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Alzheimer's disease (AD) is characterized by progressive neurodegeneration and synaptic dysfunction that begins decades before clinical symptoms emerge. While AD research has traditionally focused on the brain, increasing evidence suggests that the retina undergoes pathological remodeling that shares features with cerebral changes. Advances in retinal imaging, including optical coherence tomography (OCT), OCT angiography, and hyperspectral approaches, have identified structural, vascular, and functional abnormalities in individuals with mild cognitive impairment (MCI) and early-stage AD. This supports the potential utility of the retina as a non-invasive biomarker for detecting neurodegenerative processes. Furthermore, postmortem studies have demonstrated accumulation of amyloid-β and phosphorylated tau, increased vulnerability of retinal ganglion cells (RGC), synaptic alterations in the inner plexiform layer (IPL), and significant activation of glial cells and complement-mediated inflammatory pathways. Melanopsin RGCs appear to be selectively affected, suggesting a mechanistic link between retinal pathology and the circadian or sleep disturbances commonly observed in AD. This review synthesizes human clinical data from imaging, histopathological, and proteomic studies supporting retinal involvement in AD, with emphasis on convergent mechanisms, including mitochondrial dysfunction, oxidative stress, microglial activation, and synaptic degeneration. Key limitations and sources of variation in current retinal biomarker studies, including cohort heterogeneity, comorbid ocular disease, and methodological variability, are discussed, and future directions are outlined to strengthen retinal diagnostics and therapeutic monitoring of visual system dysfunction in AD.

The accurate and timely diagnosis of inherited retinal diseases (IRDs) represents an unmet clinical need in ophthalmology, as the current pathways rely on resource-intensive phenotyping, multidisciplinary expertise and genetic testing. Here we developed Retina4IRD, an artificial intelligence (AI)-based clinician decision support system (CDSS) that predicts 17 genotype categories from retina images. Retina4IRD uses a Vision Transformer model pretrained with RETFound. We then trained and validated Retina4IRD using multimodal data with color fundus photographs and optical coherence tomography scans from 1,843 genetically confirmed patients (3,376 eyes) across China, South Korea and Poland. The top-5 prediction accuracy was 0.904 (95% confidence interval (CI): 0.896-0.912) and 0.856 (95% CI: 0.850-0.863) for internal and external validation, respectively. We conducted a randomized controlled trial with 300 participants with suspected IRD randomized 1:1 to either Retina4IRD-assisted specialist arm or specialist-only arm. Of these, 295 participants (median age 33 years, 114 (38.6%) females) with available next-generation sequencing reports were included in the final analysis. The primary outcome was met: top-5 genetic accuracy was significantly higher in the Retina4IRD-assisted specialist arm versus the specialist-only arm (88.5% versus 67.3%, P < 0.001). For secondary endpoints, top-1 to top-4 accuracies all favored the Retina4IRD-assisted specialist arm, with top-1 accuracy of 37.8% versus 22.4% and top-4 accuracy of 81.8% versus 53.1%, respectively. Post hoc analyses demonstrated that, with Retina4IRD assistance, clinicians made better management decisions, and the composite downstream management score indicated significantly higher scores relative to the control group (37.7 versus 28.5, P < 0.001). Our study shows that Retina4IRD is a CDSS tool prior to genetic testing and aligns with clinical workflow for patients with suspected IRDs. ClinicalTrials.gov identifier: NCT06839170 .

Alport syndrome (AS) is a hereditary glomerulopathy often associated with ocular abnormalities, yet structural retinal biomarkers remain underutilized in nephrology. Here, we evaluated the Temporal Thinning Index Maximum (TTIMax), a subject-level optical coherence tomography (OCT) metric, as a potential diagnostic biomarker for inherited podocytopathies. We evaluated TTIMax derived from OCT in 93 genetically confirmed patients with AS and 136 controls (84 with chronic kidney disease and 52 healthy individuals). Genetic diagnosis served as the reference standard and TTIMax as the index test. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis with calculation of sensitivity and specificity. TTIMax stratified disease severity across genotypes (severe X-linked AS-Male/autosomal recessive AS: 11.8%; intermediate X-linked AS-Female/autosomal dominant AS: 7.3-8.1%; controls: 5.3-5.8%) and remained significantly associated with disease severity after adjustment for age, eGFR, and blood pressure. ROC analysis demonstrated excellent discrimination for severe AS (area under the curve (AUC) 0.98; 95% Confidence Interval 0.96- 1.00) with an optimal threshold of 8.4% (sensitivity 93%, specificity 99%). TTIMax distinguished severe AS from primary immune-mediated focal segmental glomerulosclerosis (FSGS) (AUC 0.97;0.94-1.00) and differentiated COL4A-related FSGS from primary FSGS (AUC 0.91; 0.77-1.00). Longitudinal follow-up (four-14 years) demonstrated stability of TTIMax despite changes in kidney function CONCLUSIONS: TTIMax provides a widely accessible, non-invasive structural biomarker that complements genetic testing and may aid in diagnosing inherited podocytopathies and interpreting COL4 variants of uncertain significance.

Hypertension is a major cardiovascular risk factor arising from endothelial dysfunction driven by dysregulated endothelial nitric oxide synthase (eNOS) activity. Although eNOS turnover is regulated by post-translational modifications, the precise mechanisms remain unclear. Endophilin A2 (EndoA2) is uniquely enriched in the cardiovascular system and may influence eNOS activity and endothelial function. The primary objective of this study was to investigate the function of EndoA2 in blood pressure homeostasis with particular emphasis on elucidating its mechanism in regulating eNOS protein stability. Global and endothelial cell-specific EndoA2 knockout mice were generated to determine the effects of EndoA2 on hypertension, employing radiotelemetry, alongside histological, cellular, molecular, and biochemical approaches. Reduced EndoA2 expression was consistently observed in the aortic tissues of three hypertensive animal models. Global or endothelial cell-specific ablation of EndoA2 in mice induced spontaneous hypertension, vascular remodelling, and impaired endothelium-dependent vasodilation. Conversely, endothelial cell-specific EndoA2 overexpression ameliorated vascular remodelling and hypertension by maintaining endothelial homeostasis. Mechanistically, EndoA2 interacted with eNOS through its proline-rich domain (PRD), competing with the E3 ubiquitin ligase Itch for eNOS binding. This competition suppressed the Itch-mediated K48-linked ubiquitination of eNOS at lysine 834, thereby stabilizing eNOS. Notably, the PRD-mimetic peptide recapitulated the beneficial effects of EndoA2 by attenuating eNOS degradation and hypertension in mice. EndoA2 is a critical regulator of eNOS stability by antagonizing Itch-dependent ubiquitination. The PRD-mimetic peptide preserves eNOS homeostasis and alleviates hypertension, suggesting the therapeutic potential of targeting the EndoA2-Itch-eNOS axis in endothelial dysfunction-related cardiovascular diseases including hypertension.

Hypoxia in the tumor microenvironment (TME) is a hallmark of solid tumors and is tightly associated with the development of chemoresistance and immunosuppression, severely compromising the efficacy of mainstream clinical oncological treatments. Platinum-based metallodrugs, especially oxaliplatin (Oxa), serve as first-line chemotherapeutics in clinical practice. However, their clinical utility is greatly restricted by acquired drug resistance, insufficient tumor accumulation, and weak immunostimulatory capacity. Herein, we synthesize a platinum-ruthenium nanohybrid prodrug (denoted as PR) via self-assembly, which integrates Oxa PR and ruthenium ions for synergistic chemo-/chemodynamic-/immunotherapy of hypoxic tumors. The PR nanohybrid possesses intrinsic multi-enzyme activities (catalase, peroxidase, and glutathione peroxidase), enabling efficient oxygen generation, hydroxyl radical production, and glutathione depletion. These cascading events enhance chemosensitivity, trigger robust immunogenic cell death, and activate the cGAS-STING signaling pathway. Furthermore, nanocatalytic modulation of the hypoxic TME alleviates hypoxia-driven immunosuppression, downregulates PD-L1 expression on cancer cells, and reinforces antitumor immune responses. In vitro and in vivo investigations demonstrate that PR nanohybrid exhibits superior anticancer efficacy over free Oxa and displays promising potential in combination with PD-1 blockade therapy. These findings highlight the PR nanohybrid as a versatile TME-modulating platform for hypoxic tumor treatment, offering a novel strategy to advance platinum-based combination cancer therapy.

3D printing is reshaping ophthalmic biomaterials, tissue models, implants, biosensors, and drug-delivery systems, but its clinical value depends on matching each printing strategy to ocular-specific requirements rather than on printing capability alone. This review classifies ophthalmic 3D printing into extrusion-based, inkjet-based, electric field-assisted, and light-assisted approaches, while clarifying the boundary between acellular material inks and cell-laden bioinks. We summarize how ink formulation, spatial resolution, optical transparency, mechanical stiffness, degradation, sterilization, immune response, and regulatory classification influence applications in corneal, conjunctival, lens, retinal, orbital, sensing, and drug-delivery contexts. We further discuss hybrid printing and artificial intelligence (AI)-assisted process control as emerging strategies that may improve patient-specific design, reproducibility, and quality assurance. By emphasizing current limitations, clinical translation barriers, and actionable priorities, this review aims to provide a balanced roadmap from basic ophthalmic 3D-printing research toward clinically meaningful transformation. STATEMENT OF SIGNIFICANCE: Ophthalmic diseases affect millions worldwide, yet traditional treatments like eye drops suffer from poor efficacy due to the eye's complex biological barriers. Three-dimensional (3D) printing offers a revolutionary solution by enabling the creation of customized, structurally precise biomaterials. This review provides a comprehensive overview of how advanced 3D printing technologies are being used to engineer delicate eye tissues (cornea, conjunctiva, and retina) and develop novel drug delivery systems (microneedles and smart contact lenses). Furthermore, we introduce the concept of 'dynamic bioprinting,' highlighting how smart materials can adapt to the ocular microenvironment over time. This work bridges the gap between biomaterial structure-function design and clinical ophthalmology, providing a roadmap for future personalized vision therapies.

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.

Naïve T cells maintain a delicate balance between quiescence and rapid activation, which involves multiple layers of regulation beyond transcription. Here, we identify the RNA modification N6,2'-O-dimethyladenosine (m6Am) and its methyltransferase PCIF1 as critical enforcers of T cell quiescence. During CD4+ T cell activation, m6Am levels are dynamically downregulated. T-cell-specific PCIF1 knockout (cKO) mice exhibit potent tumor suppression, driven by enhanced Th1 differentiation and subsequent amplification of NK cell cytotoxicity. Mechanistically, PCIF1 represses STAT1 translation via m6Am modification of its mRNA, thereby constraining Th1 commitment. Activation-induced PCIF1 downregulation releases this translational brake, enabling rapid Th1 polarization. Crucially, we identify Suramin as a pharmacological PCIF1 inhibitor that disrupts m6Am modification, boosts Th1 responses, and suppresses tumor growth. Our findings establish the PCIF1-m6Am-STAT1 axis as a translational checkpoint governing T cell differentiation and suggest that targeting PCIF1 represents a potential strategy for tumor immunotherapy.

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.

Artemisia pollen is a major allergen of seasonal allergic rhinitis (SAR) in northern China. Although Artemisia annua sublingual immunotherapy (SLIT) has been approved for treating SAR, large-scale and long-term evidence regarding its efficacy, durability, safety, and immunological mechanisms remains limited. This prospective, open-label, multicenter phase IV clinical trial was conducted across eight centers in northern China. Adults with A. annua-induced SAR received SLIT for two consecutive pollen seasons (Y1, Y2), followed by 1-year post-treatment observation (Y3). The primary endpoint was the combined symptom and medication score (CSMS) during the peak pollen period (PPP). Secondary endpoints included individual nasal and ocular symptoms, medication use, and safety outcomes. Exploratory analyses assessed immunoglobulin profiles in serum and nasal secretions and serum inflammatory protein profiles using Olink proteomics. Among 316 patients included in the full analysis set, CSMS decreased significantly from last autumn (Y0, 4.03 ± 0.75) to the Y1 PPP (1.74 ± 0.92, p < 0.0001) and Y2 PPP (1.25 ± 0.74, p < 0.0001) during treatment, and remained stable during the Y3 PPP (1.34 ± 0.93, p = 0.7864) with no significant rebound in symptoms or medication use. SLIT also significantly reduced nasal and ocular symptoms and increased the proportion of medication-free days during the PPP. Serum total IgE showed a transient increase in Y1 and returned to baseline by Y2, while sIgA and sIgG4 increased in both serum and nasal secretions, with an early and significant rise in the sIgA/sIgE ratio in the nasal secretions in Y1. Proteomic analysis identified dynamic regulation of inflammation-related proteins, including downregulation of CCL3, IL-8, OSM, and ST1A1 during long-term treatment. A. annua SLIT was well tolerated, with most adverse events being mild and self-limiting. Artemisia annua SLIT is a safe and effective treatment for A. annua-induced SAR. Two years of SLIT achieved durable symptom control with reduced medication use, accompanied by immunological signatures of enhanced local immune tolerance and attenuated chronic inflammation.

To evaluate rates of vision screening failure, eye exam completion, eyeglass prescribing, and follow-up recommendations from a school-based vision program (SBVP). Retrospective cross-sectional analysis. Pre-kindergarten through 5th grade students (ages 4-13) who underwent school-based screening in Fort Worth, Texas in 2022-2024. Students who failed screening were offered school-based eye exams. Parent-reported demographics and school-level economic disadvantage (Free and Reduced-Price Meals; FARM%) were extracted. Mixed-effects logistic regression evaluated associations of grade, gender, race, ethnicity, eyeglass wear at screening, and FARM% for screening failure, eye exam after failure, and eyeglass prescription among exam completers. Associations between ocular diagnoses and follow-up interval, categorized as <6 months or ≥6 months, were tested using chi-square or Fisher's exact tests. Rates of screening failure, eye exam completion, eyeglass prescription, and follow-up interval. Among 41,236 students screened across 81 schools (median FARM%: 93.9%), 64.0% were Hispanic. Overall, 8,682 (21.1%) failed screening; 3,873 (44.6%) completed an eye exam. Hispanic and Black students had higher odds of screening failure (OR 1.35, 95% CI 1.25-1.46; 1.36, 95% CI 1.25-1.48, respectively) compared to non-Hispanic and non-Black students, respectively. After screening failure, Hispanic students had higher odds of completing an eye exam (OR 1.27, 95% CI 1.08-1.48), whereas Black students had lower odds (OR 0.82, 95% CI 0.69-0.97). Students with greater school-level economic disadvantage had higher odds of screening failure (OR 1.17 per 10% FARM increase, 95% CI 1.14-1.21) and completing an exam after failure (OR 1.24 per 10% increase, 95% CI 1.13-1.38). Among 3,767 students examined, 14.2% were recommended follow-up <6 months. Earlier follow-up was more common among those with amblyopia/amblyopia suspect (68.9% vs 6.6%) and strabismus (64.1% vs 13.3%) compared to those without (both p<0.001). In a predominantly Hispanic, economically disadvantaged district, this SBVP identified substantial unmet vision needs with disparities in screening failure and eye exam completion. Earlier follow-up recommendations were more common for high-risk diagnoses. Future work should focus on understanding whether students successfully connect to follow-up care after referral and developing guidelines to support children with ongoing eye care needs beyond SBVPs.

Identify genetic variants associated with amblyopia in African American (AFR) and Admixed American (AMR) ancestry groups, expanding upon a previous studies conducted in European ancestry. Retrospective ancestry-stratified genome-wide association study (GWAS) and gene-level rare variant association study (RVAS). Participants in the All of Us Research Program from AFR and AMR ancestry groups with whole genome sequencing available. Cases and controls were distinguished based on presence of ICD-9/10/SNOMED diagnosis codes for amblyopia in electronic health records. This yielded ancestry-stratified subsets of 269 cases and 71,585 controls of AMR ancestry and 366 cases and 79,460 controls of AFR ancestry. Stratified logistic regression models adjusted for age, sex, and the top 10 principal components of genomic ancestry. GWAS was limited to common variants (mean allele frequency or MAF > 1%) and RVAS was limited to rare variants with coding sequence-altering effects (MAF < 1%, exonic only, excluded synonymous variants) aggregated at the gene level using the SKAT algorithm. Downstream analyses of the significant variants were performed using KEGG and GO pathway analysis and STRING database queries for protein-protein interactions and gene-gene interactions. Single-nucleotide polymorphisms (SNPs) were determined to have genome-wide significance if p < 5e-8 in the GWAS and genes were determined to have significant association with amblyopia in the RVAS if p < 8.0 x 10-4. In the AMR GWAS, 245 unique SNPs mapping to 97 distinct loci were identified, notably within neurodevelopmental and axonal guidance genes, including ROBO1, SEMA4B, PTPRD, NRXN1, and CAMK2D. The AFR GWAS identified 11 significant variants corresponding to 6 loci mapping primarily to long-noncoding RNAs and pseudogenes. The AMR RVAS identified 15 genes, including axonal transport genes (KIF1B, KIF7) and growth factor signaling genes (EGF, ERBIN, and AKAP17A). The AFR RVAS identified a single gene, DLG2, which encodes the postsynaptic protein PSD-93, which promotes the closure of the sensitive period of neuroplasticity for vision in early childhood. Genetic risk architectures for amblyopia differ across ancestries but fundamentally converge on neurodevelopmental signaling, cortical synapse assembly, and sensitive period plasticity rather than ocular structural dynamics.

To review the evidence on neurodevelopmental outcomes after intravitreal anti-vascular endothelial growth factor (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.

In patients with asymptomatic severe aortic stenosis (AS), exercise stress testing is recommended to unmask symptoms and guide the timing of intervention, yet it is infrequently used in clinical practice. This registry-based follow-up of the Evaluation of TAVR Compared to Surveillance for Patients With Asymptomatic Severe Aortic Stenosis (EARLY TAVR) trial evaluates how treadmill stress testing (TST), used during screening for EARLY TAVR to confirm asymptomatic status, informed subsequent aortic valve replacement and clinical outcomes. To evaluate clinical outcomes in patients with asymptomatic severe AS and a positive TST result and to identify predictors of a positive TST result. This prespecified TST registry of the EARLY TAVR trial involved 75 clinical sites across the US. Between July 2017 and December 2021, apparently asymptomatic patients with severe AS underwent standardized TST. Those with normal TST results were randomized to transcatheter aortic valve replacement or clinical surveillance, whereas those with positive TST results were invited to enroll in a prospective registry and were followed up with through 2 years. Of 1250 patients screened, 962 met trial criteria. Of these, 816 (84.8%) had a normal TST result and 146 (15.2%) had a positive TST result. Of these, 105 consented to enroll in the EARLY TAVR Treadmill Registry. Data were analyzed from August 2025 to January 2026. Positive TST result. TST-related safety, 2-year all-cause mortality, and rates of subsequent aortic valve replacement (AVR). Baseline predictors of a positive TST result were identified using multivariable logistic regression models. Of the 105 patients included in the present analysis, the mean (SD) age was 76.1 (6.5) years, and 80 participants (76.2%) were male. TST was found to be safe, with no reported deaths, syncope, or cardioversions. Multivariable baseline predictors of a positive TST included higher peak velocity, lower ejection fraction, prior coronary artery bypass, and prior stroke. The 2-year Kaplan-Meier rate for all-cause mortality was 5.7%. Among patients with positive TST results, the rates of AVR at 1 and 2 years were 79.9% and 85.9%, respectively. Rates of mortality and AVR were similar for patients who had a class I indication for AVR (symptoms during testing) and those with a class IIa indication (drop in systolic blood pressure). In patients with asymptomatic severe AS, TST was found to be safe and identified symptoms and AVR indication in approximately 15% of patients. However, 20% of those patients remained untreated at 1 year, despite having an indication for prompt treatment. ClinicalTrials.gov Identifier: NCT03042104.

Retinomorphic hardware, inspired by the human visual system, integrates sensing and preprocessing within the same device and requires optoelectronic pixels capable of electrically encoding photoresponse into antagonistic ON and OFF pathways. Existing approaches generally rely on gated architecture or high-voltage polarization switching (typically >1 V), which increases circuit complexity and dynamic power consumption for device reconfiguration. Here, we report a vertical two-terminal organic optoelectronic design based on a single-layered-doped conducting polymer, n-doped poly(benzodifurandione) (n-PBDF), with asymmetric electrodes. Leveraging electrode asymmetric work function and polymer doping engineering, the proposed device achieves continuous analog tuning of photoresponse polarity from negative to positive at low operational voltage (<0.2 V), enabling the emulation of antagonistic visual encoding. The n-PBDF-based device also exhibits robust reversible negative-to-positive photoresponse switching for 106 cycles and stable retention for 78 days under ambient conditions. These characteristics, together with its structurally compact pixel, enable crossbar array-level in-sensor image processing, including edge enhancement and trainable image classification. The results establish a compact organic hardware primitive for low-voltage, reconfigurable, retina-inspired vision systems.

Clinical translation of nanomedicines is greatly hindered by insufficient understanding of their in vivo process, yet a key challenge lies in quantifying the encapsulated versus free drug forms in tissues and cells. Herein, we present a facile, versatile anti-PEG single-chain variable-fragment antibody (PEG-scFv)-based method enabling quantitative measurement of both forms in various biofluids (e.g., interstitial fluid, cytoplasm). By this method, we map the in vivo process of PEGylated liposomal doxorubicin (sLip/Dox) at unprecedented resolution. In the bloodstream, doxorubicin remains largely encapsulated in liposomes (>99%). In liver as the main organ for drug elimination, less drug was distributed in the interstitium (>80% encapsulated) but more in liver cells (mainly in Kupffer cells) released in a time-dependent manner, accompanying doxorubicin transferred to hepatocytes most in free form by 12 h postinjection. After extravasation into tumors, there was a limited access of sLip/Dox to tumor cells, confining most of the drug in the interstitium mainly being encapsulated (more than 75%), and the internalized fraction underwent a gradual release process in both tumor-associated macrophages and tumor cells. These findings revealed that for sLip/Dox, which primarily underwent drug release intracellularly, cellular internalization rates could be the key factor in determining its in vivo performance. Given widespread PEGylation on developing nanomedicines and the cost-effectiveness of scFv production, PEG-scFv offers a broadly applicable tool for dissecting in vivo processes of nanomedicines to establish dose-effect relationships like small-molecule drugs, further to guide rational nanotherapeutic design.

In clinical research, statistically significant effects do not necessarily indicate that an intervention provides benefits that are meaningful to patients. This is particularly important for patient-reported outcomes, where thresholds used to interpret clinical relevance are often derived from within-person changes, such as the minimal clinically important difference, and then inappropriately applied to between-group effects in randomised trials and meta-analyses. This article clarifies the conceptual distinction between within-group change and between-group effects, and argues that the latter should be the focus when judging the comparative value of healthcare interventions. We introduce the smallest worthwhile effect (SWE) as a patient-centred, intervention-specific construct representing the smallest between-group effect of an intervention over a comparator that patients consider worthwhile when weighed against harms, costs and other inconveniences. We describe the main methods used to estimate the SWE, including benefit-harm trade-off studies and discrete choice experiments, and illustrate its application by reinterpreting a randomised trial of physiotherapy for low back pain and a meta-analysis of discectomy versus non-surgical care for sciatica. We also show how the SWE can inform judgements of imprecision within the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, offering a patient-derived threshold for distinguishing trivial from worthwhile effects. By focusing on patient-derived thresholds rather than arbitrary statistical or within-group approaches, the SWE construct can help researchers, clinicians and other stakeholders make more transparent and meaningful judgements about the worthwhileness of compared healthcare interventions from a patient perspective.

Advanced aniridia-related keratopathy (ARK) is a progressive ocular surface disorder associated with limbal stem cell deficiency and limited effective treatment options. To evaluate the safety, feasibility, and clinical outcomes of Real Architecture for 3D Tissues-Ocular Surface (RAFT-OS), a tissue-engineered collagen scaffold incorporating allogeneic limbal epithelial stem cells and stromal keratocytes, in adults with advanced ARK. This single-arm, open-label nonrandomized clinical trial was conducted at a tertiary referral center in London, United Kingdom. Adults with congenital aniridia and advanced ARK underwent RAFT-OS transplant. Untreated fellow eyes served as natural history comparators. Recruitment occurred between February 2022 and April 2024, with final study completion in April 2025. Follow-up was 12 months. Data analysis was performed from May 2025 through February 2026. Surgical transplant of a good manufacturing practice-manufactured RAFT-OS construct. The primary end points were safety and ocular surface normalization at 3 and 12 months, assessed using the Ocular Surface Score (OSS). Secondary outcomes included best-corrected visual acuity (BCVA, via Early Treatment Diabetic Retinopathy Study [ETDRS] acuity charts) and patient-reported outcomes (Visual Function Questionnaire [VFQ-25], 36-Item Short Form Survey [RAND-36]). Nine participants were included (3 female [33%]; mean [SD] age, 50.6 [11.6] years). One early serious adverse event prompted amendment of the manufacturing protocol; no further major RAFT-OS-related safety events occurred. Two participants developed persistent epithelial defects. In treated eyes, mean (SD) OSS was 9.4 (1.9) at baseline, 5.9 (2.4) at 3 months (mean difference from baseline, -3.6; 95% CI, -5.6 to -1.6), and 6.7 (2.4) at 12 months (mean difference, -2.8; 95% CI, -4.5 to -1.0). In untreated fellow eyes, mean (SD) OSS was 8.4 (2.7) at baseline, 8.4 (2.4) at 3 months (mean difference, 0; 95% CI, -2.5 to 2.5), and 8.0 (2.5) at 12 months (mean difference, -0.4; 95% CI, -2.4 to 1.5). Mean (SD) treated eye BCVA was 2.23 (0.16) logMAR (Snellen equivalent, <20/1600) at baseline and 1.77 (0.67) logMAR (20/1280) at 12 months (mean difference, -0.47; 95% CI, -0.97 to 0.04). Mean (SD) fellow eye BCVA was 1.47 (0.71) logMAR (Snellen equivalent, 20/640) at baseline and 1.44 (0.75) logMAR (20/640) at 12 months (mean difference, -0.04; 95% CI, -0.44 to 0.37). In this 9-participant nonrandomized clinical trial, RAFT-OS transplant was feasible and associated with early ocular surface improvement, partly sustained through 12 months, without substantial safety concerns. Additional controlled studies with longer follow-up are needed to define safety and clinical effects. ClinicalTrials.gov Identifier: NCT05044598.

Retinal neurodegeneration leads to progressive and irreversible vision loss driven by retinal ganglion cell (RGC) death, yet effective neuroprotective therapies remain lacking. Recent studies suggest that small non-coding RNAs play key roles in central nervous system injury, but their relevance to retinal neurodegeneration remains incompletely understood. Here, we identify a significant increase in 5'tiRNA-His-GTG, an ANG-generated tRNA-derived fragment, in mouse models of retinal neurodegeneration. Functionally, elevated 5'tiRNA-His-GTG promotes reactive gliosis and contributes to RGC degeneration through Müller cell-RGC crosstalk. Conversely, inhibition of 5'tiRNA-His-GTG attenuates glial activation, preserves RGC survival, and improves visual function and vision-dependent behaviors. Mechanistically, 5'tiRNA-His-GTG induces neurodegenerative changes by suppressing the LPCAT1-mediated phosphatidylcholine (PC) biosynthetic pathway and perturbing glycerophospholipid metabolism. Notably, restoration of LPCAT1 expression or PC levels reverses 5'tiRNA-His-GTG-induced neurodegeneration both in vitro and in vivo. These findings uncover a previously unrecognized 5'tiRNA-His-GTG-LPCAT1-PC regulatory pathway that contributes to retinal neurodegeneration. Collectively, our study identifies 5'tiRNA-His-GTG as a critical mediator of glial-driven neuroinflammation and neuronal loss, and highlights this signaling axis as a potential therapeutic target for retinal neurodegeneration.

Acid mine drainage (AMD) is a widespread environmental pollution that releases millions of tons of acidic, metal-laden mine effluents into surface waters, where steep pH gradients (from strongly acidic (pH < 3) to near-neutral) promote the continuous formation of metastable ferrihydrite (Fh). Under light irradiation, Fh can undergo photochemical reactions that influence iron redox cycling and contaminant behavior; however, how Fh formation pH controls its subsequent photochemical reactivity and environmental function remains poorly understood. Herein, Fh was synthesized via the hydrolysis of Fe3+ under pH conditions ranging from 3 to 7 to simulate its formation, and its structural and physicochemical properties (including morphology, crystallinity, and particle size) as well as photochemical activities were then systematically characterized. The results revealed that Fh synthesized under lower pH conditions (e.g., pH ∼3 in AMD upstream) exhibits low crystallinity and pronounced photoreduction, leading to substantial Fe2+ release, continuous surface renewal, and potential dissolution-precipitation-driven iron redistribution; whereas in neutral downstream environments (pH ∼7), elevated pH drives the formation of Fh with higher crystallinity, resulting in weakened photoreduction activity, reduced Fe2+ release, and mineral deposition. Importantly, structure-activity fitting revealed that abundant surface Fe-OH govern the photolysis and ligand-to-metal charge transfer (LMCT) activity of Fh, which in turn influences •OH generation. These results indicate that Fh in AMD systems functions not as a passively aging mineral particle, but as a dynamically renewed photoreactive phase whose redox activity, aging behavior, and phase transformation are preconditioned by Fh formation pH. This study provides novel insights into the spatial variability of iron mobility and contaminant fate in AMD systems, with implications for predictive modeling and remediation strategies.

The retina, as an extension of the central nervous system, shares a common embryological origin with the brain. In Alzheimer's disease (AD), studies of human tissue and animal models have revealed that hallmark AD pathologies, including amyloid-β (Aβ) deposits and pathological tau protein tangles, also appear in the retina. These findings, coupled with advances in high-resolution retinal imaging techniques, suggest the potential to detect and characterize AD-related molecular and structural changes in the retina. However, retinal findings across different AD mouse models have significant discrepancies and show limited concordance with human phenotypes, complicating the identification of AD-specific alterations and the selection of optimal models for translational research. Moreover, the temporal sequence and functional significance of retinal abnormalities across the AD continuum, from preclinical stages to mild cognitive impairment and overt dementia, remain poorly defined. Addressing these knowledge gaps is essential to establish the retina as a reliable, non-invasive screening and monitoring approach. This review synthesizes current evidence on the spectrum of retinal alterations in AD, including vascular dysfunction, neuroinflammation, impaired Aβ clearance, and neurodegeneration, as observed in diverse mouse models. We compare these manifestations across species and between different models, highlighting findings along the disease continuum to delineate convergent and divergent pathways. We further discuss how emerging technologies enable the identification of AD-specific retinal alterations, and advocate for a paradigm shift from non-specific morphological assessment ("seeing shapes") toward molecular-level interrogation ("seeing components"). Interdisciplinary efforts and technological integration are crucial to establish retina as a dynamic mirror of pathology in AD.

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.

While hockey has been listed as a leading sport associated with eye injuries by the American Academy of Ophthalmology, characterization of hockey-related ocular trauma and injury severity and type remain limited. To characterize epidemiologic trends and hockey-related ocular trauma in the US. This was a cross-sectional study conducted from January 2004 to December 2023 using the National Electronic Injury Surveillance System (NEISS). NEISS was queried for hockey-related eye injuries based on product codes for hockey and body part code for eyeball. NEISS's built-in algorithm for estimating national incidence was used, and patient demographic characteristics, hockey type, and injury mechanism, diagnosis, and severity were analyzed. Data were analyzed from January to March 2025. Hockey participation. National incidence of injuries, injury type, and severity. A total of 215 cases were identified, extrapolating to 6466 US cases (95% CI, 3736-9195) over the last 20 years. Of 215 patients, 169 were male (79%), 148 were pediatric (<18 years; 69%), and 178 had equipment-related trauma (83%). Protective goggle use was reported in only 4 cases (2%). Injury incidence was similar among ice (23 [11%]), field (21 [10%]), and street hockey (23 [11%]). Minor anterior segment injuries were common (136 [63.3%]). Thirty-two (15%) patients had multiple ocular injuries. Of 259 total diagnoses, 32 (12%) were vision-threatening injuries. Pediatric patients had more minor anterior segment injuries (95 of 148) compared with adults (31 of 67; 64% vs 46%; difference, 18%; 95% CI, 3.8-31.9; P = .02), while adult patients had more major posterior segment injuries (4 of 67; 6% vs 0%; difference, 6%; 95% CI, 1.6-14.4; P = .009). Male individuals had more major anterior segment injuries (35 of 169) than female individuals (1 of 46; 21% vs 2%; difference, 19%; 95% CI, 7.9-25.5; P = .002). Hockey-related eye injuries can be severe and vision threatening. Optimal care may require prompt and thorough assessment and appropriate management of ocular and periorbital trauma. The low prevalence of reported goggle use in this investigation supports the need for greater awareness and advocacy for protective eyewear to reduce the risk of vision-threatening hockey-related injuries.

Current osmotic tissue expanders suffer from protein adsorption, bacterial colonization, and excessive fibrotic encapsulation that compromise device performance. In this study, we synthesized zwitterionic hydrogels using methyl methacrylate, n-vinyl pyrrolidone, and varying percentages (5-50%) of [2-(Methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) to simultaneously enhance swelling capacity while reducing biological fouling. In vitro characterization demonstrated that SBMA incorporation significantly increased swelling potential while maintaining the mechanical integrity required for effective tissue expansion. Zwitterionic hydrogels exhibited superior resistance to lysozyme, fibrinogen, and bovine serum albumin (BSA) adsorption compared to ionized controls. Bacterial attachment studies revealed reduced Staphylococcus aureus attachment on zwitterionic surfaces, particularly in lysozyme-containing environments that mimic physiological conditions. Subcutaneous implantation in Sprague Dawley rats for 14 days showed that hydrogels with 5-30% SBMA formed significantly thinner fibrous capsules compared to ionized controls, with the 30% SBMA formulation producing the most uniform and loose capsular matrix. These results demonstrate that zwitterionic hydrogels represent a significant advancement in osmotic tissue expansion technology, addressing key limitations of current devices through bulk incorporation of zwitterionic monomers, potentially improving clinical outcomes and reducing the need for revision surgeries. STATEMENT OF SIGNIFICANCE: Tissue expanders are medical devices used to stretch skin and soft tissues for reconstructive surgery, but current osmotic expanders fail due to protein buildup, bacterial infections, and excessive scar tissue formation. We developed new hydrogel materials incorporating zwitterionic compounds, i.e., molecules with balanced positive and negative charges, that resist biological fouling while maintaining effective tissue expansion properties. Our zwitterionic hydrogels demonstrated superior resistance to protein adsorption and bacterial attachment compared to conventional materials. Most importantly, when implanted in rats, these hydrogels formed significantly thinner, less dense scar tissue capsules, particularly the 30% zwitterionic formulation. This breakthrough addresses major clinical limitations of current tissue expanders and could reduce surgical complications and the need for revision procedures, ultimately improving patient outcomes in reconstructive surgery.

Biological visual systems provide a blueprint for intelligent perception in complex dynamic environments. Inspired by the optical role of retinal oil droplets in raptor vision, we report a plasmonic nanofocusing synaptic array (PNSA) for bioinspired visual sensing and motion perception. The pivotal design is a wafer-scale Au@MoS2 core-shell heterojunction that enhances light concentration like the retinal oil droplets of raptors. Leveraging strong localized surface plasmon resonance in the Au core and efficient hot-carrier generation in the MoS2 shell, the PNSA exhibits an ultrafast relaxation time of 2.2 ms, corresponding to a theoretical refresh rate of ∼450 Hz. Uniform 2-inch wafer-scale fabrication enables a 32 × 32 optoelectronic synaptic array with 100% yield and only 2.2% device-to-device variation. The array supports 5-bit optical programming and generates temporally encoded motion representations that achieve 98.95% accuracy in motion-direction classification after 10 training epochs. This work establishes a scalable materials platform for bioinspired visual sensing, offering a promising route toward on-chip vision perception.

Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders. We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076). Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions. CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.

To evaluate the safety and effectiveness of eye-preserving therapies in patients with American Joint Committee on Cancer (AJCC) eighth edition cT3c retinoblastoma presenting with neovascular glaucoma (NVG) without buphthalmos (defined as early cT3c), focusing on overall survival and eye preservation. Retrospective, single-center cohort study. 132 patients diagnosed with early cT3c retinoblastoma from May 2014 through October 2024. The patients were divided into primary enucleation (50 patients) and primary eye-preserving groups (82 patients). They were followed up for survival status and ocular outcomes. Overall survival, high-risk pathological features, globe salvage and vision preservation. After a median follow-up of 52.9 months, one death occurred in each group, and overall survival did not differ significantly between the primary eye-preserving and primary enucleation groups (log-rank test, P = 0.775). Eye-preserving therapies were associated with a lower incidence of high-risk pathological features (odds ratio [OR], 0.21; P = 0.003), with attenuated severity of both choroidal (OR, 0.25; P = 0.002) and optic nerve invasion (OR, 0.23; P = 0.008). The globe salvage rate was 49.4% (41/83) in the primary eye-preserving group. And among these preserved eyes, 46.3% (19/41) regained light projection or better after receiving eye-preserving therapies. Importantly, presenting intraocular pressure (IOP) ≥32 mmHg (hazard ratio [HR], 2.37; P = 0.010) and corneal edema (HR, 2.86; P = 0.007) were high risk factors for globe salvage failure. Compared with intravenous chemotherapy (IVC) alone, application of intra-arterial chemotherapy (IAC; HR, 0.13; P = 0.001) alone and combined IVC-IAC regimens (HR, 0.15; P = 0.001) demonstrated a significantly association with better globe salvage outcomes. Additionally, cryotherapy (HR, 0.14; P < 0.001) was identified as an independent protective factor for overall globe salvage. Primary eye-preserving therapies can secure high rates of globe salvage with partial visual function in patients with early cT3c retinoblastoma, without jeopardizing patient survival. However, eyes exhibiting corneal edema or IOP ≥32 mmHg demonstrate markedly inferior salvage outcomes, the treatment strategy for such patients must therefore be cautiously individualized.

Glaucoma drainage devices (GDDs) are widely used to lower intraocular pressure (IOP) and slow disease progression; however, existing designs often lack intrinsic protection against early postoperative hypotony, show limited adaptability to evolving distal outflow resistance during bleb maturation, and rely on bulky or complex components that constrain implantation and MRI compatibility. Here, we present a compact, fully passive, self-adjustable glaucoma implant designed to maintain IOP within the physiological range by dynamically modulating its hydraulic resistance without external control or postoperative adjustment. The device consists of a circular microvalve incorporating a thin, pre-stressed compliant membrane that responds to pressure conditions at the inlet and outlet. Valve performance was investigated using fully coupled fluid-structure interaction (FSI) simulations and parametric analyses, followed by fabrication and in vitro characterization, and ex vivo assessment of surgical feasibility in enucleated porcine eyes. The results demonstrate effective pressure regulation across physiologically relevant conditions, with mitigation of early hypotony and attenuation of pressure elevation under increasing downstream resistance. Ex vivo implantation confirmed ease of placement, appropriate anatomical fit, and compatibility with standard surgical workflows. Owing to its compact form factor, passive operation, and simplified, cost-effective design, the proposed implant addresses key limitations of current GDDs and shows strong potential for clinical translation.

Neurons depend on the ubiquitin system to maintain proteostasis, which plays crucial roles in processes of neuronal death and axon regeneration after injuries and diseases. Developing druggable targets within the ubiquitin system that simultaneously support neuroprotection and axon regeneration has been considered an attractive therapeutic strategy. To systematically identify druggable molecules within the ubiquitin signaling pathway and evaluate their efficacy in neuroprotection. To this end, we screened 181 ubiquitination-related small-molecule compounds for neuroprotective effects by performing excitotoxic interventions in HT22 cell lines and mouse primary neurons. Subsequently, using a mouse optic nerve crush model, we demonstrated the neuroprotective effect of BC1618 through RGC survival and axon regeneration. To investigate the mechanism, we employed LC-MS, co-IP, and RNA-seq to delineate the BC1618-FBXO48-SERBP1 regulatory axis and its downstream regulation of mRNA expression. To further evaluate the translational potential of BC1618, we assessed cell survival rates and behavioral impairments using both MPTP-induced mouse Parkinson's disease model and MPP+-induced apoptosis model of iPSC-derived dopaminergic neurons. We identified BC1618 as an effective neuroprotectant that prevented glutamate-induced excitotoxicity in vitro and enhanced neurite outgrowth in immature neurons. Additionally, we showed its effectiveness in an optic nerve crush model, where BC1618 supported RGC survival and encouraged axon regeneration. Mechanistically, BC1618 inhibited FBXO48-mediated K63-linked ubiquitination of SERBP1 at K52, which protected SERBP1 from autophagic degradation. Our findings established SERBP1 as a key regulator that coordinates downstream mRNA expression to mediate neuroprotection. Notably, our results demonstrated that BC1618 mitigated MPTP-induced degeneration of dopaminergic neurons and motor deficits, while also exhibiting robust neuroprotective effects in MPP+-stimulated human-derived dopaminergic neurons. These findings highlight that targeting FBXO48 with BC1618 promotes axon regeneration and alleviates symptoms of Parkinson's disease by reducing the degradation of SERBP1, revealing a novel therapeutic target for clinical translation.

To identify donor, lenticule preparation, recipient, and operative factors associated with 1-year Descemet membrane endothelial keratoplasty (DMEK) success in the Diabetes Endothelial Keratoplasty Study (DEKS). This prospective cohort study was a pre-specified secondary analysis of the DEKS randomized, double-masked, multi-center clinical trial. Individuals undergoing DMEK to treat corneal endothelial dysfunction at 28 clinical sites. Eyes undergoing DMEK were randomized to receive a cornea from a donor without or with diabetes in a 2:1 ratio. Donor, tissue preparation, recipient and operative factors were recorded prospectively. The study excluded eyes with a prior penetrating keratoplasty or glaucoma tube shunt. Graft failures were classified as follows. If the recipient stroma was cloudy in the first postoperative week and did not clear or required a regraft within 8 weeks, it was classified as primary donor failure in the absence of operative complications, or as early failure associated with operative complications. If the recipient stroma cleared in the first postoperative week or cleared after being cloudy in the first postoperative week and later required a regraft or became cloudy without clearing for 90 days, it was classified as late failure. Proportional hazards and logistic regression were used to estimate risk ratios. DMEK success rate at 1 year RESULTS: Of 1421 DMEK grafts, 1374 (97%) were clear at 1 year, 32 were primary donor failures, 12 were early failures, and 3 were late failures. The 78 cases (5.5%) with operative complications had a reduced success rate (88%; hazard ratio for graft failure 4.0, 95% CI 1.9-8.6, p<0.001). Three additional factors were associated with slightly higher graft success rates in multivariate analysis without reaching the defined statistical significance threshold of P<.01: baseline donor endothelial cell density ≥ 2500 vs. <2500 cells/mm2 (97% vs. 95% success, P=.03), tissue peeled by surgeon vs. eye bank (99% vs. 96% success, P=.02), and recipient diabetes status: no vs. yes (97% vs. 94% success, P=.02). DMEK was highly successful across a wide range of donor, lenticule preparation, recipient, and surgical technique variations. Not surprisingly, graft success was lower in cases with operative complications.

In TROPION-Breast01 (NCT05104866), datopotamab deruxtecan (Dato-DXd) improved progression-free survival by blinded independent central review versus investigator's choice of chemotherapy (ICC) in patients with inoperable/metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, who had disease progression on endocrine therapy and for whom endocrine therapy was unsuitable, and who had received 1-2 prior lines of chemotherapy in the inoperable/metastatic setting. We report detailed safety data and patient-reported outcomes (PROs) from the final analysis. Patients received Dato-DXd (6 mg/kg every 3 weeks) or ICC (eribulin/capecitabine/vinorelbine/gemcitabine). Mouthwash was advised (steroid mouthwash strongly recommended for Dato-DXd), and ophthalmologic assessments were carried out per protocol. Safety and time to deterioration (TTD) in global health status/quality of life (GHS/QoL), pain, and physical functioning, using the European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30, were secondary endpoints; exploratory PROs were also assessed. With Dato-DXd (n = 360), nausea was the most common treatment-related adverse event (AE; 51.9%, grade ≥3: 1.4%). The AEs of special interest (grouped terms), treatment-related oral mucositis/stomatitis and ocular surface events, occurred in 57.2% (grade ≥3: 7.2%) and 43.9% (grade ≥3: 1.9%) of patients, respectively. Per protocol recommendations, most patients receiving Dato-DXd received anti-emetics (76.7%), prophylactic mouthwash (77.2%), or artificial tears (71.7%). Adjudicated drug-related interstitial lung disease/pneumonitis with Dato-DXd was mostly low-grade (3.9%; grade ≥3: 0.8%; one grade 5 event). Hematologic toxicity was the most notable feature of the ICC safety profile (n = 351). TTD in GHS/QoL, pain, and physical functioning was delayed with Dato-DXd versus ICC. Patient-reported symptomatic AEs were generally consistent with the clinician-reported AE profile in both arms. Safety and PRO data from TROPION-Breast01 complement the improvements in efficacy demonstrated with Dato-DXd versus ICC, supporting Dato-DXd as a treatment option for patients with previously treated, inoperable/metastatic HR+/HER2- breast cancer.

Astrocyte loss occurs in various neurological conditions and can disrupt local tissue homeostasis. While astrocytes surrounding border-forming lesions adopt reactive states without restoring astrocyte networks, how astrocytes respond to spatially confined astrocyte loss remains poorly understood. Here we used longitudinal in vivo two-photon microscopy, combined with spatiotemporal transcriptional profiling, to examine astrocyte responses following focal aquaporin-4 antibody-mediated ablation in the somatosensory cortex of adult mouse brain, a model of astrocytopathy relevant to neuromyelitis optica spectrum disorder. Here we show that perilesional astrocytes undergo pronounced structural remodeling during lesion repopulation, characterized by cell proliferation, prolonged multinucleated astrocyte states, polarized process extension into the depleted area and gradual displacement of nuclei into previously unoccupied astrocyte territories. Spatial transcriptomics reveal an injury-associated molecular response that resolves as the astrocyte network is restored. Together, our findings delineate the spatiotemporal dynamics of astrocyte regeneration after astrocyte loss, extending current understanding of astroglial plasticity in the adult brain.

Autoimmune uveitis is a vision-threatening inflammatory disorder driven by dysregulated T helper 17 (Th17) responses, yet therapeutic strategies targeting Th17 differentiation are lacking. Through transcriptomic screening of an experimental autoimmune uveitis (EAU) model and validation in peripheral blood mononuclear cells from Vogt-Koyanagi-Harada patients, we identified MAP1S (microtubule-associated protein 1S) as a pivotal, conserved regulator. Here, we demonstrate that MAP1S constrains pathogenic Th17 responses and alleviates EAU through a dual mechanism coordinating transcriptional control and autophagic degradation. Mechanistically, MAP1S binds to EGR2 (early growth response 2) and restrains its acetylation at Lys368, thereby suppressing Lcn2 (lipocalin 2) transcription. Besides, MAP1S facilitates autophagosome biogenesis and lysosomal trafficking, promoting the autophagic clearance of LCN2 protein. Notably, MAP1S deficiency enhances EGR2 acetylation, increases Lcn2 transcription, disrupts autophagosome trafficking, impairs LCN2 degradation, and promotes LCN2 accumulation, collectively driving Th17 polarization and exacerbating EAU pathology. Adoptive transfer of cervical lymph node cells from map1s knockout mice reproduced severe disease in wild-type recipients. Moreover, pharmacological activation of MAP1S with spermidine suppressed Th17 responses and alleviated disease severity. Our findings establish MAP1S as a critical node integrating acetylation signaling of EGR2 and autophagic flux to govern LCN2 homeostasis and Th17 pathogenicity, revealing a promising therapeutic target for autoimmune uveitis and potentially other Th17-mediated diseases.Abbreviations: AAV: adeno-associated virus; ACOD1: aconitate decarboxylase 1; AU: autoimmune uveitis; BCL2: B cell leukemia/lymphoma 2; CDLNs: cervical draining lymph nodes; CFA: complete Freund's adjuvant; ChIP: chromatin immunoprecipitation; Co-IP: co-immunoprecipitation; CQ: chloroquine; EAU: experimental autoimmune uveitis; EGR2: early growth response 2; GDF15: growth differentiation factor 15; HDAC4: histone deacetylase 4; HDAC6: histone deacetylase 6; IL17: interleukin 17; IL17f: interleukin 17f; IL22: interleukin 22; K: lysine; KAT2A/GCN5: K(lysine) acetyltransferase 2A; KO: knockout; LCN2: lipocalin 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1S: microtubule-associated protein 1S; MS: mass spectrometry; PBMC: peripheral blood mononuclear cell; PCR: polymerase chain rection; PPI: protein-protein interaction; PTX: pertussis toxin; qPCR: quantitative PCR; RT-qPCR: reverse transcription and quantitative real-time RCR; SAA3: serum amyloid A3; SPD: spermidine; Th1 cells: T helper 1 cells; Th17 cells: T helper 17 cells; TF: transcriptional factor; Tregcells: regulatory T cells; VKH disease: Vogt-Koyanagi-Harada disease; WT: wild-type.

To assess long-term safety and exploratory ophthalmic outcomes in patients treated with voretigene neparvovec-rzyl (VN) in US clinical practice. Prospective, multicenter, observational post-authorization safety study. Eighty-seven patients (169 eyes) receiving VN at 10 ocular gene therapy treatment centers. Eligible patients were ≥12 months old with viable retinal photoreceptors and received VN in ≥1 eye. Subretinal delivery followed a 3-port pars plana vitrectomy modified at surgeons' discretion (e.g., automated foot pedal delivery, pre-bleb injection, cannula cut, use of dye for visualization). Safety outcomes included treatment-emergent adverse events (TEAEs) and occurrence of chorioretinal atrophy (CRA). Exploratory assessments included changes in best-corrected visual acuity (BCVA) and full-field stimulus threshold (FST). Outcomes were analyzed descriptively; relative risk (RR) was estimated for subgroup comparisons. With a median 3.7 years of follow-up (range, 2.9-4.9), most patients (95%) reported ≥1 TEAE (387 events); 67% were procedure related, 9% were attributed to VN, and 82% were mild. CRA, including related terms retinal degeneration and retinal depigmentation, occurred in 24 patients (28%; 45 eyes), typically within 1 year, and was mild (80%) or moderate (20%). The area of CRA mostly localized to the retinotomy or bleb area, with 40% of eyes with CRA having atrophy outside the bleb area and highly correlated between fellow eyes (r=0.97; P<0.0001). CRA risk was higher with automated foot pedal administration of VN (RR, 5.33; 95% CI, 1.27-22.40) and in patients with myopia (RR, 8.40; 95% CI, 1.16-60.69). At 3 years, treated eyes showed sustained improvements in BCVA (-0.13 logMAR) and FST (-1.68 log10 cd·s/m2). BCVA and FST were comparable between CRA and non-CRA eyes, although a subset of CRA eyes showed greater FST improvement at most time points up to Year 3. This interim analysis supports the long-term safety of VN in a real-world US cohort, consistent with clinical trial results. CRA did not appear to diminish sustained functional and anatomical benefits with a minimum follow-up of nearly 3 years. Ongoing data collection will further clarify the occurrence, impact, and risk factors for CRA while continuing to monitor VN safety in clinical practice.

Most genetic risk variants linked to ocular diseases are nonprotein coding and presumably contribute to disease through dysregulation of gene expression; however, understanding their mechanisms has been impeded by incomplete annotation of transcriptional regulatory elements across retinal cell types. To address this, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome, and three-dimensional (3D) chromatin architecture in human retina, macula, and retinal pigment epithelium/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 retinal cell types. Comparative analysis of chromatin landscapes between human and mouse retina cells further revealed both evolutionarily conserved and divergent retinal gene-regulatory programs. Leveraging the advancements in deep-learning techniques, we developed sequence-based predictors to interpret noncoding risk variants of retinal diseases. Our study establishes retina-wide, single-cell transcriptome, epigenome, and 3D genome atlases and provides a resource for studying the gene regulatory programs of the human retina and ocular diseases.