Faculty Bibliography
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department:Ophthalmology
recent-years:2
school:SOM
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353
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
Bayesian Analysis of Valacyclovir Treatment Effect in the Zoster Eye Disease Study
PMID: 40940003
ISSN: 1549-4713
CID: 5980052
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
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
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
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
Logistical, Ethical, and Technical Considerations in the World's First Face and Whole Eye Transplantation
BACKGROUND:Whole eye transplantation (WET) has long been looked to as a potential solution for the aesthetic and functional deficits caused by severe ocular pathology and trauma. Here, we describe the first successful combined face and whole eye transplantation (FT/WET), highlighting the logistical, ethical, and technical considerations that enabled this milestone. METHODS:A 46-year-old male with severe facial and ocular deficits underwent multidisciplinary evaluation and was deemed a candidate for FT/WET. Subsequently, a surgical algorithm was developed through rigorous preoperative planning and team based surgical simulations. This process focused on techniques that would allow for efficient graft procurement and inset, while simultaneously limiting trauma to the globe and its adnexa. RESULTS:Longitudinal monitoring demonstrated maintained graft viability throughout the postoperative period. Fluorescein angiography and ICG angiography confirmed robust retinal and choroidal perfusion. Diffusion-weighted MRI revealed structural preservation of the optic tracts, despite inner retinal atrophy. The patient has also experienced significant improvement in facial aesthetics and functionality with no episodes of graft rejection to date. CONCLUSIONS:This case demonstrates the feasibility of addressing deficits once deemed irreparable through advanced surgical techniques, preoperative planning, and multidisciplinary collaboration. Although functional vision recovery has not been observed, this innovation expands the reconstructive options available for patients with severe facial and ocular deficits, paving the way for future advancements in vascularized composite allotransplantation.
PMID: 41467696
ISSN: 1529-4242
CID: 5985642
An Episcleral Lesion in a Patient With Neurofibromatosis Type 1
Neurofibroma can present in a myriad of body tissues, including, very rarely, in the sclera; a unique presentation that is described herein. We describe a case of a 21-year-old man with neurofibromatosis type 1, who presented with 2 weeks of a blue-gray scleral discoloration overlying a protrusion of the sclera. His presentation was initially concerning for scleritis; however, histopathological analysis revealed an epibulbar neurofibroma. Recognition of rare manifestations of neurofibromatosis is essential to properly diagnose and manage ocular findings in this condition.
PMID: 41347665
ISSN: 1537-2677
CID: 5975282
Connectome of a human foveal retina
What makes human brains distinctive? The answer is hidden at least partially in the myriad synaptic connections made between neurons - the connectome. The foveal retina is a primate specialization which presents a feasible site for deriving a complete connectome of a human CNS structure. In the fovea, cells and circuits are miniaturized and compressed to densely sample the visual image at highest resolution and initiate form, color and motion perception. Here we provide a draft connectome of all neurons in a human fovea. We found synaptic connections, distinct to humans, linking short-wavelength sensitive cones to color vision pathways. Moreover, by reconstructing excitatory synaptic pathways arising from cone photoreceptors we found that over 95% of foveal ganglion cells contribute to only three major pathways to the brain. Our study reveals unique features of a human neural system and opens a door to a complete foveal connectome.
PMCID:12340841
PMID: 40799563
ISSN: 2692-8205
CID: 5930822
Impact of the Diabetes Endothelial Keratoplasty Study
PMID: 41105098
ISSN: 2168-6173
CID: 5955242
