental outcomes were found to be worse among those infants treated with intravitreal bevacizumab (IVB) for primary treatment in 4 studies and among those treated with LPC for primary treatment in 2 studies. Only 5 studies (19%) included intelligence quotient (IQ) testing beyond 4 years of age, and none detected a statistically significant difference in IQ between those who received anti-VEGF (IVB in 4 studies and intravitreal ranibizumab in 1 study) compared with those who received LPC for primary treatment of ROP. Although no level I evidence was available, systematically reviewed studies with level II and III evidence showed no evidence that neurodevelopmental outcomes differed among infants who received anti-VEGF compared with LPC for primary treatment of ROP. A limitation to this assessment was that no study was powered for neurodevelopmental outcomes or to detect small differences in neurodevelopmental outcomes. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Accurate assessment of uncorrected visual acuity (UCVA) is fundamental to pediatric vision screening. Although the HOTV letter-matching test is recommended for pediatric vision screening, the tumbling E test remains widely used globally despite its higher cognitive demands for young children. Evidence directly comparing UCVA outcomes between the 2 tests across pediatric age groups is limited. To compare UCVA outcomes from HOTV and tumbling E vision tests and evaluate their suitability for pediatric vision screening. In this cross-sectional observational study, each participant underwent UCVA testing with both HOTV and tumbling E logMAR charts in a randomized sequence, with a 30-minute rest period between tests to minimize fatigue. The study was conducted in Shanghai as part of a national multicenter cohort study in China. Participants included 995 children aged 3 to 15 years who completed both vision tests, cycloplegic refraction, and comprehensive ophthalmic examinations. These data were analyzed from January 2025 to June 2026. UCVA assessments using HOTV and tumbling E logMAR tests. The primary outcome was mean UCVA (logMAR). Secondary outcomes included referral rates for reduced UCVA, screening performance for amblyopia and refractive errors, testability, and time required for vision test. Overall, mean (SD) UCVA was 0.15 (0.22) (20/25) with HOTV and 0.20 (0.20) (20/32) with tumbling E (95% CI, -0.07 to -0.02; P < .001). The difference between the 2 tests decreased with age, initially 1 logMAR line in children aged 3 to younger than 4 years, more than 3 letters in those younger than 8 years, and reducing to 1 or less letters by age 8 years or older. Among 183 preschool children, HOTV test showed a lower referral rate (n = 34 [18.6%]) than tumbling E (n = 57 [31.2%]) (mean difference, -12.6%; 95% CI, -19.2% to -5.9%; P < .001), along with a higher true positive rate (0.68 vs 0.44; P < .001) and better specificity (0.93 vs 0.79; P < .001), with similar measures in older children. These findings support the use of the HOTV test for children younger than 8 years. Its use could reduce unnecessary referrals, especially in the context of growing global emphasis on pediatric vision screening and early detection of myopia. ClinicalTrials.gov Identifier: NCT05770661.

Accumulating data implicate Type III interferons (IFN-λs) in autoimmune disorders, prompting our exploration of their role in uveitis pathogenesis. Serum and peripheral blood mononuclear cells (PBMCs) from patients with active Vogt-Koyanagi-Harada (VKH) and active Behçet's disease (BD) were analyzed for IFN-λ expression by enzyme-linked immunosorbent assay and real-time quantitative PCR. Experimental autoimmune uveitis (EAU) was induced in IFNLR1-/- mice to evaluate disease severity, inflammatory responses, and blood-retinal barrier (BRB) integrity. RNA sequencing and bioinformatic analyses were performed to identify related genes and associated signaling pathways. IFN-λ levels were significantly elevated in active VKH and BD patients and effectively distinguished them from healthy controls. Compared with wild-type mice, IFNLR1-/- mice developed more severe EAU, characterized by increased Th1/Th17 responses, reduced Treg frequency, and disrupted blood-retinal barrier integrity, which was evidenced by decreased tight junction proteins ZO-1, Claudin-5, and Occludin. Both retinal pigment epithelium (RPE) cells from IFNLR1-/- mice and human primary retinal pigment epithelium (RPE) cells with silenced IFNLR1 secreted higher levels of interleukin (IL)-6, IL-8, IL-1β, and MCP-1, which were suppressed by recombinant IFN-λ1 and IFN-λ2. RNA sequencing revealed an enrichment of T-cell and NOD-like receptor signaling pathways in IFNLR1-/- EAU mice. Consistent with this transcriptional profile, the expression of NLRP3 and NLRP1 was upregulated in RPE cells. Knockdown of these inflammasomes reduced proinflammatory cytokine production and upregulated the tight junction proteins. These results suggest that IFN-λs may alleviate uveitis by targeting RPE cells, primarily through downregulation of NLRP1/NLRP3 inflammasome activity, thereby attenuating inflammatory responses and preserving BRB integrity.

Autoimmune uveitis (AU) is an autoimmune disease of the eye that can lead to irreversible vision loss. Current therapies are limited by suboptimal efficacy and substantial side effects, highlighting the urgent need for the discovery of novel therapeutic targets. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme controlling the NAD+ salvage pathway and also exerts immunoregulatory and anti-inflammatory effects. However, its role in AU remains unclear. To investigate NAMPT's effects on AU and underlying mechanisms. Single-cell RNA sequencing (scRNA-seq) was performed on cervical draining lymph node (CDLN) cells from normal, experimental autoimmune uveitis (EAU), and NAMPT inhibitor-treated EAU mice. The influence of NAMPT inhibition on immune cell subsets, transcriptional programs, and intercellular communication networks was comprehensively analyzed. Additionally, scRNA-seq was performed on peripheral blood mononuclear cells (PBMCs) collected from Vogt-Koyanagi-Harada (VKH) disease patients and healthy controls (HC) to assess NAMPT expression and its modulation in human CD4+ T cells. In vivo and in vitro experiments, flow cytometry, and adoptive transfer experiments confirmed NAMPT's role in uveitis. NAMPT inhibition significantly ameliorated the clinical and histopathological manifestations of EAU. scRNA-seq revealed that NAMPT blockade reshaped immune cell composition and reversed disease-associated transcriptional programs, particularly within CD4+ T cells. It suppressed pro-inflammatory T helper (Th)-17 and Th1 responses while promoting regulatory T cell (Treg) populations. Mechanistically, NAMPT inhibition modulated the Th17/Treg balance by downregulation of Hif1α expression. In VKH patients, CD4+ T cells exhibited elevated NAMPT expression, which led to increased Th17 and Th1 cells and reduced Tregs. NAMPT knockdown reproduced the protective phenotype observed with FK866 treatment, suggesting a conserved NAMPT-Hif1α axis in human uveitis. Inhibiting NAMPT can reverse the imbalance of effector T (Teff)/Treg cells by suppressing the expression of Hif1α in CD4+T cells, thereby effectively alleviating the symptoms of EAU. Therefore, NAMPT might be a potential target for AU.

To assess for the likely presence of artificial intelligence (AI)-generated text in the published ophthalmology literature. Abstract text from 27 142 research articles published in 22 journals between May 2020 and May 2025 was evaluated for changes in word-frequency usage with a focus on stylistic words previously found to be associated with large language model (LLM)-generated text. Four commercial AI-detection services (ZeroGPT, Writer.com, Winston AI, GPTZero) were first validated against control articles with GPTZero showing the best performance, which was then used to detect the presence of AI-generated text in 50 full articles from each journal. For the large-scale screening, research articles and commentary publications (e.g., editorials) were scored at the section and sentence level and compared in the pre- versus post-ChatGPT publication time periods. Since the release of ChatGPT in 2022, a marked increase in previously rarely used stylistic words was observed with at least a 2-fold usage increase observed in 20% of ophthalmology abstracts. With full article text evaluation, GPTZero scores increased after the release of ChatGPT across all research article sections (e.g., abstract, introduction) and commentary articles. By 2025, 25.7% of sampled research articles and 21.6% of commentary articles contained AI-likelihood scores of more than 2 standard deviations above the baseline. Sentence-level analysis showed that among those publications containing outlier scores, 22.3% of sentences in research articles and 90% of sentences in commentary articles were likely written by AI. Use of AI was not disclosed among any of the publications with outlier scores. Artificial intelligence brings significant promise in its ability to facilitate both scientific and medical advances. As these tools become more powerful, disclosure regarding the manner of their use becomes increasingly important. We show that LLM-generated text is increasingly present in the ophthalmic literature and is rarely disclosed. Without disclosure requirements and editorial oversight, there is a significant risk that undisclosed LLM usage will continue to increase and may jeopardize authorship integrity and long-term reliability of published findings. Proprietary or commercial disclosure may be found after the references.

Vestibular hair cells (HCs) are essential for maintaining balance and detecting head movements. In mammals, following vestibular damage HC regeneration derives from epithelial non-hair cells (ENHCs), which possess limited capacity for proliferation and reprogramming. To examine the role of BMP4 in reprogramming utricular HCs following ototoxic injury in postnatal mice. The study utilized both wild-type mice and transgenic strains on a C57BL/6J background, including Notch1flox/flox, Pou4f3+/DTR, ROSA26tdTomato, Atoh1-eGFP; Sox9-CreERT2, and Fos-CreERT2, to investigate and lineage-trace the reprogramming of new HCs initiated by BMP4 protein. Advanced sequencing techniques, including single-cell RNA sequencing, bulk RNA sequencing, and CUT&Tag sequencing, were employed for transcriptomic and epigenomic analyses. To induce vestibular dysfunction, intraperitoneal injections of IDPN were administered to postnatal day 30 (P30) mice. Vestibular function was assessed through behavioral tests, including vestibulo-ocular reflex, off-vertical axis rotation, and gait analysis, to evaluate the functional outcomes of HC regeneration. For cellular studies, sphere or explant tissues from P2 mice, with gentamicin or small molecule cocktail in vitro, were used to evaluate proliferation and differentiation of ENHCs through EdU labelling or tdTomato lineage tracing, histological analyses, immunofluorescence staining, and Western blot analysis. We found that increased BMP4 expression enhances ENHC reprogramming, accompanied by elevated levels of key HC transcription factors, including Gfi1, Pou4f3, and Atoh1, via c-Fos activation. Moreover, exogenous BMP4 further sensitized ENHCs to Notch inhibition and Wnt pathway activation, thus amplifying the regenerative outcomes. Conversely, inhibition of c-Fos or BMP4 diminished these effects, demonstrating that BMP4 is essential for both Notch inhibition and Wnt activation. Notably, the use of a combination of small molecules targeting these pathways successfully restored vestibular function and promoted HC regeneration in adult mice. Our findings suggest that BMP4 and its associated signaling pathways represent promising therapeutic targets for the restoration of hearing and balance.

Retinoblastoma is an aggressive intraocular tumor that originates from the developing retina in early childhood. Biallelic loss of RB1 has long been considered the main event for initiating RB development in most cases. Additional genetic events following RB1 loss, such as MYCN amplification, were found to be required for RB progression. Advancements in next-generation sequencing technologies have enabled a deeper understanding of the contributors to RB origin and development, revealing that secondary genetic alterations following RB1 inactivation are infrequent. In contrast, epigenetic changes were shown to be critical promoters of RB tumorigenesis. Several epigenetic regulators, including DNA methylation, histone modifications and noncoding RNAs, have been proven to be dysregulated in RB, contributing to its progression. Understanding the underlying mechanisms involved in RB and exploring new treatment strategies is a crucial step toward developing more effective and less invasive therapeutic approaches that can improve patient outcomes. This review summarizes the significant genetic and epigenetic alterations involved in RB tumorigenesis, current therapeutic strategies, and future treatment prospects for patients with RB.

Virtual reality-based digital defocus vision training (DDVT) may offer a home-based strategy to slow myopia progression in children, but evidence is limited. To evaluate efficacy and safety of a head-mounted virtual reality-based DDVT system on myopia progression. This randomized clinical trial was conducted among children aged 6 to 12 years with myopia enrolled in July 2024, with follow-up completed in September 2025. The trial was conducted at a single center in Guangzhou, China. Data were analyzed from September 2025 to October 2025. Participants were randomized to DDVT plus single-vision spectacles (SVS) or SVS alone. Participants in the DDVT group used a head-mounted virtual reality device at home for 15 minutes per day under parental supervision after an initial in-hospital training session. The primary outcome was the between-group difference in axial length (AL) change from baseline to 6 months. The secondary outcome was between-group difference in spherical equivalent refraction (SER) change. Of 120 randomized participants, 57 of 60 participants in the DDVT group (95%) and 59 of 60 participants in the SVS group (98%) completed the study. At baseline, mean (SD) ages in the DDVT and SVS groups were 9.42 (1.52) years and 9.31 (1.13) years, respectively, and 53 of 116 participants (45.7%) were female. Mean (SD) AL and spherical equivalent in the DDVT and SVS groups were 24.35 (0.81) mm and 24.40 (0.81) mm and -1.91 (1.11) diopter (D) and -2.04 (1.06) D, respectively. Mean best-corrected visual acuity was -0.04 logMAR (Snellen equivalent, 20/18) and -0.03 logMAR (20/19), respectively. At 6 months, AL increased by 0.15 mm and 0.25 mm in the DDVT and SVS groups, respectively (difference = 0.11 mm; 95% CI, 0.07-0.15 mm; P < .001). SER changed by -0.23 D and -0.46 D (difference = -0.23 D; 95% CI, -0.35 to -0.11 D; P = .003). Visual acuity change at 6 months was -0.02 logMAR (Snellen equivalent, 20/18) and 0.01 logMAR (20/20) in the DDVT and SVS groups, respectively (difference = 0.03 logMAR [Snellen equivalent, 20/21]; 95% CI, 0.02-0.05 [20/21-20/22]; P < .001). No training-related adverse events were observed. In this randomized clinical trial, the DDVT group had a small absolute reduction in AL and SER myopic progression compared with SVS alone over 6 months in 120 children with myopia aged 6 to 12 years. The clinical relevance of these differences over the short and long term cannot be determined from this trial but support additional studies to assess this intervention as a promising adjunctive approach for pediatric myopia control. ClinicalTrials.gov Identifier: NCT07042022.