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.

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.

Metabolomics and Biomarkers in Retinal and Choroidal Vascular Diseases.

The retina is one of the most important structures in the eye, and the vascular health of the retina and choroid is critical to visual function. Metabolomics provides an analytical approach to endogenous small molecule metabolites in organisms, summarizes the results of "gene-environment interactions", and is an ideal analytical tool to obtain "biomarkers" related to disease information. This study discusses the metabolic changes in neovascular diseases involving the retina and discusses the progress of the study from the perspective of metabolomics design and analysis. This study advocates a comparative strategy based on existing studies, which encompasses optimization of the performance of newly identified biomarkers and the consideration of the basis of existing studies, which facilitates quality control of newly discovered biomarkers and is recommended as an additional reference strategy for new biomarker discovery. Finally, by describing the metabolic mechanisms of retinal and choroidal neovascularization, based on the results of existing studies, this study provides potential opportunities to find new therapeutic approaches.

A review of study designs and data analyses in metabolomics studies in myopia.

Metabolomics analyzes the entire range of small molecule metabolites in biological systems to reveal the response signals that are transmitted from "genetics and environment", which could help us understand complex phenotypes of diseases. Metabolomics has been successfully applied to the study of eye diseases including age-related macular degeneration, glaucoma, and diabetic retinopathy. In this review, we summarize the findings of myopic metabolomics and discuss them from a design and analysis perspective. Finally, we provide new ideas for the future development of myopia metabolomics research based on the broader ocular metabolomics study.

Safety and preliminary efficacy of argatroban plus dual antiplatelet therapy for acute mild to moderate ischemic stroke with large artery atherosclerosis.

OBJECTIVE: Previous studies suggest the benefit of dual antiplatelet therapy (DAPT) for acute ischemic stroke with large artery atherosclerosis (LAA) etiology, but there is no study about the effect of DAPT plus anticoagulant in this population. METHODS: A prospective single arm trial was performed to determine the effect of DAPT combined with argatroban on acute mild to moderate ischemic stroke patients with LAA, which was compared with historical populations. The main outcome was the proportion of early neurological deterioration (END). The secondary outcomes included scores of 0 to 1 and 0 to 2 on the modified Rankin Scale (mRS) at 90 days, and changes in National Institutes of Health Stroke Scale (NIHSS) from baseline to day 7 after admission. The safety outcomes included intracranial hemorrhage at 7 days, organ hemorrhage, and all-cause mortality at 90 days. RESULTS: A total of 120 patients with argatroban plus DAPT were prospectively enrolled and 529 patients with only DAPT were retrospectively collected. There was no significant difference in baseline characteristics between groups. Compared with control group, combined treatment group had lower proportion of END (4.2% vs. 10.0%, adjusted p = .046), more reduction in NIHSS score from the baseline to day 7 after admission (1.06 ± 2.03 vs. 0.39 ± 1.97, adjusted p = .003), and higher proportion of mRS (0-2) at 90 days (87.5% vs. 79.2%, adjusted p = .048). No intracranial hemorrhage was found between groups. CONCLUSIONS: This is the first report that short-term argatroban combined with DAPT seems to be safe and may effectively prevent END and improve neurological prognosis for acute mild to moderate ischemic stroke patients with LAA; however, interpretation of the conclusion required caution due to nonrandomized controlled trial with medium sample size.

Metabolomics in Diabetic Retinopathy: A Systematic Review.

Purpose: Diabetic retinopathy (DR), a common microvascular complication of diabetes, is the leading cause of acquired blindness in the working-age population. Individuals with diabetes still develop DR despite appropriate glycemic and blood pressure control, highlighting the pressing need to identify useful biomarkers for risk stratification. The purpose of this review is to systematically summarize potential metabolic biomarkers and pathways of DR, which could facilitate developing an understanding of the disease mechanisms, as well as new therapeutic measures. Methods: We searched PubMed and Web of Science for relevant metabolomics studies on humans published before September 30, 2020. Information regarding authors, title, publication date, study subjects, analytical platforms, methods of statistical analysis, biological samples, directions of change of potential metabolic biomarkers, and predictive values of metabolic biomarker panels was extracted, and the quality of the studies was assessed. Pathway analysis, including enrichment analysis and topology analysis, was derived from integrating differential metabolites using MetaboAnalyst 3.0, based on the Kyoto Encyclopedia of Genes and Genomes and Human Metabolome Database. Results: We found nine studies focused on the identification of potential biomarkers. Repeatedly identified metabolites including l-glutamine, l-lactic acid, pyruvic acid, acetic acid, l-glutamic acid, d-glucose, l-alanine, l-threonine, citrulline, l-lysine, and succinic acid were found to be potential biomarkers of DR. It was observed that l-glutamine and citrulline changed in all biological samples. Dysregulation of metabolic pathways involved amino acid and energy metabolism. Conclusions: This review summarizes potential biomarkers and metabolic pathways, providing insights into new pathogenic pathways for this microvascular complication of diabetes.

Metabolomics in Glaucoma: A Systematic Review.

Purpose: Glaucoma remains a poorly understood disease, and identifying biomarkers for early diagnosis is critical to reducing the risk of glaucoma-related visual impairment and blindness. The aim of this review is to provide current metabolic profiles for glaucoma through a summary and analysis of reported metabolites associated with glaucoma. Methods: We searched PubMed and Web of Science for metabolomics studies of humans on glaucoma published before November 11, 2020. Studies were included if they assessed the biomarkers of any types of glaucoma and performed mass spectrometry-based or nuclear magnetic resonance-based metabolomics approach. Pathway enrichment analysis and topology analysis were performed to generate a global view of metabolic signatures related to glaucoma using the MetaboAnalyst 3.0. Results: In total, 18 articles were included in this review, among which 13 studies were focused on open-angle glaucoma (OAG). Seventeen metabolites related to OAG were repeatedly identified, including seven amino acids (arginine, glycine, alanine, lysine, methionine, phenylalanine, tyrosine), two phosphatidylcholine (PC aa C34:2, PC aa C36:4), three complements (acetylcarnitine, propionylcarnitine, butyrylcarnitine), carnitine, glutamine, hypoxanthine, spermine, and spermidine. The pathway analysis implied a major role of amino metabolism in OAG pathophysiology and revealed the metabolic characteristics between different biological samples. Conclusions: In this review, we summarize existing metabolomic studies related to glaucoma biomarker identification and point out a series of metabolic disorders in OAG patients, providing information on the molecular mechanism changes in glaucoma. Additional studies are needed to validate existing findings, and future research will need to explore the potential overlap between different biological fluids.

Intracranial Atherosclerotic Plaque as a Potential Cause of Embolic Stroke of Undetermined Source.

BACKGROUND: Previous studies investigated the potential mechanism of embolic stroke of undetermined source (ESUS) from extracranial artery plaque, but there has been no study other than a case report on high-risk intracranial plaque in ESUS. OBJECTIVES: The aim of this study was to investigate the issue by evaluating the morphology and composition of intracranial plaque in patients with ESUS and small-vessel disease (SVD) using 3.0-T high-resolution magnetic resonance imaging. METHODS: Two hundred forty-three consecutive patients with ESUS and 160 patients with SVD-associated stroke between January 2015 and December 2019 were retrospectively enrolled. Multidimensional parameters involving the presence of plaque on both sides, including remodeling index (RI), plaque burden, presence of discontinuity of plaque surface, thick fibrous cap, intraplaque hemorrhage, and complicated American Heart Association type VI plaque at the maximal luminal narrowing site, were evaluated using intracranial high-resolution magnetic resonance imaging. RESULTS: Among 243 patients with ESUS, the prevalence of intracranial plaque was much higher in the ipsilateral than the contralateral side (63.8% vs. 42.8%; odds ratio [OR]: 5.25; 95% confidence interval [CI]: 2.83 to 9.73), a finding that was not evident in patients with SVD (35.6% vs. 30.6%; OR: 2.14; 95% CI: 0.87 to 5.26; p = 0.134). Logistic analysis showed that RI was independently associated with ESUS in model 1 (OR: 2.329; 95% CI: 1.686 to 3.217; p < 0.001) and model 2 (OR: 2.295; 95% CI: 1.661 to 3.172; p < 0.001). RI alone with an optimal cutoff of 1.162, corresponding to an area under the curve of 0.740, had good diagnostic efficiency for ESUS. CONCLUSIONS: The present study supports an etiologic role of high-risk nonstenotic intracranial plaque in ESUS.

Metabolomics in Age-Related Macular Degeneration: A Systematic Review.

Purpose: Age-related macular degeneration (AMD) is one of the leading causes of blindness among the elderly, and the exact pathogenesis of the AMD remains unclear. The purpose of this review is to summarize potential metabolic biomarkers and pathways of AMD that might facilitate risk predictions and clinical diagnoses of AMD. Methods: We obtained relevant publications of metabolomics studies of human beings by systematically searching the MEDLINE (PubMed) database before June 2020. Studies were included if they performed mass spectrometry-based or nuclear magnetic resonance-based metabolomics approach for humans. In addition, AMD was assessed from fundus photographs based on standardized protocols. The metabolic pathway analysis was performed using MetaboAnalyst 3.0. Results: Thirteen studies were included in this review. Repeatedly identified metabolites including phenylalanine, adenosine, hypoxanthine, tyrosine, creatine, citrate, carnitine, proline, and maltose have the possibility of being biomarkers of AMD. Validation of the biomarker panels was observed in one study. Dysregulation of metabolic pathways involves lipid metabolism, carbohydrate metabolism, nucleotide metabolism, amino acid metabolism, and translation, which might play important roles in the development and progression of AMD. Conclusions: This review summarizes the potential metabolic biomarkers and pathways related to AMD, providing opportunities for the construction of diagnostic or predictive models for AMD and the discovery of new therapeutic targets.

Treatment with Delipid Extracorporeal Lipoprotein Filter from Plasma after Intravenous Thrombolysis for Acute Ischemic Stroke: A Single-Center Experience.

INTRODUCTION: The delipid extracorporeal lipoprotein filter from plasma (DELP) has been approved for the treatment of acute ischemic stroke (AIS) by the China Food and Drug Administration, but its effectiveness and mechanism are not yet fully determined. The purpose of this study was to evaluate the effect of DELP treatment on AIS patients after intravenous thrombolysis. METHODS: A retrospective study was performed on AIS patients with no improvement within 24 h after intravenous thrombolysis who were subsequently treated with or without DELP. Primary outcome was the proportion with a modified Rankin scale (mRS) of 0-1 at 90 days. Secondary outcomes were changes in National Institute of Health Stroke Scale (NIHSS) score from 24 h to 14 days after thrombolysis, and the rate of improvement in stroke-associated pneumonia (SAP). The main safety outcomes were the rates of symptomatic intracranial hemorrhage and mortality. To investigate its mechanisms, serum biomarkers were measured before and after DELP. RESULTS: A total of 252 patients were recruited, 63 in the DELP group and 189 matched patients in the NO DELP group. Compared with the NO DELP group, the DELP group showed an increase in the proportion of mRS 0-1 at 90 days (p = 0.042). More decrease in NIHSS from 24 h to 14 days (p = 0.024), a higher rate of improvement in SAP (p = 0.022), and lower mortality (p = 0.040) were shown in DELP group. Furthermore, DELP decreased levels of interleukin (IL)-1ß, E-selectin, malondialdehyde, matrix metalloprotein 9, total cholesterol, low-density lipoprotein, and fibrinogen, and increased superoxide dismutase (p< 0.05). CONCLUSIONS: DELP following intravenous thrombolysis should be safe, and is associated with neurological function improvement, possibly through multiple neuroprotective mechanisms. Prospective trials are needed.

Quantity of Cerebral Microbleeds, Antiplatelet Therapy, and Intracerebral Hemorrhage Outcomes: A Systematic Review and Meta-analysis.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) increase future intracerebral hemorrhage (ICH) risk after ischemic stroke (IS) or transient ischemic attack (TIA). However, whether CMB-related ICH risk depends on CMB quantity, CMB location, or antithrombotic agents is unclear. We performed a systematic review and meta-analysis to investigate CMB-related ICH risk, stratifying patients according to the quantity of CMB, the location of CMB, and the type of antithrombotic therapy used. METHODS: Literature databases were searched for prospective cohorts reporting ICH outcomes in patients with IS or TIA with baseline CMB evaluation. We calculated pooled relative ratios (RRs) for ICH among patients with and without CMBs. Pooled RRs of CMB-related ICH were further calculated in subgroups stratified by CMB quantity, CMB location, and antithrombotic therapy. RESULTS: Among the 10 included studies, the pooled RR of future ICH was 7.73 (95% confidence interval [CI], 4.07-14.70; P < .001) in CMB versus non-CMB patients. Subgroup analysis revealed that compared with non-CMB patients, multiple-CMB patients were at an increased risk for future ICH (RR = 8.02; 95% CI, 3.21-20.01; P < .001), whereas single-CMB patients did not incur this risk (RR = 2.33; 95% CI, .63-8.63; P = .205). A strong association was found between CMB presence and subsequent ICH in antiplatelet users (RR = 16.56; 95% CI, 3.68-74.42; P < .001). Studies on CMB-related ICH according to CMB locations and in anticoagulant users are lacking for subgroup analysis. CONCLUSION: Our study revealed that patients with IS or TIA with multiple CMBs may incur a higher risk of future ICH, and the presence of CMBs in patients with IS or TIA using antiplatelet agents may significantly increase the subsequent ICH risk.