Spectrum of retinal microvascular ischemia in patients with COVID-19 based on multimodal imaging.

Purpose: To describe and evaluate the multimodal imaging findings in retinal microvascular ischemia associated with COVID-19 infection. Methods: Patients with COVID-19 associated retinal microvascular ischemia and visiting the outpatient Department of Ophthalmology, Shanghai General Hospital from December 2022, to February 2023, were documented and their multimodal images were retrospectively reviewed. Retinal microvascular ischemia was defined as the presence of isolated or multiple focal retinal whitening(s) on color fundus images. Patients with retinal vessel occlusion or retinopathies secondary to systematic disorders diagnosed before infection were excluded. Results: A total of 32 eyes from 21 patients were included, 24 (75.00 %) eyes with multiple retinal whitenings, while 8 (25.00 %) eyes with isolated lesions. When divided by the types of ischemia, 9 (28.13 %) eyes had only inner retinal involvement (known as cotton wool spot, CWS), 4 (12.50 %) eyes had only middle retinal involvement (known as paracentral acute middle maculopathy, PAMM), and 19 (59.38 %) eyes had both. In addition, 4 (12.50 %) eyes had coincident angular sign of Henle fiber layer hyperreflectivity (ASHH). Patients with hypertension tended to have multiple lesions rather than isolated lesion of retinal microvascular ischemia (P = 0.008). Transient uncontrolled high blood pressure or acute kidney injury was simultaneously detected in some cases. Conclusions: Ocular manifestation of COVID-19 associated microvascular ischemia can be variable, including CWS, PAMM and ASHH. Multimodal fundus imaging technologies are useful tools to reveal involved retinal layers, extent, and severity. Moreover, ocular manifestations may serve as a window of COVID-19 related microcirculation in other systems throughout the body.

Preoperative OCT-Derived Nasal Perifoveal Retinal Nerve Fiber Layer Thickness Predictively Correlates Long-Term Visual Acuity Post Oil Removal Surgery.

Purpose: With the widespread application of silicone oil in vitreoretinal surgery, the purpose of this study was to determine the risk factors of long-term vision loss 12 months post oil removal in retina-detached eyes treated with vitrectomy and silicone oil tamponade. Methods: Of the 592 patients approached, eligible eyes completed the investigation up to 12 months post-oil-removal. Eligible eyes underwent pars-plana vitrectomy following oil tamponade. Oil removal was performed after 3 to 28 months in different individuals, under the condition that the retina has reattached as well as the hemorrhage and inflammation has dissolved. Postoperative best-corrected visual acuity (BCVA), age, sex, and interval between tamponade and removal were recorded, and retinal thickness was determined using optical coherence tomography (OCT). Results: Fifty eyes of 50 participants aged 31 to 83 years were enrolled. BCVA (LogMAR) 12 months post-oil-removal improved in 25 of 40 (62.5%) patients, varying from 0.05 (20/22) to 1.0 (20/200) (mean ± SD = 0.55 ± 0.32). Pre-oil-removal nasal perifoveal retinal nerve fiber layer thickness varied from 16 to 83 µm (38.40 ± 18.50), and was significantly linked with post-oil-removal BCVA (0.5%, 95% confidence interval 0.0%-1.0%; P = 0.046). Conclusions: This study demonstrates the risk factors and prognosis of visual function after long-term regeneration post vitrectomy, oil tamponade, and oil removal, thereby underscoring the need for a complete, dynamic examination of retinal structure via OCT measurement. Related studies should be conducted on a larger scale to facilitate the stratification of late-period vision damage in retina-detached eyes. Translational Relevance: This study developed OCT-based clinical markers for the postoperative visual prognosis of eyes affected by retinal detachment.

Efficacy and Safety of Efdamrofusp Alfa versus Aflibercept in Participants with Neovascular Age-Related Macular Degeneration: A Randomized, Double-Masked, Active-Controlled, Noninferiority, Phase II Trial.

PURPOSE: To evaluate efficacy and safety of efdamrofusp alfa compared with aflibercept in neovascular age-related macular degeneration (nAMD). DESIGN: Randomized, double-masked, multicenter, active-controlled, noninferiority phase II study. PARTICIPANTS: A total of 231 treatment-naive and previously treated participants with active choroidal neovascularization secondary to nAMD were enrolled. METHODS: Eligible participants were randomized (1:1:1) to 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa, or 2 mg aflibercept groups. Participants in all groups received 3 initial monthly loading doses, followed by treatment every 8 weeks, with assessment every 4 weeks up to week 52. MAIN OUTCOME MEASURES: The primary end point was the mean best-corrected visual acuity (BCVA) change from baseline to week 36. The prespecified noninferiority margin was set as -5 letters (80% confidence interval [CI]). RESULTS: Each treatment group included 77 participants. The mean BCVA changes from baseline to week 36 for 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa and aflibercept groups were +10.6, +11.4, and +12.0 letters, respectively; least squares mean difference were -1.4 (80% CI: -3.5 to 0.7) between 2 mg efdamrofusp alfa and aflibercept, and -0.6 (80% CI: -2.7 to 1.6) between 4 mg efdamrofusp alfa and aflibercept. Mean central retinal thickness changes were consistent across groups. Adverse event rate was comparable among the groups. CONCLUSIONS: Efdamrofusp alfa demonstrated noninferiority to aflibercept in BCVA improvement, accompanied by a similar safety profile. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Comprehensive assessment of the impact of intravitreal faricimab on retinal diseases: A systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Faricimab stands as the inaugural and sole bispecific antibody approved by the US Food and Drug Administration (FDA) for intravitreal injection. Nonetheless, the efficacy and safety of intravitreal faricimab remained uncertain. OBJECTIVES: The purpose of this study was to evaluate faricimab. METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (CRD42023398320). Five databases (Pubmed, Embase, Web of science, Cochrane Library, ClinicalTrials gov) were searched. We calculated pooled standard mean difference or odds ratio with 95 % confident interval under a random-effect model or fixed-effect model. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was employed to ascertain the reliability of the analyses. Trial sequential analysis was performed to gauge the statistical reliability of the data in the cumulative meta-analysis. RESULTS: 8 studies (3975 participants) were included. The use of faricimab was associated with central subfield thickness (CST) change, but no difference was found in other primary efficacy outcomes. Apart from that, a correlation was observed between the use of faricimab and the risk of vitreous floaters. Based on TSA, strong evidence indicates that compared to the control group, faricimab aided in reducing CST but increasing the risk of vitreous floaters. CONCLUSIONS: In this study, a correlation existed between the use of faricimab and a reduction in CST, indicating a superior therapeutic effect. Moreover, participants treated with faricimab demonstrated a higher risk of vitreous floaters. More randomized controlled trials are essential to further explore the efficacy and safety of faricimab.

Contribution of ferroptosis and SLC7A11 to light-induced photoreceptor degeneration.

Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss. Ferroptosis has been demonstrated to be associated with retinal degenerative diseases. However, the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored. Bioinformatics and biochemical analyses in this study revealed xC-, solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model. This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway, through which cystine depletion, iron ion accumulation, and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment. We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo. Conversely, solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H2O2-induced ferroptosis of 661W cells. These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.

Clinical and Molecular Characterization of AIPL1-Associated Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy.

PURPOSE: This study aimed to characterize the clinical features, genetic findings, and genotype-phenotype correlations of patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD) harboring biallelic AIPL1 pathogenic variants. DESIGN: Retrospective case series. METHODS: This study consecutively enrolled 51 patients from 47 families with a clinical diagnosis of LCA/EOSRD harboring disease-causing variants in the AIPL1 gene, from October 2021 to September 2023. Molecular genetic findings, medical history, and ophthalmic evaluation including visual acuity (VA), multimodal retinal imaging, and electrophysiologic assessment were reviewed. RESULTS: Of the 51 patients (32 with LCA and 19 with EOSRD), 27 (53%) were females, and age at last review ranged from 0.5 to 58.4 years. We identified 28 disease-causing AIPL1 variants, with 18 being novel. In patients with EOSRD, the mean (range) VA was 1.3 (0.7-2.7) logMAR and 1.3 (0.5-2.3) logMAR for right and left eyes respectively, with an average annual decline of 0.03 logMAR (R2 = 0.7547, P < .01). For patients with LCA, the VA ranged from light perception to counting fingers. Optical coherence tomography imaging demonstrated preservation of foveal ellipsoid zone in the 5 youngest EOSRD patients and 9 LCA children. Electroretinography showed severe cone-rod patterns in 78.6% (11/14) of patients with EOSRD, while classical extinguished pattern was documented in all patients with LCA available for the examination. The most common mutation was the nonsense variants of c.421C>T, with an allele frequency of 53.9%. All patients with EOSRD carried at least one missense mutation, of whom 13 identified with c.152A>G and 5 with c.572T>C. Twenty-six patients with LCA harbored two null AIPL1 variants, while 18 were homozygous for c.421C>T and 6 were heterozygous for c.421C>T with another loss-of-function variant. CONCLUSIONS: This study reveals distinct clinical features and variation spectrum between AIPL1-associated LCA and EOSRD. Patients harboring at least one nonnull mutation, especially c.152A>G and c.572T>C, were significantly more likely to have a milder EOSRD phenotype than those with two null mutations. Residual foveal outer retinal structure observed in the youngest proportion of patients suggests an early window for gene augmentation therapy.

The central retinal thickness and its related genotype in ABCA4-related retinopathy.

PURPOSE: To further explore the influence of genotype, including mutation type and structural domain, on the severity of macular atrophy, we measured the central retinal thickness (CRT) in patients with ABCA4-related retinopathy. METHODS: A total of 66 patients were included in the cohort. This was a retrospective investigation. The patients were tested using whole exon sequencing and ophthalmic exams, including slip lamp exams, best-corrected visual acuity, optical coherence tomography, fundus photo, and fundus autofluorescence. RESULTS: In this study, we discovered that mutations on nucleotide binding domains (NBD) lead to less CRT (45.00 ± 25.25µm, 95% CI: 31.54-58.46) had significantly less CRT than the others (89.75 ± 71.17µm, 95% CI: 30.25-149.25, p = 0.032), and could accelerate the rate of CRT decrease. CONCLUSIONS: Our study provides new perspectives in the understanding of ABCA4-related retinopathy.

GENETIC FACTORS AND CHARACTERISTICS ON SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY ARE ASSOCIATED WITH CHOROIDAL THICKNESS IN ABCA4 -RELATED RETINOPATHY.

PURPOSE: To investigate the possible correlation factors of choroidal thickness in ABCA4 -related retinopathy. METHODS: A total of 66 patients were included in the cohort. It is a retrospective, cross-sectional laboratory investigation. The patients were tested using whole-exon sequencing and ophthalmic examinations, including slit-lamp examinations, best-corrected visual acuity, spectral-domain optical coherence tomography, fundus photograph, and fundus autofluorescence. RESULTS: Besides demographic characteristics (age, onset age, duration), we selected genetic factors and ocular characteristics on spectral-domain optical coherence tomography as the candidates related to choroidal thickness. Mutation type (inframe mutation or premature termination codon), epiretinal membrane, retinal pigment epithelium- Bruch membrane integrity, and macular curvature changes were identified as related factors to choroidal thickness in ABCA4 -related retinopathy after the adjustment of Logistic LASSO regression. CONCLUSION: Mutation type, epiretinal membrane, retinal pigment epithelium-Bruch membrane integrity, and macular curvature changes are related factors to choroidal thinning. These findings could provide us a further understanding for the pathological process and clinical features of ABCA4 mutation.

Dynamic changes in macrophage morphology during the progression of choroidal neovascularization in a laser-induced choroidal neovascularization mouse model.

BACKGROUND: Neovascular age-related macular degeneration (AMD) is responsible for the majority of severe vision loss cases and is mainly caused by choroidal neovascularization (CNV). This condition persists or recurs in a subset of patients and regresses after 5 or more years of anti-vascular endothelial growth factor (VEGF) treatment. The precise mechanisms of CNV continue to be elucidated. According to our previous studies, macrophages play a critical role in CNV. Herein, we aimed to determine the morphological changes in macrophages in CNV to help us understand the dynamic changes. METHODS: Mice were subjected to laser injury to induce CNV, and lesion expansion and macrophage transformation were examined by immunofluorescence and confocal analysis. Several strategies were used to verify the dynamic changes in macrophages. Immunofluorescence and confocal assays were performed on choroidal flat mounts to evaluate the morphology and phenotype of macrophages in different CNV phases, and the results were further verified by western blotting and RT-PCR. RESULTS: The location of infiltrated macrophages changed after laser injury in the CNV mouse model, and macrophage morphology also dynamically changed. Branching macrophages gradually shifted to become round with the progression of CNV, which was certified to be an M2 phenotypic shift. CONCLUSIONS: Dynamic changes in macrophage morphology were observed during CNV formation, and the round-shaped M2 phenotype could promote neovascularization. In general, the changes in morphology we observed in this study can help us to understand the critical role of macrophages in CNV progression and exploit a potential treatment option for CNV indicated by a shift in macrophage polarity.

Identification and Validation of an Aging-Associated circRNA-miRNA-mRNA Network in Neovascular Age-Related Macular Degeneration.

INTRODUCTION: Neovascular age-related macular degeneration (NVAMD) is a leading cause of severe vision impairment in the elderly. Aging is one of the most pivotal underlying molecular mechanisms of NVAMD. METHODS: In this study, we identified the potential aging-related genes involved in NVAMD. Considering that noncoding RNAs are vital regulators of NVAMD progression, we further explored and constructed an aging-originated circRNA-miRNA-mRNA network of NVAMD. Differential expression of 23 aging-associated genes was identified based on sequencing data and the Human Aging Genomic Resources tool at a threshold of p < 0.05, and log2|fold change| > 1. RESULTS: We screened 12 microRNAs (miRNAs) using public datasets and miRNet database. A total of 13 circRNAs were subsequently mined using the starBase tool. Merging these 13 circRNAs, 12 miRNAs, and 15 genes together, we obtained 281 pairs of circRNA-miRNA and 30 pairs of miRNA-mRNA. CONCLUSION: We created an aging-related circRNA-miRNA-mRNA network, which could be a promising target for future AMD treatments.

Rapid and Sensitive Diagnosis of Leber Hereditary Optic Neuropathy Variants Using CRISPR/Cas12a Detection.

Leber hereditary optic neuropathy (LHON) is the most common maternally inherited mitochondrial disease, with >90% of cases harboring one of three point variants (m.3460G>A, m.11778G>A, and m.14484T>C). Rapid and sensitive diagnosis of LHON variants is urgently needed for early diagnosis and timely treatment after onset, which is currently limited. Herein, we adapted the Cas12a-based DNA detection platform for LHON mitochondrial variant diagnosis. Single-strand guide CRISPR RNAs and enzymatic recombinase amplification primers were first screened, the CRISPR/Cas12a system was then optimized with restriction enzymes, and finally compared with Sanger sequencing and next-generation sequencing (NGS) in multicenter clinical samples. This approach can be completed within 30 minutes using only one drop of blood and could reach a sensitivity of 1% of heteroplasmy. Among the 182 multicenter clinical samples, the CRISPR/Cas12a detection system showed high consistency with Sanger sequencing and NGS in both specificity and sensitivity. Notably, a sample harboring a de novo 3.78% m.11778G>A variant detected by NGS, but not by Sanger sequencing, was successfully confirmed using the CRISPR/Cas12a assay, which proved the effectiveness of our method. Overall, our CRISPR/Cas12a detection system provides an alternative for rapid, convenient, and sensitive detection of LHON variants, exhibiting great potential for clinical practice.

Association between previous cataract surgery and cognition among middle-aged and older Chinese: the China health and retirement longitudinal study (CHARLS).

BACKGROUND: Cataract is the primary cause of blindness globally, and surgery offers the only method by which to remove cataracts. We aimed to examine whether previous cataract surgery is associated with cognitive function. METHODS: Our study included 13,824 participants. Data from the baseline of the China Health and Retirement Longitudinal Study (CHARLS) were used. The participants were categorized into two groups: with and without previous cataract surgery. Weighted multiple linear regression was used to obtain the ß and 95% confidence intervals (CI). RESULTS: The participants who had previous cataract surgery (n = 261) scored lower in cognition, including both memory and mental state, than those without previous cataract surgery. After adjusting for socioeconomic factors and metabolic measures, a negative association was evident between previous cataract surgery and cognition (ß = -0.647, 95% CI: -1.244, - 0.049). Furthermore, the participants who were older and female demonstrated a decline in cognition, while living in cities and having higher levels education were associated with higher cognition. CONCLUSIONS: Better cognitive function was associated with less previous cataract surgery or cataract occurrence. This suggests that a period of vision loss due to cataract leads to cognitive decline, however further studies are need to dissect the impact of vision loss and cataract surgery on cognitive decline.

METTL3-mediated m6A modification of HMGA2 mRNA promotes subretinal fibrosis and epithelial-mesenchymal transition.

Subretinal fibrosis is a major cause of the poor visual prognosis for patients with neovascular age-related macular degeneration (nAMD). Myofibroblasts originated from retinal pigment epithelial (RPE) cells through epithelial-mesenchymal transition (EMT) contribute to the fibrosis formation. N6-Methyladenosine (m6A) modification has been implicated in the EMT process and multiple fibrotic diseases. The role of m6A modification in EMT-related subretinal fibrosis has not yet been elucidated. In this study, we found that during subretinal fibrosis in the mouse model of laser-induced choroidal neovascularization, METTL3 was upregulated in RPE cells. Through m6A epitranscriptomic microarray and further verification, high-mobility group AT-hook 2 (HMGA2) was identified as the key downstream target of METTL3, subsequently activating potent EMT-inducing transcription factor SNAIL. Finally, by subretinal injections of adeno-associated virus vectors, we confirmed that METTL3 deficiency in RPE cells could efficiently attenuate subretinal fibrosis in vivo. In conclusion, our present research identified an epigenetic mechanism of METTL3-m6A-HMGA2 in subretinal fibrosis and EMT of RPE cells, providing a novel therapeutic target for subretinal fibrosis secondary to nAMD.

The association between obesity and glaucoma in older adults: evidence from the China Health and Retirement Longitudinal Study.

OBJECTIVES: This study evaluated the association between obesity and glaucoma in middle-aged and older people. A population-based retrospective cohort study was conducted using data from the China Health and Retirement Longitudinal Study. METHODS: Glaucoma was assessed via self-reports. Multivariate logistic regression analysis and a Cox proportional hazards model were used to assess the relationship between obesity and glaucoma risk. RESULTS: Older males living in urban areas who were single, smokers, and non-drinkers were found to have a significantly higher incidence of glaucoma (all p<0.05). Diabetes, hypertension, and kidney disease were also associated with higher glaucoma risk, while dyslipidemia was associated with lower risk (all p<0.05). After the model was adjusted for demographic, socioeconomic, and health-related variables, obesity was significantly associated with a 10.2% decrease in glaucoma risk according to the Cox proportional hazards model (hazard ratio, 0.90; 95% confidence interval [CI], 0.83 to 0.97) and an 11.8% risk reduction in the multivariate logistic regression analysis (odds ratio, 0.88; 95% CI, 0.80 to 0.97). A further subgroup analysis showed that obesity was associated with a reduced risk of glaucoma in people living in rural areas, in smokers, and in those with kidney disease (all p<0.05). Obesity also reduced glaucoma risk in people with diabetes, hypertension, or dyslipidemia more than in healthy controls (all p<0.05). CONCLUSIONS: This cohort study suggests that obesity was associated with a reduced risk of glaucoma, especially in rural residents, smokers, and people with kidney disease. Obesity exerted a stronger protective effect in people with diabetes, hypertension, or dyslipidemia than in healthy people.

OUTER RETINAL TUBULATION IN BIETTI CRYSTALLINE DYSTROPHY ASSOCIATED WITH THE RETINAL PIGMENT EPITHELIUM ATROPHY.

PURPOSE: To determine the prognostic value of outer retinal tubulation (ORT) in the eyes of a Chinese cohort with Bietti crystalline dystrophy (BCD). METHODS: This retrospective, multicenter cohort study enrolled 42 patients with clinically and genetically diagnosed BCD. Eighty eyes with good-quality images of spectral domain optical coherence tomography were included. Demographic details and clinical data were collected. The characteristics of ORT, including prevalence, location, and morphologic characteristics were analyzed. RESULTS: Forty-two patients with BCD harbored potentially CYP4V2 disease-causing mutations. The mutation spectrum comprised 17 unique variants, 9 of which were novel. Fifty-two of these 80 eyes demonstrated evidence of ORT. The incidence of ORT is significantly higher in Stage 2 than other stages ( P < 0.001). ORT was mainly bilateral and located at the margin of the atrophic area of retinal pigment epithelium (RPE), and dynamically changed with the progressive RPE atrophy. The process of RPE atrophy was slower in eyes with ORT ( P = 0.017), with significantly longer intact RPE width in Stage 3 ( P = 0.024). Eyes with ORT had slower vision loss than eyes without ORT ( P = 0.044). CONCLUSION: ORT may be a sign of the onset of RPE atrophy in early-stage BCD and may suggest less risk of rapid progression in late-stage BCD.

PFKFB3 knockdown attenuates Amyloid ß-Induced microglial activation and retinal pigment epithelium disorders in mice.

Age-related macular degeneration (AMD) is characterized by progressive accumulation of drusen deposits and retinal pigment epithelium (RPE) disorders. As the main component of drusen, amyloid ß (Aß) plays a critical role in activating microglia and causing neuroinflammation in AMD pathogenesis. However, the role of activated microglia-mediated neuroinflammation in RPE senescence remains unclear. Recent evidence indicates that inflammatory microglia are glycolytic and driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme described as the master regulator of glycolysis. In this study, we mimicked the retinal inflammatory microenvironment of AMD by intravitreal injection of oligomeric Aß1-40 in mice, which resulted in activation of microglia and upregulation of PFKFB3. RNA sequencing was performed to evaluate PFKFB3-mediated microglial activation. The effect of microglial activation on RPE disorders was assessed using gene knockout experiments, immunofluorescence, CCK-8 assay, and ß-galactosidase staining. Intravitreal Aß1-40 injection induced proinflammatory activation of microglia by upregulating PFKFB3 and resulted in RPE disorders, which was verified in heterozygous Pfkfb3-deficient mice (Pfkfb3+/-) mice, Aß1-40-activated microglial cell line BV2, and co-culture of RPE cell line ARPE19. RNA sequencing revealed that PFKFB3 mainly affected innate immune processes during Aß1-40-induced retinal inflammation. PFKFB3 knockdown inhibited RPE disorders and rescued the retinal structure and function. Overall, the modulation of PFKFB3-mediated microglial glycolysis and activation is a promising strategy for AMD treatment.

Compressive mechanical properties of vitrified porcine menisci are superior to frozen and similar to fresh porcine menisci.

The common practice of freezing meniscal allograft tissue is limited due to the formation of damaging ice crystals. Vitrification, which eliminates the formation of damaging ice crystals, may allow the mechanical properties of meniscal allograft tissue to be maintained during storage and long-term preservation. The primary objective of this study was to investigate the differences between fresh, frozen, and vitrified porcine lateral menisci examining compressive mechanical properties in the axial direction. Unconfined compressive stress-relaxation testing was conducted to quantify the mechanical properties of fresh, frozen and vitrified porcine lateral menisci. The compressive mechanical properties investigated were peak and equilibrium stress, secant, instantaneous and equilibrium modulus, percent stress-relaxation, and relaxation time constants from three-term Prony series. Frozen menisci exhibited inferior compressive mechanical properties in comparison with fresh menisci (significant differences in peak and equilibrium stress, and secant, instantaneous and equilibrium modulus) and vitrified menisci (significant differences in peak stress, and secant and instantaneous modulus). Interestingly, fresh and vitrified menisci exhibited comparable compressive mechanical properties (stress, modulus and relaxation parameters). These findings are significant because (1) vitrification was successful in maintaining mechanical properties at values similar to fresh menisci, (2) compressive mechanical properties of fresh menisci were characterized providing a baseline for future research, and (3) freezing affected mechanical properties confirming that freezing should be used with caution in future investigations of meniscal mechanical properties. Vitrification was superior to freezing for preserving compressive mechanical properties of menisci which is an important advance for vitrification as a preservation option for meniscal allograft transplantation.

A Novel Bispecific Fusion Protein Targeting C3b/C4b and VEGF in Patients With nAMD: A Randomized, Open-Label, Phase 1b Study.

PURPOSE: To evaluate the safety, tolerability, and efficacy of efdamrofusp alfa in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Prospective randomized, open-label, multiple ascending-dose, phase 1b study. METHODS: Patients aged 50 years or older with active choroid neovascularization (CNV) secondary to nAMD were screened from 2 hospitals in 2 provinces in China. The first 9 patients were randomized 2:1 to intravitreally receive efdamrofusp alfa 2 mg at weeks 0, 4, and 8 or aflibercept 2 mg at weeks 0, 4, 8, and 16. After the dose-limiting toxicity assessment, 9 additional patients were randomized 2:1 to intravitreally receive efdamrofusp alfa 4 mg at weeks 0, 4, and 8 or aflibercept 2 mg at weeks 0, 4, 8, and 16. All patients were followed until week 20. Primary outcomes were safety and tolerability of efdamrofusp alfa. Secondary outcomes included changes from baseline in best-corrected visual acuity (BCVA), central subfield thickness (CST) as measured by spectral domain optical coherence tomography (SD-OCT), and CNV area as measured by fluorescein angiography (FA). RESULTS: A total of 18 patients were enrolled. Six each of them received efdamrofusp alfa 2 mg, efdamrofusp alfa 4 mg, or aflibercept 2 mg, respectively. No dose-limiting toxicity was reported, and all patients completed the study. No ocular serious adverse events were reported. All ocular treatment-emergent adverse events were intravitreal injection related and were mild or moderate in severity. At week 20, mean changes from baseline in BCVA were 5.64 ± 3.56, 8.93 ± 3.59, and 7.92 ± 3.55 letters for patients receiving efdamrofusp alfa 2 mg, efdamrofusp alfa 4 mg and aflibercept 2 mg, respectively. Meanwhile, CST and CNV area reductions indicative of anatomic improvement were observed in the majority of the patients receiving both doses of efdamrofusp alfa and aflibercept. CONCLUSIONS: Intravitreal efdamrofusp alfa dosed up to 4 mg every 4 weeks was well tolerated in nAMD patients with similar vision acuity and anatomic improvements.

Growth of nonexudative macular neovascularization in age-related macular degeneration: an indicator of biological lesion activity.

PURPOSE: To investigate the growth of nonexudative macular neovascularization (MNV) in age-related macular degeneration (AMD) using swept-source optical coherence tomography angiography (SS-OCTA). METHODS: Patients with treatment-naïve nonexudative AMD in one eye and exudative AMD in the fellow eye who underwent SS-OCTA imaging for at least 12 months were retrospectively reviewed. The MNV area measurement was quantified in eyes with treatment-naïve nonexudative MNV using ImageJ for analysing the correlation between MNV growth and the onset of exudation, as well as evaluating the consistency of the MNV growth rate during the subclinical and exudative stages. Kaplan-Meier survival analysis and logistic regression analyses were used. RESULTS: In total, 45 eyes with treatment-naïve nonexudative AMD from 45 patients were enrolled. Treatment-naïve nonexudative MNV was identified in 21 eyes (46.67%) at baseline. The development of exudative findings was noted in eight eyes (17.78%), including six eyes with previously noted nonexudative MNV. Eyes with growing MNV (increase in area ≥50% within 12 months) had an increased risk of exudation and developed exudation earlier than eyes with stable MNV (13.60 [6.43-20.77] months versus 31.11 [26.61-35.62] months, P < 0.0001, Log-rank test). Consistent growth pattern of MNV lesions was further identified in eyes with growing MNV during anti-VEGF treatment. CONCLUSION: SS-OCTA allows to qualitatively and quantitatively evaluate nonexudative MNV in AMD patients. Growing MNV involved higher probabilities and a faster onset of exudation compared to stable MNV. Identifying the growth of MNV on OCTA might be helpful for establishing treatment strategies and follow-up planning.