An eyecare foundation model for clinical assistance: a randomized controlled trial

Nature Medicine · 2025-08-28 · 18 citations

Operationalizing a research-oriented learning healthcare system across covered entities: cross-institutional strategies and innovations

npj Health Systems · 2025-12-16 · 1 citations

The concept of a Learning Health System (LHS) has been widely discussed in academic literature, yet its practical implementation remains a challenge. This paper describes the institutional journey, leadership structure, data governance policies, and technical innovations that together support a scalable and sustainable Research-Oriented LHS. Additionally, we propose an expanded data vision that aligns with interdisciplinary and translational research needs. Supplementary materials provide technical details for those interested in implementing such a model.

Safety and Longevity of Intraocular Pressure Control After Bimatoprost Implant Administration: Interim Analysis of a Phase 3b Clinical Trial (TRITON)

Drugs · 2025-02-22 · 3 citations

BACKGROUND: Bimatoprost implant 10 µg is an intracameral, biodegradable implant that slowly releases bimatoprost to lower intraocular pressure (IOP). This study was designed to evaluate safety and the duration of the IOP-lowering effect after single and as-needed repeat administration of the bimatoprost implant in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). PATIENTS AND METHODS: This study is an interim analysis of an ongoing, prospective, open-label, multicenter study in patients with OAG or OHT who are inadequately managed with topical IOP-lowering medication for reasons other than efficacy. IOP-lowering rescue treatment is allowed if implant retreatment criteria are not met. The primary endpoint is time to retreatment/rescue after the initial implant administration analyzed with the Kaplan-Meier method. Key safety measures include treatment-emergent adverse events (TEAEs) and reading-center evaluation of central corneal endothelial cell density (CECD). Analysis of data collected through 15 September 2023 focused on outcomes after a single or two implants. RESULTS: In total, 441 patients received the 10-µg bimatoprost implant in the study eye on day 1 (cycle 1), 179 patients received a second administration (cycle 2), and 378 patients had at least 12 months of follow-up data available. The median time (95% confidence interval) from the first administration to a second administration or rescue was 392 (369, 485) days; the probability of not requiring retreatment or rescue by day 360 was 57.5%. A second implant administration similarly provided a long duration of IOP control. The baseline mean (standard error, SE) IOP was 25.6 (0.14) mmHg; the mean (SE) change from baseline IOP in unrescued eyes after a single administration was - 7.5 (0.21) mmHg at week 24 and - 6.4 (0.28) mmHg at month 12. Conjunctival hyperemia, typically associated with the administration procedure, was the most common ocular TEAE (cycle 1, 14.3%; cycle 2, 12.8%). Mean (SE) percentage change in CECD from baseline at 12 months after administration was - 4.3 (0.81)% in cycle 1 and - 8.5 (2.22)% in cycle 2. The cycle 1 implant was no longer visible or ≤ 25% of initial size in 66.3% and 94.3% of study eyes at months 12 and 24, respectively. CONCLUSIONS: In this interim analysis based on available data, the IOP-lowering effect of the initial administration of the 10-µg bimatoprost implant was well maintained for > 1 year in most patients. Results after a second administration were comparable. The safety profile of initial and repeat administration was acceptable. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT03850782; registered 20 February 2019.

Peripapillary scleral stiffening increases optic nerve head shear deformation in porcine eyes during IOP elevation

Experimental Eye Research · 2025-10-15

Computational models predicted that peripapillary sclera (PPS) stiffening may reduce intraocular pressure (IOP) induced stresses and strains at the optic nerve head (ONH). Experimental studies in animal models of glaucoma however did not confirm such benefit. In this study, we used high-resolution ultrasound elastography to quantify PPS and ONH strains to evaluate biomechanical changes associated with PPS stiffening. Sixteen pairs of porcine globes were used. One globe in each pair was randomly assigned to the stiffening or the control group. Inflation tests were performed before and after treatment with 1.25% glutaraldehyde (stiffening group) or saline (control group). IOP was raised from 5 to 30 mmHg while 2D cross-sectional images of the PPS and ONH were obtained using a 50MHz ultrasound probe. PPS and ONH displacements and strains were calculated using a validated ultrasound speckle tracking algorithm. In the stiffening group, there was an increase in ONH shear strain (by 11.8%, P=0.025) and an increase in the posterior displacement of the ONH relative to PPS (P<0.001). In contrast, ONH shear strain decreased (by 9.1%, P=0.012) and the relative ONH posterior displacement did not change in the control group. ONH tangential strains were reduced in both groups, but more so in the stiffening group. These results suggest that the biomechanical effects of PPS stiffening are complex. While a reduction of ONH tangential strain could be protective, the concomitant increase in ONH shear strain and ONH posterior displacement could be detrimental. Future studies are needed to optimize PPS biomechanical properties for neuroprotection. • High-frequency ultrasound elastography was used to image ONH and PPS deformation. • ONH tangential strains decreased after PPS stiffening. • ONH shear strains increased after PPS stiffening. • Posterior displacement of ONH relative to PPS increased after PPS stiffening. • This relative posterior displacement was correlated with ONH/PPS junction shear strain.

Objective Grading of Tonography Tracings for the Measurement of Outflow Facility

Translational Vision Science & Technology · 2025-02-06

Purpose: Tonography is the standard method for non-invasive measurement of aqueous humor outflow facility. However, assessment of tonography tracing quality is currently subjective, and acceptance of poor-quality data or inappropriately discarding valid data can bias results. The purpose of this study was to develop an objective method for assessing the quality of tonography tracings. Methods: Pneumatonography tracings were obtained from glaucoma and ocular hypertension patients as part of an ongoing multicenter study of aqueous humor dynamics. Intraocular pressure (IOP) was captured digitally at 40 Hz over 2 minutes. Root mean square error (RMSE) of a linear best-fit line was obtained for each tracing. Each tracing was also graded by seven experienced tonographers using a scale of 1 (worst) to 10 (best) for quality (Expert score). A Reference set of 35 tracings was used to determine the relationship between RMSE values and Expert scores using a logarithmic curve. This relationship was used to calculate a predicted score in a second Test set of 20 tracings. A logarithmic curve was used to account for the fixed range of Expert scores and unbounded upper range for RMSE values. The differences between the predicted scores and the Expert scores were evaluated using Bland-Altman analysis. Results: There was a very strong correlation between predicted and Expert scores (R = 0.94). The mean difference between Expert and predicted scores was -1.01 ± 0.84, and the limits of agreement were between -2.65 and +0.63. Conclusions: Objective assessment of pneumatonography tracings can be performed using RMSE of a fitted line and calculation of a predicted quality score that closely matches scores given by expert graders. Translational Relevance: Tonography tracing quality can now be objectively assessed.

Understanding Individual Intraocular Pressure Response to Treatment with Latanoprost and Timolol

Journal of Ocular Pharmacology and Therapeutics · 2025-04-14 · 4 citations

Purpose: To identify reasons for variable intraocular pressure (IOP) responses to latanoprost and timolol in healthy volunteers and to generate the control group as part of Eye Dynamics and Engineering Network. Methods: In this multicenter, randomized, crossover study (NCT01677507), both eyes of 106 healthy subjects (212 eyes) were treated with latanoprost or timolol for 7 days, with a 6-week washout between treatments. Ocular biometrics, tonometry, and aqueous humor dynamics (AHD) were assessed at baseline and day 8 of each treatment. Subjects were divided into responders and nonresponders using cutoffs of &gt;15% or &gt;10% IOP reduction. Treatment effects and correlations were analyzed with paired t-tests. Results: More subjects responded to latanoprost (54%) than timolol (27%) at &gt;15% cutoff ( p &lt; 0.01). Responders had higher mean baseline IOP than nonresponders for both drugs at both cutoffs ( p &lt; 0.01). Among timolol nonresponders ( n = 56), 39% responded to latanoprost in both eyes, 20% in one eye, and 41% in neither. Among latanoprost nonresponders ( n = 31), 13% responded to timolol in both eyes, 13% in one eye, and 74% in neither. Latanoprost increased uveoscleral outflow, while timolol reduced aqueous flow and outflow facility. Low baseline uveoscleral outflow was associated with latanoprost response. Conclusions: Higher baseline IOP predicted better responses to both drugs. Higher baseline uveoscleral outflow predicted nonresponse to latanoprost. No AHD differences were linked to the timolol response. Timolol nonresponders were often responsive to latanoprost, but not vice versa.

P167: Variants in RPAP3 are associated with normal-pressure glaucoma*

Genetics in Medicine Open · 2025-01-01 · 1 citations

or moderate; there was 1 serious AE (gastroenteritis unrelated to the study drug, which occurred during the post-treatment safety follow-up period).Linear PK was observed over the titrated dose range.A one-compartment linear population PK model was developed.Apparent clearance of 1.89 L/h, apparent volume of distribution of 20.2 L, half-life of 7.4 h, and 24-hour steady-state area under the curve (AUC24) of 381 gh/mL were estimated for a child with PMS who weighs 30 kg.All 15 participants who received 13 weeks of treatment with NNZ-2591 had an AUC24 > 300 gh/mL and showed symptomatic improvement on the PMS-anchored Clinical Global Impression-Improvement scale.Exposure projections indicate > 80% of children are expected to achieve the target minimum exposure of 300 gh/mL at a dose of 12 or 13 mg/kg twice daily for children weighing > 20 or 20 kg, respectively.Conclusion: NNZ-2591 appeared safe and well tolerated in children and adolescents with PMS.Both clinicians and caregivers observed improvements in clinically important aspects of PMS, including communication, behavior, cognition/learning, and socialization.The efficacy of NNZ-2591 is supported by exposure-response modeling that shows the target minimum exposure can be achieved with the evaluated dosage.

Splicing variants in MYRF cause partial loss of function in the retinal pigment epithelium

bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-25 · 1 citations

ABSTRACT Myelin Regulatory Factor (MYRF) regulates retinal pigment epithelial (RPE) development and variants in the C-terminus are linked to isolated nanophthalmos, while loss-of-function variants cause syndromic disease. To define the molecular mechanism of this discrepancy, in vitro and animal studies were performed on a pathogenic C-terminal variant (p.Gly1126fs30* or dG-MYRF). ARPE-19 cells transduced with dG-MYRF revealed reduced target gene expression compared to WT-MYRF, with reduced steady state levels of C-terminal MYRF cleavage product, but intact cleavage and localization. A homozygous humanized MYRF C-terminal ( Myrf humdG/humdG ) mouse model was embryonic lethal by embryonic day (E) 18.5, while humanized wildtype ( Myrf humWT/humWT ) showed normal expression and survival. Bioinformatic analysis on integrated single cell RNA-seq from humanized E17.5 and knockout Rx-Cre;Myrf fl/fl (E15.5 and P0) mice supported shared differentially expressed genes with decreased effect size in Myrf humdG/humdG eyes. These findings, and the viability differences, support that dG-MYRF is a hypomorphic allele. Further, two novel MYRF splicing variants were identified in families with isolated nanophthalmos, with one confirmed to alter 40% of spliced transcripts, creating a nonfunctional isoform. These cases corroborate that isolated nanophthalmos results from hypomorphic alleles of MYRF, supporting a tissue-specific threshold effect and suggests that the C-terminus has unique roles in the RPE.

Aqueous Humor Dynamics Changes and Predictors of IOP Response to Latanoprost in Healthy Subjects

Journal of Glaucoma · 2025-05-08 · 1 citations

PRÉCIS: In our study of the factors predictive of latanoprost response, we found that normotensive subjects with higher intraocular pressure, lower uveoscleral outflow, and higher body mass index had a greater response to 1-week treatment. PURPOSE: To evaluate relationships between variable intraocular pressure (IOP) responses to latanoprost and participant characteristics, baseline values and changes in aqueous humor dynamics (AHD) parameters. METHODS: We assessed 226 eyes from 113 healthy participants. AHD parameters measured at baseline and after 1-week treatment with latanoprost included: IOP by pneumatonometry, episcleral venous pressure (EVP) by venomanometry, aqueous humor flow rate by fluorophotometry, outflow facility by 2-minute pneumatonography, and uveoscleral outflow calculated using the modified Goldmann equation. IOP responses were categorized into 4 groups: nonresponders (<10% reduction), all-responders (≥10% reduction), medium-responders (10%-20% reduction), and high-responders (≥20% reduction). Generalized estimating equation models were used to analyze treatment effects and compare groups. RESULTS: Baseline IOP was higher in high-responders than medium-responders and nonresponders ( P =0.007 and P <0.001, respectively). Body mass index (BMI) was significantly higher in high-responders and all-responders compared with nonresponders ( P =0.02 and P =0.03, respectively). Responders had lower baseline uveoscleral outflow ( P =0.03). There were no significant differences in other baseline characteristics including EVP, outflow facility, and aqueous flow rate between the 4 groups. IOP decreased while outflow facility and uveoscleral outflow increased after latanoprost treatment in all responder groups but did not change in nonresponders. EVP and aqueous flow rate did not change significantly in any group. The change in uveoscleral outflow was greater in high-responders than in nonresponders ( P =0.004). CONCLUSIONS: In healthy subjects, higher baseline IOP, lower uveoscleral outflow and higher BMI are predictors of a greater IOP reduction by latanoprost. A greater increase in uveoscleral outflow is responsible for this larger response.

<i>Letter:</i> Effect of Aqueous Tears on Topical Fluorescein Tracer Emission Signal from Cornea and Anterior Chamber

Journal of Ocular Pharmacology and Therapeutics · 2025-03-10