Faculty Bibliography
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department:Ophthalmology
recent-years:2
school:SOM
Total Results:
373
CaBLAM: a high-contrast bioluminescent Ca2+ indicator derived from an engineered Oplophorus gracilirostris luciferase
Monitoring intracellular calcium is central to understanding cell signaling across nearly all cell types and organisms. Fluorescent genetically encoded calcium indicators (GECIs) remain the standard tools for in vivo calcium imaging, but require intense excitation light, leading to photobleaching, background autofluorescence and phototoxicity. Bioluminescent GECIs, which generate light enzymatically, eliminate these artifacts but have been constrained by low dynamic range and suboptimal calcium affinities. Here we show that CaBLAM ('calcium bioluminescence activity monitor'), an engineered bioluminescent calcium indicator, achieves an order-of-magnitude improvement in signal contrast and a tunable affinity matched to physiological cytosolic calcium. CaBLAM enables single-cell and subcellular activity imaging at video frame rates in cultured neurons and sustained imaging over hours in awake, behaving animals. These capabilities establish CaBLAM as a robust and general alternative to fluorescent GECIs, extending calcium imaging to regimes where excitation light is undesirable or infeasible.
PMID: 41331138
ISSN: 1548-7105
CID: 5974882
De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa
Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.
PMID: 41513982
ISSN: 1546-1718
CID: 5981482
Holographic transcranial ultrasound neuromodulation enhances stimulation efficacy by cooperatively recruiting distributed brain circuits
Precision-targeted ultrasonic neuromodulation offers immense potential for studying brain function and treating neurological diseases. Yet, its application has been limited by challenges in achieving precise spatio-temporal control and monitoring of ultrasound effects on brain circuits. Here we show that transcranial ultrasound elicits direct and highly focal responses, which can be dynamically steered at spatio-temporal scales relevant for neural function. Furthermore, holographic transcranial ultrasound stimulation allows direct control of the stimulated volume and actively modulates local and mid-range network projections, effectively lowering the activation threshold by an order of magnitude. To better understand this previously unexplored excitability regime not fully explained by the conventional pressure-frequency dyad, we developed a dual modelling framework, where both an empirical and a mechanistic model were constructed to capture the intricacies of holographic transcranial ultrasound stimulation. These models achieve qualitative agreement with our experimental results, suggesting that these findings are predominantly driven by putative network interactions. Our results bring insight on the complex interaction mechanisms of ultrasound with neural tissue and highlight its potential for the noninvasive interfacing of distributed brain networks.
PMID: 40624336
ISSN: 2157-846x
CID: 5890532
Prevalence of novel Sjögren's antibodies in a multi-center cohort of dry eye patients
PURPOSE/OBJECTIVE:To assess the prevalence of novel Sjögren's disease (SjD) autoantibodies in dry eye disease (DED) patients with or without SjD. PARTICIPANTS/METHODS:DED patients were recruited from two tertiary care clinics and categorized by SjD status per the 2016 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria. METHODS:Participants underwent a battery of DED evaluations (unanesthetized Schirmer's test, tear film break up time, corneal and conjunctival vital dye staining), and unstimulated salivary flow rate assessment. Blood specimens were tested for Salivary Protein-1 (SP-1), Carbonic Anhydrase VI (CA VI), and Parotid Secretory Protein (PSP) antibodies. Salivary gland biopsies were offered when necessary to determine SjD status. RESULTS:304 participants completed bloodwork testing and 38 (12.5 %) were diagnosed with SjD. SjD participants had significantly higher positive rates of IgA SP-1 (21 % vs. 10 %; p = 0.049), any SP-1 autoantibody isotype (42 % vs. 24 %; p = 0.02), and a higher mean number of novel autoantibody-positive results (SjD 1.5 (1.1); non-SjD 1.0 (1.0); p = 0.005). The positive labial salivary gland biopsy group had a significantly higher rate of any PSP autoantibody isotype than the negative biopsy group (47 % vs. 22 %; p = 0.04). CONCLUSIONS:SjD participants had significantly higher rates of IgA SP-1, any SP-1 autoantibody isotype, and a higher number of positive novel autoantibodies in general. Participants with positive salivary gland biopsies had a significantly higher prevalence of any PSP autoantibody isotype. Positivity of these tests may indicate the inflammatory nature of dry eye in these patients and could be useful for informing treatment and follow-up.
PMID: 41386587
ISSN: 1937-5913
CID: 5980402
Early Antibiotic Use and Retinopathy of Prematurity: A Single-Center Retrospective Cohort Study
OBJECTIVE/UNASSIGNED:Retinopathy of prematurity (ROP) has been linked to neonatal sepsis, with antibiotic use suggested as a connection. Given the role of antibiotics in gut dysbiosis and the gut-retina axis, we assessed whether exposure to different antibiotic classes is associated with the incidence of treatment-necessary ROP. DESIGN/UNASSIGNED:Retrospective cohort study. SUBJECTS/UNASSIGNED:Preterm infants born at the University of Chicago Medicine and screened for ROP between January 2012 and December 2023. METHODS/UNASSIGNED:Retrospective analysis was performed to compare systemic antibiotic exposure within the first 2 months of life between infants with type 1 ROP (ie, required treatment) and those that did not require treatment. Multivariable adjustment included birth weight (BW), gestational age (GA), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage, necrotizing enterocolitis (NEC), and neonatal sepsis. To reduce potential confounding by indication, propensity score matching was performed. MAIN OUTCOME MEASURES/UNASSIGNED:Type 1 ROP by systemic exposure to antibiotic classes. RESULTS/UNASSIGNED:= 0.014). CONCLUSIONS/UNASSIGNED:Early exposure to broad-spectrum antibiotic classes, particularly cephalosporins, carbapenems, and monobactams, may be associated with type 1 ROP. FINANCIAL DISCLOSURES/UNASSIGNED:The authors has no/the authors have no proprietary or commercial interest in any materials discussed in this article.
PMCID:12548081
PMID: 41140899
ISSN: 2666-9145
CID: 5995892
The gut-retina axis in age-related macular degeneration: immune crosstalk and metabolite production
Current therapies slow down advanced features but do not halt or reverse degeneration and neovascularization in dry and wet age-related macular degeneration (AMD). Recent research implicates the gastrointestinal microbiome as a potential critical modulator in AMD pathogenesis through the gut-retina axis. Dysbiosis, characterized by imbalanced microbial diversity, composition and function, can exacerbate systemic and retinal inflammation through microglial priming, inflammasome activation, and secretion of pro-angiogenic cytokines (IL-6, IL-1β, TNF-α, VEGF). Additionally, microbiome-derived metabolites such as short-chain fatty acids and bile acids may exert modulatory roles in host immunity and homeostasis. Their depletion in conjunction with enrichment of specific microbial taxa have been linked to progression of advanced AMD. Together, these complex systems of immune crosstalk in relation to dysbiosis highlight the gut-retina axis as a promising therapeutic target. Dietary modifications, particularly Mediterranean and high-fiber diets, enhance production of protective metabolites and are associated with decreased AMD progression risk compared to Western dietary patterns. Experimental strategies such as fecal microbiota transplantation in animal models and drug repurposing strategies show promise in modulating disease severity. This review synthesizes current mechanistic insights into microbial-immune crosstalk in AMD, emphasizing the interplay of dysbiosis, immune activation, and metabolite signaling.
PMCID:12968045
PMID: 41809655
ISSN: 1535-3699
CID: 6015582
U.S. trends of anti-vascular endothelial growth factor use from 2017-2023: An analysis of medicare, medicaid, and commercial insurance
PURPOSE/OBJECTIVE:Anti-vascular endothelial growth factor medications are a cornerstone in the treatment of many macular diseases in modern ophthalmology. These medications accrue significant economic burdens to individuals and health systems, and recent data on health-system level practice patterns involving agent selection is lacking. We sought to examine utilization of intravitreal anti-VEGF agents from 2017 to 2023 across various payors and diagnoses in the United States in order to analyze trends in usage. METHODS:A retrospective cross-sectional study was performed. Data were obtained from the Epic Cosmos database, comprised of de-identified data from the electronic health record, Epic, of 238 million patients from all 50 states from January 1, 2017 to December 31, 2023. Encounters where a patient received an intravitreal injection in an ophthalmology clinic were categorized by intravitreal medication ordered, visit diagnosis, and primary insurance payor. The overall usage rates of each medication across different diagnoses and primary payor were compared. Total number of injections per year of anti-VEGF medication, the rate per 100000 ophthalmology encounters (OE), and the rate in different retinal conditions and with various insurance providers were the main outcome measures. RESULTS:From 2017-2023, there were 571,545 anti-VEGF injections administered, with 53.6% aflibercept 2 mg (306,247/571,545; 625.8/000 OE), 34.8% bevacizumab 1.25 mg (198,696/571,545; 414.7/100000 OE), 7.83% ranibizumab 0.3 mg and 0.5 mg (44,803/571,545; 99.2/100000 OE), and 3.43% faricimab 6 mg (19,624/571,545; 32.8/100000 OE). Brolucizumab 6 mg, ranibizumab-eqrn 0.5 mg, ranibizumab-nuna 0.5 mg, and aflibercept 8 mg accounted for <1% of all injections. From 2017-2023, the rate of aflibercept 2 mg increased from 361.3 injections/100000 OE to 913.1, bevacizumab increased from 274.1 to 538.1, and ranibizumab decreased from 92.4 to 64.0. The rate of faricimab increased from 37.9/100000 OE to 189.9 from 2022-2023. Patients with Medicare received aflibercept 2 mg at higher rates than bevacizumab (364.3/100000 OE vs 187.1, respectively) [t(6) = 5.67, p = 0.001] and faricimab (19.4/100000 OE), a pattern not seen in commercially insured [t(6)=2.07, p > 0.05] patients. Medicaid patients had a marginally significant difference in use of bevacizumab (M = 19.9/100000 OE, SD = 7.32) and aflibercept 2 mg (16.1/100000 OE, SD = 7.22) [t(6)]=2.95, p = 0.026]. CONCLUSIONS:Aflibercept 2 mg was the most common drug used overall from 2017-2023. Faricimab had the highest absolute and relative increase in utilization from 2022-2023. Patients with Medicare B or C were significantly more likely to receive aflibercept over bevacizumab.
PMCID:12798985
PMID: 41529044
ISSN: 1932-6203
CID: 5986102
Predicting Intraocular Pressure From Glaucoma Patients Receiving Medication Treatment Using Explainable Machine Learning
Glaucoma is a chronic neurodegenerative disease of the visual system, and treatment is targeted toward lowering intraocular pressure. However, some patients fail to respond to treatment and their intraocular pressure levels remain high, risking continuous vision loss. Explainable machine learning provides a mechanism for both individual prognostication and the identification of factors associated with treatment outcome. Here, we used explainable machine learning to predict intraocular pressure for glaucoma patients receiving medication treatment. We accessed the UK Biobank to obtain information on 290 eyes from 161 participants who reported a diagnosis of glaucoma and were receiving treatment. Features were divided into three distinct datasets containing demographic data only, physiometabolic parameters and medication prescription data, and all data combined. We evaluated five machine learning techniques for each feature set in terms of their ability to predict intraocular pressure at a follow-up visit in a classification task. We then calculated SHapley Additive exPlanation (SHAP) values for the best performing model to determine feature importance, stability, and interactions. We found that eXtreme Gradient Boosting (XGBoost) outperformed all other models when trained and tested on the combined feature set with an area under receiver operating characteristic curve (AUC) of 0.708. Insulin-like growth factor 1 (IGF-1), low-density lipoprotein (LDL), and lymphocyte count ranked as the three most important features for this model. LDL and IGF-1 exhibited a low degree of global variability in contribution to the model output across all cross-validation repeats. SHAP values demonstrated the strongest interactions being between LDL and IGF-1. In summary, our studies indicated the importance of blood LDL and IGF-1 in contributing to the outcomes of intraocular pressure lowering treatment and demonstrated the ability of XGBoost to predict these outcomes.
PMID: 41880118
ISSN: 2314-6141
CID: 6018232
Ab-Externo MicroShunt vs. Trabeculectomy in Primary Open-Angle Glaucoma: 5-Year Safety Results from a Randomized, Multicenter Study
PURPOSE/OBJECTIVE:To compare the long-term safety of MicroShunt implantation with trabeculectomy in eyes with primary open-angle glaucoma. DESIGN/METHODS:A 3-year observational extension of a 2-year prospective randomized trial. PARTICIPANTS/METHODS:The extension study enrolled 279 patients (217 MicroShunt, 62 trabeculectomy), with 256 (198 and 58, respectively) completing the month 60 visit. METHODS:This trial compared clinical outcomes of MicroShunt implantation with trabeculectomy, both augmented with mitomycin C. Adverse events (AEs), intraocular pressure (IOP), and IOP-lowering medication use were recorded 36, 48, and 60 months after initial randomization. MAIN OUTCOME MEASURES/METHODS:The primary outcome was the cumulative incidence of sight-threatening AEs. Secondary outcomes included all other AEs/complications, secondary interventions, and reductions in IOP and number of glaucoma medications. RESULTS:Rates of sight-threatening AEs were 2% (n = 4) in the MicroShunt group and 0% in the trabeculectomy group, with 1 eye each in the MicroShunt group having central retinal artery occlusion, choroidal hemorrhage (after placement of a glaucoma drainage device), progressive endothelial cell loss, and pseudophakic bullous keratopathy. Only 2 of the 4 sight-threatening AEs in the MicroShunt group were deemed related to the study device or procedure. Four eyes in the MicroShunt group experienced device erosion through the conjunctiva. Increased IOP requiring treatment was more frequent (26% vs. 8%, P = 0.0017), whereas hypotony (3% vs. 13%, P = 0.038), epiretinal membrane formation (2% vs. 8%; P = 0.028), and blepharoptosis (4% vs. 11%, P = 0.048) were less frequent in the MicroShunt group. Four patients in the trabeculectomy group required surgical revision for hypotony. Changes in endothelial cell density were similar in the MicroShunt (-19% ± 22%) and trabeculectomy (-19% ± 22%) groups, with a mean between-group difference of 0.1% (P = 0.98). In the mean ± standard deviation, IOP was reduced from 20.8 ± 4.9 mmHg at baseline to 14.2 ± 4.1 mmHg at month 60 in MicroShunt eyes (mean reduction, 5.5 mmHg [26%]) and from 20.1 ± 3.9 mmHg to 10.4 ± 3.7 mmHg in trabeculectomy eyes (mean reduction, 9.1 mmHg [45%]), with a between-group difference of -4.6 mmHg (P < 0.0001). CONCLUSIONS:Both filtering procedures demonstrated favorable safety profiles over 5 years. Most AEs through 5 years did neither necessitate reoperation nor result in vision-threatening complications. FINANCIAL DISCLOSURE(S)/BACKGROUND:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PMID: 40912402
ISSN: 2589-4196
CID: 5987902
Predicting Intraocular Pressure From Glaucoma Patients Receiving Medication Treatment Using Explainable Machine Learning
Glaucoma is a chronic neurodegenerative disease of the visual system, and treatment is targeted toward lowering intraocular pressure. However, some patients fail to respond to treatment and their intraocular pressure levels remain high, risking continuous vision loss. Explainable machine learning provides a mechanism for both individual prognostication and the identification of factors associated with treatment outcome. Here, we used explainable machine learning to predict intraocular pressure for glaucoma patients receiving medication treatment. We accessed the UK Biobank to obtain information on 290 eyes from 161 participants who reported a diagnosis of glaucoma and were receiving treatment. Features were divided into three distinct datasets containing demographic data only, physiometabolic parameters and medication prescription data, and all data combined. We evaluated five machine learning techniques for each feature set in terms of their ability to predict intraocular pressure at a follow-up visit in a classification task. We then calculated SHapley Additive exPlanation (SHAP) values for the best performing model to determine feature importance, stability, and interactions. We found that eXtreme Gradient Boosting (XGBoost) outperformed all other models when trained and tested on the combined feature set with an area under receiver operating characteristic curve (AUC) of 0.708. Insulin-like growth factor 1 (IGF-1), low-density lipoprotein (LDL), and lymphocyte count ranked as the three most important features for this model. LDL and IGF-1 exhibited a low degree of global variability in contribution to the model output across all cross-validation repeats. SHAP values demonstrated the strongest interactions being between LDL and IGF-1. In summary, our studies indicated the importance of blood LDL and IGF-1 in contributing to the outcomes of intraocular pressure lowering treatment and demonstrated the ability of XGBoost to predict these outcomes.
PMCID:12858418
PMID: 41623694
ISSN: 2314-6141
CID: 5999462
