Rhegmatogenous retinal detachment in highly myopic eyes with implantable collamer lens.

AIM: To investigate the clinical characteristics, treatment methods and outcomes of rhegmatogenous retinal detachment (RRD) in highly myopic eyes with implantable collamer lens (ICL). METHODS: High myopia patients who received treatment for nontraumatic RRD after ICL implantation surgery at the Retinal Department of Zhongshan Ophthalmic Center from Jan 2018 to Dec 2022 were reviewed. Comprehensive ophthalmologic examinations including visual acuity measurement and digital fundus photography were performed in each patient. RESULTS: A total of nine RRD eyes from nine patients who received V4c-ICL implantation were included. The mean time from ICL implantation surgery to the diagnosis of RRD was 32.44±22.56mo (range, 1-60mo). At the initial visit for RRD, giant retinal tear (GRT), horseshoe tear, simple round hole, and horseshoe tear combined with round hole were detected in 3, 3, 2, and 1 eye(s), respectively, with macula-off in eyes. Eight patients received surgical treatment, and one patient was treated by retinal laser photocoagulation alone. The ICL was preserved in 7 eyes. At the last follow-up, the mean best corrected visual acuity (BCVA) improved significantly from 1.76±1.06 logMAR at presentation to 0.81±1.01 logMAR (P=0.035), and no case of recurrent retinal detachment was found. CONCLUSION: The morphological presentation of retinal breaks is diverse in this study. The ICL can be preserved in most cases during the course of retinal detachment repair surgery in our data, companied with acceptable visual and anatomical outcomes.

Acrizanib as a Novel Therapeutic Agent for Fundus Neovascularization via Inhibitory Phosphorylation of VEGFR2.

Purpose: The present study aimed to evaluate the effect of acrizanib, a small molecule inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), on physiological angiogenesis and pathological neovascularization in the eye and to explore the underlying molecular mechanisms. Methods: We investigated the potential role of acrizanib in physiological angiogenesis using C57BL/6J newborn mice, and pathological angiogenesis using the mouse oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models. Moreover, vascular endothelial growth factor (VEGF)-treated human umbilical vein endothelial cells (HUVECs) were used as an in vitro model for studying the molecular mechanism underlying acrizanib's antiangiogenic effects. Results: The intravitreal injection of acrizanib did not show a considerable impact on physiological angiogenesis and retinal thickness, indicating a potentially favorable safety profile. In the mouse models of OIR and CNV, acrizanib showed promising results in reducing pathological neovascularization, inflammation, and vascular leakage, indicating its potential efficacy against pathological angiogenesis. Consistent with in vivo results, acrizanib blunted angiogenic events in VEGF-treated HUVECs such as proliferation, migration, and tube formation. Furthermore, acrizanib inhibited the multisite phosphorylation of VEGFR2 to varying degrees and the activation of its downstream signal pathways in VEGF-treated HUVECs. Conclusions: This study suggested the potential efficacy and safety of acrizanib in suppressing fundus neovascularization. Acrizanib functioned through inhibiting multiple phosphorylation sites of VEGFR2 in endothelial cells to different degrees. Translational Relevance: These results indicated that acrizanib might hold promise as a potential candidate for the treatment of ocular vascular diseases.

CNKSR2 expression is correlated with immune infiltrates in Cervical Cancer as a favorable prognostic factor.

Connector enhancer of kinase suppressor of Ras 2 (CNKSR2) is a scaffold protein that mediates mitogen-activated protein kinase pathways. However, the molecular function of CNKSR2 in cervical squamous cell carcinoma (CESC) remains unknown. This study aimed to characterize the role of CNKSR2 in patients with CESC. Immunohistochemistry revealed that the expression of CNKSR2 in CESCs is relatively low compared with that in normal cells. We also explored the gene expression profile of high- and low-CNKSR2 expression in patients with cervical cancer. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the expression of CNKSR2 was upregulated in synapse assembly, which was coordinately regulated using the cAMP signaling pathway and calcium signaling pathway. The correlation between CNKSR2 and cancer immune cell infiltration was investigated via single-sample gene set enrichment analysis (ssGSEA). High CNKSR2 expression was associated with better overall survival (OS) and disease-free survival (DFS). Interestingly, high CNKSR2 expression was a good predictor of the survival outcome in cervical cancer patients. Additionally, CNKSR2 expression was strongly correlated with diverse immune cells in CESCs, including NK cells and T cells. These findings suggest that CNKSR2 is correlated with prognosis and immune infiltration, laying the foundation for future studies on the functional role of CNKSR2 in CESC.

Adaptive Safe Reinforcement Learning With Full-State Constraints and Constrained Adaptation for Autonomous Vehicles.

High-performance learning-based control for the typical safety-critical autonomous vehicles invariably requires that the full-state variables are constrained within the safety region even during the learning process. To solve this technically critical and challenging problem, this work proposes an adaptive safe reinforcement learning (RL) algorithm that invokes innovative safety-related RL methods with the consideration of constraining the full-state variables within the safety region with adaptation. These are developed toward assuring the attainment of the specified requirements on the full-state variables with two notable aspects. First, thus, an appropriately optimized backstepping technique and the asymmetric barrier Lyapunov function (BLF) methodology are used to establish the safe learning framework to ensure system full-state constraints requirements. More specifically, each subsystem's control and partial derivative of the value function are decomposed with asymmetric BLF-related items and an independent learning part. Then, the independent learning part is updated to solve the Hamilton-Jacobi-Bellman equation through an adaptive learning implementation to attain the desired performance in system control. Second, with further Lyapunov-based analysis, it is demonstrated that safety performance is effectively doubly assured via a methodology of a constrained adaptation algorithm during optimization (which incorporates the projection operator and can deal with the conflict between safety and optimization). Therefore, this algorithm optimizes system control and ensures that the full set of state variables involved is always constrained within the safety region during the whole learning process. Comparison simulations and ablation studies are carried out on motion control problems for autonomous vehicles, which have verified superior performance with smaller variance and better convergence performance under uncertain circumstances. The effectiveness of the safe performance of overall system control with the proposed method accordingly has been verified.

Assessment of Osteoporosis at the Lumbar Spine Using Ultrashort Echo Time Magnetization Transfer (UTE-MT) MRI.

BACKGROUND: Bone collagen-matrix contributes to the mechanical properties of bone by imparting tensile strength and elasticity, which can be indirectly quantified by ultrashort echo time magnetization transfer ratio (UTE-MTR) to assess osteoporosis. PURPOSE: To evaluate osteoporosis at the human lumbar spine using UTE-MTR. STUDY TYPE: Prospective. POPULATION: One hundred forty-eight-volunteers (age-range, 50-85; females, N = 90), including 81-normal bone density, 35-osteopenic, and 32-osteoporotic subjects. Ten additional healthy volunteers were recruited to study the intrasession reproducibility of the UTE-MT. FIELD STRENGTH/SEQUENCE: 3T/UTE-MT, short repetition-time adiabatic inversion recovery prepared UTE (STAIR-UTE), and iterative decomposition of water-and-fat with echo-asymmetry and least-squares estimation (IDEAL-IQ). ASSESSMENT: Fracture risk was calculated using Fracture-Risk-Assessment-Tool (FRAX). Region-of-interests (ROIs) were delineated on the trabecular area in the maps of bone-mineral-density, UTE-MTR, collagen-bound water proton-fraction (CBWPF), and bone-marrow fat fraction (BMFF). STATISTICAL TESTS: Linear-regression and Bland-Altman analysis were performed to assess the reproducibility of UTE-MTR measurements in the different scans. UTE-MTR and BMFF were correlated with bone-mineral-density using Pearson's regression and with FRAX scores using nonlinear regression. The abilities of UTE-MTR, CBWPF, and BMFF to discriminate between the three patient subgroups were evaluated using receiver-operator-characteristic (ROC) analysis and area-under-the-curve (AUC). Decision-curve-analysis (DCA) and clinical-impact curves were used to evaluate the value of UTE-MTR in clinical diagnosis. The DeLong test was used to compare the ROC curves. P-value <0.05 was considered statistically significant. RESULTS: Excellent reproducibility was obtained for the UTE-MT measurements. UTE-MTR strongly correlated with bone-mineral-density (r = 0.76) and FRAX scores (r = -0.77). UTE-MTR exhibited higher AUCs (≥0.723) than BMFF, indicating its superior ability to distinguish between the three patient subgroups. The DCA and clinical-impact curves confirmed the diagnostic value of UTE-MTR. UTE-MTR and CBWPF showed similar performance in correlation with bone-mineral-density and cohort classification. DATA CONCLUSION: UTE-MTR strongly correlates with bone-mineral-density and FRAX and shows great potential in distinguishing between normal, osteopenic, and osteoporotic subjects. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Association between choroidopathy and photoreceptors during the early stage of diabetic retinopathy: a cross-sectional study.

PURPOSE: To explore the role of choroidopathy in diabetic retinopathy (DR) by investigating the correlation between alterations of choroidal vessel and photoreceptors during the early stage of DR. METHODS: We performed a cross-sectional comparison of diabetic patients without DR (NDR group; n=16) and those with mild nonproliferative diabetic retinopathy (NPDR group; n=39). Optical coherence tomography (OCT) images of choroidal vessel alterations and photoreceptor structures were evaluated using the choroidal vascularity index (CVI) and adjusted ellipsoid zone (EZ) reflectivity, respectively. To evaluate the function of cone photoreceptors, the fundamental, harmonic amplitudes, the parameters S and Rmp3 were calculated from the electroretinogram (ERG). These factors were compared between groups. The correlation between the CVI and parameters describing the function and structure of the photoreceptors was evaluated. RESULTS: The significant decrease was observed in the CVI in the NPDR group compared to the NDR group (0.67 ± 0.04 vs. 0.70 ± 0.06; p = 0.028), but not in the adjusted EZ reflectivity or ERG parameters. In NPDR group and merging the 2 groups, CVI was moderately positively correlated with the fundamental amplitude obtained by the flicker ERG (NPDR only: r = 0.506; p = 0.001; merge the 2 groups: r = 0.423; p = 0.001), which was regulated by the response of the cone photoreceptors. The CVI was positively and moderately correlated with the logS (NPDR only: r = 0.462; p = 0.003; merge the 2 groups: r = 0.355; p = 0.008), indicating the sensitivity of cone cell light transduction. CONCLUSION: Compared to eyes without DR, CVI decreased representing choroidal vascular changes in eyes with mild NPDR. These changes may be related to the functional impairment of cone photoreceptors, especially phototransduction sensitivity, as the DR develops.

Efficacy and Safety of Biosimilar QL1207 vs. the Reference Aflibercept for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Phase 3 Trial.

INTRODUCTION: This trial aimed to compare the efficacy and safety between biosimilar QL1207 and the reference aflibercept for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: This randomized, double-blind, phase 3 trial was conducted at 35 centers in China. Patients aged ≥ 50 years old with untreated subfoveal choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) letter score of 73-34 were eligible. Patients were randomly assigned to receive intravitreous injections of QL1207 or aflibercept 2 mg (0.05 ml) in the study eye every 4 weeks for the first 3 months, followed by 2 mg every 8 weeks until week 48, stratified by baseline BCVA ≥ or < 45 letters. The primary endpoint was BCVA change from baseline at week 12. The equivalence margin was ± 5 letters. The safety, immunogenicity, pharmacokinetics (PK), and plasma vascular endothelial growth factor (VEGF) concentration were also evaluated. RESULTS: A total of 366 patients were enrolled (QL1207 group, n = 185; aflibercept group, n = 181) from Aug 2019 to Jan 2022 with comparable baseline characteristics. The least-squares mean difference in BCVA changes was - 1.1 letters (95% confidence interval - 3.0 to 0.7; P = 0.2275) between the two groups, within the equivalence margin. The incidences of treatment-emergent adverse events (TEAE; QL1207: 71.4% [132/185] vs. aflibercept: 71.8% [130/181]) and serious TEAE (QL1207: 14.1% [26] vs. aflibercept: 12.7% [23]) appeared comparable between treatment groups, and no new safety signal was found. Anti-drug antibody, PK profiles, and VEGF concentration were similar between the two groups. CONCLUSIONS: QL1207 has equivalent efficacy to aflibercept for nAMD with similar safety profiles. It could be used as an alternative anti-VEGF agent for clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05345236 (retrospectively registered on April 25, 2022); National Medical Products Administration of China: CTR20190937 (May 20, 2019).

The action logic of the older adults about health-seeking in South Rural China.

BACKGROUND: The Chinese government has invested significant resources to build many rural healthcare stations. However, in the face of convenient medical paths and accessible medical resources, the utilization rate of health services for older adults in rural areas is surprisingly low. This study explored why health-seeking behavior among older adults in rural China was not active. METHODS: Data were collected through participatory rural appraisal (PRA) with 108 participants in 12 villages in southern China. Daily schedule and social and resource mapping were employed to outline the range of activities and the routine of the older adults, as well as in-depth interviews to understand the logic of their healthcare choices. Data collected were analyzed by content analysis. RESULTS: Three themes were generated: (1) perceptions of health status (being healthy or sick): the rural older adults used the ability to handle routine chores as a measure of health status; (2) prioritization of solving symptoms over curing diseases: the older adults preferred the informal self-medication to cope with diseases, as long as there were no symptoms and no pain; (3) 'unpredictable' troubles: they tended to favor the 'optimal' solution of keeping their lives in order rather than the best medical treatment options. CONCLUSION: This study showed that the medical practices of the rural elderly were profoundly influenced by their perceptions of health and their life experiences. In the face of diseases, they tended to keep their lives in order, preferring self-treatment practices that address symptoms or selectively following medical advice rather than medical and science-based clinical solutions. In the future, the construction of rural health care should focus on changing the 'inaccessibility' of healthcare resources at the subjective level of the rural elderly and develop culturally adaptable health education.

Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission.

Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.

Six-Year Change in Cataract Surgical Coverage and Postoperative Visual Outcomes in Rural Southern China: The Yangxi Eye Study.

PURPOSE: The purpose of this study was to investigate a 6-year change in cataract surgical coverage (CSC), effective cataract surgical coverage (eCSC), and visual outcomes in an elderly population in rural southern China. DESIGN: This is a prospective population-based study with a 6-year follow-up. METHODS: The study included rural residents aged 50 years and above in southern China with comprehensive eye examinations at baseline and follow-up in 2014 and 2020, respectively. RESULTS: Five thousand six hundred thirty-eight participants underwent baseline examinations (mean age 66.1±10.2 y, 50.8% women); and 3141 (64.9%) of 4841 eligible survivors attended the 6-year follow-up. Cataract surgical coverage was 41.7% and 40.6% at baseline and follow-up, respectively, while eCSC were 32.6% and 26.6%. In multivariate models, the 6-year likelihood of cataract surgery decreased with older age [odds ratio (OR)=0.97 per year, 95% confidence interval (CI): 0.94, 0.99, P =0.012] and worse baseline presenting uncorrected visual acuity (PVA) in the worse-seeing eye (OR=0.35 per unit logarithm of the minimum angle of resolution (logMAR), 95% CI: 0.25, 0.48, P <0.001), and increased with prior cataract surgical history at baseline (OR=3.88, 95% CI: 1.91, 7.09, P <0.001). The likelihood of receiving effective cataract surgery decreased with worse baseline PVA in the worse eye (OR=0.49 per unit logMAR, 95% CI: 0.24, 0.97, P =0.042) and better-seeing eye (OR=0.68 per unit logMAR, 95% CI: 0.48, 0.95, P =0.026). Posterior capsular opacification was the main reason for PVA <6/18, reporting it in logMAR (0.5) in operated eyes (38.4% at baseline; 28.1% at follow-up). CONCLUSIONS: World Health Organization has established a global target of increasing eCSC by 30% before 2030, but no increase was found in rural southern China between 2014 and 2020, let alone reaching the World Health Organization target of 56.3%. Strategies to improve surgery incidence should focus on older persons and those with worse preoperative PVA.

Impaired immune responses and prolonged viral replication in lung allograft recipients infected with SARS-CoV-2 in the early phase after transplantation.

PURPOSE: Lung transplant recipients are at increased risk of severe disease following infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) due to high-dose immunosuppressive drugs and the lung is the main organ affected by Coronavirus disease 2019 (COVID-19). Several studies have confirmed increased SARS-CoV-2-related mortality and morbidity in patients living with lung allografts; however, detailed immunological studies of patients with SARS-CoV-2 infection in the early phase following transplantation remain scarce. METHODS: We investigated patients who were infected with SARS-CoV-2 in the early phase (18-103 days) after receiving double-lung allografts (n = 4, LuTx) in comparison to immunocompetent patients who had not received solid organ transplants (n = 88, noTx). We analyzed SARS-CoV-2-specific antibody responses against the SARS-CoV-2 spike and nucleocapsid proteins using enzyme-linked immunosorbent assays (ELISA), chemiluminescence immunoassays (CLIA), and immunoblot assays. T cell responses were investigated using Elispot assays. RESULTS: One LuTx patient suffered from persistent infection with fatal outcome 122 days post-infection despite multiple interventions including remdesivir, convalescent plasma, and the monoclonal antibody bamlanivimab. Two patients experienced clinically mild disease with prolonged viral shedding (47 and 79 days), and one patient remained asymptomatic. Antibody and T cell responses were significantly reduced or undetectable in all LuTx patients compared to noTx patients. CONCLUSION: Patients in the early phase following lung allograft transplantation are vulnerable to infection with SARS-CoV-2 due to impaired immune responses. This patient population should be vaccinated before LuTx, protected from infection post-LuTx, and in case of infection treated generously with currently available interventions.

Deep Learning Performance of Ultra-Widefield Fundus Imaging for Screening Retinal Lesions in Rural Locales.

Importance: Retinal diseases are the leading cause of irreversible blindness worldwide, and timely detection contributes to prevention of permanent vision loss, especially for patients in rural areas with limited medical resources. Deep learning systems (DLSs) based on fundus images with a 45° field of view have been extensively applied in population screening, while the feasibility of using ultra-widefield (UWF) fundus image-based DLSs to detect retinal lesions in patients in rural areas warrants exploration. Objective: To explore the performance of a DLS for multiple retinal lesion screening using UWF fundus images from patients in rural areas. Design, Setting, and Participants: In this diagnostic study, a previously developed DLS based on UWF fundus images was used to screen for 5 retinal lesions (retinal exudates or drusen, glaucomatous optic neuropathy, retinal hemorrhage, lattice degeneration or retinal breaks, and retinal detachment) in 24 villages of Yangxi County, China, between November 17, 2020, and March 30, 2021. Interventions: The captured images were analyzed by the DLS and ophthalmologists. Main Outcomes and Measures: The performance of the DLS in rural screening was compared with that of the internal validation in the previous model development stage. The image quality, lesion proportion, and complexity of lesion composition were compared between the model development stage and the rural screening stage. Results: A total of 6222 eyes in 3149 participants (1685 women [53.5%]; mean [SD] age, 70.9 [9.1] years) were screened. The DLS achieved a mean (SD) area under the receiver operating characteristic curve (AUC) of 0.918 (0.021) (95% CI, 0.892-0.944) for detecting 5 retinal lesions in the entire data set when applied for patients in rural areas, which was lower than that reported at the model development stage (AUC, 0.998 [0.002] [95% CI, 0.995-1.000]; P < .001). Compared with the fundus images in the model development stage, the fundus images in this rural screening study had an increased frequency of poor quality (13.8% [860 of 6222] vs 0%), increased variation in lesion proportions (0.1% [6 of 6222]-36.5% [2271 of 6222] vs 14.0% [2793 of 19 891]-21.3% [3433 of 16 138]), and an increased complexity of lesion composition. Conclusions and Relevance: This diagnostic study suggests that the DLS exhibited excellent performance using UWF fundus images as a screening tool for 5 retinal lesions in patients in a rural setting. However, poor image quality, diverse lesion proportions, and a complex set of lesions may have reduced the performance of the DLS; these factors in targeted screening scenarios should be taken into consideration in the model development stage to ensure good performance.

Choroidal Vortex Vein Drainage System in Central Serous Chorioretinopathy Using Ultra-Widefield Optical Coherence Tomography Angiography.

Purpose: To evaluate differences in the choroidal vortex vein drainage system (VV) in eyes between patients with central serous chorioretinopathy (CSC) and unaffected individuals using ultra-widefield optical coherence tomography angiography (UWF-OCTA). Methods: In this cross-sectional observational study, 40 eyes of patients with CSC and 28 eyes of healthy volunteers were included. The analysis involved the use of UWF-OCTA to analyze the proportion of the choroidal vortex vein drainage system (VV%), choroidal thickness, choroidal vascular volume (CVV), and choroidal vascularity index (CVI) of the VV in each drainage quadrant. The location relationship between the leakage points in fluorescein angiography and the VV was also explored. Results: A within-group analysis of VV% showed a statistically significant difference in the CSC group (P < 0.001) but not in the control group (P = 0.270). Compared to healthy eyes, CSC eyes had a significantly larger CVV and higher CVI in all regions (all P < 0.05). The superotemporal (ST) drainage system had the largest CVV and thickest choroidal layer among the four drainage quadrants (all P < 0.05) in CSC eyes. The leakage rate in the ST quadrant was significantly higher than that in the inferotemporal quadrant (P < 0.001). Conclusions: CSC eyes have an asymmetric vortex vein drainage system, with relative hyperperfusion in all VV. Further, the preferential drainage route of the submacular choroid may be the ST drainage system in CSC eyes. Translational Relevance: Targeting the imbalanced drainage system could be a potential therapeutic approach for CSC.

An artificial intelligence system for the whole process from diagnosis to treatment suggestion of ischemic retinal diseases.

Ischemic retinal diseases (IRDs) are a series of common blinding diseases that depend on accurate fundus fluorescein angiography (FFA) image interpretation for diagnosis and treatment. An artificial intelligence system (Ai-Doctor) was developed to interpret FFA images. Ai-Doctor performed well in image phase identification (area under the curve [AUC], 0.991-0.999, range), diabetic retinopathy (DR) and branch retinal vein occlusion (BRVO) diagnosis (AUC, 0.979-0.992), and non-perfusion area segmentation (Dice similarity coefficient [DSC], 89.7%-90.1%) and quantification. The segmentation model was expanded to unencountered IRDs (central RVO and retinal vasculitis), with DSCs of 89.2% and 83.6%, respectively. A clinically applicable ischemia index (CAII) was proposed to evaluate ischemic degree; patients with CAII values exceeding 0.17 in BRVO and 0.08 in DR may be associated with increased possibility for laser therapy. Ai-Doctor is expected to achieve accurate FFA image interpretation for IRDs, potentially reducing the reliance on retinal specialists.

Red Light-Triggered Anti-Angiogenic and Photodynamic Combination Therapy of Age-Related Macular Degeneration.

Choroidal neovascularization (CNV) is the key pathological event of wet age-related macular degeneration (wAMD) leading to irreversible vision loss. Currently, anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) agents has become the standard treatment for wAMD, while it is still subject to several limitations, including the safety concerns of monthly intravitreal administration and insufficient efficacy for neovascular occlusion. Combined therapy with photodynamic therapy (PDT) and anti-angiogenic agents has emerged as a novel treatment paradigm. Herein, a novel and less-invasive approach is reported to achieve anti-angiogenic and photodynamic combination therapy of wAMD by intravenous administration of a photoactivatable nanosystem (Di-DAS-VER NPs). The nanosystem is self-assembled by reactive oxygen species (ROS)-sensitive dasatinib (DAS) prodrug and photosensitizer verteporfin (VER). After red-light irradiation to the diseased eyes, intraocular release of anti-angiogenic DAS is observed, together with selective neo-vessels occlusion by VER-generated ROS. Notably, Di-DAS-VER NPs demonstrates promising therapeutic efficacy against CNV with minimized systemic toxicity. The study enables an efficient intravenous wAMD therapy by integrating a photoactivation process with combinational therapeutics into one simple nanosystem.

Development and validation of a prognostic nomogram for predicting cancer-specific survival in advanced endometrial carcinoma after surgery: a retrospective analysis of the SEER Database.

OBJECTIVE: We aimed to construct and validate a prognostic nomogram to predict cancer-specific survival (CSS) after surgery in patients with advanced endometrial carcinoma (EC). DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: The Surveillance, Epidemiology, and End Results (SEER) Database contains cancer incidence and survival data from population-based cancer registries in the USA. A total of 5445 patients from the SEER Database diagnosed with advanced EC between 2004 and 2015 were included and randomised 7:3 into a training cohort (n=3812) and a validation cohort (n=1633). OUTCOME MEASURE: CSS. RESULTS: The nomograms for CSS included 10 variables (positive regional nodes, age, tumour size, International Federation of Gynecology and Obstetrics (FIGO) stage, grade, ethnicity, income, radiation, chemotherapy and historical stage) based on the forward stepwise regression results. They revealed discrimination and calibration using the concordance index (C-index) and area under the time-dependent receiver operating characteristic curve, with a C-index value of 0.7324 (95% CI=0.7181 to 0.7468) and 0.7511 (95% CI=0.7301 to 0.7722) for the training and validation cohorts, respectively. Using calibration plots, a high degree of conformance was shown between the predicted and observed results. Additionally, a comparison of the nomogram and FIGO staging based on changes in the C-index, net reclassification index and integrated discrimination improvement demonstrated that the nomogram had better accuracy and efficacy. CONCLUSIONS: We successfully constructed an accurate and effective nomogram to predict CSS in patients with advanced EC, which may help clinicians determine optimal individualised treatment strategies for patients with advanced EC. The predictive performance of the nomogram was evaluated thoroughly, but only internally. Therefore, further validation using different data sources is warranted in future related studies.

KRT18 regulates trophoblast cell migration and invasion which are essential for embryo implantation.

Female infertility is a worldwide concern that impacts the quality of life and well-being of affected couples. Failure of embryo implantation is a major cause of early pregnancy loss and is precisely regulated by a programmed molecular mechanism. Recent studies have shown that proper trophoblast adhesion and invasion are essential for embryo implantation. However, the potential regulatory mechanism involved in trophoblast adhesion and invasion has yet to be fully elucidated. KRT18 has been reported to play a critical role in early embryonic development, but its physiological function in embryo implantation remains unclear. In the present study, we revealed that KRT18 was highly expressed in trophoblast cells and that knockdown of KRT18 in mouse embryos inhibited embryo adhesion and implantation. In vitro experiments further showed that silencing KRT18 disturbed trophoblast migration and invasion. More importantly, we provide evidence that KRT18 directly binds to and stabilizes cell surface E-cadherin in trophoblast cells through microscale thermophoresis (MST) analysis and molecular biology experiments. In brief, our data reveal that KRT18, which is highly expressed in trophoblast cells, plays an important role in the regulation of trophoblast invasion and adhesion during embryo implantation by directly binding to E-cadherin.

Therapeutic Benefit of Melatonin in Choroidal Neovascularization During Aging Through the Regulation of Senescent Macrophage/Microglia Polarization.

Purpose: This study aimed to investigate the age-dependent anti-angiogenic capability of melatonin in choroidal neovascularization (CNV) and to explore the underlying molecular mechanisms. Methods: In the present study, a laser-induced CNV model was established in both young (three months of age) and old (18 months of age) mice, and the size of CNV lesions and vascular leakage was detected by morphological and imaging examination. Next, Western blot and immunostaining were used to observe the levels of M2 markers, senescence-related markers, and molecules involved in IL-10/STAT3 pathway. Additionally, colivelin was used to study the effect of IL-10/STAT3 pathway activation on the expression of M2 markers and senescence-related markers by Western blot and immunostaining. Finally, the effects of colivelin on melatonin-induced reduction of CNV size and vascular leakage in mice at different ages were assessed using morphological and imaging examination. Results: Our results revealed that aging promoted M2 macrophage/microglia polarization, and aggravated CNV and vascular leakage. Melatonin significantly inhibited the M2 polarization of senescent macrophage/microglia and reduced the CNV area and vascular leakage. Moreover, melatonin markedly suppressed IL-10/STAT3 pathway activation in the macrophage/microglia of old mice, and STAT3 activator colivelin reversed the suppressive effect of melatonin on M2 polarization of senescent macrophage/microglia and laser-induced CNV in old mice. Conclusions: Our data demonstrated that melatonin significantly prevented the M2 polarization of senescent macrophage/microglia by inhibiting the IL-10/STAT3 pathway, and eventually attenuated senescence-associated CNV. These findings suggested that melatonin could serve as a promising therapeutic agent to treat CNV and other age-related ocular diseases.

Impact of Cataract Surgery on Income in Rural Southern China: The SUCCESS Randomized Controlled Trial.

PURPOSE: Visual impairment from cataracts is closely associated with low income, but trial evidence regarding the impact of surgery on income is lacking. We investigated whether cataract surgery could increase personal income. DESIGN: A 2-arm, parallel-group, open-label, randomized controlled trial (ClinicalTrials.gov, NCT03020056). METHODS: Persons aged 50 years or older in rural Guangdong, China, with best-corrected visual acuity <6/19 in both eyes due to cataracts were randomly assigned (1:1) to receive surgery within 4 weeks (intervention group), or 1 year later (control group). All participants were interviewed at baseline and end-line regarding demographic characteristics, income, and quality of life. RESULTS: Among the 292 eligible persons (5.40%, mean age = 74.0 y, 61.0% women) randomly assigned to intervention (n = 146) or control (n = 146) groups, 12 participants (8.22%) in the intervention group and 1 (0.68%) in the control did not receive the allocated intervention. By study closeout, 18 participants (6.16%) were lost to follow-up. The mean 1-year income increase of the intervention group ($2469-$3588; change = $1119) was significantly larger than that of the controls ($2258-$2052; change = $-206), a between-group difference of $1325 (relative increase = 54.0%; 95% CI = $739 to $1911; P < 0.001). In multivariable modeling, intervention group membership was associated with greater income increase (ß = 1143.2; 95% CI = 582.0 to 1704.3; P < 0.001). Greater improvement in best-corrected visual acuity was associated with income increase in univariable modeling (ß = 1626.9; 95% CI = 1083.6 to 2170.1; P < 0.001). CONCLUSIONS: Cataract surgery substantially increases personal income in rural China, offering a strategy for poverty alleviation. The strong association between increased income and change in visual acuity enhances the biological plausibility of the result.

Longitudinal Changes of Parafoveal Vessel Density in Diabetic Patients without Clinical Retinopathy Using Optical Coherence Tomography Angiography.

PURPOSE: The purpose of this study was to identify the rate of parafoveal vessel density (VD) changes associated with the progression from non-diabetic retinopathy (NDR) to early stages of DR over a year. METHODS: This longitudinal cohort study enrolled diabetic patients from the Guangzhou community in China. The patients with NDR at baseline were included and underwent comprehensive examinations at baseline and after 1 year. A commercial OCTA device (Triton Plus, Topcon, Tokyo, Japan) was employed to quantify the parafoveal VD in the superficial and deep capillary plexuses. The rates of change in parafoveal VD over time in the incident DR and NDR groups were compared after a year. RESULTS: A total of 448 NDR patients were included in the study. Among them, 382 (83.2%) were stable and 66 (14.4%) developed incident DR during the 1-year follow-up. The average parafoveal VD in the superficial capillary plexus (SCP) reduced significantly more quickly in the incident DR group than in the NDR group (-1.95 ± 0.45%/year vs. -0.45 ± 0.19/year, p = 0.002). The VD reduction rate for the deep capillary plexus (DCP) was not significantly different for the groups (p = 0.156). CONCLUSIONS: The incident DR group experienced a significantly faster reduction in parafoveal VD in the SCP compared with the stable group. Our findings further provide supporting evidence that parafoveal VD in the SCP may be used as an early indicator of the pre-clinical stages of DR.