PURPOSE:To compare associations of BMI, total body fat percentage, and fat distribution with dry eye disease (DED) and assess metabolites mediation. DESIGN:Retrospective cross-sectional study. METHODS:This retrospective cross-sectional study included 483,115 UK Biobank participants (14,570 with DED and 468,545 without DED). Adiposity was assessed by baseline anthropometry and bioelectrical impedance, and DED was identified using primary care Read codes, self-reports, and medication records. Multivariable logistic regression adjusted for demographic, metabolic, medication, and lifestyle factors. Sex-specific exploratory mediation analyses evaluated baseline NMR metabolites between adiposity and incident DED. RESULTS:In women, after full adjustment including total body fat percentage, each 1% increase in trunk fat percentage was associated with 2.8% higher odds of DED (OR = 1.028, 95% CI 1.015-1.040; P < 0.001), whereas each 1% increase in arm and leg fat percentages was associated with 1.7% (OR = 0.983, 95% CI 0.975-0.990; P < 0.001) and 2.0% lower odds of DED (OR = 0.980, 95% CI 0.971-0.990; P < 0.001), respectively. Mediation analyses implicated GlycA-related inflammation, HDL remodeling, and energy metabolism. In men, BMI≥40 kg/m² was associated with 46.1% higher odds of DED (OR = 1.461, 95% CI 1.172-1.821; P < 0.001), and body fat >35% was associated with 22.4% higher odds (OR = 1.224, 95% CI 1.070-1.399; P = 0.003). Metabolites related to lipid and lipoprotein metabolism were identified as candidate intermediary metabolites in men. CONCLUSION:Adiposity showed sex-specific associations with DED, characterized by central obesity in women and higher overall body fat percentage in men. These retrospective cross-sectional findings do not establish causation.
PURPOSE:To evaluate the association between cumulative atopic disease burden and keratoconus (KC) in a large, diverse United States cohort. DESIGN:Longitudinal and cross-sectional cohort study. PARTICIPANTS:A total of 283,040 keratoconus-free adults from the All of Us Research Program contributing 498 incident KC events over a median of 9.0 years (longitudinal cohort), and 508,527 adults including 741 with KC (cross-sectional cohort). METHODS:A cumulative atopic burden score (0-3) was defined by the presence of asthma, atopic dermatitis, and allergic rhinitis. Cox proportional hazards and multivariable logistic regression estimated associations with incident and prevalent KC, adjusted for demographics, socioeconomic variables, and healthcare utilization, with a prespecified analysis restricted to participants aged 18-40 years at baseline and a matched case-control analysis in the age-appropriate window. Allergic conjunctivitis was evaluated as an independent covariate and, exploratorily, as a mediator. MAIN OUTCOME MEASURES:Incident keratoconus (longitudinal) and prevalent keratoconus (cross-sectional). RESULTS:Baseline atopic burden was associated with incident KC in a dose-dependent manner (per-condition trend HR 1.59; 95% CI, 1.30-1.94). Among participants aged 18-40 years at baseline, the association was stronger (trend HR 1.74; 95% CI, 1.31-2.32) and incident cases were diagnosed at a median age of 38 years. Cross-sectionally, the dose-response persisted after full adjustment (per-condition trend OR 1.33; 95% CI, 1.21-1.47). Adjustment for healthcare utilization attenuated the crude association, and a matched case-control analysis equalizing administrative presence further attenuated the gradient (OR 1.03; 95% CI, 0.77-1.38); this matched analysis was underpowered (105 cases) and did not exclude a residual effect. Allergic conjunctivitis was independently associated with KC (OR 2.81; 95% CI, 2.15-3.62). Atopy preceded KC coding in most co-affected patients. CONCLUSIONS:Cumulative atopic burden was associated with incident keratoconus in a reproducible, dose-dependent manner, with atopy coding preceding keratoconus in a majority of co-affected patients. Differential healthcare ascertainment likely contributes to this association, although the matched analysis quantifying it was underpowered and did not exclude a true residual effect. These hypothesis-generating findings identify multi-condition atopy as a candidate marker warranting prospective, imaging-based evaluation.
OBJECTIVE:To characterize the real-world eligibility based on systemic medical criteria of patients receiving anti-VEGF injections for DME, including potential rates of trial exclusion and associated patient demographics. DESIGN:Cross-sectional study. SUBJECTS:Patients who received at least one anti-VEGF injection for treatment of DME with recorded pre-injection blood pressure (BP) and hemoglobin A1c (A1c) measurements. METHODS:Data was sourced from United States healthcare organizations enrolled in the TriNetX database. Trial selection criteria were sourced from ClinicalTrials.gov. MAIN OUTCOME MEASURES:The primary outcome was the overall rate of trial exclusion across all participants. Secondary outcomes comprised the rate of exclusion based on patient demographics. RESULTS:The most inclusionary ("liberal") criteria allowed for participation with BP ≤180/100, A1c ≤12.0%, no history of myocardial infarction (MI) or cerebrovascular accident (CVA) within 3 months prior to first injection, and no history of end stage renal disease (ESRD). The most exclusionary ("stringent") criteria required BP ≤160/95, A1c ≤10.0%, no history of MI or CVA within 6 months prior to first injection, and no history of ESRD. Application of the liberal and stringent criteria excluded 25.7% and 59.1% of real-world patients, respectively. Compared to White individuals, Black individuals were significantly more likely to be excluded by the liberal criteria (Odds ratio [OR] 1.97; 95% CI, 1.57 to 2.46; Padj < .001) as well as stringent criteria (OR, 2.29; 95% CI, 1.82 to 2.87; Padj < .001). Individuals of Other race(s) were significantly more likely to be excluded by the liberal criteria (OR, 1.94; 95% CI, 1.33 to 2.84; Padj = .004). CONCLUSIONS:Systemic medical selection criteria for clinical trials of anti-VEGF therapy for DME exclude a significant portion of real-world patients, with members of racial minority groups being disproportionately affected.
Rapid and reliable identification of multivariate geochemical anomalies is critical for delineating prospective mineralized zones and reducing uncertainty in mineral exploration targeting. Extended isolation forest (EIF) is a powerful unsupervised ensemble learning algorithm that efficiently isolates anomalies from high-dimensional geochemical datasets using randomly oriented hyperplane partitions. Previous studies have demonstrated the effectiveness of EIF in multivariate geochemical anomaly detection and mineral potential modeling. However, its performance can be significantly affected by stochastic variability arising from random partitioning and random subsampling during isolation tree construction, which may result in unstable anomaly patterns and inconsistent exploration targets in complex geological environments. To mitigate this limitation, we developed a robust unsupervised framework for the identification of multivariate geochemical anomalies associated with gold mineralization in the Southwestern Yilgarn Craton, Australia. The proposed framework integrates robust factor analysis (RFA), a Jaccard-based stability index and EIF to enhance the reliability and reproducibility of anomaly detection. RFA was first applied to compositional soil geochemical data to identify the most significant pathfinder elements associated with gold mineralization, which were subsequently used as input variables for the EIF model. The model was then optimized using a Jaccard-based stability criterion to ensure consistent anomaly detection across repeated independent runs. Model performance was assessed using area under the receiver operating characteristic curve (AUC). The obtained AUC value of 0.82 indicates strong predictive capacity, confirming that the generated anomaly map effectively delineates mineralization-related geochemical patterns and provides a reliable proxy for mineral prospectivity mapping. Overall, the proposed framework offers a robust and reproducible unsupervised approach for multivariate geochemical anomaly detection with strong applicability in both greenfield and brownfield mineral exploration settings.
OBJECTIVE:To characterize temporal changes in clinical severity, bacterial spectrum, and antimicrobial susceptibility in acute postcataract endophthalmitis over 23 years. DESIGN:Retrospective comparative cohort study. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS:This study included 234 eyes of 234 patients presenting within 6 weeks after cataract surgery at 2 French tertiary referral centers. The historical cohort comprised 126 eyes managed from 2002 through 2007, and the recent cohort comprised 108 eyes managed from 2016 through 2025. METHODS, INTERVENTION, OR TESTING:Microbiological analyses included conventional cultures and 16S polymerase chain reaction on aqueous and/or vitreous samples. Antimicrobial susceptibility testing was performed on bacterial isolates. Baseline clinical severity, pathogen distribution, and resistance profiles were compared between cohorts. MAIN OUTCOME MEASURES:Pathogen distribution, cefuroxime susceptibility, methicillin resistance among staphylococci, and markers of clinical severity at presentation. RESULTS:Bacterial identification was obtained in 85 of 126 eyes (67.5%) in the historical cohort and 63 of 108 eyes (58.3%) in the recent cohort. Coagulase-negative staphylococci decreased from 38% to 25% of isolates, whereas Enterococcus faecalis increased from 2% to 10%; Gram-negative bacteria increased from 3.1% to 7.3%. Cefuroxime resistance increased from 26.0% (13/50) to 66.1% (adjusted OR, 3.75; 95% CI, 1.59-8.82; P = .003) of tested isolates. Among staphylococci, methicillin resistance increased from 30.3% to 75.0% (adjusted OR, 6.75; 95% CI, 1.99-22.83; P = .002), and multidrug-resistant phenotypes increased from 3.0% to 37.5% (P = .003). Eyes in the recent cohort had milder clinical presentation, with visual acuity of 20/400 or better in 29.0% versus 11.2%, visible fundus in 24.1% versus 9.6%, and pars plana vitrectomy performed in 51.9% versus 63.5%. Interpretation is limited by the retrospective design and incomplete susceptibility data. CONCLUSIONS:This retrospective comparative cohort study of 234 cases across two periods spanning 23 years was associated with a marked shift in the bacterial spectrum of acute postcataract endophthalmitis, with fewer coagulase-negative staphylococci and more Enterococcus faecalis isolates, alongside increased cefuroxime and methicillin resistance. Continued microbiological surveillance is warranted to guide empiric therapy and future prophylactic strategies.
PURPOSE:To describe the molecular genetic spectrum and age-related clinical features of USH2A-associated retinitis pigmentosa in Korean patients. DESIGN:Retrospective cohort study. METHODS:A total of 182 Korean patients with biallelic pathogenic or likely pathogenic USH2A variants were included. Patients were classified as Usher syndrome (USH) or non-syndromic retinitis pigmentosa (NSRP), and stratified by the number of truncating USH2A variants (0, 1, or 2). Best-corrected visual acuity (BCVA), Goldmann visual field, ellipsoid zone (EZ) band length on optical coherence tomography, and ultra-widefield fundus and autofluorescence imaging were assessed. Age-related changes were modeled using restricted cubic splines with generalized estimating equations. RESULTS:The cohort comprised 56 patients with USH (30.8%) and 126 with NSRP (69.2%); mean age was 44.3 ± 12.7 years. Among 364 pathogenic or likely pathogenic alleles, c.2802T>G (p.Cys934Trp) was the most common (23.6%), followed by c.8559-2A>G (12.1%). The European hotspots c.2299delG and c.2276G>T were not identified. Missense variants accounted for 53.8% of alleles. At least one c.2802T>G allele was present in 82 patients (45.1%), including 4 homozygotes. Both Usher syndrome and an increasing truncating variant burden were associated with worse age-adjusted patterns of visual acuity, visual field, and EZ band length. CONCLUSION:USH2A-associated retinitis pigmentosa in Korean patients follows an East Asian variant spectrum that is distinct from European populations. Approximately half of patients carried at least one c.2802T>G allele, supporting inclusion of East Asian patients in emerging exon 13-targeted therapies.
OBJECTIVE OR PURPOSE:To evaluate the efficacy and safety of 0.75% phentolamine ophthalmic solution (POS) for the treatment of dim light disturbances (DLD) in subjects with reduced mesopic low-contrast vision, including post-keratorefractive subjects. DESIGN:Phase 3, multicenter, double-masked, randomized, placebo-controlled trial SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: 145 subjects with self-reported symptoms of DLD, mesopic pupil diameter of ≥5 mm, and 30 ETDRS letters (equivalent to 20/63 Snellen) or worse mesopic low-contrast best-corrected distance visual acuity (mLCVA) in the study eye, were randomized 1:1 to receive POS or placebo. The largest subset (25) of the enrolled subjects was status post-keratorefractive surgery. METHODS, INTERVENTION, OR TESTING:One drop of POS or placebo was self-administered in each eye once nightly for 14 days. MAIN OUTCOME MEASURES:Assessments included visual acuity testing, pupil diameter measurement, wavefront aberrometry, intraocular pressure (IOP), slit-lamp biomicroscopy, and a questionnaire assessing visual symptoms. RESULTS:POS-treated subjects demonstrated significant improvement in mLCVA at Day 8 (13% vs. 3% placebo; p<0.05) and Day 15 (21% vs. 3% placebo; p<0.01). Subjects receiving POS reported significant reduction in overall severity of DLD (on a scale of 1-7), and photic phenomena including glare, halos and starburst (on a scale of 0-3) at Day 8 and 15 (p<0.01). There was no significant difference between arms in conjunctival hyperemia or vital signs. Results from post-hoc analysis of post-keratorefractive surgery patients also showed significant improvement in mLCVA at Day 8 and 15 and significant improvement in patient reported outcome measures, such as overall severity of DLD. CONCLUSIONS:POS significantly improved mesopic low-contrast best-corrected distance visual acuity in subjects with reduced mesopic vision and dim light disturbances of varying etiologies, including post-keratorefractive patients. Treatment-emergent adverse events were predominantly mild and transient. These findings suggest POS may warrant further clinical investigation as a potential pharmacologic approach for patients experiencing dim light disturbances associated with reduced mesopic low-contrast visual acuity and photic symptoms.
PURPOSE:Null studies, in which the primary outcome is not statistically significant, are essential for unbiased evidence-based medicine and help reveal selective dissemination of research. We estimated the prevalence of null studies and characterized differences between null and positive studies in ophthalmology journals. DESIGN:Retrospective analysis of original studies published from January 1, 2014, through December 31, 2025. SUBJECTS:Original studies published in 90 PubMed-indexed journals listed in the Ophthalmology category of the 2025 Journal Citation Reports. METHODS:Study characteristics were derived using rule-based processing, except classification of the main study result as null versus positive, which used a large language model pipeline (gpt-4.1) applied to abstracts. Large language model performance was evaluated against a prespecified manual validation set of 500 abstracts, achieving kappa 0.87 (prespecified threshold 0.75). MAIN OUTCOME MEASURES:Prevalence and differences in study characteristics between null and positive studies. RESULTS:A total of 93,963 studies were included, of which 19,231 (20.5%) were null studies. The proportion of null studies declined from 25.6% in 2014 to 15.1% in 2025 (p <0.001). Positive studies were more often funded than null studies (68.4% vs 58.0%; risk difference 95% CI 9.6 to 11.2; p<0.001) and were more often prospective in design (17.5% vs 16.0%; risk difference 95% CI 0.9 to 2.0; p<0.001), whereas randomized design was similarly common between groups (6.5% vs 6.5%, p=0.867). Positive studies were also more often drug-focused (13.6% vs 11.8%), device-focused (9.3% vs 6.9%), or surgery-focused (13.4% vs 9.3%) (all p<0.001). Null studies were published in journals with lower mean impact factor (2.59±1.62 vs 2.73±1.69; mean difference 95% CI 0.11 to 0.17; p<0.001), and worse mean journal rank (40.11 ± 22.6 vs 37.80 ± 22.2; mean difference 95% CI -2.67 to -1.95; p<0.001) compared to positive studies. CONCLUSIONS:In this large-scale analysis of ophthalmology journals, one in five studies had a null primary outcome. Overall, null studies became less common over time and were more often published in lower-impact, lower-ranked journals and were more likely to be unfunded. These findings suggest systematic differences in the characteristics and dissemination of null versus positive studies in ophthalmology.
TOPIC:Biallelic RPE65-associated inherited retinal disorders (IRDs) cause progressive vision loss, impaired light sensitivity, and reduced mobility. Voretigene neparvovec-rzyl (LUXTURNA), the first FDA-approved gene therapy for this condition, is a disease-modifying option whose clinical benefits and harms warrant synthesis. CLINICAL RELEVANCE:Patients with biallelic RPE65-associated IRDs often have severe functional impairment despite variable BCVA changes. Understanding treatment effects on BCVA, light sensitivity, VF, and adverse events is essential for referral timing, counseling, and monitoring. METHODS:Ovid MEDLINE, Embase, and the Cochrane Library were searched from January 2000 through October 2025 for randomized trials and observational studies evaluating voretigene neparvovec-rzyl in RPE65-associated IRDs. The primary outcome was BCVA; secondary outcomes included full-field stimulus threshold (FST), visual field (VF), and adverse events including chorioretinal atrophy and central retinal thickness (CRT) change. Findings were synthesized narratively for the systematic review, with random-effects meta-analyses for perifoveal atrophy incidence and CRT change where data allowed. RESULTS:Twenty-eight studies met inclusion criteria, encompassing 376 individuals and 673 treated eyes. BCVA outcomes were variable and generally modest, with somewhat greater gains in pediatric than adult cohorts. Light sensitivity improved consistently on FST, evident by 1 month and sustained through 6 months in the largest cohort (mean change -18.24 dB); one study reported greater 12-month gains in children (13 dB) than adults (8 dB). VF improved substantially in the pivotal trial cohort (92% mean increase at 1 year, sustained to 3-4 years), with more equivocal findings in real-world pediatric cohorts. Chorioretinal atrophy and intraocular inflammation were the most frequently reported adverse events. Pooled analysis of 3 studies estimated 75% of treated eyes (95% CI, 57%-89%) developed new or progressive perifoveal atrophy; CRT changes ranged from a mean increase of 8.3 µm to a decrease of 27.5 µm. Severe complications such as retinal tears and detachment were infrequent. CONCLUSION:Voretigene neparvovec-rzyl is associated with improvements in light sensitivity and VF in pediatric patients treated before advanced degeneration, while BCVA gains are variable and usually modest. Chorioretinal atrophy, including perifoveal atrophy in a majority of treated eyes, is a common structural finding warranting monitoring alongside functional benefits.
PURPOSE:To review current and emerging biomaterials in retinal surgery - vitreous tamponade agents, retinal prostheses, retinal pigment epithelium (RPE) transplant scaffolds, intraocular drug delivery platforms, and gene therapy vectors - with emphasis on the authors' oxime-crosslinked hyaluronic acid vitreous substitute. DESIGN:Narrative expert review. Systematic review methodology was not used; no protocol registration, pre-specified eligibility criteria, dual independent screening, or PRISMA flow diagram was undertaken. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS:Published preclinical animal studies, Phase I-III clinical trials, US Food and Drug Administration approvals, and real-world evidence on biomaterials in posterior segment surgery. No individual patient data were accessed. METHODS, INTERVENTION, OR TESTING:A structured literature search of PubMed/MEDLINE, supplemented by Google Scholar, was performed from January 2018 to March 2026 across five domains: vitreous tamponade agents; retinal prostheses; scaffold-based RPE transplantation; nanoparticle and sustained-release drug delivery; and gene therapy vectors. Peer-reviewed investigations, trial reports, and regulatory data were prioritized. The authors' preclinical hydrogel data are presented as original data within a review context. MAIN OUTCOME MEASURES:Best-corrected visual acuity, intraocular pressure, electroretinography, retinal microstructure on optical coherence tomography, prosthetic visual acuity, ellipsoid zone area loss, injection frequency, and in vivo biocompatibility. RESULTS:The PRIMA photovoltaic subretinal implant produced a clinically meaningful improvement in visual acuity in 26 of 32 patients (81%) with geographic atrophy at 12 months. A 44-channel suprachoroidal prosthesis showed no device-related serious adverse events at 2.7 years. The authors' oxime-crosslinked hyaluronic acid hydrogel demonstrated density 1.01 g/mL and refractive index 1.356, with preserved electroretinography and intraocular pressure of 13.5-25.9 mmHg in rabbits. Scaffold-based RPE transplantation has entered Phase I/IIa trials. 2025 approvals included a refillable ranibizumab port delivery system for diabetic retinopathy and the first encapsulated cell therapy implant for macular telangiectasia type 2. Three Phase 3 anti-VEGF gene therapy trials are ongoing. CONCLUSIONS:Biomaterial engineering is transforming retinal disease management from stabilization toward tissue replacement and vision restoration. Principal limitations are the preclinical status of the hydrogel data and early-phase status of RPE scaffold trials. Outstanding challenges include long-term in vivo stability, immunological management of allogeneic constructs, scalable manufacturing, and definitive efficacy trials.
PURPOSE:To investigate the long-term incidence of structural glaucoma conversion and associated ocular and systemic risk factors in a large Korean health screening cohort. DESIGN:Retrospective cohort study. PARTICIPANTS:A total of 17,212 Korean adults with no evidence of glaucomatous structural change at baseline who underwent health screening at the Seoul National University Hospital Healthcare System Gangnam Center and had follow-up fundus photographs 10 years or more after baseline. METHODS:Serial fundus photographs were reviewed to identify incident reproducible glaucomatous structural change. Glaucoma conversion was defined as the development of definite structural glaucomatous change in eyes with normal baseline findings. Incidence was estimated using Kaplan-Meier analysis, and associated risk factors were evaluated using Cox proportional hazards models. MAIN OUTCOME MEASURES:Incidence of structural glaucoma conversion and ocular and systemic risk factors associated with conversion. RESULTS:During a mean follow-up of 13.0 ± 2.0 years, structural glaucoma conversion occurred in 399 participants (2.3%), with an incidence rate of 180.2 cases per 100,000 person-years. In multivariable Cox models, glaucoma conversion was independently associated with older age (per 1-year increase; hazard ratio [HR], 1.017; 95% CI, 1.006-1.028), higher intraocular pressure (per 1-mmHg increase; HR, 1.158; 95% CI, 1.117-1.199), retinal arteriosclerosis (HR, 1.459; 95% CI, 1.247-1.708), higher serum uric acid (per 1-mg/dL increase; HR, 1.080; 95% CI, 1.002-1.164), and total cholesterol (per 10-mg/dL increase; HR, 1.096; 95% CI, 1.003-1.199). CONCLUSIONS:In this large Korean health screening cohort, retinal arteriosclerosis detected on routine fundus photographs was associated with structural glaucoma conversion. These findings suggest that microvascular changes, together with intraocular pressure and systemic metabolic factors, may help refine glaucoma risk stratification in preventive eye screening settings.
Water conservancy and hydropower projects enhance regional climate resilience and watershed water security yet inevitably trigger large-scale involuntary reservoir resettlement. As representative involuntarily displaced populations, reservoir resettlees' social identity directly impacts local social stability and regional sustainable socioeconomic development. Based on a ten-year longitudinal qualitative investigation including in-depth interviews and participant observation in Village Y of Wuxikou Reservoir, Jiangxi Province, this paper divides the entire resettlement process into three stages: relocation, stabilization and development. From the dual perspectives of host community identity and out-groups identity, this study explores the dynamic evolutionary rules of resettlees' social identity. The results indicate that resettlees sequentially develop alienated identity, superficial adaptive identity and segregated identity across different phases. On this basis, the core concept of differential identity is proposed, which features a dual structure of vertical temporal differentiation and horizontal spatial differentiation. This paper expands the applicable scope and explanatory power of the “differential mode of association” and social identity theory in involuntary resettlement contexts. Grounding on the differential identity framework, this paper puts forward targeted integrated governance solutions to break intergroup segregation, facilitate cross-group integration and build resilient resettlement communities consistent with Sustainable Development Goals (SDGs) 11 and 13.
The discrimination of ore deposit types is primarily based on geological, geochemical, and isotopic characteristics. Conventionally, these types are identified using specific element diagrams. However, traditional geochemical methods often fail to determine scheelite deposit types of the complex Xuefengshan Sb-Au-W metallogenic belt in China, where mineralization resulted from the superposition of multiphase geological events. Machine learning (ML) methods, have been increasingly applied to identify deposit genesis by establishing relationships between deposit characteristics and genetic types using extensive datasets. However, inaccurate data labels, the limitations of single models, and poor model interpretability lead to decreased accuracy. This study proposes a ML framework based on interpretable ensemble learning. We collects geochemical element data from typical orogenic and magmatic-hydrothermal scheelite deposits globally. Deep clustering is used to filter data and overcome the subjectivity of original data labels. An ensemble learning model is used to construct a classifier to improve the model's robustness and generalization ability. An interpretable model is introduced to analyze the contribution of individual feature elements, revealing the metallogenic genesis. This method demonstrates high accuracy on the test set. According to this method, the scheelite deposit type of the Xuefengshan metallogenic belt is primarily magmatic-hydrothermal in origin, with orogenic superposition. This helps resolve a long-standing controversy in the region and establishes a repeatable and interpretable new paradigm for ML-based discrimination of ore deposit genetic types.
