An Immunoreceptor-Targeting Strategy with Minimalistic C3b Peptide Fusion Enhances SARS-CoV-2 RBD mRNA Vaccine Immunogenicity.

Introduction: The clinical success of mRNA vaccine during the COVID-19 pandemic has inspired emerging approaches to elevate mRNA vaccine immunogenicity. Among them, antigen fusion protein designs for improved immune cell targeting have been shown to augment humoral immunity against small antigen targets. Methods: This research demonstrates that SARS-CoV-2 receptor binding domain (RBD) fusion with a minimalistic peptide segment of complement component 3b (C3b, residues 727-767) ligand can improve mRNA vaccine immunogenicity through antigen targeting to complement receptor 1 (CR1). We affirm vaccines' antigenicity and targeting ability towards specific receptors through Western blot and immunofluorescence assay. Furthermore, mice immunization studies help the investigation of the antibody responses. Results: Using SARS-CoV-2 Omicron RBD antigen, we compare mRNA vaccine formulations expressing RBD fusion protein with mouse C3b peptide (RBD-mC3), RBD fusion protein with mouse Fc (RBD-Fc), and wild-type RBD. Our results confirm the proper antigenicity and normal functionality of RBD-mC3. Upon validating comparable antigen expression by the different vaccine formulations, receptor-targeting capability of the fusion antigens is further confirmed. In mouse immunization studies, we show that while both RBD-mC3 and RBD-Fc elevate vaccine immunogenicity, RBD-mC3 leads to more sustained RBD-specific titers over the RBD-Fc design, presumably due to reduced antigenic diversion by the minimalistic targeting ligand. Conclusion: The study demonstrates a novel C3b-based antigen design strategy for immune cell targeting and mRNA vaccine enhancement.

Revealing the key antioxidant compounds and potential action mechanisms of Chinese Cabernet Sauvignon red wines by integrating UHPLC-QTOF-MS-based untargeted metabolomics, network pharmacology and molecular docking approaches.

In recent years, red wine drinking has become more popular in China owing to its antioxidant effects. However, the key antioxidant compounds and their action mechanisms of Chinese red wines are still unclear. Herein, the antioxidant activities and chemical compositions of 45 Chinese Cabernet Sauvignon red wine samples were determined using chemical antioxidant assays and an UHPLC-QTOF-MS-based untargeted metabolomics method. The key antioxidant compounds in red wines and potential action mechanisms were revealed by integrating network pharmacology and molecular docking approaches. Results showed that there are 8 key antioxidant compounds in the red wine samples. These compounds are involved in several metabolic pathways in the body, particularly PI3K/AKT. What's more, they bind to the core antioxidant targets through hydrogen bonding and hydrophobic interaction. Among them, myricetin, laricitrin, 2,3,8-tri-O-methylellagic acid and AKT1 have the highest binding energies. This study could provide the theoretical basis for further investigation of physiological activities and functions of Chinese red wines.

Reply to "Matters arising: cost-effectiveness of first-line immunotherapy combinations with or without chemotherapy for advanced non-small cell lung cancer: a modelling approach".

In this article, we read with great attention the correspondence by Bullement et al., regarding our published study on cost-effectiveness of first-line immunotherapy combinations with or without chemotherapy for advanced non-small cell lung cancer. We referred to a few the most important comments from Bullement et al. in our opinion, including proportional hazard (PH) assumption, accelerated failure time (AFT) model, and health utility, and made some explanations.

Medication use patterns in pregnant women with psoriasis: A nationwide study in Taiwan.

BACKGROUND: Psoriasis, an autoimmune skin condition, affects 2%-4% of the global population, with significant prevalence among women of childbearing age. Pregnancy presents challenges in managing psoriasis due to hormonal changes and treatment safety concerns. Understanding treatment patterns in pregnant women is crucial, given limited real-world evidence. OBJECTIVES: Explore the utilization patterns of medications among pregnant women diagnosed with psoriasis within a real-world data, utilizing data sourced from a nationwide database in Taiwan. METHODS: This nationwide study utilized Taiwan's National Health Insurance (NHI) database and Birth Certificate Application. It included registered pregnant women diagnosed with psoriasis from 2005 to 2014. Medication usage was tracked three years before conception to three years after delivery. Medications were categorized based on Anatomical Therapeutic Chemical (ATC) codes, and statistical analyses were conducted using SAS software. RESULTS: A total of 30,267 pregnant women with psoriasis were studied. 11,651 (38.49%) mothers had received at least one prescription during follow-up (exposed group), and >60% had never received medication (unexposed group). Demographics and comorbidities were similar between these two groups. Topical corticosteroids were the most prescribed treatment, followed by phototherapy, with systemic drugs and biologics less common. During the study period, 11,096 women with psoriasis had used topical corticosteroids, 3,376 had used non-steroidal topical agents, 218 had used systemic agents or biologics, and 519 had received treatment with phototherapy. Medication usage declined during pregnancy, reaching its lowest in the third trimester but rebounded postpartum. CONCLUSIONS: Psoriasis medications, systemic, biological, or topical, were largely discontinued during pregnancy, sometimes up to 2 years before and extending postpartum. Research is needed to understand its impact on maternal and child health.

Evaluating artificial intelligence-enhanced digital urine cytology for bladder cancer diagnosis.

BACKGROUND: This study evaluated the diagnostic effectiveness of the AIxURO platform, an artificial intelligence-based tool, to support urine cytology for bladder cancer management, which typically requires experienced cytopathologists and substantial diagnosis time. METHODS: One cytopathologist and two cytotechnologists reviewed 116 urine cytology slides and corresponding whole-slide images (WSIs) from urology patients. They used three diagnostic modalities: microscopy, WSI review, and AIxURO, per The Paris System for Reporting Urinary Cytology (TPS) criteria. Performance metrics, including TPS-guided and binary diagnosis, inter- and intraobserver agreement, and screening time, were compared across all methods and reviewers. RESULTS: AIxURO improved diagnostic accuracy by increasing sensitivity (from 25.0%-30.6% to 63.9%), positive predictive value (PPV; from 21.6%-24.3% to 31.1%), and negative predictive value (NPV; from 91.3%-91.6% to 95.3%) for atypical urothelial cell (AUC) cases. For suspicious for high-grade urothelial carcinoma (SHGUC) cases, it improved sensitivity (from 15.2%-27.3% to 33.3%), PPV (from 31.3%-47.4% to 61.1%), and NPV (from 91.6%-92.7% to 93.3%). Binary diagnoses exhibited an improvement in sensitivity (from 77.8%-82.2% to 90.0%) and NPV (from 91.7%-93.4% to 95.8%). Interobserver agreement across all methods showed moderate consistency (κ = 0.57-0.61), with the cytopathologist demonstrating higher intraobserver agreement than the two cytotechnologists across the methods (κ = 0.75-0.88). AIxURO significantly reduced screening time by 52.3%-83.2% from microscopy and 43.6%-86.7% from WSI review across all reviewers. Screening-positive (AUC+) cases required more time than negative cases across all methods and reviewers. CONCLUSIONS: AIxURO demonstrates the potential to improve both sensitivity and efficiency in bladder cancer diagnostics via urine cytology. Its integration into the cytopathological screening workflow could markedly decrease screening times, which would improve overall diagnostic processes.

Impact of chronic kidney disease and end-stage renal disease on the mid-term adverse outcomes in diabetic patients with cardiovascular diseases.

The evidence for the impact of renal dysfunction in patients with diabetes mellitus (DM) and first cardiovascular diseases on mid-term adverse outcomes remain scarce. This study included the data of patients with DM having first atherosclerotic cardiovascular disease (ASCVD) or congestive heart failure (CHF) from the Taipei Medical University Clinical Research Database. A Cox proportional hazards regression model was used to assess the impact of chronic kidney disease (CKD) or end-stage renal disease (ESRD) on the 1-year mortality and recurrent ASCVD/CHF outcomes. We enrolled 21,320 patients with DM hospitalized for ASCVD or CHF; of them, 18,185, 2639, and 496 were assigned to the non-CKD, CKD, and ESRD groups, respectively. After propensity score matching, compared with the non-CKD group, the CKD and ESRD groups had higher mid-term all-cause mortality (adjusted hazard ratio 1.72 [95% confidence interval 1.48-1.99] and 2.77 [2.05-3.73], respectively), cardiovascular death (1.84 [1.44-2.35] and 1.87 [1.08-3.24], respectively), and recurrent hospitalization for ASCVD (1.44 [1.24-1.68] and 2.33 [1.69-3.23], respectively) and CHF (2.08 [1.75-2.47] and 1.50 [1.04-2.17], respectively). The advancing age was associated with mortality in CKD/ESRD groups. In CKD group, male sex was associated with all-cause mortality and recurrent ASCVD risk; the diuretics usage was associated with mortality and recurrent CHF risks. Our findings suggest that CKD and ESRD are significant risk factors for mid-term adverse outcomes in patients with DM and established cardiovascular diseases. Additionally, old age, male sex and diuretics usage requires attention. Further good quality studies are needed in the future.

Contribution of international cooperation in the management of the first documented case of Lonomia caterpillar envenoming (Lonomism) in Guyana.

Severe Lonomia caterpillar envenoming is an increasing hazard in South America. It can trigger severe coagulation disorders that can progress to systemic complications and death. We report the first documented case of severe Lonomia caterpillar envenoming in Guyana. It was managed using antivenom provided by the Brazilian Ministry of Health as part of humanitarian support. This case describes a successful international collaboration driving a favorable outcome for the envenomed patient.

Through the lens: A qualitative exploration of nurses' experiences of smart glasses in urgent care.

AIM: To investigate the real-world experiences of nurses' using smart glasses to triage patients in an urgent care centre. DESIGN: A parallel convergent mixed-method design. METHODS: We collected data through twelve in-depth interviews with nurses using the device and a survey. Recruitment continued until no new themes emerged. We coded the data using a deductive-thematic approach. Qualitative and survey data were coded and then mapped to the most dominant dimension of the sociotechnical framework. Both the qualitative and quantitative findings were triangulated within each dimension of the framework to gain a comprehensive understanding of user experiences. RESULTS: Overall, nurses were satisfied with using smart glasses in urgent care and would recommend them to others. Nurses rated the device highly on ease of use, facilitation of training and development, nursing empowerment and communication. Qualitatively, nurses generally felt the device improved workflows and saved staff time. Conversely, technological challenges limited its use, and users questioned its sustainability if inadequate staffing could not be resolved. CONCLUSION: Smart glasses enhanced urgent care practices by improving workflows, fostering staff communication, and empowering healthcare professionals, notably providing development opportunities for nurses. While smart glasses offered transformative benefits in the urgent care setting, challenges, including technological constraints and insufficient organisational support, were barriers to sustained integration. IMPLICATIONS FOR PRACTICE: These real-world insights encompass both the benefits and challenges of smart glass utilisation in the context of urgent care. The findings will help inform greater workflow optimisation and future technological developments. Moreover, by sharing these experiences, other healthcare institutions looking to implement smart glass technology can learn from the successes and barriers encountered, facilitating smoother adoption, and maximising the potential benefits for patient care. REPORTING METHOD: COREQ checklist (consolidated criteria for reporting qualitative research). PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Time-dependent efficacy analysis of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. METHODS: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. RESULTS: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. CONCLUSIONS: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

The Relationship Between Physical Activity and Mental Health Among Individuals With Spinal Cord Injury: Protocol for a Scoping Review.

BACKGROUND: Spinal cord injury (SCI) is a devastating condition that often leads to significant impairments in physical function, leading to disability and mental health disorders. Hence, understanding the prevalence of SCI and the relationship between physical activity and mental health in individuals with SCI is crucial for informing rehabilitation strategies and optimizing outcomes. OBJECTIVE: This study aims to comprehensively analyze existing research on the link between physical activity and mental health and identify the level of physical activity and mental health status, the barriers to physical activity, and SCI's impacts on psychological well-being in individuals with SCI. METHODS: An electronic search strategy will be used to identify prevalence studies published since 1993 in health-related databases such as PubMed, MEDLINE, COCHRANE Library, and Wiley Library using the following query: "Spinal Cord Injury" OR "Paraplegia" OR "Tetraplegia" AND "Physical Activity" OR "Exercise" AND "Mental Health" OR "Mental Illness" OR "Mental Disorder." Bibliographies of primary studies and review articles meeting the inclusion criteria will be searched manually to identify further eligible studies. The risk of bias in the included studies will be appraised using the Joanna Briggs Institute checklist for prevalence studies by 2 review authors. Any disagreement will be resolved by reaching a consensus. RESULTS: Funding was received in October 2023, data collection will commence in July 2024, and the results are expected by 2025. We will summarize the selection of the eligible studies using a flowchart. The data from the studies will be extracted and tabulated. This scoping review will be published in a peer-reviewed journal in accordance with PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. CONCLUSIONS: This scoping review underscores the complex relationship between physical activity and mental health among individuals with SCI, highlighting the level of physical activity and mental health status, barriers to physical activity engagement, and psychological implications. Understanding these dynamics is crucial in devising tailored interventions aimed at enhancing mental well-being. This synthesis of evidence emphasizes the need for personalized strategies to promote physical activity, addressing unique challenges faced by this population to foster improved mental health outcomes and overall quality of life. TRIAL REGISTRATION: Open Science Framework osf.io/ugx7d; https://osf.io/ugx7d/. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/56081.

Feasibility and effect of cognitive-based board game and multi-component exercise interventions on older adults with dementia.

BACKGROUND: Taiwan is an aging society, and the number of people with dementia is rapidly increasing. Due to a decline in cognitive and physical function, older adults with dementia not only gradually lose the ability to complete daily living tasks on their own, but are also at a higher risk of falls and injurious falls. It is important to develop interventions that combine cognitive and exercise training for older adults with dementia to promote or maintain their cognitive and physical functions and reduce their risk of falls. This study aimed to investigate the feasibility and effect of cognitive-based board games and multi-component exercise interventions on cognitive function, physical fitness, and fall risk in older adults with dementia. METHODS: This was a quasi-experimental study with a single-group pretest and post-test design. The study participants were 41 community-dwelling older adults with mild to moderate dementia. They received cognitive-based board games and multi-component exercise interventions once a week for 12 weeks. The interventions included 1 hour of exercise training and 1 hour of cognitive training. Scores for the Taiwan version of the Montreal Cognitive Assessment (MoCA-T), physical fitness, and the St. Thomas Risk Assessment Tool for Falling Elderly Inpatients (STRATIFY) were measured as outcome indicators at baseline and after the 12-week period. RESULTS: The overall MoCA-T score increased significantly (effect size = 0.402), with participants with mild dementia showing a greater increase (effect size = 0.522) than those with moderate dementia (effect size = 0.310). Participants' physical fitness performance improved. Female participants exhibited significant improvements in the 30-second chair stand test (effect size = 0.483) and 8-foot up-and-go test (effect size = 0.437). The fall risk score decreased by 0.05 points, the change was not significant. CONCLUSION: The cognitive-based board game and multi-component exercise interventions used in this study are beneficial for improving cognitive function and physical fitness in older adults with dementia. These interventions are feasible and suitable for promotion among community-dwelling and institution-dwelling older adults with mild cognitive impairment or dementia to delay the decline in cognitive and physical function.

Dual inhibition of the TrkA and JAK2 pathways using entrectinib and pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers.

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.

[Effect of Integrated Landscape Characteristics Around Chaohu Lake on River Water Quality Based on Watershed Units].

Considering the impact of differences in watershed characteristics on river water quality, with the Chaohu Lake Basin as the research object, based on the data of water quality, meteorology, topography, soil, and remote sensing images of the river monitoring points from October 2019 to September 2020, the watershed unit at each monitoring point was divided through digital terrain analysis, and the comprehensive landscape characteristics based on the watershed unit were explored through the comprehensive use of correlation analysis, redundancy analysis, and multiple regression analysis to investigate the influence of comprehensive landscape characteristics based on watershed units (including land use, climate, topography, soil, etc.) on the water quality of rivers around Chaohu Lake. The results showed that:① the water quality of rivers around Chaohu Lake had large spatial differences, with the main pollutants being total nitrogen and ammonia nitrogen. Most of the rivers had total nitrogen concentrations exceeding the Class V water quality standards, and the areas with serious nitrogen and phosphorus pollution were concentrated in the urban area of Hefei and the surrounding rivers, as well as in the middle and lower reaches of the Fengle and Hangbu Rivers. ② The comprehensive landscape characteristics of the watershed unit had a significant impact on the river water quality. Among them, the proportion of built-up land, the density of patches, the dispersion and juxtaposition index, and the Shannon diversity index were positively correlated with the water quality indicators, whereas the proportion of forest and grassland and the spreading index were negatively correlated with the water quality indicators. ③ In different seasons, the effect of the integrated landscape characteristics of the watershed unit on river water quality was stronger in the wet season than in the dry season, which was mainly caused by the difference in precipitation in the dry and wet seasons.

[Multi-factor Impact Analysis of Grassland Phenology Changes on the Qinghai-Xizang Plateau Based on Interpretable Machine Learning].

The vegetation phenology of the Qinghai-Xizang Plateau is changing significantly in the context of climate change. However, there are many hydrothermal factors affecting the phenology, and few studies have focused on the effects of multiple factors on the phenology of the Qinghai-Xizang Plateau, resulting in a lack of understanding of the mechanisms underlying phenological changes on the Qinghai-Xizang Plateau. In this study, we used remote sensing data interpretation to analyze the spatial and temporal variability of grassland phenology on the Qinghai-Xizang Plateau from 2002 to 2021, focusing on precipitation, temperature, altitude, soil, and other aspects to reveal the dominant factors of phenological variability using an interpretable machine learning method (SHAP) and to quantify the interactive effects of multiple factors on phenology. The results showed that:① The growing season start (SOS) of grasslands on the Qinghai-Xizang Plateau mostly ranged from 110 to 150 d, with 56.32 % of grasslands showing an early SOS trend; the growing season end (EOS) mostly ranged from 290-320 d, with 67.65 % of grasslands showing a delayed EOS trend; and the growing season length (LOS) mostly ranged from 120 to 210 d, with 65.50 % of the grasslands showing a trend towards longer growing season lengths. ② SOS in grasslands on the Qinghai-Xizang Plateau was mainly influenced by moisture conditions, in which soil moisture between 10 and 25 kg·m-2 in the 0-10 cm soil layer in March promoted the advancement of SOS and peaked at approximately 20 kg·m-2. EOS was mainly influenced by temperature, with higher temperatures in September and October having a stronger effect on EOS latency promotion and peaking at over 8 ℃ and -0.5 ℃, respectively. The main influencing factors of LOS were more consistent with SOS, in which soil moisture between 15 and 25 kg·m-2 in the 0-10 cm soil layer in March promoted the prolongation of LOS and peaked at approximately 18 kg·m-2. ③ There was an obvious interactive effect of water and heat and other factors on phenology; after soil moisture reached 20 kg·m-2 in the 0-10 cm soil layer in March, SOS was more advanced in low-precipitation and low-altitude areas. Better moisture conditions were more conducive to EOS delay at temperatures above 0 ℃ in October, and soil moisture in high precipitation areas promoted LOS prolongation more when soil moisture was between 12 and 22 kg·m-2 in 0-10 cm in March. The results also demonstrated that interpretable machine learning methods could provide a new approach to the analysis of the multifactorial effects of phenological change.

Imbalance in Unc80 RNA Editing Disrupts Dynamic Neuronal Activity and Olfactory Perception.

A-to-I RNA editing, catalyzed by the ADAR protein family, significantly contributes to the diversity and adaptability of mammalian RNA signatures, aligning with developmental and physiological needs. Yet, the functions of many editing sites are still to be defined. The Unc80 gene stands out in this context due to its brain-specific expression and the evolutionary conservation of its codon-altering editing event. The precise biological functions of Unc80 and its editing, however, are still largely undefined. In this study, we first demonstrated that Unc80 editing occurs in an ADAR2-dependent manner and is exclusive to the brain. By employing the CRISPR/Cas9 system to generate Unc80 knock-in mouse models that replicate the natural editing variations, our findings revealed that mice with the "gain-of-editing" variant (Unc80G/G) exhibit heightened basal neuronal activity in critical olfactory regions, compared to the "loss-of-editing" (Unc80S/S) counterparts. Moreover, an increase in glutamate levels was observed in the olfactory bulbs of Unc80G/G mice, indicating altered neurotransmitter dynamics. Behavioral analysis of odor detection revealed distinctive responses to novel odors-both Unc80 deficient (Unc80+/-) and Unc80S/S mice demonstrated prolonged exploration times and heightened dishabituation responses. Further elucidating the olfactory connection of Unc80 editing, transcriptomic analysis of the olfactory bulb identified significant alterations in gene expression that corroborate the behavioral and physiological findings. Collectively, our research advances the understanding of Unc80's neurophysiological functions and the impact of its editing on the olfactory sensory system, shedding light on the intricate molecular underpinnings of olfactory perception and neuronal activity.

Clinical outcome in hypertensive patients treated with amlodipine plus bisoprolol or plus valsartan.

OBJECTIVE: Several guidelines do not recommend beta-blocker as the first-line treatment for hypertension because of its inferior efficacy in stroke prevention. Combination therapy with beta-blocker is commonly used for blood pressure control. We compared the clinical outcomes in patients treated with amlodipine plus bisoprolol (A + B), a ß1-selective beta-blocker and amlodipine plus valsartan (A + V). METHODS: A population-based cohort study was performed using data from the Taiwan National Health Insurance Research Database. From 2012 to 2019, newly diagnosed adult hypertensive patients who received initial amlodipine monotherapy and then switched to A + V or A + B were included. The efficacy outcomes included all-cause death, atherosclerotic cardiovascular disease (ASCVD) event (cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization), hemorrhagic stroke, and heart failure. Multivariable Cox proportional hazards model was used to evaluate the relationship between outcomes and different treatments. RESULTS: Overall, 4311 patients in A + B group and 10980 patients in A + V group were included. After a mean follow-up of 4.34 ± 1.79 years, the efficacy outcomes were similar between the A + V and A + B groups regarding all-cause death (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI] 0.83-1.18), ASCVD event (aHR 0.97, 95% CI 0.84-1.12), and heart failure (aHR 1.06, 95% CI 0.87-1.30). The risk of hemorrhagic stroke was lower in A + B group (aHR 0.70, 95% CI 0.52-0.94). The result was similar when taking death into consideration in competing risk analysis. The safety outcomes were similar between the 2 groups. CONCLUSIONS: There was no difference of all-cause death, ASCVD event, and heart failure in A + B vs. A + V users. But A + B users had a lower risk of hemorrhagic stroke.