Near-Infrared II Fluorescence Imaging and Image-Guided siRNA Therapy of Atherosclerosis.

Targeting Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.

Evaluating the Causal Effects of Low Density Lipoprotein Cholesterol Levels on Ischemic Stroke: A Mendelian Randomization Study.

Background: Ischemic stroke (IS) is the leading cause of disability and mortality worldwide. Low-density lipoprotein cholesterol (LDL-C) levels hadno potential risk on ischemic stroke. However, higher LDL-C levels were closely related to IS. Based on two antagonistic viewpoints, a Mendelian randomization (MR) study was designed to evaluate the causal effects of LDL-C levels on IS. Methods: Datasets of LDL-C levels and ischemic stroke were acquired from genome-wide association studies (GWAS). Weighted median method was conducted for main analysis, and MR-Egger and inverse-variance weighted (IVW) methods were performed for auxiliary analyses. Heterogeneity and pleiotropic tests were utilized to confirm the reliability of this study. Results: A total of 359 single nucleotide polymorphisms (SNPs) were associated with LDL-C levels (P < 5 × 10-8) and 337 SNPs were available in ischemic stroke with eliminating outliers. LDL-C levels were significantly associated with ischemic stroke (OR = 1.104, 95%CI = 1.019 - 1.195, P = 1.52 × 10-2). MR-Egger and IVW showed directionally similar estimates (MR-Egger: OR = 1.120, 95%CI = 1.040 - 1.207, P = 3.12 × 10-3; IVW: OR = 1.120, 95%CI = 1.064 - 1.178, P = 1.17 × 10-5). Conclusion: LDL-C levels had causal effects on IS, providing insights into the design of future interventions to reduce the burden of ischemic stroke.

Uric acid levels and heart failure: A mendelian randomization study.

BACKGROUND AND AIMS: Uric acid, the end-product of purine metabolism within the human body, has been the subject of studies exploring its potential association with cardiovascular and cerebrovascular diseases. However, the precise relationship between uric acid levels and heart failure remains elusive. METHODS AND RESULTS: In this particular study, aggregated data from genome-wide association studies on uric acid and heart failure were utilized to perform a two-sample Mendelian randomization (MR) analysis utilizing R software. The aim was to uncover any causal link between these variables. The primary outcome was assessed using inverse variance weighted (IVW) methodology, while sensitivity analyses employed MR-Egger, weighted median (WME), and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) techniques. IVW results revealed a possible causal relationship between elevated uric acid levels and an increased risk of heart failure (OR: 1.09, 95 % CI: 1.01-1.17, P < 0.05). Encouragingly, the directions provided by MR-Egger and WME aligned with IVW findings, and no anomalies were detected in the remaining sensitivity analyses. CONCLUSION: These outcomes indicate the stability of the results of the study, thereby suggesting that heightened uric acid levels may contribute to an augmented risk of heart failure.

The effects of self-esteem and parental phubbing on adolescent internet addiction and the moderating role of the classroom environment: a hierarchical linear model analysis.

BACKGROUND: With the advent of the new media era, the understanding of adolescent internet addiction needs to be enriched. It is also necessary to distinguish the related factors of adolescent internet addiction at different levels to clarify the mechanisms of this phenomenon. METHODS: This study used hierarchical linear model analysis to explore the effects of student-level factors and school-level factors on adolescent internet addiction, along with cross-level moderating effects. A total of 1,912 students between the 4th and 8th grades in China participated in the study. Participants completed the Self-Esteem Scale, Parents Phubbing Scale, Classroom Environment Scale, and the Diagnostic Questionnaire of Internet Addiction. RESULTS: Correlational analyses revealed that internet addiction was found to be negatively correlated with both self-esteem and the teacher-student relationship (p < 0.01), while father phubbing, mother phubbing, and learning burden were shown to positively correlate with internet addiction (p < 0.01). Hierarchical linear model analysis suggested that student-level variables, including self-esteem, and mother phubbing, were significant predictors of internet addiction (ß = -0.077, p < 0.001 and ß = 0.028, p < 0.01, respectively). At the school level, learning burden significantly and negatively predicted internet addiction (ß = 0.073, p < 0.05). Furthermore, the relationship between self-esteem and internet addiction was significantly moderated by learning burden (ß = -0.007, p < 0.05). Meanwhile, the teacher-student relationship also had a significant moderating effect on the association between mother phubbing and internet addiction (ß = -0.005, p < 0.01). CONCLUSIONS: This study revealed the relationships between self-esteem, parental phubbing, and classroom environment with adolescent internet addiction, and these findings could provide insights into reducing adolescent internet addiction from the perspective of individuals, families, and schools.

Risk Factors for Primary Angle-closure Glaucoma: A Systematic Review and Meta-analysis of 45 Studies.

SIGNIFICANCE: This study summarized primary angle-closure glaucoma (PACG)-related factors across different dimensions. OBJECTIVES: This review aimed at systematically summarizing the associated factors of PACG in published literatures. METHODS: A systematic review and meta-analysis were conducted by searching the electronic databases including PubMed, EMBASE, and Web of Science from their inception to November 2021. The pooled risk estimates of continuous and categorical variables were calculated using weighted mean difference (WMD) and odds ratio (OR; 95% confidence intervals [CIs]), respectively. RESULTS: We included 45 studies in this review. In the meta-analysis, intraocular pressure (WMD, 3.13; 95% CI, 2.37 to 3.89), anterior chamber depth (WMD, -0.52; 95% CI, -0.70 to -0.34), axial length (WMD, -0.77; 95% CI, -1.26 to -0.28), retinal nerve fiber layer (WMD, -21.23; 95% CI, -30.21 to -12.25), and spherical equivalent (WMD, 1.02; 95% CI, 0.66 to 1.38) were the most common ophthalmic anatomic factors, and lower body weight (WMD, -3.65; 95% CI, -6.48 to -0.82) was the most significant general morphological indicators. The presence of cataract (OR, 3.77; 95% CI, 3.46 to 4.11) and hyperlipidemia (OR, 1.10; 95% CI, 1.02 to 1.20) were significantly associated with PACG. Increased level of triglyceride (WMD, 0.17; 95% CI, 0.06 to 0.27) was associated with PACG. In addition, an association between short-term antidepressant exposure (OR, 1.36; 95% CI, 1.08 to 1.70) and acute angle-closure glaucoma was observed. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This review identified a few consistent factors related to PACG, providing important information for primary care physicians, general ophthalmologists, and public health professionals to counsel their patients on PACG risks.

Myopic maculopathy among Chinese children with high myopia and its association with choroidal and retinal changes: the SCALE-HM study.

AIMS: To investigate myopic maculopathy in Chinese children with high myopia and its association with choroidal and retinal changes. METHODS: This cross-sectional study included Chinese children aged 4-18 years with high myopia. Myopic maculopathy was classified by fundus photography and retinal thickness (RT) and choroidal thickness (ChT) in the posterior pole were measured by swept-source optical coherence tomography. A receiver operation curve was used to determine the efficacy of fundus factors in classifying myopic maculopathy. RESULTS: In total, 579 children aged 12.8±3.2 years with a mean spherical equivalent of -8.44±2.20 D were included. The proportions of tessellated fundus and diffuse chorioretinal atrophy were 43.52% (N=252) and 8.64% (N=50), respectively. Tessellated fundus was associated with a thinner macular ChT (OR=0.968, 95% CI: 0.961 to 0.975, p<0.001) and RT (OR=0.977, 95% CI: 0.959 to 0.996, p=0.016), longer axial length (OR=1.545, 95% CI: 1.198 to 1.991, p=0.001) and older age (OR=1.134, 95% CI: 1.047 to 1.228, p=0.002) and less associated with male children (OR=0.564, 95% CI: 0.348 to 0.914, p=0.020). Only a thinner macular ChT (OR=0.942, 95% CI: 0.926 to 0.959, p<0.001) was independently associated with diffuse chorioretinal atrophy. When using nasal macular ChT for classifying myopic maculopathy, the optimal cut-off value was 129.00 µm (area under the curve (AUC)=0.801) and 83.85 µm (AUC=0.910) for tessellated fundus and diffuse chorioretinal atrophy, respectively. CONCLUSION: A large proportion of highly myopic Chinese children suffer from myopic maculopathy. Nasal macular ChT may serve as a useful index for classifying and assessing paediatric myopic maculopathy. TRIAL REGISTRATION NUMBER: NCT03666052.

Machine Learning-Based Integration of Metabolomics Characterisation Predicts Progression of Myopic Retinopathy in Children and Adolescents.

Myopic retinopathy is an important cause of irreversible vision loss and blindness. As metabolomics has recently been successfully applied in myopia research, this study sought to characterize the serum metabolic profile of myopic retinopathy in children and adolescents (4-18 years) and to develop a diagnostic model that combines clinical and metabolic features. We selected clinical and serum metabolic data from children and adolescents at different time points as the training set (n = 516) and the validation set (n = 60). All participants underwent an ophthalmologic examination. Untargeted metabolomics analysis of serum was performed. Three machine learning (ML) models were trained by combining metabolic features and conventional clinical factors that were screened for significance in discrimination. The better-performing model was validated in an independent point-in-time cohort and risk nomograms were developed. Retinopathy was present in 34.2% of participants (n = 185) in the training set, including 109 (28.61%) with mild to moderate myopia. A total of 27 metabolites showed significant variation between groups. After combining Lasso and random forest (RF), 12 modelled metabolites (mainly those involved in energy metabolism) were screened. Both the logistic regression and extreme Gradient Boosting (XGBoost) algorithms showed good discriminatory ability. In the time-validation cohort, logistic regression (AUC 0.842, 95% CI 0.724-0.96) and XGBoost (AUC 0.897, 95% CI 0.807-0.986) also showed good prediction accuracy and had well-fitted calibration curves. Three clinical characteristic coefficients remained significant in the multivariate joint model (p < 0.05), as did 8/12 metabolic characteristic coefficients. Myopic retinopathy may have abnormal energy metabolism. Machine learning models based on metabolic profiles and clinical data demonstrate good predictive performance and facilitate the development of individual interventions for myopia in children and adolescents.

Uric acid levels and their association with vascular dementia and Parkinson's disease dementia: a meta-analysis.

OBJECTIVES: To explore the association between uric acid (UA) levels and vascular dementia (VaD) and Parkinson's disease dementia (PDD), a meta-analysis was conducted. METHODS: The relevant studies were identified by searching PubMed, Embase, Web of Science, and Cochrane Collaboration Database up to May 2022. Pooled analysis, sensitivity analysis, and publication bias examination were all conducted. All analyses were performed by using STATA 16. RESULTS: Twelve studies with a total of 2097 subjects were included. The pooled analysis showed that UA levels were not associated with VaD (WMD = - 10.99 µmol/L, 95% CI (- 48.05, 26.07), P = 0.561) but were associated with PDD (WMD = - 25.22 µmol/L, 95% CI (- 43.47, - 6.97), P = 0.007). The statistical stability and reliability were evaluated using sensitivity analysis and publication bias outcomes. CONCLUSION: UA levels are associated with PDD but not with VaD. This study will help to strengthen our knowledge of the pathophysiologies of VaD and PDD, and promote the development of prevention and treatment strategies.

Metabolomics facilitates the discovery of metabolic profiles and pathways for myopia: A systematic review.

BACKGROUND: Myopia is one of the major eye disorders and the global burden is increasing rapidly. Our purpose is to systematically summarize potential metabolic biomarkers and pathways in myopia to facilitate the understanding of disease mechanisms as well as the discovery of novel therapeutic measures. METHODS: Myopia-related metabolomics studies were searched in electronic databases of PubMed and Web of Science until June 2021. Information regarding clinical and demographic characteristics of included studies and metabolomics findings were extracted. Myopia-related metabolic pathways were analysed for differential metabolic profiles, and the quality of included studies was assessed based on the QUADOMICS tool. Pathway analyses of differential metabolites were performed using bioinformatics tools and online software such as the Metaboanalyst 5.0. RESULTS: The myopia-related metabolomics studies included in this study consisted of seven human and two animal studies. The results of the study quality assessment showed that studies were all phase I studies and all met the evaluation criteria of 70% or more. The myopia-control serum study identified 23 differential metabolites with the Sphingolipid metabolism pathway beings enriched. The high myopia-cataract aqueous humour study identified 40 differential metabolites with the Arginine biosynthesis pathway being enriched. The high myopia-control serum study identified 43 differential metabolites and 4 pathways were significantly associated with metabolites including Citrate cycle; Alanine, aspartate and glutamate metabolism; Glyoxylate and dicarboxylate metabolism; Biosynthesis of unsaturated fatty acids (all P value < 0.05). CONCLUSIONS: This study summarizes potential metabolic biomarkers and pathways in myopia, providing new clues to elucidate disease mechanisms.

Antiplatelet therapy for secondary prevention of lacunar stroke: a systematic review and network meta-analysis.

PURPOSE: To comprehensively compare the efficacy of different antiplatelet therapies for secondary prevention of lacunar stroke (LS). METHODS: The relevant studies were identified by searching PubMed, EMBASE, Web of Science, and Cochrane Collaboration Database up to May 2022. Cardiovascular and cerebrovascular events were chosen to evaluate the efficacy of antiplatelet therapy for secondary prevention. Loop-specific approach and node-splitting analysis were used to evaluate consistency and inconsistency, respectively. The value of the surface under the cumulative ranking (SUCRA) was calculated and ranked. Funnel-plot symmetry was used to evaluate publication bias. The meta-analysis was performed by using STATA 16.0. RESULTS: Thirteen studies with a total of 33,011 subjects were included in this network meta-analysis. Compared with placebo, aspirin, clopidogrel, cilostazol, ticlopidine, aspirin plus dipyridamole, and aspirin plus clopidogrel were associated with reducing cardiovascular and cerebrovascular events. The SUCRA estimated relative ranking of treatments showed that cilostazol may be the most effective (RR 0.56, 95% CI 0.42-0.74, SUCRA 95.8). No significant inconsistency or publication bias was found in the study. CONCLUSIONS: This meta-analysis suggests that cilostazol may be a priority option for secondary prevention of patients with LS. These findings still need further study in the future.