Investigative ophthalmology & visual science最新文献

Purpose: To examine the influence of subfoveal choroidal thickness (SFCT) and choroidal vascularity index (CVI) on axial length (AL) elongation over a 2-year period in highly myopic children.

Methods: In this is prospective, longitudinal, observational study, 163 participants (74%), who were 8 to 18 years of age with bilateral high myopia (sphere ≤ -6.0 D) and without pathologic myopia, completed follow-up visits over 2 years. All participants underwent baseline and follow-up ocular examinations, including swept-source optical coherence tomography (SS-OCT) and AL measurements. SFCT and CVI were derived from SS-OCT scans using a deep-learning-based program for choroidal structure assessment.

Results: The mean age of the participants at baseline was 15.0 years (±2.3), with males constituting 47% of the cohort. An inverse relationship was observed between AL elongation and increases in baseline age, baseline SFCT, and CVI, as well as a decrease in baseline AL. Adjusting for other factors, every 10-µm increase in SFCT and each 1% increase in CVI were associated with decreases in AL elongation of 0.007 mm (95% confidence interval [CI], -0.013 to -0.002; P = 0.011) and 0.010 mm (95% CI, -0.019 to 0.000; P = 0.050), respectively. The incorporation of SFCT or CVI into predictive models improved discrimination over models using only age, gender, and baseline AL (both P < 0.05, likelihood ratio test).

Conclusions: Our findings suggest a possible association between a thinner choroid and increased AL elongation over 2 years in children with high myopia, after adjusting for potential baseline risk factors such as age, gender, and initial AL.

Purpose: Local recurrence predicts dismal prognosis in eyelid sebaceous carcinoma (SC). Recurrence predictors vary across studies. Accurate recurrence estimation is essential for individualized therapy in eyelid SC. This study aims to identify recurrence predictors and develop a nomogram for personalized prediction in eyelid SC.

Methods: We conducted a multicenter retrospective cohort study. Chart reviews were performed in 418 consecutive patients with eyelid SC. All patients were followed up after their initial surgery. Multivariate Cox regression was used to explore the independent predictors of recurrence. A nomogram for recurrence prediction was developed and validated with bootstrap resampling. The predictive accuracy and discriminative ability were compared with the Tumor, Node, Metastasis (TNM) staging system.

Results: Over a median of 60-month follow-up, 167 patients (40%) had local recurrence. The median time from diagnosis to recurrence was 14 months. The 1-year cumulative recurrence rate was 18%. Diagnostic delay (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 1.00-1.01, P = 0.001), orbital involvement (HR = 4.47, 95% CI = 3.04-6.58, P < 0.001), Ki67 (HR = 1.01, 95% CI = 1.00-1.02, P = 0.008) and initial surgery of Mohs micrographic surgery with intraoperative frozen section control (HR = 0.53, 95% CI = 0.35-0.80, P = 0.003) were independent influencing factors of recurrence. A nomogram integrating these four factors combined with pagetoid spread displayed satisfactory discriminative ability (C-index = 0.80-0.83; area under the curve [AUC] = 0.82-0.84), which compared favorably than TNM staging (all P < 0.05).

Conclusions: The recurrence rate is high in eyelid SC. Early detection and primary resection with Mohs micrographic surgery are recommended in controlling recurrence. Patients with orbital involvement, high Ki67 expression, and pagetoid spread may require adjuvant measures. This nomogram offers more accurate recurrence estimates, aiding in therapeutic decision making.

Purpose: The purpose of this study was to investigate the molecular mechanisms underlying anti-vascular endothelial growth factor (anti-VEGF) efficacy and response variability in neovascular age-related macular degeneration (nAMD) using longitudinal proteomic and metabolomic analysis alongside three-dimensional lesion measurements.

Methods: In this prospective study, 54 treatment-naive patients with nAMD underwent "3+ pro re nata" (3+PRN) anti-VEGF regimens followed for at least 12 weeks. Aqueous humors were collected pre- and post-treatment for proteomic and metabolomic analysis. Three-dimensional optical coherence tomography (OCT) and OCT angiography assessed different types of nAMD lesion volumes and areas.

Results: There were 1350 proteins and 1268 metabolites that were identified in aqueous humors, with 301 proteins and 353 metabolites significantly altered during anti-VEGF treatment, enriched in pathways of angiogenesis, energy metabolism, signal transduction, and neurofunctional regulation. Sixty-seven changes of (Δ) molecules significantly correlated with at least one type of ΔnAMD lesion. Notably, proteins FGA, TALDO1, and ASPH significantly decreased during treatment, with their reductions correlating with greater lesion regression in at least two lesion types. Conversely, despite that YIPF3 also showed significant downregulation, its decrease was associated with poorer regression in total nAMD lesion and subretinal hyper-reflective material.

Conclusions: This study identifies FGA, TALDO1, and ASPH as potential key molecules in the efficacy of anti-VEGF therapy, whereas YIPF3 may be a key factor in poor response. The integration of longitudinal three-dimensional lesion analysis with multi-omics provides valuable insights into the mechanisms and response variability of anti-VEGF treatment in nAMD.

Purpose: Metastatic uveal melanoma (UM) treatment is difficult, and effective treatments are urgently needed. We aimed to explore the role of heme oxygenase 1 (HO-1) in UM and provide new therapeutic strategies for UM.

Methods: Bioinformatics was used to analyze the relationship between HMOX1 and immunity in UM and other tumors. Cell Counting Kit-8, Western blot, immunofluorescence staining, wound healing, and Transwell assays were used. A subcutaneous transplanted UM tumor model was used in mice to verify the therapeutic effect.

Results: In UM, the expression level of HMOX1 was strongly correlated with the immune score and the infiltration level of various immune cells. ZnPP can inhibit the growth of UM cells, promote cell apoptosis, and block the cell cycle at G0/G1 phase in vitro. HO-1 knockout can effectively inhibit the proliferation of UM cells. ZnPP effectively inhibited the growth of UM and promoted the infiltration of CD8+ T cells in a subcutaneous tumor transplantation model.

Conclusions: These results indicate that targeting HO-1 in UM has the potential for independent targeted immunotherapy or adjuvant immunotherapy.

Purpose: Uveal melanoma (UM) is the most common primary intraocular malignancy with a high probability of metastatic disease. Although excellent treatment options for primary UM are available, therapy for metastatic disease remain limited. Drug discovery studies using mouse models have thus far failed to provide therapeutic solutions, highlighting the need for novel models. Here, we optimize zebrafish xenografts as a potential model for drug discovery by showcasing the behavior of multiple cell lines and novel findings on mutation-dependent compound synergism/antagonism using Z-Tada; an algorithm to objectively characterize output measurements.

Methods: Prognostic relevant primary (N = 4) and metastatic UM (N = 1) cell lines or healthy melanocytes (N = 2) were inoculated at three distinct inoculation sites. Standardized quantifications independent of inoculation site were obtained using Z-Tada; an algorithm to measure tumor burden and the number, size, and distance of disseminated tumor cells. Sequentially, we utilized this model to validate combinatorial synergism or antagonism seen in vitro.

Results: Detailed analysis of 691 zebrafish xenografts demonstrated perivitelline space inoculation provided robust data with high probability of cell dissemination. Cell lines with more invasive behavior (SF3B1mut and BAP1mut) behaved most aggressive in this model. Combinatorial drug treatment illustrated synergism or antagonism is mutation-dependent, which were confirmed in vivo. Combinatorial treatment differed per xenograft-model, as it either inhibited overall tumor burden or cell dissemination.

Conclusions: Perivitelline space inoculation provides robust zebrafish xenografts with the ability for high-throughput drug screening and robust data acquisition using Z-Tada. This model demonstrates that drug discovery for uveal melanoma must take mutational subclasses into account, especially in combinatorial treatment discoveries.

Purpose: To investigate retinal wound healing, we created a new porcine model of retinal hole and identified the cells involved in hole closure.

Methods: Sixteen landrace pigs underwent vitrectomy, and a subretinal bleb was created before cutting a retinal hole using a 23G vitrector. No tamponade was used. Before surgery and one, two, and four weeks after surgery, the eyes were examined by optical coherence tomography and color fundus photos. At the end of follow-up, the eyes were enucleated for histology. Tissue sections of 5 µm were prepared for hematoxylin-eosin staining and immunohistochemical analysis with antibodies to retinal glial and epithelial cells.

Results: Retinal holes below 1380 µm in diameter closed spontaneously within four weeks, whereas larger holes remained open. Hole closure was mediated by central movement of the edges of the hole and in most cases the formation of a gliotic plug. Fluorescence microscopy revealed that the plug consisted of cells positive for glial fibrillary acidic protein, indicating the presence of macroglial cell types. Specifically, the plug was positive for S100 calcium-binding protein B, mainly representing astrocytes, while it was negative for anti-glutamine syntethase, representing Müller glia. These findings suggest that astrocytes are the predominating cell type in the plug. Minimal glial reaction was seen in the retinal holes that did not close.

Conclusions: We present a new porcine model for investigating large retinal holes. The retinal holes closed by approximation of hole edges, and the remnant retinal defect was closed with an astroglial plug.

Purpose: To explore the long-term effect of diabetic retinopathy on response to anti-vascular endothelial growth factor (VEGF) treatment in age-related macular degeneration-associated type 1 macular neovascularization (MNV) using optical coherence tomography angiography (OCTA).

Methods: A total of 45 eyes with exudative neovascular age-related macular degeneration (nAMD) with type 1 MNV were included in the analysis. Among them, 24 eyes of 24 patients had no history of diabetes mellitus (DM) in their anamnesis and were assigned to the Not Diabetic group; 21 eyes of 21 patients had mild diabetic retinopathy and were included in the Diabetic group. We considered the following outcome measures: (1) best-corrected visual acuity changes; (2) central macular thickness; (3) MNV lesion area; and (4) MNV flow area. The OCTA acquisitions were performed at the following time points: (1) baseline visit, which corresponded to the day before the first injection; (2) post-loading phase (LP), which was scheduled at 1 month after the last LP injection; and (3) 12-month follow-up visit.

Results: All morphofunctional parameters showed a significant improvement after the LP and at the 12-month follow-up visit. Specifically, both the Diabetic group and the Not Diabetic group displayed a significant reduction of MNV lesion areas at both the post-LP assessment (P = 0.026 and P = 0.016, respectively) and the 12-month follow-up (P = 0.039 and P = 0.025, respectively). Similarly, the MNV flow area was significantly decreased in both the Diabetic group and the Not Diabetic group at the post-LP assessment (P < 0.001 and P = 0.012, respectively) and at the 12-month follow-up (P = 0.01 and P = 0.035, respectively) compared to baseline. A smaller reduction in the MNV lesion area was observed in the Diabetic group at both the post-LP evaluation (P = 0.015) and the 12-month follow-up (P = 0.032). No other significant differences were found between the groups for the other parameters (P > 0.05).

Conclusions: Our results indicated that the Diabetic group exhibited a smaller reduction in MNV lesion area after 12 months of anti-VEGF treatment. This highlights the importance of considering diabetic retinopathy as a potential modifier of treatment outcomes in nAMD management, with DM serving as a crucial risk factor during anti-angiogenic treatment.

Purpose: The purpose of this study was to analyze the clinical spectrum and natural history of CDH23-associated Usher syndrome type ID (USH1D).

Methods: Molecularly-confirmed individuals had data extracted from medical records. Retinal imaging was extracted from an in-house database. The main outcome measurements were retinal imaging and electroretinography (ERG) and clinical findings, including age of onset, symptoms, best-corrected visual acuity (BCVA), outer nuclear layer (ONL) thickness, ellipsoid zone width (EZW), and hyperautofluorescent ring area.

Results: Thirty-one patients were identified, harboring 40 variants in CDH23 (10 being novel). The mean (range, ±SD) age of symptom onset was 10.1 years (range = 1-18, SD = ±4.1). The most common visual symptoms at presentation were nyctalopia (93.5%) and peripheral vision difficulties (61.3%). The mean BCVA at baseline was 0.25 ± 0.22 in the right eyes and 0.35 ± 0.58 LogMAR in the left eyes. The mean annual loss rate in BCVA was 0.018 LogMAR/year over a mean follow-up of 9.5 years. Individuals harboring the c.5237G>A p.(Arg1746Gln) allele had retinitis pigmentosa (RP) sparing the superior retina. Seventy-seven percent of patients had hyperautofluorescent rings in fundus autofluorescence. Full-field and pattern ERGs indicated moderate-severe rod-cone or photoreceptor dysfunction with relative sparing of macular function in most patients tested. Optical coherence tomography (OCT) revealed intraretinal cysts in the transfoveal B-scan of 13 individuals (43.3%). The rate of EZW and ONL thickness loss was mild and suggestive of a wide window of macular preservation.

Conclusions: Despite the early onset of symptoms, USH1D has a slowly progressive phenotype. There is high interocular symmetry across all parameters, making it an attractive target for novel therapies.

Purpose: To investigate the contributions of the microstructural and metabolic brain environment to glaucoma and their association with visual field (VF) loss patterns by using advanced diffusion magnetic resonance imaging (dMRI), proton magnetic resonance spectroscopy (MRS), and clinical ophthalmic measures.

Methods: Sixty-nine glaucoma and healthy subjects underwent dMRI and/or MRS at 3 Tesla. Ophthalmic data were collected from VF perimetry and optical coherence tomography. dMRI parameters of microstructural integrity in the optic radiation and MRS-derived neurochemical levels in the visual cortex were compared among early glaucoma, advanced glaucoma, and healthy controls. Multivariate regression was used to correlate neuroimaging metrics with 16 archetypal VF loss patterns. We also ranked neuroimaging, ophthalmic, and demographic attributes in terms of their information gain to determine their importance to glaucoma.

Results: In dMRI, decreasing fractional anisotropy, radial kurtosis, and tortuosity and increasing radial diffusivity correlated with greater overall VF loss bilaterally. Regionally, decreasing intra-axonal space and extra-axonal space diffusivities correlated with greater VF loss in the superior-altitudinal area of the right eye and the inferior-altitudinal area of the left eye. In MRS, both early and advanced glaucoma patients had lower gamma-aminobutyric acid (GABA), glutamate, and choline levels than healthy controls. GABA appeared to associate more with superonasal VF loss, and glutamate and choline more with inferior VF loss. Choline ranked third for importance to early glaucoma, whereas radial kurtosis and GABA ranked fourth and fifth for advanced glaucoma.

Conclusions: Our findings highlight the importance of non-invasive neuroimaging biomarkers and analytical modeling for unveiling glaucomatous neurodegeneration and how they reflect complementary VF loss patterns.

Purpose: A retinal mosaic, the spatial organization of a population of homotypic neurons, is thought to sample a specific visual feature into the feedforward visual pathway. The purpose of this study was to propose a universal modeling approach for precisely generating retinal mosaics and overcoming the limitations of previous models, especially in modeling abnormal mosaic patterns under disease conditions.

Methods: Here, we developed the optimization-based pairwise interaction point process (O-PIPP). It incorporates optimization techniques into previous simulation approaches, enabling directional control of the simulation process according to the user-designed optimization target. For the convenience of the community, we implemented the O-PIPP approach into a Python package and a website application.

Results: We showed that the O-PIPP can generate more precise neural spatial patterns of healthy and diseased mosaics compared to previous phenomenological approaches. Notably, through modeling the retinal neural circuitry with O-PIPP-simulated retinitis pigmentosa cone mosaics, we elucidated how the cone mosaic rearrangement impacted the information processing of ganglion cells.

Conclusions: The O-PIPP provides a precise and universal tool to simulate realistic mosaics, which could help to investigate the function of retinal mosaics in vision.