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Investigative Ophthalmology & Visual... Jun 2024In age-related macular degeneration (AMD), choriocapillaris flow deficits (CCFDs) under soft drusen can be measured using established compensation strategies. This study...
PURPOSE
In age-related macular degeneration (AMD), choriocapillaris flow deficits (CCFDs) under soft drusen can be measured using established compensation strategies. This study investigated whether CCFDs can be quantified under calcified drusen (CaD).
METHODS
CCFDs were measured in normal eyes (n = 30) and AMD eyes with soft drusen (n = 30) or CaD (n = 30). CCFD density masks were generated to highlight regions with higher CCFDs. Masks were also generated for soft drusen and CaD based on both structural en face OCT images and corresponding B-scans. Dice similarity coefficients were calculated between the CCFD density masks and both the soft drusen and CaD masks. A phantom experiment was conducted to simulate the impact of light scattering that arises from CaD.
RESULTS
Area measurements of CCFDs were highly correlated with those of CaD but not soft drusen, suggesting an association between CaD and underlying CCFDs. However, unlike soft drusen, the detected optical coherence tomography (OCT) signals underlying CaD did not arise from the defined CC layer but were artifacts caused by the multiple scattering property of CaD. Phantom experiments showed that the presence of highly scattering material similar to the contents of CaD caused an artifactual scattering tail that falsely generated a signal in the CC structural layer but the underlying flow could not be detected. Similarly, CaD also caused an artifactual scattering tail and prevented the penetration of light into the choroid, resulting in en face hypotransmission defects and an inability to detect blood flow within the choriocapillaris. Upon resolution of the CaD, the CC perfusion became detectable.
CONCLUSIONS
The high scattering property of CaD leads to a scattering tail under these drusen that gives the illusion of a quantifiable optical coherence tomography angiography signal, but this signal does not contain the angiographic information required to assess CCFDs. For this reason, CCFDs cannot be reliably measured under CaD, and CaD must be identified and excluded from macular CCFD measurements.
Topics: Humans; Tomography, Optical Coherence; Choroid; Retinal Drusen; Female; Aged; Male; Fluorescein Angiography; Regional Blood Flow; Calcinosis; Aged, 80 and over; Macular Degeneration; Middle Aged; Phantoms, Imaging; Fundus Oculi
PubMed: 38884553
DOI: 10.1167/iovs.65.6.26 -
Translational Vision Science &... Jun 2024To establish the reliability and validity of five performance-based activities of daily living task tests (ADLTT), to correlate structure to function, to evaluate the...
PURPOSE
To establish the reliability and validity of five performance-based activities of daily living task tests (ADLTT), to correlate structure to function, to evaluate the impact of visual impairment (VI) on age-related macular degeneration (AMD), and to develop new outcome measures.
METHODS
A multidisciplinary team developed five ADLTTs: (1) reading test (RT); (2) facial expression (FE) recognition; (3) item search (IS) task; (4) money counting (MC) task; and (5) making a drink (MD), tested with binocular and monocular vision. ADLTTs were tested for known-group (i.e., difference between AMD group and controls) and convergent (i.e., correlation to other measures of visual function), validity metrics, and test-retest reliability in 36 patients with VI (visual acuity (logMAR VA > 0.4) in at least one eye caused by AMD versus 36 healthy controls without VI.
RESULTS
Compared to controls, AMD patients had a slower reading speed (-77.41 words/min; P < 0.001); took longer to complete MC using monocular worse eye and binocular vision (15.13 seconds and 4.06 seconds longer compared to controls, respectively; P < 0.001); and MD using monocular worse eye vision (9.37 sec; P = 0.033), demonstrating known-group validity. Only RT and MC demonstrated convergent validity, showing correlations with VA, contrast sensitivity, and microperimetry testing. Moderate to good test-retest reliability was observed for MC and MD (interclass correlation coefficient = 0.55 and 0.77; P < 0.001) using monocular worse eye vision.
CONCLUSIONS
Real-world ADL functioning associated with VI-related AMD can be assessed with our validated ADLTTs, particularly MC and MD.
TRANSLATIONAL RELEVANCE
This study validates visual function outcome measures that are developed for use in future clinical practice and clinical trials.
Topics: Humans; Activities of Daily Living; Macular Degeneration; Female; Male; Aged; Visual Acuity; Reproducibility of Results; Aged, 80 and over; Middle Aged; Vision Tests; Vision, Binocular; Reading
PubMed: 38884546
DOI: 10.1167/tvst.13.6.9 -
Medical Research Archives Oct 2023We briefly review our recently published approach to mining digenic genotype patterns, which consist of two genotypes each originating in a different DNA variant. We do...
We briefly review our recently published approach to mining digenic genotype patterns, which consist of two genotypes each originating in a different DNA variant. We do this for a genetic case-control study by evaluating all possible pairs of genotypes, distributing the workload over numerous CPUs (threads) in a high-performance computing environment and apply our methods to two known datasets, age-related macular degeneration (AMD) and Parkinson Disease (PD). Based on a list of (e.g., 100,000) genotype pairs with largest genotype pair frequency differences between cases and controls, we determine the number of unique variants occurring in this list. For each unique variant, we find the number of genotype pairs it participates in, which identifies a set of variants "connected" with the given unique variant. Among the total of variants "connected" with all unique variants, only a subset of variants is unique. The ratio of all connected variants divided by that subset of variants is a measure for the overall density or connectedness of variants interacting with each other. We find that variants for the AMD data are much more interconnected than those for PD, at least based on the 100,000 genotype pairs with largest chi-square we investigated. Further, for each of the unique variants, we use the number of variants connected with it as a test statistic, weighted by the inverse of the rank at which the unique variant first occurred in the original list of genotype patterns. This weighing scheme ties the number of connections to the genetics of the trait and allows us to obtain, for each of the unique variants, an empirical significance level by permuting ranks. We find 12 and 8 significant, highly connected variants for AMD and PD, respectively, some of which have previously been identified by other machine learning methods, thus providing credence to our approach. Among the 100,000 genotype pairs investigated for each of AMD and PD, significant variants showed connections with up to 7,093 and 3,777 other variants, respectively. Our approach has been implemented in a freely available piece of software, the . Thus, our statistical genetics method can provide important information on the genetic architecture of polygenic traits.
PubMed: 38882238
DOI: 10.18103/mra.v11i10.4604 -
Clinical Ophthalmology (Auckland, N.Z.) 2024Photodynamic therapy (PDT) with verteporfin involves intravenous administration of a photosensitizer followed by its laser light activation at the target site to inhibit... (Review)
Review
Photodynamic therapy (PDT) with verteporfin involves intravenous administration of a photosensitizer followed by its laser light activation at the target site to inhibit aberrant choroidal vascularization. This narrative review provides an overview of the role verteporfin PDT plays in the management of chorioretinal conditions. A PubMed literature review of all English-language articles published through October 19, 2023, was conducted to identify relevant references. Verteporfin PDT has been shown to be safe and effective for the treatment of patients with choroidal neovascularization (CNV) due to neovascular age-related macular degeneration and is often used in combination with a vascular endothelial growth factor (VEGF) inhibitor. Additionally, patients with polypoidal choroidal vasculopathy, a subtype of neovascular age-related macular degeneration, also benefit from verteporfin PDT combined with a VEGF inhibitor for improving visual acuity. Verteporfin PDT has also been effective in treating patients with peripapillary CNV, as well as eyes with CNV due to ocular histoplasmosis and pathologic myopia. Reduced dose and/or fluence PDT protocols have been effective in patients with central serous chorioretinopathy while reducing adverse effects. In eyes with choroidal hemangioma, tumor regression and visual outcomes have been improved with verteporfin PDT treatment. Photodynamic therapy with verteporfin continues to play an important role in the management of chorioretinal conditions.
PubMed: 38881707
DOI: 10.2147/OPTH.S464371 -
Ophthalmology Science 2024Knowing the surgical safety of anterior chamber liquid biopsies will support the increased use of proteomics and other molecular analyses to better understand disease...
PURPOSE
Knowing the surgical safety of anterior chamber liquid biopsies will support the increased use of proteomics and other molecular analyses to better understand disease mechanisms and therapeutic responses in patients and clinical trials. Manual review of operative notes from different surgeons and procedures in electronic health records (EHRs) is cumbersome, but free-text software tools could facilitate efficient searches.
DESIGN
Retrospective case series.
PARTICIPANTS
A total of 1418 aqueous humor liquid biopsies from patients undergoing intraocular surgery.
METHODS
Free-text EHR searches were performed using the Stanford Research Repository cohort discovery tool to identify complications associated with anterior chamber paracentesis and subsequent endophthalmitis. Complications of the surgery unrelated to the biopsy were not reviewed.
MAIN OUTCOME MEASURES
Biopsy-associated intraoperative complications and endophthalmitis.
RESULTS
A total of 1418 aqueous humor liquid biopsies were performed by 17 experienced surgeons. EHR free-text searches were 100% error-free for surgical complications, >99% for endophthalmitis (<1% false positive), and >93.6% for anesthesia type, requiring manual review for only a limited number of cases. More than 85% of cases were performed under local anesthesia without ocular muscle akinesia. Although the most common indication was cataract (50.1%), other diagnoses included glaucoma, diabetic retinopathy, uveitis, age-related macular degeneration, endophthalmitis, retinitis pigmentosa, and uveal melanoma. A 50- to 100-μL sample was collected in all cases using either a 30-gauge needle or a blunt cannula via a paracentesis. The median follow-up was >7 months. There was only one minor complication (0.07%) identified: a case of a small tear in Descemet membrane without long-term sequelae. No other complications occurred, including other corneal injuries, lens or iris trauma, hyphema, or suprachoroidal hemorrhage. There was no case of postoperative endophthalmitis.
CONCLUSIONS
Anterior chamber liquid biopsy during intraocular surgery is a safe procedure and may be considered for large-scale collection of aqueous humor samples for molecular analyses. Free-text EHR searches are an efficient approach to reviewing intraoperative procedures.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38881613
DOI: 10.1016/j.xops.2024.100517 -
Ophthalmology Science 2024We used exact matching and inverse propensity score weighting (IPSW) using real-world data (RWD) from the American Academy of Ophthalmology IRIS® Registry (Intelligent...
PURPOSE
We used exact matching and inverse propensity score weighting (IPSW) using real-world data (RWD) from the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) to emulate the 2 pro re nata () treatment arms from the Comparison of AMD Treatment Trial (CATT) and to compare the outcomes of the RWD arms to the 2 monthly treatment arms from the clinical trial.
DESIGN
Retrospective cohort study utilizing deidentified electronic health record registry data and patient-level deidentified clinical trial data.
SUBJECTS
All treatment-naive patient eyes with neovascular age-related macular degeneration treated with ranibizumab or bevacizumab only for 1 year from either the CATT or the IRIS Registry.
METHODS
Patients were identified in the IRIS Registry between October 1, 2015 and December 31, 2019. After all nonimaging-based inclusion and exclusion criteria from the CATT were applied, patient eyes receiving bevacizumab or ranibizumab only on a basis were identified as the eligible cohort. Exact matching and ISPW was applied based on age, gender, and baseline visual acuity.
MAIN OUTCOME MEASURES
Mean change in visual acuity, in approximated ETDRS letters, between baseline and 1 year for the IRIS Registry prn treatment arms generated by exact matching and IPSW.
RESULTS
We identified 427 eyes treated with ranibizumab and 771 eyes treated with bevacizumab . Using exact matching, 98% (n = 281) of CATT patient eyes in the bevacizumab monthly treatment arm and 87% (n = 261) of CATT patient eyes in the ranibizumab monthly treatment arm were matched to a patient eye in the IRIS Registry. For the ranibizumab treatment arm, patient eyes generated using exact matching gained 1.9 letters and those generated using IPSW gained 2.8 letters (exact matching: 1.9 letters ± 14.0 vs. IPSW: 2.8 letters ± 15.0 letters, = 0.43). For the bevacizumab treatment arm, patient eyes generated using exact matching gained 2.4 letters and those generated using IPSW gained 2.1 letters (exact matching: 2.4 letters ± 15.4 vs. IPSW: 2.1 letters ± 16.0 letters, = 0.79).
CONCLUSIONS
Both exact matching and IPSW produced similar results in emulating the treatment arms of the CATT using IRIS Registry data and patient-level clinical trial data. Similar to prior real-world studies, the clinical outcomes were significantly worse in the IRIS Registry treatment arms compared with the clinical trial.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38881608
DOI: 10.1016/j.xops.2024.100524 -
Ophthalmology Science 2024To assess the efficacy and safety of the PRIMA neurostimulation system with a subretinal microchip for improving visual acuity (VA) in patients with geographic atrophy...
OBJECTIVE
To assess the efficacy and safety of the PRIMA neurostimulation system with a subretinal microchip for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months postimplantation.
DESIGN
Feasibility clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.govNCT03333954).
SUBJECTS
Five patients with GA, no foveal light perception, and VA of logarithm of the minimum angle of resolution (logMAR) 1.3 to 1.7 (20/400-20/1000) in their worse-seeing "study" eye.
METHODS
In patients subretinally implanted with a photovoltaic neurostimulation array containing 378 pixels of 100 μm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 m. The system's external components, augmented reality glasses, and pocket computer provide image processing capabilities, including zoom.
MAIN OUTCOME MEASURES
Visual acuity using ETDRS charts with and without the system, as well as light sensitivity in the central visual field, measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and OCT up to 48 months postimplantation.
RESULTS
All 5 subjects met the primary end point of light perception elicited by the implant in the scotoma area. In 1 patient, the implant was incorrectly inserted into the choroid. One subject died 18 months postimplantation due to study-unrelated reasons. ETDRS VA results for the remaining 3 subjects are reported here. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to a mean logMAR of 1.39, or Snellen of 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (standard error 5.1) 95% confidence intervals (13.4, 49.9; < 0.0001). Natural peripheral visual function in the treated eye did not decline after surgery or during the 48-month follow-up period ( = 0.08).
CONCLUSIONS
Subretinal implantation of PRIMA in subjects with GA experiencing profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48 months. Prosthetic central vision provided by photovoltaic neurostimulation enabled patients to reliably recognize letters and sequences of letters, and with zoom, it improved VA of up to 8 ETDRS lines.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38881600
DOI: 10.1016/j.xops.2024.100510 -
Ophthalmology Science 2024To evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan-VEGF receptor inhibitor packaged in a bioerodible delivery technology...
PURPOSE
To evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan-VEGF receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy.
DESIGN
Phase I, multicenter, prospective, open-label, dose-escalation trial.
PARTICIPANTS
Patients with wAMD and evidence of prior anti-VEGF therapy response.
METHODS
Patients received a single intravitreal injection of EYP-1901.
MAIN OUTCOME MEASURES
The primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates.
RESULTS
Seventeen patients enrolled in the 440 μg (3 patients), 1030 μg (1 patient), 2060 μg (8 patients), and 3090 μg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline in BCVA was -1.8 letters and -5.4 letters at 6 and 12 months. Mean change from baseline in CST was +1.7 μm and +2.4 μm at 6 and 12 months. Reduction in treatment burden was 74% and 71% at 6 and 12 months. Of 16 study eyes, 13, 8, and 5 were injection-free up to 3, 6, and 12 months.
CONCLUSION
In the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing phase II and planned phase III trials to assess efficacy and safety.
FINANCIAL DISCLOSURES
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
PubMed: 38881599
DOI: 10.1016/j.xops.2024.100527 -
Scientific Reports Jun 2024We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with...
We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with treatment-resistant diabetic macular edema (DME). The medical records of 15 patients with DME who had received IVA injection ≥ 3 months before were retrospectively reviewed. The best-corrected visual acuity, central macular thickness (CMT) on optical coherence tomography, and mean blur rate (MBR) of all disc areas on laser speckle flowgraphy were measured before, 1 week after, and 4 weeks after IVA and IVF, respectively. The changes in visual acuity showed no significant difference after switching from IVA to IVF (P = 0.732). The mean CMT decreased significantly during the follow-up period (both P < 0.001). MBR showed no significant difference during the follow-up period (P = 0.26). However, it decreased significantly 4 weeks after IVF (P = 0.01) compared with the baseline value, but not 4 weeks after IVA (P = 0.074). A significant association was observed between decreased MBR and decreased CMT in patients who received IVF (correlation coefficient: 0.501, P = 0.005) but not in those who received IVA (P = 0.735). Thus, IVF maintained ocular blood flow reduction, although no significant differences in visual acuity and CMT changes were observed compared to IVA.
Topics: Humans; Macular Edema; Male; Female; Intravitreal Injections; Recombinant Fusion Proteins; Receptors, Vascular Endothelial Growth Factor; Middle Aged; Diabetic Retinopathy; Aged; Retrospective Studies; Visual Acuity; Tomography, Optical Coherence; Angiogenesis Inhibitors; Regional Blood Flow; Eye
PubMed: 38877041
DOI: 10.1038/s41598-024-63435-8 -
The Journal of Biological Chemistry Jun 2024The complement system plays a critical role in the innate immune response, acting as a first line of defense against invading pathogens. However, dysregulation of the...
The complement system plays a critical role in the innate immune response, acting as a first line of defense against invading pathogens. However, dysregulation of the complement system is implicated in the pathogenesis of numerous diseases, ranging from Alzheimer's to age-related macular degeneration (AMD) and rare blood disorders. As such, complement inhibitors have enormous potential to alleviate disease burden. While a few complement inhibitors are in clinical use, there is still a significant unmet medical need for the discovery and development of novel inhibitors to treat patients suffering from disorders of the complement system. A key hurdle in the development of complement inhibitors has been the determination of their mechanism of action. Progression along the complement cascade involves the formation of numerous multimeric protein complexes, creating the potential for inhibitors to act at multiple nodes in the pathway. This is especially true for molecules that target the central component C3 and its fragment C3b, which serve a dual role as a substrate for the C3 convertases and as a scaffolding protein in both the C3 and C5 convertases. Here, we report a step-by-step in vitro reconstitution of the complement alternative pathway using bio-layer interferometry. By physically uncoupling each step in the pathway, we were able to determine the kinetic signature of inhibitors that act at single steps in the pathway and delineate the full mechanism of action of known and novel C3 inhibitors. The method could have utility in drug discovery and further elucidating the biochemistry of the complement system.
PubMed: 38876307
DOI: 10.1016/j.jbc.2024.107467