Race/Ethnicity Analysis of Vascular Alterations in Optical Coherence Tomography Angiography in Diabetic Patients.

PURPOSE: Racial and ethnic minorities have a higher prevalence of diabetic retinopathy (DR) and present at advanced stages of disease. In an urban hospital population, we investigated microvascular differences in optical coherence tomography angiography (OCTA) between racial/ethnic groups while adjusting for socioeconomic status (SES). METHODS: 3 × 3 mm2 macular OCTA scans were obtained for analysis of foveal avascular zone (FAZ) area, FAZ perimeter as well as superficial (SCP) and deep capillary plexus (DCP) vessel density (VD), vessel length density (VLD), and adjusted flow index (AFI). SES was measured using the Area Deprivation Index. Multivariable regression models were used to adjust estimates for relevant confounders. RESULTS: 217 non-diabetic and 1,809 diabetic patients were included in the study, consisting of 42.2% Hispanic, 24.9% non-Hispanic (NH) Asian, 6.8% NH Black, 9.7% NH White and 16.3% Other patients. NH White was used as the reference group. Hispanic, NH Asian, and NH Black patients had significantly greater FAZ areas and FAZ perimeters, and lower DCP VD and VLD, among both non-diabetic and diabetic patients (Benjamini-Hochberg adjusted P-values <0.05). The addition of SES scores in the models did not modify any regressions significantly. CONCLUSIONS: In patients with and without diabetes, racial and ethnic minorities have significant retinal microvasculature differences when compared to NH White patients, regardless of SES. These differences are pronounced in DCP and may predispose racial/ethnic minorities to worse outcomes in DR, thus widening disparities in ophthalmic care.

Microvascular disease not type 2 diabetes is associated with increased cortical porosity: A study of cortical bone microstructure and intracortical vessel characteristics.

Introduction: Fracture risk is elevated in type 2 diabetes (T2D) despite normal or even high bone mineral density (BMD). Microvascular disease (MVD) is a diabetic complication, but also associated with other diseases, for example chronic kidney disease. We hypothesize that increased fracture risk in T2D could be due to increased cortical porosity (Ct.Po) driven by expansion of the vascular network in MVD. The purpose of this study was to investigate associations of T2D and MVD with cortical microstructure and intracortical vessel parameters. Methods: The study group consisted of 75 participants (38 with T2D and 37 without T2D). High-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) of the ultra-distal tibia were performed to assess cortical bone and intracortical vessels (outcomes). MVD was defined as ≥1 manifestation including neuropathy, nephropathy, or retinopathy based on clinical exams in all participants. Adjusted means of outcomes were compared between groups with/without T2D or between participants with/without MVD in both groups using linear regression models adjusting for age, sex, BMI, and T2D as applicable. Results: MVD was found in 21 (55 %) participants with T2D and in 9 (24 %) participants without T2D. In T2D, cortical pore diameter (Ct.Po.Dm) and diameter distribution (Ct.Po.Dm.SD) were significantly higher by 14.6 µm (3.6 %, 95 % confidence interval [CI]: 2.70, 26.5 µm, p = 0.017) and by 8.73 µm (4.8 %, CI: 0.79, 16.7 µm, p = 0.032), respectively. In MVD, but not in T2D, cortical porosity was significantly higher by 2.25 % (relative increase = 12.9 %, CI: 0.53, 3.97 %, p = 0.011) and cortical BMD (Ct.BMD) was significantly lower by -43.6 mg/cm3 (2.6 %, CI: -77.4, -9.81 mg/cm3, p = 0.012). In T2D, vessel volume and vessel diameter were significantly higher by 0.02 mm3 (13.3 %, CI: 0.004, 0.04 mm3, p = 0.017) and 15.4 µm (2.9 %, CI: 0.42, 30.4 µm, p = 0.044), respectively. In MVD, vessel density was significantly higher by 0.11 mm-3 (17.8 %, CI: 0.01, 0.21 mm-3, p = 0.033) and vessel volume and diameter were significantly lower by -0.02 mm3 (13.7 %, CI: -0.04, -0.004 mm3, p = 0.015) and - 14.6 µm (2.8 %, CI: -29.1, -0.11 µm, p = 0.048), respectively. Conclusions: The presence of MVD, rather than T2D, was associated with increased cortical porosity. Increased porosity in MVD was coupled with a larger number of smaller vessels, which could indicate upregulation of neovascularization triggered by ischemia. It is unclear why higher variability and average diameters of pores in T2D were accompanied by larger vessels.

Bilaterally subluxed diffractive intraocular lenses: big expectations and even bigger comorbidities.

A 78-year-old woman with an ocular history of cataract surgery with a diffractive intraocular lens (IOL) in each eye has developed fluctuating vision, greater in the right eye than the left eye, after 4 years. She has a history of inactive central serous retinopathy and a vision potential of 20/25 + 2 in the right eye and 20/25 in the left eye. She has well-controlled diabetes, hypertension, and hypercholesterolemia. She has enjoyed her spectacle independence for some time and wishes to have her vision restored. On examination, her uncorrected distance visual acuity (UDVA) was 20/50 in the right eye and 20/25 in the left eye and her uncorrected near visual acuity (UNVA) was J3 in the right eye and J1 in the left eye. Intraocular pressures (IOPs) measured 22 mm Hg in the right eye and 18 mm Hg in the left eye. Pupils had limited reactivity with irregularity in the right eye but no obvious relative afferent pupillary defect. Motility and confrontation visual fields were unremarkable in both eyes. Retinal acuity meter was 20/20 in both eyes, and manifest refraction was plano -1.25 × 105 20/40, J3 in the right eye and +0.50 × 20/25, J1 in the left eye. Pertinent findings on slitlamp examination included temporal iris atrophy and transillumination defects greater in the right eye than the left eye, peripupillary pseudoexfoliative changes in both eyes, significant inferior subluxation of a diffractive 3-piece posterior chamber IOL in the capsular bag with lens-pitting peripherally and few central, moderate pseudophacodonesis, and an open posterior capsule in the right eye. In the left eye, she had mild inferior subluxation of a single-piece acrylic diffractive IOL in the capsular bag with moderate pseudophacodonesis and an open posterior capsule (Figure 1JOURNAL/jcrs/04.03/02158034-202403000-00019/figure1/v/2024-02-20T193212Z/r/image-tiff). All other anterior segment findings were unremarkable. On dilated posterior examination, she had a cup-to-disc ratio of 0.50 in the right eye and 0.65 in the left eye without edema hemorrhage or pallor. There were attenuated vessels in both eyes, posterior vitreous detachment in both eyes, and a few small drusen peripherally in both eyes. There was retinal pigment epithelium irregularity and dropout parafoveal in the right eye and subfoveal in the left eye (Figure 2). There was no evidence of macular edema, subretinal fluid, choroidal thickening, or neovascular membranes. The periphery was unremarkable in both eyes.JOURNAL/jcrs/04.03/02158034-202403000-00019/figure2/v/2024-02-20T193212Z/r/image-tiff What testing would you obtain preoperatively to help guide your decision-making? How would you counsel the patient regarding comorbid conditions and expectations?

Feasibility demonstration of a device for vitreous liquid biopsy incidental to intravitreal injection.

PURPOSE: VitreoDx is an experimental device enabling push-button collection of a neat vitreous liquid biopsy incidental to an intravitreal injection. We explored the ability of the device to collect a sample usable for proteomic biomarker discovery and testing. DESIGN: Pilot study using ex vivo human eyes. METHODS: Non-vitrectomized, human eyes from nine donors 75-91 years of age were refrigerated in BSS and used within 5 days of death. Four VitreoDx devices fitted with 25G needles, and four staked needle insulin syringes with 30G needles, were inserted at equal intervals through the pars plana of each eye and held in place by a fixture. The sampling mode of each VitreoDx device was triggered to attempt to acquire a liquid biopsy up to 70 µL. The plunger of each insulin syringe was retracted to attempt to obtain a liquid biopsy with a maximum volume of 50 µL. Samples acquired with the VitreoDx were extracted to polypropylene cryovials, refrigerated to -80 ºC, and sent for offsite proteomic analysis by proximity extension assay with a focus on panels containing approved and pipelined drug targets for neovascular disease and inflammatory factors. RESULTS: Of the attempted liquid biopsies with the novel 25G VitreoDx, 92% (66 of 72) resulted in successful acquisition (>25 µL) while 89% (64 of 72) attempted by a traditional 30G needle resulted in a successful acquisition. Sample volume sufficient for proteomics array analysis was acquired by the VitreoDx for every eye. Detectable protein was found for 151 of 166 unique proteins assayed in at least 25% of eyes sampled by VitreoDx. CONCLUSIONS: The high acquisition rate achieved by the prototype was similar to that achieved in previous clinical studies where a standard syringe was used with a 25G needle to biopsy vitreous fluid directly prior to standard intravitreal injection. Successful aspiration rates were likewise high for 30G needles. Together, these suggest that it is possible to routinely acquire liquid vitreous biopsies from patients who typically receive intravitreal injections with an injection device using a standard size needle without a vitreous cutter. Protein analysis shows that proteins of interest survive the sampling mechanism and may have potential to direct care in the future.

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Vitreous Biomarkers for Proliferative Vitreoretinopathy Prognostication in Patients Undergoing Primary Retinal Detachment Repair.

Purpose: To compare baseline levels of exploratory biomarkers in the vitreous fluid of patients with primary retinal detachment who subsequently develop proliferative vitreoretinopathy (PVR) versus those who do not. Methods: In this exploratory case-control study, we evaluated the baseline protein biomarker levels from a biobank containing the vitreous fluid of patients who had undergone primary pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment. Undiluted samples were collected at the time of PPV and stored at -80°C. Samples from 13 patients who developed PVR within 6 months (PVR group) and 13 age- and gender-matched controls who did not develop PVR (control group) were included. Protein abundance levels were evaluated using a proximity extension assay, and a confirmatory enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of vimentin. Results: Baseline vimentin (Normalized Protein eXpression [NPX], 8.6 vs. 6.4, P < 0.0001) and heme oxygenase 1 (NPX 8.9 vs. 7.0, P < 0.001) levels were found to be elevated in vitreous fluid of patients who subsequently developed PVR compared to those who did not. Confirmatory analysis using ELISA demonstrated mean vimentin concentrations of 7254 vs. 2727 ng/mL in the PVR versus control groups (P = 0.0152). The odds ratio for developing PVR was 14 (confidence interval, 1.4-168; P = 0.03), assuming a baseline vimentin threshold of 7500 ng/mL. Conclusions: Vimentin is an intermediate filament protein expressed by retinal glial cells, and our data combined with prior evidence suggest that it may serve as an early vitreous biomarker for subsequent PVR formation and reactive gliosis. Furthermore, we found, for the first time, elevated baseline levels of heme oxygenase 1, a measurable indicator of oxidative stress. Translational Relevance: Our positive findings could impact clinical care for retinal detachment patients by facilitating risk stratification for targeted interventions or closer monitoring in those at the highest risk of developing PVR.

Association of Male Sex and Microvascular Alterations on Optical Coherence Tomography Angiography in Diabetes.

Purpose: Epidemiologically, men have a higher incidence, severity, and progression of diabetic retinopathy (DR) than women. We investigated microvascular differences between men and women with diabetes on optical coherence tomography angiography (OCTA). Methods: Three × 3 mm OCTA macula scans of non-diabetic and patients with diabetes were obtained. Vascular parameters included parafoveal vessel density (VD), vessel length density (VLD), and flow index (FI) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) as well as foveal avascular zone (FAZ) area and perimeter. Multivariable linear regression was used for statistical analysis. Results: There were 1809 patients with diabetes and 217 non-diabetic participants that were included in this study. Diabetic individuals included those with no DR (n = 1356), mild non-proliferative DR (NPDR; n = 286), moderate NPDR (n = 126), and severe NPDR/proliferative DR (PDR; n = 41). Male sex was significantly associated with smaller FAZ area/perimeter and lower DCP VLD in both non-diabetic subjects and patients with diabetes. Male sex in the diabetic group was additionally associated with lower SCP VD/VLD and DCP VD. Addition of an interaction between male sex and diabetes status in the interaction analysis showed that being male and diabetic conferred increased reduction in DCP VD and VLD compared to sex-based changes in non-diabetics. Larger FAZ perimeter, lower SCP VD/VLD, and lower DCP VLD were associated with poorer visual acuity in diabetics. Conclusions: On OCTA, male patients with diabetes may have more severe microvascular disease especially in the DCP compared to women. Translational Evidence: Sex-based alterations in diabetic microvascular disease has the potential to influence future basic and clinical studies as well as the implementation of OCTA disease markers.

Ultra-Widefield Imaging as a Teleophthalmology Screening Tool for Ocular Pathology.

Background: Prior studies have validated ultra-widefield imaging as a remote screening tool for diabetic retinopathy. The aim of this study was to determine its use in screening for any fundus pathology in a routine patient population. Methods: In this prospective randomized study, patients underwent both slit lamp indirect ophthalmoscopy and ultra-widefield imaging. Ultra-widefield images were independently reviewed by two optometrists, and discrepancies were adjudicated by a retina specialist. Clinical findings from slit-lamp examiners and image-reviewers were coded into themes and clinically meaningful findings were extracted. Cohen's kappa was used to estimate agreement for these findings between the two image-reviewers and between the image-reviewers and slit-lamp examiners. Results: Nine-hundred eyes of 450 patients were examined and imaged, of which 616 eyes were analyzed. At least one abnormal fundus finding was present on ophthalmoscopy in 71 eyes (11%) and on adjudicated image interpretation in 166 eyes (27%). Agreement between the two image-reviewers was moderate to substantial for most clinically meaningful findings, including optic disc hemorrhage (κ = 0.8), macular exudates (κ = 0.7), and macular pigmentary changes (κ = 0.7). Agreement between examiners and image-reviewers was moderate to substantial for optic disc hemorrhage (κ = 1), indistinct optic disc margins (κ = 0.5), drusen (κ = 0.4), pigmentary changes (κ = 0.4), and hemorrhage (κ = 0.8). A total of 187 findings were detected by imaging but not examination, compared with 42 that were detected on examination but not imaging. Conclusion: In a routine patient population, ultra-widefield imaging agreed with standard-of-care slit-lamp examinations and detected more fundus findings.

Modified intrascleral haptic fixation of the light adjustable lens in a case of spontaneous adult-onset bilateral lens subluxation.

Purpose: To describe the application of the light adjustable lens (LAL) using an intrascleral haptic fixation (ISHF) technique for the correction of aphakia and post-operative refractive error. Observation: The LAL was placed using a modified trocar-based ISHF technique for visual rehabilitation following removal of bilateral cataracts in a patient with ectopia lentis. She ultimately obtained an excellent refractive outcome after adjustment with micro-monovision. Conclusions and Importance: Secondary intraocular lens placement has a much higher risk of residual ametropia than traditional in-the-bag lens placement. The ISHF technique with the LAL presents a solution for eliminating postoperative refractive error in patients requiring scleral-fixated lenses.

Aqueous Fluid Transcriptome Profiling Differentiates Between Non-Neovascular and Neovascular AMD.

Purpose: Early and intermediate non-neovascular AMD (NN-AMD) has the potential to progress to either advanced NN-AMD with geographic atrophy, or to neovascular AMD (N-AMD) with CNV. This exploratory study performed an unbiased analysis of aqueous humor transcriptome in patients with early or intermediate NN-AMD vs. treatment-naïve N-AMD to determine the feasibility of using this method in future studies investigating pathways and triggers for conversion from one form to another. Methods: Aqueous humor samples were obtained from 20 patients with early or intermediate NN-AMD and 20 patients with untreated N-AMD, graded on clinical examination and optical coherence tomography. Transcriptome profiles were generated using next-generation sequencing methods optimized for ocular samples. Top-ranked transcripts were compared between groups, and pathway enrichment analysis was performed. Results: Seventy-eight differentially expressed transcripts were identified. Unsupervised clustering of differentially expressed transcripts was able to successfully differentiate between the two groups based on aqueous transcriptome alone. Pathway analysis highlighted changes in expression of genes associated with mitochondrial respiration, oxidative stress, ubiquitination, and neurogenesis between the two groups. Conclusions: This pilot study compared the aqueous fluid transcriptome of patients with early or intermediate NN-AMD and untreated N-AMD. Differences in transcripts and transcriptome pathways identified in the aqueous of patients with early or intermediate NN-AMD compared with patients with N-AMD are consistent with those previously implicated in the pathogenesis of these distinct AMD subtypes. The findings from this exploratory study warrant further investigation using a larger, prospective study design, with the inclusion of a control group of eyes without AMD.

Proximity Extension Assay (PEA) Platform to Detect Vitreous Biomarkers of Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the leading causes of blindness, affecting more than 100 million people worldwide. Currently, DR prognosis and management are based mainly on biomarkers identified by direct retinal fundus observation or by imaging devices. The use of molecular biology to discover biomarkers of DR has great potential to impact the standard of care, and the vitreous humor can serve as an indirect source for those molecular biomarkers because it is rich in proteins secreted by the retina. Proximity extension assay (PEA) is a technology that combines antibody-based immunoassays with DNA-coupled methodology to obtain information on the abundance of multiple proteins while using minimal sample volume, with high specificity and sensitivity. Matched antibodies labelled with a complementary sequence of oligonucleotides are used to simultaneously bind a target protein in solution, and when in proximity, the complementary sequences on each antibody hybridize, serving as template for DNA polymerase-dependent extension and the generation of a unique double-stranded DNA "barcode." PEA works well with vitreous matrix and has great potential to support the identification of novel predictive and prognostic biomarkers of DR.

Right versus left eye asymmetry of microvasculature in diabetes revealed by optical coherence tomography angiography.

In this study, we explored inter-ocular asymmetry (between the two eyes of the same patient) using optical coherence tomography angiography (OCTA) in patients with diabetes mellitus (DM) at different retinopathy stages. A total of 258 patients were divided into four groups: no DM, DM without diabetic retinopathy (DR), non-proliferative DR (NPDR), and proliferative DR (PDR). Superficial and deep vessel density (SVD, DVD), superficial and deep perfusion density (SPD, DPD), foveal avascular zone (FAZ) area, perimeter and circularity were calculated, and asymmetry index (AI) was used to evaluate the asymmetry of two eyes of the same subject. AIs of SPD, SVD, FAZ area and FAZ perimeter in the PDR group were larger than all other 3 groups (all p < 0.05). The AIs of DPD, DVD, FAZ area and FAZ perimeter in males were larger than in females (p = 0.015, p = 0.023, p = 0.006 and p = 0.017). Hemoglobin A1c (HbA1c) was positively correlated with AI of FAZ perimeter (p = 0.02) and circularity (p = 0.022). In conclusion, PDR patients' eyes were significantly asymmetric in both vascular density and FAZ metrics. Male sex and HbA1c are risk factors that influenced symmetry. This study highlights that right-left asymmetry should be taken into account in DR-related studies, particularly those analyzing microvascular changes with OCTA.

Individual and Systems-Based Risk Factors for Diabetic Vitrectomy in an Urban Safety-Net Hospital.

OBJECTIVE: To identify individual and systems-focused risk factors for pars plana vitrectomy among patients with proliferative diabetic retinopathy (PDR) in a diverse, urban, safety-net hospital setting. DESIGN: Single-center, retrospective, observational, case-control study at Zuckerberg San Francisco General Hospital and Trauma Center between 2017 and 2022. SUBJECTS: Two hundred twenty-two patients with PDR over a 5-year span (2017-2022), consisting of 111 cases who underwent vitrectomy for vision-threatening complications (tractional retinal detachment, nonclearing vitreous hemorrhage, and neovascular glaucoma) and 111 controls with PDR with no history of vitrectomy or vision-threatening complications. Controls were matched 1:1 through incidence density sampling. METHODS: Medical records were reviewed from time of entry into hospital system to vitrectomy date (or date-matched clinic visit for controls). Individual-focused exposures included age, gender, ethnicity, language, homelessness, incarceration, smoking status, area deprivation index, insurance status, baseline retinopathy stage, baseline visual acuity, baseline hemoglobin A1c, panretinal photocoagulation status, and cumulative anti-VEGF treatments. System-focused exposures included external department involvement, referral route, time within hospital and ophthalmology systems, interval between screening and ophthalmology appointment, interval between conversion to proliferative disease and panretinal photocoagulation or first treatment, and loss-to-follow-up in intervals of active proliferative disease. MAIN OUTCOME MEASURES: Odds ratios (ORs) for each exposure on vision-threatening diabetic complications requiring vitrectomy. RESULTS: The absence of panretinal photocoagulation was the primary significant individual-focused risk factor for vitrectomy in the multivariable analysis (OR, 4.78; P = 0.011). Systems-focused risk factors included longer interval between PDR diagnosis and initial treatment (weeks; OR, 1.06; P = 0.024) and greater cumulative duration of loss-to-follow-up during intervals of active PDR (months; OR, 1.10; P = 0.002). Greater duration in the ophthalmology system was the primary systems-focused protective factor against vitrectomy (years; OR, 0.75; P = 0.035). CONCLUSIONS: Largely modifiable variables modulate risk of complications requiring diabetic vitrectomy. Each additional month of loss-to-follow-up for patients with active proliferative disease increased odds of vitrectomy by 10%. Optimizing modifiable factors to promote earlier treatment and maintain critical follow-up in proliferative disease may reduce vision-threatening complications requiring vitrectomy in a safety-net hospital setting. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Longitudinal fundus imaging and its genome-wide association analysis provide evidence for a human retinal aging clock.

Biological age, distinct from an individual's chronological age, has been studied extensively through predictive aging clocks. However, these clocks have limited accuracy in short time-scales. Here we trained deep learning models on fundus images from the EyePACS dataset to predict individuals' chronological age. Our retinal aging clocking, 'eyeAge', predicted chronological age more accurately than other aging clocks (mean absolute error of 2.86 and 3.30 years on quality-filtered data from EyePACS and UK Biobank, respectively). Additionally, eyeAge was independent of blood marker-based measures of biological age, maintaining an all-cause mortality hazard ratio of 1.026 even when adjusted for phenotypic age. The individual-specific nature of eyeAge was reinforced via multiple GWAS hits in the UK Biobank cohort. The top GWAS locus was further validated via knockdown of the fly homolog, Alk, which slowed age-related decline in vision in flies. This study demonstrates the potential utility of a retinal aging clock for studying aging and age-related diseases and quantitatively measuring aging on very short time-scales, opening avenues for quick and actionable evaluation of gero-protective therapeutics.

Developing and Validating Models to Predict Progression to Proliferative Diabetic Retinopathy.

Purpose: To develop models for progression of nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR) and determine if incorporating updated information improves model performance. Design: Retrospective cohort study. Participants: Electronic health record (EHR) data from a tertiary academic center, University of California San Francisco (UCSF), and a safety-net hospital, Zuckerberg San Francisco General (ZSFG) Hospital were used to identify patients with a diagnosis of NPDR, age ≥ 18 years, a diagnosis of type 1 or 2 diabetes mellitus, ≥ 6 months of ophthalmology follow-up, and no prior diagnosis of PDR before the index date (date of first NPDR diagnosis in the EHR). Methods: Four survival models were developed: Cox proportional hazards, Cox with backward selection, Cox with LASSO regression and Random Survival Forest. For each model, three variable sets were compared to determine the impact of including updated clinical information: Static0 (data up to the index date), Static6m (data updated 6 months after the index date), and Dynamic (data in Static0 plus data change during the 6-month period). The UCSF data were split into 80% training and 20% testing (internal validation). The ZSFG data were used for external validation. Model performance was evaluated by the Harrell's concordance index (C-Index). Main Outcome Measures: Time to PDR. Results: The UCSF cohort included 1130 patients and 92 (8.1%) patients progressed to PDR. The ZSFG cohort included 687 patients and 30 (4.4%) patients progressed to PDR. All models performed similarly (C-indices ∼ 0.70) in internal validation. The random survival forest with Static6m set performed best in external validation (C-index 0.76). Insurance and age were selected or ranked as highly important by all models. Other key predictors were NPDR severity, diabetic neuropathy, number of strokes, mean Hemoglobin A1c, and number of hospital admissions. Conclusions: Our models for progression of NPDR to PDR achieved acceptable predictive performance and validated well in an external setting. Updating the baseline variables with new clinical information did not consistently improve the predictive performance. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

External Subretinal Fluid Drainage in Scleral Buckling: Before Versus after Cryotherapy and Buckle Placement, A Pilot Study.

In this retrospective comparative case series at a teaching hospital, we reviewed adult patients with rhegmatogenous retinal detachment who underwent scleral buckling surgery with external drainage of subretinal fluid performed before versus after placement of the scleral buckle. Eight eyes in each group were roughly matched for age, sex, baseline visual acuity (VA), and detachment characteristics. The complication rate was 0% for the "before" group and 37% for the "after" group (p = 0.100). In the "after" group, two eyes (25%) developed iatrogenic retinal holes and one eye (12%) developed self-limited subretinal hemorrhage during external needle drainage. The duration of surgery was significantly shorter for the "before" group (mean 89 ± 16 min) compared to the "after" group (118 ± 20 min) (p = 0.008). The primary anatomic success rate was 100% for the "before" group and 75% for the "after" group (p = 0.233). Final VA was not significantly different between the groups or from baseline. In conclusion, while limited by our small sample size, this pilot study suggests that drainage of subretinal fluid before scleral buckle placement may be safer and more efficient compared to draining after buckle placement. Initial drainage may facilitate retinochoroid apposition to allow targeted cryopexy and precise buckle placement.

Rapid pre-retinal ossification presenting as a vascularized lesion over an area of chronic retinal detachment.

Purpose: To describe the clinical, optical coherence tomography (OCT), and histopathological findings of a patient who was found to have ossification of a pre-retinal membrane after multiple surgical repairs for retinal detachment. Methods: The patient had comprehensive ophthalmic examinations during seven years of follow-up and underwent surgical removal of her pre-retinal membrane. Results: A 24-year-old woman with a history of retinal detachment and multiple retina surgeries presented with baseline vision of 20/200 and refractory glaucoma in the left eye (right eye with no light perception due to prior failed retinal detachment repair). OCT showed a thick epiretinal membrane with hypo-reflective intraretinal spaces in the macula, and exam revealed a chronic retinal detachment superotemporally surrounded by laser barricade. She was stable for six years and then experienced vision loss and decreasing eye pressure, concurrent with rapid evolution of pre-retinal fibrosis, leading to a vascularized consolidation in the mid-periphery, for which she underwent vitrectomy and membrane peel. The vascularized lesion over the area of detachment in the superotemporal retina was removed en bloc through the anterior chamber. Pathological findings revealed woven bone formation anterior to the internal limiting membrane, and the tissue was GFAP negative. Conclusions: Our case adds to the limited knowledge of the chronology, presentation, and surgical management of intraocular ossification, especially of the rarer pre-retinal type. Our patient highlights that development of ossification can happen more quickly than previously thought (year or years rather than decades), can be hidden under vascularized lesions, and is dynamic, with simultaneous release of traction in one area and increased traction in another. Diligent follow-up is indicated even in cases of vitreous membranes from retinal detachment that otherwise appear to have been stable for years.

Efficacy of the Fluocinolone Acetonide (Yutiq) Intravitreal Implant as Monotherapy for Uveitis.

PURPOSE: To evaluate the efficacy of the fluocinolone acetonide intravitreal implant (Yutiq) as monotherapy for uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients at a single academic health-care institution. METHODS: Medical record review of patients with non-infectious uveitis actively suppressed on an alternative anti-inflammatory regimen who received a fluocinolone acetonide implant. The primary outcome was continued control of inflammation based on clinical examination, optical coherence tomography, and fluorescein angiography. RESULTS: Thirteen patients (19 eyes) received an implant. Median follow-up was 6 months. Uveitis control was achieved in 14 eyes (74%), though three (21%) required a topical steroid after insertion. The remaining five eyes (26%) required additional intraocular treatments. CONCLUSION: The fluocinolone acetonide implant may not suffice as monotherapy for all patients with uveitis, but it may be effective as an adjunctive treatment. We propose a clinical workflow for the selection and treatment of patients who may benefit from it.

Duration of Diabetes as a Risk Factor for Retinal Microvasculature Alterations Detected with Optical Coherence Tomography Angiography in Patients without Clinical Retinopathy.

In this study, we examined the impact of diabetes mellitus (DM) disease duration on optical coherence tomography angiography (OCTA) parameters in diabetic patients without diabetic retinopathy (DR). A total of 1118 eyes from 1118 DM patients without DR were divided into three groups by DM duration: 0−5 years (short cohort; n = 571), 6−10 years (medium cohort; n = 306), and >10 years (long cohort; n = 241). Ultra-widefield fundus photography and nine OCTA parameters derived from the superficial retinal capillary plexus were analyzed. Perfusion density (PD) and vessel length density (VD) were significantly decreased within the 1 mm patch in patient OCTAs from the medium cohort compared to the short cohort. Conversely, PD and VD were significantly decreased within the 6 mm patch and inner ring among the long cohort compared to the short and medium cohorts. These findings remained consistent after controlled analysis. Patients in the medium cohort had the largest FAZ area, while patients in the long cohort had the smallest FAZ area, with a statistically significant difference between the two groups. Superficial PD and VD significantly decreased among the medium and long cohorts compared to the short cohort, confirming that subclinical, progressive macular vasculature change is associated with longer DM duration. However, while FAZ area significantly increased in the medium cohort, the long cohort exhibited decreased FAZ area, suggesting the latter may possess protective factors that decrease overall risk of DR development.