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Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.

Background: Vitreoretinal lymphoma (VRL) often presents with features resembling uveitis and is commonly associated with central nervous system lymphoma (CNSL). Intravitreal methotrexate (IVMTX) is widely used as local therapy; however, objective markers for treatment response and prognosis remain limited. This study investigated choroidal structural changes after IVMTX via enhanced depth imaging optical coherence tomography (EDI-OCT) and explored prognostic indicators for subsequent CNSL development. Methods: This retrospective study included 18 patients (27 eyes) with VRL treated with IVMTX at Tokushima University Hospital between 2006 and 2021. EDI-OCT was conducted at baseline and at 1 and 3 months after IVMTX. Choroidal thickness and luminal and stromal areas were quantified through image binarization. The stromal/choroidal area (S/C) ratio and its association with CNSL onset were statistically analyzed. Results: The mean number of IVMTX injections administered over 3 months was 5.9 ± 1.3. Foveal retinal thickness did not significantly change, whereas foveal choroidal thickness significantly decreased from 275.8 ± 15.8 µm at baseline to 257.5 ± 14.7 µm at 1 month (p < 0.01). Total choroidal and stromal areas, particularly in the outer choroidal layer, were significantly decreased after IVMTX (p < 0.0001), whereas the luminal area in the inner layer modestly reduced (p < 0.05). The S/C ratio significantly declined at 1 month post-treatment (p < 0.001). Patients who developed CNSL within 2 years of VRL onset demonstrated higher baseline S/C ratios (p < 0.05). Conclusions: IVMTX induces measurable reductions in choroidal areas and stromal proportion, indicating decreased inflammatory infiltration. The baseline S/C ratio observed on EDI-OCT is a potential noninvasive biomarker of VRL activity and a prognostic indicator for early CNSL development.

This study aimed to conduct a comparative epidemiological survey of uveitis across various healthcare settings and elucidate the clinical characteristics. We conducted a retrospective cross-sectional study in the Ube-City medical region in Yamaguchi prefecture and recruited 268 patients from a university hospital (151 patients), municipal hospitals (51 patients), and private eye clinics (58 patients). Medical records of patients newly diagnosed with uveitis between January 2018 and December 2019 in the institutes were included, reviewed, and compared. The main outcomes included the number of uveitis causes, treatment methods, and visual acuity. Panuveitis, which is associated with systemic diseases, such as Vogt–Koyanagi–Harada disease and sarcoidosis, was more prominent in university hospital patients. Conversely, anterior uveitis, including traumatic iritis, was prominently detected in general hospitals and private eye clinics. The best-corrected visual acuity improved to 1.0 (logMAR = 0); an improvement of 74%, 61%, and 54% was observed in private eye clinic, general hospital, and university hospital patients, respectively. This study identified differences in uveitis presentation and treatment across diverse clinical settings. The results of this study provide valuable data for differentiating the causes of uveitis at university hospitals, general hospitals, and private eye clinics.

Purpose To report the characteristics of a case series of ocular inflammatory events following COVID-19 vaccination in Japan. Study design Retrospective multicenter study Methods In this retrospective multicenter survey, a questionnaire was sent to 16 Japanese hospitals that had uveitis specialty clinics. Information on patients who developed ocular inflammatory events within 14 days of COVID-19 vaccination between February 2021 and December 2021 was collected. Results Thirty-seven patients were diagnosed with ocular inflammatory events following COVID-19 vaccination. The mean age was 53.4 ± 16.4 years (range, 26-86 years), and the mean time to onset after vaccination was 6.3 ± 4.2 days (range, 1-14 days). Vogt-Koyanagi-Harada disease (VKH) was the most common event (n = 17 patients, 46%), followed by anterior uveitis (n = 6), infectious uveitis (n = 3), acute zonal occult outer retinopathy (AZOOR) (n = 2), sarcoidosis-associated uveitis (n = 1), acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (n = 1), optic neuritis (n = 1), multiple evanescent white dot syndrome (MEWDS) (n = 1), Posner-Schlossman syndrome (n = 1), and unclassified uveitis (n = 4). Twenty-eight cases occurred after BNT162b2 vaccination (Pfizer-BioNTech) and 8 after mRNA-1273 vaccination (Moderna), whilst 1 patient had no information about vaccine type. Conclusions COVID-19 vaccination can be related to various types of ocular inflammatory events. When we encounter patients with ocular inflammatory disease, we should consider that it may be an adverse effect of COVID-19 vaccination.

We evaluated the real-world efficacy of intravitreal faricimab for diabetic macular edema (DME) and its relationship with visual and retinal anatomical changes using optical coherence tomography. We retrospectively assessed 174 patients (214 eyes) with DME from 13 Japan Clinical REtina Study Group (J-CREST) sites who received ≥ 1 faricimab injection and were followed ≥ 6 months, and compared treatment-naïve (with no prior anti-VEGF treatment) and previously treated groups. Both groups showed significant improvements in best-corrected visual acuity (BCVA) and central subfield thickness (CST BCVA gain was greater in the treatment-naïve group ( p  = 0.0109), whereas CST reduction showed little difference ( p  = 0.31). Resolution of cystoid macular oedema, diffuse retinal thickening, and subretinal fluid (SRF) was observed in both groups. Resolution of inner nuclear layer (INL) oedema and SRF significantly correlated with ≥ 0.2 log MAR BCVA improvement in the treatment-naïve group ( p  = 0.043 and p  = 0.022, respectively). Mean number of injections was comparable between groups. One case of anterior chamber inflammation occurred; however, no serious systemic events were observed. In conclusion, faricimab significantly improved visual and anatomical outcomes in DME, especially in treatment-naïve eyes. Early resolution of INL oedema and SRF may serve as a potential biomarker for visual prognosis.

Purpose Non-infectious uveitis associated with Vogt-Koyanagi-Harada (VKH) disease or sarcoidosis is commonly treated with systemic corticosteroids (SCS). We assessed the use of SCS for non-infectious uveitis relapses in Japanese clinical practice. Study design Multicenter, retrospective chart review (UMIN Clinical Trial Registry; UMIN000032390). Methods One hundred fifty-seven patients (15– ≤ 75 years; 103 VKH disease, 54 sarcoidosis) given SCS to treat a relapse of non-infectious intermediate, posterior, or panuveitis accompanying VKH disease or sarcoidosis were studied (August 2011–December 2018). SCS dose and duration, concomitant medications, subsequent relapses, and steroid-related adverse drug reactions (ADRs) were analyzed for 12 months after target relapse treatment. Relationships between background factors and total SCS dose were analyzed (logistic regression). Results Mean (± SD) total SCS dose over 12 months after target relapse treatment was 3874 ± 2775 mg, and was higher in patients with immunosuppressants than in those without (4575 mg vs 3496 mg). Immunosuppressant use was the only factor significantly associated with higher total SCS dose (p = 0.0196). Mean duration of SCS treatment for relapse was 318.7 ± 89.3 days. Only 29.3% of patients were steroid-free after 12 months; the percentage was higher in patients without immunosuppressants (36.3% vs 16.4%). Subsequent relapse was experienced by 39.5% of patients, and 13.4% had a steroid-related ADR (mostly glaucoma or diabetes). Conclusion In Japanese clinical practice, many patients with recurrent uveitis accompanying VKH disease or sarcoidosis received SCS for relapse for ≥ 300 days, suggesting that reducing corticosteroids is challenging in patients with difficulty suppressing inflammation.

Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.

Osteoclasts are specialized cells essential for bone resorption, a crucial process in bone remodeling, and dysregulation of osteoclastogenesis can lead to pathological bone loss such as osteoporosis and rheumatoid arthritis. Therefore, understanding the precise mechanisms governing osteoclast differentiation is crucial for developing effective therapies for skeletal diseases. In osteoclastogenesis, as well as other differentiated cells, it is well understood that cell cycle arrest is essential for terminal differentiation and is tightly regulated by CDK inhibitors such as Cip/Kip family and Ink4 family protein. In this manuscript, we identified p15 Ink4b , a member of the Ink4 family, as a novel regulator of osteoclastogenesis by comprehensive single-cell RNA sequence data reanalyzing. Furthermore, histological analysis and in vitro osteoclast differentiation assay revealed that p15 Ink4b functionally regulates osteoclastogenesis. Our findings may not only provide insights into the molecular mechanisms of osteoclast differentiation but also underscore the potential of harnessing cell cycle mechanisms to develop novel therapeutic strategies for bone diseases.

Dietary ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) and lutein each protect against age-related macular degeneration (AMD). We here examined the effects of ω-3 LCPUFAs and lutein supplementation in a mouse model of AMD. Mice were assigned to four groups: (1) a control group fed an ω-3 LCPUFA-free diet, (2) a lutein group fed an ω-3 LCPUFA-free diet with oral administration of lutein, (3) an ω-3 group fed an ω-3 LCPUFA-supplemented diet, and (4) an ω-3 + lutein group fed an ω-3 LCPUFA-supplemented diet with oral administration of lutein. Mice were fed the defined diets beginning 2 weeks before, and received lutein with an oral gavage needle beginning 1 week before, induction of choroidal neovascularization (CNV) by laser photocoagulation. The area of CNV measured in choroidal flat-mount preparations was significantly reduced in mice fed ω-3 LCPUFAs or lutein compared with those in the control group, and it was reduced in an additive manner in those receiving both ω-3 LCPUFAs and lutein. The concentrations of various inflammatory mediators in the retina or choroid were reduced in mice fed ω-3 LCPUFAs or lutein, but no additive effect was apparent. The generation of reactive oxygen species (ROS) in chorioretinal lesions revealed by dihydroethidium staining as well as the expression of NADPH oxidase 4 (Nox4) in the retina revealed by immunohistofluorescence and immunoblot analyses were attenuated by ω-3 LCPUFAs and lutein in a synergistic manner. Our results thus show that dietary intake of ω-3 LCPUFAs and lutein attenuated CNV in an additive manner and in association with suppression of inflammatory mediator production, ROS generation, and Nox4 expression. Dietary supplementation with both ω-3 LCPUFAs and lutein warrants further study as a means to protect against AMD.

In the twentieth century, a conspicuous lack of effective treatment strategies existed for managing several retinal disorders, including age-related macular degeneration; diabetic retinopathy (DR); retinopathy of prematurity (ROP); retinitis pigmentosa (RP); uveitis, including Behçet's disease; and vitreoretinal lymphoma (VRL). However, in the first decade of this century, advances in biomedicine have provided new treatment strategies in the field of ophthalmology, particularly biologics that target vascular endothelial growth factor or tumor necrosis factor (TNF)-α. Furthermore, clinical trials on gene therapy specifically for patients with autosomal recessive or X-linked RP have commenced. The overall survival rates of patients with VRL have improved, owing to earlier diagnoses and better treatment strategies. However, some unresolved problems remain such as primary or secondary non-response to biologics or chemotherapy, and the lack of adequate strategies for treating most RP patients. In this review, we provide an overview of the immunological mechanisms of the eye under normal conditions and in several retinal disorders, including uveitis, DR, ROP, RP, and VRL. In addition, we discuss recent studies that describe the inflammatory responses that occur during the course of these retinal disorders to provide new insights into their diagnosis and treatment.