Search

Purpose: The integrin αvβ3 is differentially expressed on neovascular endothelial cells. We investigated whether a novel intravenously injectable αvβ3 integrin-ligand coupled nanoparticle (NP) can target choroidal neovascular membranes (CNV) for imaging and targeted gene therapy. Methods: CNV lesions were induced in rats using laser photocoagulation. The utility of NP for in vivo imaging and gene delivery was evaluated by coupling the NP with a green fluorescing protein plasmid (NP-GFPg). Rhodamine labeling (Rd-NP) was used to localize NP in choroidal flatmounts. Rd-NP-GFPg particles were injected intravenously on weeks 1, 2, or 3. In the treatment arm, rats received NP containing a dominant negative Raf mutant gene (NP-ATPm-Raf) on days 1, 3, and 5. The change in CNV size and leakage, and TUNEL positive cells were quantified. Results: GFP plasmid expression was seen in vivo up to 3 days after injection of Rd-NP-GFPg. Choroidal flatmounts confirmed the localization of the NP and the expression of GFP plasmid in the CNV. Treating the CNV with NP-ATPm-Raf decreased the CNV size by 42% (P<0.001). OCT analysis revealed that the reduction of CNV size started on day 5 and reached statistical significance by day 7. Fluorescein angiography grading showed significantly less leakage in the treated CNV (P<0.001). There were significantly more apoptotic (TUNEL-positive) nuclei in the treated CNV. Conclusion: Systemic administration of αvβ3 targeted NP can be used to label the abnormal blood vessels of CNV for imaging. Targeted gene delivery with NP-ATPm-Raf leads to a reduction in size and leakage of the CNV by induction of apoptosis in the CNV. [ABSTRACT FROM AUTHOR]

The article focuses on traumatic lens subluxation and dislocation. An overview of the disorder is provided along with the criticalness of preoperative evaluation of zonular stability. The use of capsular support devices and the choice of appropriate intraocular lens (IOL) for implantation are cited as surgical approaches to mitigate the complications from traditional phacoemulsification. A wide range of capsular support devices are presented including capsular tension rings (CTRs), modified CTRs, capsular tension segments, and capsular support hooks.

The stability of microtubules during the cell-cycle is regulated by a number of cellular factors, some of which stabilize microtubules and others that promote breakdown. XKCM1 is a kinesin-like protein that induces microtubule depolymerization and is required for mitotic spindle assembly. We have examined the binding and depolymerization effects of XKCM1 on different tubulin polymers in order to learn about its mechanism of action. Zinc-induced tubulin polymers, characterized by an anti-parallel protofilament arrangement, are depolymerized by XKCM1, indicating that this enzyme acts on a single protofilament. GDP-tubulin rings, which correspond to the low-energy state of tubulin, are stable only under conditions that inhibit XKCM1 depolymerizing activity, but can be stabilized by XKCM1 bound to AMPPNP. Tubulin polymers made of subtilisin-treated tubulin (lacking the tubulin C-terminal tail) are resistant to XKCM1-induced depolymerization, suggesting that the interaction of the acidic tail of tubulin with basic residues in XKCM1 unique to Kin I proteins is required for depolymerization. [Copyright &y& Elsevier]

To report long-term results from a phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in patients with advanced geographic atrophy (GA). A single-arm, open-label phase 1/2a clinical trial approved by the United States Food and Drug Administration. Patients were 69-85 years of age at the time of enrollment and were legally blind in the treated eye (best-corrected visual acuity [BCVA], ≤ 20/200) as a result of GA involving the fovea. The clinical trial enrolled 16 patients, 15 of whom underwent implantation successfully. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion nonimplanted eye served as the control. The primary endpoint was at 1 year; thereafter, patients were followed up at least yearly. Safety was the primary endpoint of the study. The occurrence and frequency of adverse events (AEs) were determined by scheduled eye examinations, including measurement of BCVA and intraocular pressure and multimodal imaging. Serum antibody titers were collected to monitor systemic humoral immune responses to the implanted cells. At a median follow-up of 3 years, fundus photography revealed no migration of the implant. No unanticipated, severe, implant-related AEs occurred, and the most common anticipated severe AE (severe retinal hemorrhage) was eliminated in the second cohort (9 patients) through improved intraoperative hemostasis. Nonsevere, transient retinal hemorrhages were noted either during or after surgery in all patients as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, results show that implanted eyes were more likely to improve by > 5 letters of BCVA and were less likely to worsen by > 5 letters compared with nonimplanted eyes. This report details the long-term follow-up of patients with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well tolerated in patients with advanced dry age-related macular degeneration. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was –0·57 letters (95% CI –2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and –1·44 letters (–3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. Regeneron Pharmaceuticals and Bayer. [ABSTRACT FROM AUTHOR]

An abstract of the study "Findings in Older Children With Abusive Head Injury: Does Shaken-Child Syndrome Exist?," is presented. It aims to determine the possibility of rotational forces sufficient to cause shaken-baby syndrome-like injuries in children more than two years old. Multilayered retinal hemorrhages and acute subdural hematoma were presented in all the cases examined in the study.

Key Points: Question: In patients with nonproliferative diabetic retinopathy (NPDR) and good vision but without center-involved diabetic macular edema (CI-DME), does early aflibercept reduce disease progression and improve long-term visual acuity compared with initial observation and treatment only if disease worsens? Findings: This study presents 4-year primary outcomes of a randomized clinical trial that included 328 patients (399 eyes), randomized to 2.0 mg aflibercept injections or sham injections. Among those receiving aflibercept, proliferative diabetic retinopathy or CI-DME developed in 33.9% vs 56.9% among those who received sham—a difference that was statistically significant. Change in visual acuity was −2.7 vs −2.4 letters, a difference that was not statistically significant. Meaning: At 4 years, treatment of NPDR with aflibercept vs sham treatment resulted in statistically significant anatomic improvement, but no improvement in visual acuity. Importance: Anti–vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P <.001). The mean (SD) change in visual acuity from baseline to 4 years was −2.7 (6.5) letters with aflibercept and −2.4 (5.8) letters with sham (adjusted mean difference, −0.5 letters [97.5% CI, −2.3 to 1.3]; P =.52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333 This randomized clinical trial analyzes the effects of aflibercept injections vs sham for reducing disease progression and improving long-term visual acuity in patients with nonproliferative diabetic retinopathy. [ABSTRACT FROM AUTHOR]

To evaluate pneumatic vitreolysis (PVL) in eyes with vitreomacular traction (VMT) with and without full-thickness macular hole (FTMH). Two multicenter (28 sites) studies: a randomized clinical trial comparing PVL with observation (sham injection) for VMT without FTMH (Protocol AG) and a single-arm study assessing PVL for FTMH (Protocol AH). Participants were adults with central VMT (vitreomacular adhesion was ≤3000 μm). In Protocol AG, visual acuity (VA) was 20/32 to 20/400. In Protocol AH, eyes had a FTMH (≤250 μm at the narrowest point) and VA of 20/25 to 20/400. Pneumatic vitreolysis using perfluoropropane (C 3 F 8) gas. Central VMT release at 24 weeks (Protocol AG) and FTMH closure at 8 weeks (Protocol AH). From October 2018 through February 2020, 46 participants were enrolled in Protocol AG, and 35 were enrolled in Protocol AH. Higher than expected rates of retinal detachment and tear resulted in early termination of both protocols. Combining studies, 7 of 59 eyes (12% [95% CI, 6%–23%]; 2 eyes in Protocol AG, 5 eyes in Protocol AH) that received PVL developed rhegmatogenous retinal detachment (n = 6) or retinal tear (n = 1). At 24 weeks in Protocol AG, 18 of 23 eyes in the PVL group (78%) versus 2 of 22 eyes in the sham group (9%) achieved central VMT release without rescue vitrectomy (adjusted risk difference, 66% [95% CI, 44%–88%]; P < 0.001). The mean change in VA from baseline at 24 weeks was 6.7 letters in the PVL group and 6.1 letters in the sham group (adjusted difference, –0.8 [95% CI, –6.1 to 4.5]; P = 0.77). In Protocol AH, 10 of 35 eyes (29% [95% CI, 16%–45%]) achieved FTMH closure without rescue vitrectomy at 8 weeks. The mean change in VA from baseline at 8 weeks was –1.5 letters (95% CI, –10.3 to 7.3 letters). In most eyes with VMT, PVL induced hyaloid release. In eyes with FTMH, PVL resulted in hole closure in approximately one third of eyes. These studies were terminated early because of safety concerns related to retinal detachments and retinal tears. [ABSTRACT FROM AUTHOR]

Importance: Vitreous hemorrhage from proliferative diabetic retinopathy can cause loss of vision. The best management approach is unknown.Objective: To compare initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation for vitreous hemorrhage from proliferative diabetic retinopathy.Design, Setting, and Participants: Randomized clinical trial at 39 DRCR Retina Network sites in the US and Canada including 205 adults with vison loss due to vitreous hemorrhage from proliferative diabetic retinopathy who were enrolled from November 2016 to December 2017. The final follow-up visit was completed in January 2020.Interventions: Random assignment of eyes (1 per participant) to aflibercept (100 participants) or vitrectomy with panretinal photocoagulation (105 participants). Participants whose eyes were assigned to aflibercept initially received 4 monthly injections. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol criteria.Main Outcomes and Measures: The primary outcome was mean visual acuity letter score (range, 0-100; higher scores indicate better vision) over 24 weeks (area under the curve); the study was powered to detect a difference of 8 letters. Secondary outcomes included mean visual acuity at 4 weeks and 2 years.Results: Among 205 participants (205 eyes) who were randomized (mean [SD] age, 57 [11] years; 115 [56%] men; mean visual acuity letter score, 34.5 [Snellen equivalent, 20/200]), 95% (195 of 205) completed the 24-week visit and 90% (177 of 196, excluding 9 deaths) completed the 2-year visit. The mean visual acuity letter score over 24 weeks was 59.3 (Snellen equivalent, 20/63) (95% CI, 54.9 to 63.7) in the aflibercept group vs 63.0 (Snellen equivalent, 20/63) (95% CI, 58.6 to 67.3) in the vitrectomy group (adjusted difference, -5.0 [95% CI, -10.2 to 0.3], P = .06). Among 23 secondary outcomes, 15 showed no significant difference. The mean visual acuity letter score was 52.6 (Snellen equivalent, 20/100) in the aflibercept group vs 62.3 (Snellen equivalent, 20/63) in the vitrectomy group at 4 weeks (adjusted difference, -11.2 [95% CI, -18.5 to -3.9], P = .003) and 73.7 (Snellen equivalent, 20/40) vs 71.0 (Snellen equivalent, 20/40) at 2 years (adjusted difference, 2.7 [95% CI, -3.1 to 8.4], P = .36). Over 2 years, 33 eyes (33%) assigned to aflibercept received vitrectomy and 34 eyes (32%) assigned to vitrectomy received subsequent aflibercept.Conclusions and Relevance: Among participants whose eyes had vitreous hemorrhage from proliferative diabetic retinopathy, there was no statistically significant difference in the primary outcome of mean visual acuity letter score over 24 weeks following initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation. However, the study may have been underpowered, considering the range of the 95% CI, to detect a clinically important benefit in favor of initial vitrectomy with panretinal photocoagulation.Trial Registration: ClinicalTrials.gov Identifier: NCT02858076. [ABSTRACT FROM AUTHOR]

Background and objective: Existing ophthalmoscopy methods are unable to obtain clear fundus autofluorescence (FAF) images in gas-filled eyes. The purpose of this study was to evaluate the capability of wide-field laser ophthalmoscopy (Optos) in obtaining FAF images in gas-filled eyes for the assessment of macular hole (MH) closure after surgery. Methods: This was an interventional case series. Eighteen consecutive patients with unilateral MH underwent vitrectomy with internal limiting membrane peeling and 20% sulfur hexafluoride gas tamponade. FAF images using Optos were recorded preoperatively and postoperatively (days 1, 2, and 7). Results: On postoperative days 1, 2, and 7, FAF images were obtained from 11/18 (61.1%), 9/18 (50.0%), and 17/18 eyes (94.4%), respectively, using Optos. The quality of FAF images using Optos was sufficient to determine MH closure in 9/18 (50.0%) of gas-filled eyes postoperatively. Quantitative analysis of FAF images was helpful in determining complete or partial closure of the MH. Conclusion: FAF imaging using Optos might be a useful adjunct to optical coherence tomography as a supportive method to guide the release from facedown posturing in some cases of MH. [ABSTRACT FROM AUTHOR]