Endosomal catabolism of phosphatidylinositol 4,5-bisphosphate is fundamental in building resilience against pathogens.

Endosomes are characterized by the presence of various phosphoinositides that are essential for defining the membrane properties. However, the interplay between endosomal phosphoinositides metabolism and innate immunity is yet to be fully understood. Here, our findings highlight the evolutionary continuity of RAB-10/Rab10's involvement in regulating innate immunity. Upon infection of C. elegans with P. aeruginosa, an increase in RAB-10 activity was observed in the intestine. Conversely, when RAB-10 was absent, the intestinal diacylglycerols (DAGs) decreased, and the animal's response to the pathogen was impaired. Further research revealed that UNC-16/JIP3 acts as an RAB-10 effector, facilitating the recruitment of phospholipase EGL-8 to endosomes. This leads to a decrease in endosomal PI(4,5)P2 and an elevation of DAGs, as well as the activation of the PMK-1/p38 MAPK innate immune pathway. It is noteworthy that the dimerization of UNC-16 is a prerequisite for its interaction with RAB-10(GTP) and the recruitment of EGL-8. Moreover, we ascertained that the rise in RAB-10 activity, due to infection, was attributed to the augmented expression of LET-413/Erbin, and the nuclear receptor NHR-25/NR5A1/2 was determined to be indispensable for this increase. Hence, this study illuminates the significance of endosomal PI(4,5)P2 catabolism in boosting innate immunity, and outlines an NHR-25-mediated mechanism for pathogen detection in intestinal epithelia.

Rationally Integrating Charge-Transfer Cocrystal and Ni(II) Organometallics for Visualized Photo/Thermochromic Sensors.

Smart materials demonstrate fascinating responses to environmental physical/chemical stimuli, including thermal, photonic, electronic, humidity, or magnetic stimuli, which have attracted intensive interest in material chemistry. However, their limited/harsh stimuli-responsive behavior or sophisticated postprocessing leads to enormous challenges for practical applications. Herein, we rationally designed and synthesized thermochromic Ni(II) organometallic [(C2H5)2NH2]2NiCl4-xBrx via a facile mechanochemical strategy, which demonstrated a reversible switch from yellow to blue color with a tunable phase-transition temperature from 75.6 to 61.7 °C. The simple electrospinning technology was applied to fabricate thermochromic Ni(II) organometallic-based nanofiber membranes for temperature monitoring. Furthermore, the organic charge-transfer cocrystal with a wide spectral absorption of 300-1950 nm and a high-efficiency photothermal conversion was combined with thermochromic Ni(II) organometallics for the desired dual-stimuli photo/thermochromism. This work supplies a new strategy for realizing multiple stimuli-responsive applications, such as thermal/light sensor displays and information storage.

Identification and functional characteristics of a novel splicing heterozygote variant of COL2A1 associated with Stickler syndrome type I.

Background: Stickler syndrome type I (STL1) is an autosomal dominant disorder characterized by ocular, auditory, orofacial, and skeletal anomalies. The main causes of STL1 are variants in the COL2A1 gene, which encodes a type II collagen precursor protein. The specific focus of this study was on a newborn from China diagnosed with STL1, with the aim of providing novel insights into the effects of a newly identified intronic variant in the COL2A1 gene on pre-mRNA splicing. Methods: Trio whole exome sequencing was used to identify the causative variant in the family. The identified variant was validated using Sanger sequencing. Bioinformatics programs were used to predict the pathogenicity of the candidate variant. Additionally, an in vitro minigene assay was used to investigate the effects of the identified variant on RNA splicing. Results: The proband with STL1 had a novel heterozygous splicing variant in the intron nine acceptor donor site of COL2A1 (c.655-2A>G). This splice junction variant resulted in aberrant COL2A1 mRNA splicing, leading to the skipping of exon 10 and the production of a shorter protein that may lack the last 18 native amino acids. Conclusion: The c.655-2A>G variant in the COL2A1 gene leads to STL1 through abnormal splicing. By expanding the spectrum of variants in the COL2A1 gene, this finding improves the clinical understanding of STL1 and provides guidance for early diagnosis and disease counseling.

A tricycloquinazoline based 2D conjugated metal-organic framework for robust sodium-ion batteries with co-storage of both cations and anions.

There is growing interest in 2D conjugated metal-organic frameworks (2D c-MOFs) for batteries due to their reversible redox chemistry. Nevertheless, currently reported 2D c-MOFs based on n-type ligands are mostly focused on the storage of cations for batteries. Herein, we successfully synthesize nitrogen-rich and electron-deficient p-type ligand-based Ni3(HATQ)2 assembled from 2,3,7,8,12,13-hexaaminotricycloquinazoline (HATQ), and the ion co-storage feature of cations and anions in sodium ion batteries (SIBs) is demonstrated for 2D c-MOFs for the first time. The redox chemistry from the p-type ligand and π-d hybridization center endows the Ni3(HATQ)2 cathode with high capacity and good rate performance, especially excellent capacity retention of 95% after 1000 cycles. These findings provide a promising avenue for the exploration of other p-type multidentate chelating ligands toward new 2D c-MOFs and expand the application of 2D c-MOFs in energy storage systems.

Perioperative application of chatbots: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Patient-clinician communication and shared decision-making face challenges in the perioperative period. Chatbots have emerged as valuable support tools in perioperative care. A simultaneous and complete comparison of overall benefits and harm of chatbot application is conducted. MATERIALS: MEDLINE, EMBASE and the Cochrane Library were systematically searched for studies published before May 2023 on the benefits and harm of chatbots used in the perioperative period. The major outcomes assessed were patient satisfaction and knowledge acquisition. Untransformed proportion (PR) with a 95% CI was used for the analysis of continuous data. Risk of bias was assessed using the Cochrane Risk of Bias assessment tool version 2 and the Methodological Index for Non-Randomised Studies. RESULTS: Eight trials comprising 1073 adults from four countries were included. Most interventions (n = 5, 62.5%) targeted perioperative care in orthopaedics. Most interventions use rule-based chatbots (n = 7, 87.5%). This meta-analysis found that the majority of the participants were satisfied with the use of chatbots (mean proportion=0.73; 95% CI: 0.62 to 0.85), and agreed that they gained knowledge in their perioperative period (mean proportion=0.80; 95% CI: 0.74 to 0.87). CONCLUSION: This review demonstrates that perioperative chatbots are well received by the majority of patients with no reports of harm to-date. Chatbots may be considered as an aid in perioperative communication between patients and clinicians and shared decision-making. These findings may be used to guide the healthcare providers, policymakers and researchers for enhancing perioperative care.

MiR-196a-5p hinders vascular smooth muscle cell proliferation and vascular remodeling via repressing BACH1 expression.

Hyperproliferation of vascular smooth muscle cells (VSMCs) is a driver of hypertensive vascular remodeling. This study aimed to uncover the mechanism of BTB and CNC homology 1 (BACH1) and microRNAs (miRNAs) in VSMC growth and hypertensive vascular remodeling. With the help of TargetScan, miRWalk, miRDB, and miRTarBase online database, we identified that BACH1 might be targeted by miR-196a-5p, and overexpressed in VSMCs and aortic tissues from spontaneously hypertensive rats (SHRs). Gain- and loss-of-function experiments demonstrated that miR-196a-5p suppressed VSMC proliferation, oxidative stress and hypertensive vascular remodeling. Double luciferase reporter gene assay and functional verification showed that miR-196a-5p cracked down the transcription and translation of BACH1 in both Wistar Kyoto rats (WKYs) and SHRs. Silencing BACH1 mimicked the actions of miR-196a-5p overexpression on attenuating the proliferation and oxidative damage of VSMCs derived from SHRs. Importantly, miR-196a-5p overexpression and BACH1 knockdown cooperatively inhibited VSMC proliferation and oxidative stress in SHRs. Furthermore, miR-196a-5p, if knocked down in SHRs, aggravated hypertension, upregulated BACH1 and promoted VSMC proliferation, all contributing to vascular remodeling. Taken together, targeting miR-196a-5p to downregulate BACH1 may be a promising strategy for retarding VSMC proliferation and hypertensive vascular remodeling.

Nrf2 deficiency exacerbated pulmonary pyroptosis in maternal hypoxia-induced intrauterine growth restriction offspring mice.

Maternal prenatal hypoxia is an important contributor to intrauterine growth restriction (IUGR), which impedes fetal lung maturation and leads to the development of chronic lung diseases. Although evidence suggests the involvement of pyroptosis in IUGR, the molecular mechanism of pyroptosis is still unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been found to potentially interact with gasdermin D (GSDMD), the key protein responsible for pyroptosis, indicating its crucial role in inhibiting pyroptosis. Therefore, we hypothesized that Nrf2 deficiency is a key molecular responsible for lung pyroptosis in maternal hypoxia-induced IUGR offspring mice. Pregnant WT and Nrf2-/- mice were exposed to hypoxia (10.5 % O2) to mimic IUGR model. We assessed body weight, lung histopathology, pulmonary angiogenesis, oxidative stress levels, as well as mRNA and protein expressions related to inflammation in the 2-week-old offspring. Additionally, we conducted a dual-luciferase reporter assay to confirm the targeting relationship between Nrf2 and GSDMD. Our findings revealed that offspring with maternal hypoxia-induced IUGR exhibited reduced birth weight, catch-up growth delay, and pulmonary dysplasia. Furthermore, we observed impaired nuclear translocation of Nrf2 and increased GSDMD-mediated pyroptosis in these offspring with IUGR. Moreover, the dual-luciferase reporter assay demonstrated that Nrf2 could directly inhibit GSDMD transcription; deficiency of Nrf2 exacerbated pyroptosis and pulmonary dysplasia in offspring with maternal hypoxia-induced IUGR. Collectively, our findings suggest that Nrf2 deficiency induces GSDMD-mediated pyroptosis and pulmonary dysplasia in offspring with maternal hypoxia-induced IUGR; thus highlighting the potential therapeutic approach of targeting Nrf2 for treating prenatal hypoxia-induced pulmonary dysplasia in offspring.

pH-Responsive, Wide Color Gamut Dynamic Color Display Enabled by PDMAEMA Brush-Based Fabry-Perot Resonant Cavity.

Dynamic color-changing materials have attracted broad interest due to their widespread applications in visual sensing, dynamic color display, anticounterfeiting, and image encryption/decryption. In this work, we demonstrate a novel pH-responsive dynamic color-changing material based on a metal-insulator-metal (MIM) Fabry-Perot (FP) cavity with a pH-responsive poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) brush layer as the responsive insulating layer. The pH-responsive PDMAEMA brush undergoes protonation at a low pH value (pH < 6), which induces different swelling degrees in response to pH and thus refractive index and thickness change of the insulator layer of the MIM FP cavity. This leads to significant optical property changes in transmission and a distinguishable color change spanning the whole visible region by adjusting the pH value of the external environment. Due to the reversible conformational change of the PDMAEMA and the formation of covalent bonds between the PDMAEMA molecular chain and the Ag substrate, the MIM FP cavity exhibits stable performance and good reproducibility. This pH-responsive MIM FP cavity establishes a new way to modulate transmission color in the full visible region and exhibits a broad prospect of applications in dynamic color display, real-time environment monitoring, and information encryption and decryption.

A Mitochondria-Targeting Fluorescent Probe for the Dual Sensing of Hypochlorite and Viscosity without Signal Crosstalk in Living Cells and Zebrafish.

Hypochlorite (ClO-) and viscosity both affect the physiological state of mitochondria, and their abnormal levels are closely related to many common diseases. Therefore, it is vitally important to develop mitochondria-targeting fluorescent probes for the dual sensing of ClO- and viscosity. Herein, we have explored a new fluorescent probe, XTAP-Bn, which responds sensitively to ClO- and viscosity with off-on fluorescence changes at 558 and 765 nm, respectively. Because the emission wavelength gap is more than 200 nm, XTAP-Bn can effectively eliminate the signal crosstalk during the simultaneous detection of ClO- and viscosity. In addition, XTAP-Bn has several advantages, including high selectivity, rapid response, good water solubility, low cytotoxicity, and excellent mitochondrial-targeting ability. More importantly, probe XTAP-Bn is successfully employed to monitor the dynamic change in ClO- and viscosity levels in the mitochondria of living cells and zebrafish. This study not only provides a reliable tool for identifying mitochondrial dysfunction but also offers a potential approach for the early diagnosis of mitochondrial-related diseases.

Application of Bimetallic Hydroxide/Graphene Composites in Wastewater Treatment.

The increasing discharge of antibiotic wastewater leads to increasing water pollution. Most of these antibiotic wastewaters are persistent, strongly carcinogenic, easy to bioaccumulate, and have other similar characteristics, seriously jeopardizing human health and the ecological environment. As a commonly used wastewater treatment technology, non-homogeneous electro-Fenton technology avoids the hazards of H2O2 storage and transportation as well as the loss of desorption and reabsorption. It also facilitates electron transfer on the electrodes and the reduction of Fe3+ on the catalysts, thereby reducing sludge production. However, the low selectivity and poor activity of electro-synthesized H2O2, along with the low concentration of its products, combined with the insufficient activity of electrically activated H2O2, results in a low ∙OH yield. To address the above problems, composites of layered bimetallic hydroxides and carbon materials were designed and prepared in this paper to enhance the performance of electro-synthesized H2O2 and non-homogeneous electro-Fenton by changing the composite mode of the materials. Three composites, NiFe layered double hydroxides (LDHs)/reduced graphene oxide (rGO), NiMn LDHs/rGO, and NiMnFe LDHs/rGO, were constructed by the electrostatic self-assembly of exfoliated LDHs with few-layer graphene. The LDHs/rGO was loaded on carbon mats to construct the electro-Fenton cathode materials, and the non-homogeneous electro-Fenton oxidative degradation of organic pollutants was realized by the in situ electrocatalytic reduction of O2 to ∙OH. Meanwhile, the effects of solution pH, applied voltage, and initial concentration on the performance of non-homogeneous electro-Fenton were investigated with ceftazidime as the target pollutant, which proved that the cathode materials have an excellent electro-Fenton degradation effect.

Enhancing safety and therapeutic efficacy: PD-1 inhibitor and recombinant human endostatin combination in advanced non-small cell lung cancer patients.

OBJECTIVE: To assess the therapeutic efficacy of combining a programmed death-1 (PD-1) inhibitor with recombinant human endostatin in patients diagnosed with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively collected data from 83 patients with advanced NSCLC who received treatment at Xi'an Daxing Hospital between May 2020 and July 2022. Among them, 42 patients were treated with a PD-1 inhibitor combined with recombinant human endostatin (observation group), while 41 patients received PD-1 inhibitor monotherapy (control group). We evaluated the objective response rate, changes in serum tumor markers pre- and post-treatment, occurrence of adverse reactions, progression-free survival (PFS), 1-year survival rate, and identified independent risk factors affecting prognosis in both groups. RESULTS: The treatment efficacy in the observation group significantly surpassed that in the control group. Following treatment, the levels of cytokeratin 19 fragment antigen 21-1, carcinoembryonic antigen, and carbohydrate antigen 125 decreased significantly in the observation group compared to the control group (P < 0.001). There was no notable difference in the incidence of adverse reactions between the two groups (P < 0.001). The median PFS and 1-year survival rate were notably higher in the observation group (P < 0.001). Age, liver metastasis, and treatment regimen emerged as independent risk factors affecting poor prognosis in patients (P < 0.001). CONCLUSION: Combining a PD-1 inhibitor with recombinant human endostatin in patients with advanced NSCLC not only enhances clinical efficacy but also increases PFS and the 1-year survival rate while ensuring treatment safety. This combination therapy shows promise for clinical application.

Dynamic evolution characteristics and hazard assessment of compound drought/waterlogging and low temperature events for maize.

Hazard assessment is fundamental in the field of disaster risk management. With the increase in global warming, compound water and temperature events have become more frequent. Current research lacks risk assessments of low temperatures and their compound events, necessitating relevant hazard assessment work to improve the accuracy and diversity of maize disaster prevention and mitigation strategies. This study comparatively analyzed the dynamic evolution characteristics and hazards of compound drought/waterlogging and low temperature events (CDLEs and CWLEs) for maize in the Songliao Plain during different growth periods from 1981 to 2020. First, composite drought/waterlogging and low temperature magnitude indices (CDLMI and CWLMI) were constructed to quantify the intensity of CDLEs and CWLEs by fitting non-exceedance probabilities. Next, static and dynamic hazard assessment models were developed by fitting probability density and cumulative probability density curves to CDLMI and CWLMI. The results showed that the correlations between SPRI and LTI across different decades were mainly negative during the three growth periods. The hazard ratings for both CDLEs and CWLEs were relatively high in the northern part of the study area, consistent with the higher occurrence, duration, and severity of both CDLEs and CWLEs at higher latitudes. Relative to 2001-2010, the center of gravity of hazard shifted southward for CDLEs and northward for CWLEs in 2011-2020. The mean duration, frequency, and hazard were generally higher for CWLEs, but CDLEs were associated with more severe maize yield reductions. This study provides new insights into compound disaster risk assessment, and the research methodology can be generalized to other agricultural growing areas to promote sustainable development of agricultural systems and food security.

RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway.

Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. In addition, RBM7 negatively regulates the NF-κB cascade and an NF-κB inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer.

Sophoricoside ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury by inhibiting Bach1/Akt pathway.

BACKGROUND: The lack of effective treatments for methicillin-resistant Staphylococcus aureus (MRSA) infection, which often leads to severe acute lung injury (ALI), poses a grave threat to human life. Sophoricoside (SOP), an isoflavone glycoside abundant in the fruit of traditional Chinese herbal Sophora japonica l., showed anti-inflammatory effects against atopic dermatitis, allergic inflammation, and lipopolysaccharide-induced ALI. However, its effect and underlying mechanism on MRSA-induced ALI remain unclear. PURPOSE: The aim of this study is to assess the protective effect of SOP in MRSA-induced ALI and elucidate its underlying molecular mechanisms. METHODS: In vivo experiments were conducted using wild-type mice to establish MRSA-induced ALI mouse model, and the effects of SOP on ALI were evaluated by hematoxylin-eosin staining, flow cytometry, quantitative real-time polymerase chain reaction, and several biochemical indicators. Adoptive transfer experiments and BTB and CNC homology 1 knockout (Bach1-/-) mice were also utilized in this study. In vitro studies employed murine macrophages RAW264.7 cells, primary bone marrow-derived macrophages (BMDMs), and primary lung macrophages to explore the underlying molecular mechanisms. RESULTS: The administration of SOP ameliorated MRSA-induced ALI by improving pulmonary histological damages, reducing neutrophil infiltration, suppressing oxidative stress levels, and decreasing the expression of inflammatory cytokines. In isolation experiments with ALI mouse lung macrophages and macrophage adoptive transfer experiments, SOP prevented macrophage activation, thereby reducing the production of proinflammatory cytokines. In vitro experiments demonstrated that SOP decreased the expression of inflammatory mediators in lipoteichoic acid (LTA)-stimulated RAW264.7 cells, BMDMs, and primary lung macrophages. Additionally, SOP inhibited protein kinase B (Akt) phosphorylation and treatment with MK2206-a specific inhibitor of Akt-eliminated SOP's ability to suppress LTA-stimulated macrophage inflammation. Furthermore, stimulation with LTA or MRSA up-regulated Bach1 expression; however, deletion of Bach1 abolished the inhibitory effect of SOP on p-Akt activation as well as inflammation and ALI development. CONCLUSION: This study provides the first evidence that SOP effectively mitigates MRSA-induced ALI via suppressing macrophage activation through the inhibition of Bach1/Akt pathway. These findings highlight the potential of SOP as a novel therapeutic agent for treating MRSA-induced ALI.

Intelligent Food Packaging: Quaternary Ammonium Chitosan/Gelatin Blended Films Enriched with Blueberry Anthocyanin-Derived Cyanidin for Shrimp and Milk Freshness Monitoring.

Blueberry anthocyanin-derived cyanidin (BAC) was used to prepare a series of responsive food freshness packaging films by compounding it with quaternary chitosan (QC) and gelatin (G). The fundamental properties, pH sensitivity, and functional attributes of the films were examined. The BAC solutions exhibited notable variations in color (from red to pink to violet) under different pH conditions. The incorporation of BAC resulted in improved UV-vis shielding capabilities but compromised the mechanical strength of the films (with tensile strength values from 85.02 to 44.89 MPa, elongation at break from 13.08% to 3.6%, and water vapor transmission rates from 5.24 × 10-9 to 7.80 × 10-9 g m-1 s-1 Pa-1). The QC-G-BAC films, containing 5-15 wt% BAC, exhibited noticeable color changes in acidic/ammonia environments within a short timeframe, easily discernible to the naked eye. Furthermore, the inclusion of BAC significantly enhanced the antioxidant and antimicrobial properties of the films. The addition of 5-15 wt% BAC to QC-G-BAC films could be employed for assessing the freshness of fresh shrimp (from red to dark red) and pasteurized milk (from red to dark earthy yellow). Among them, the total color difference (ΔE) of QC-G-BAC5 film was significantly correlated with the pH, acidity, and total colony count of pasteurized milk (R = 0.846, -0.930, -0.908, respectively). This new concept in smart packaging offers a straightforward and user-friendly freshness indicator.

Complete genome sequence of human papillomavirus 31 isolated from the human cervical cell line, CIN612 9E.

Human papillomavirus genomes replicate extrachromosomally in infected tissues and derived keratinocyte cells. The cell line CIN12 9E was established from a cervical CIN1 lesion, contains replicating HPV31 genomes, and is widely used as a model to study the HPV life cycle. Here, we clone and sequence the HPV31 9E genome.

Relationship between emotional intelligence and academic support perception among nursing interns: The moderating role of bullying behaviors in nursing education.

AIM: This study aims to investigate the status of academic support perception among nursing interns and explore the correlation between academic support perception, emotional intelligence, and bullying behaviors in nursing education, especially the moderating role of bullying behavior on the relationship between emotional intelligence and academic support perception. BACKGROUND: Academic support perception is closely related to the nursing interns' mental health and academic performance. To some extent, it can reflect nursing interns' satisfaction and happiness during their internship, affecting their motivation to continue their studies. However, little is known about the nursing interns' academic support perception in China. METHODS: A total of 1020 nursing interns participated in this study. A sociodemographic information questionnaire, Bullying Behaviors in Nursing Education Scale, Wong and Law's Emotional Intelligence Scale, and Academic Support in the Practicum Scale were used to collect data. FINDINGS: Bullying behaviors and emotional intelligence were significantly associated with nursing interns' academic support perception. In addition, bullying behaviors in nursing education moderated the association between emotional intelligence and academic support perception. DISCUSSION: Nursing interns who possess high emotional intelligence and experience less bullying in nursing education tend to perceive higher academic support in clinical practice. The positive effects of emotional intelligence on nursing interns' academic support perceptions are contingent on the level of bullying behavior experienced in nursing education. Less bullying behaviors in nursing education enhance the impact of emotional intelligence on academic support perception. CONCLUSION AND IMPLICATIONS FOR NURSING: Strategies should be created to promote emotional intelligence and decrease bullying behaviors in nursing education to improve the perception of academic support among nursing interns.

Association between glaucoma and stroke: A bidirectional mendelian randomization study.

Purpose: Observational studies have reported positive associations between glaucoma and stroke; however, controversial results exist. Importantly, the nature of the relationship remains unknown since previous studies were not designed to test causality. Therefore, we aimed to investigate the possible causal relationships between glaucoma and stroke. Methods: Our two-sample Mendelian randomization (MR) encompassed multi-ethnic large-scale genome-wide association studies with more than 20000 cases and 260000 controls for glaucoma, and more than 80000 cases and 630000 controls for stroke. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. To avoid potential pleiotropic effects, we adjusted the main results by excluding genetic variants associated with metabolic factors. The weighted median and MR-Egger methods were also used for the sensitivity analysis. Results: Our MR analysis revealed that glaucoma and its subtypes, including primary open-angle glaucoma and primary angle-closure glaucoma, exhibited no causal role in relation to any stroke (AS), any ischemic stroke (AIS), large-artery atherosclerotic stroke (LAS), small-vessel stroke (SVS), or cardioembolic stroke (CES) across MR analyses (all P â€‹> â€‹0.05). The null associations remained robust even after adjusting for metabolic-related traits and were consistent in both the European and Asian populations. Furthermore, reverse MR analyses also did not indicate any significant causal effects of AS, AIS, LAS, or CES on glaucoma risk. Conclusions: Evidence from our series of causal inference approaches using large-scale population-based MR analyses did not support causal effects between glaucoma and stroke. These findings suggest that the relationship of glaucoma management and stroke risk prevention should be carefully evaluated in future studies. In turn, stroke diagnosis should not be simply applied to glaucoma risk prediction.