Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.

BACKGROUND: Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. METHODS: We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. RESULTS: We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. CONCLUSIONS: We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

Molecular Simulation for Guiding the Design and Optimization of Mixed Matrix Membranes (MMMs) in the Pervaporation Process.

Molecular simulation has been used extensively in the study of pervaporation membranes as a new economical and environmentally friendly research method. In this paper, A-SiO2/PDMS-PTFE mixed matrix membranes (MMMs) were prepared by molecular-simulation-guided experiments to achieve the separation of dimethyl carbonate/methanol (DMC/MeOH)) azeotropes. The interaction energy, X-ray diffraction pattern mean square displacement, and density field between PDMS and inorganic particles were analyzed by molecular dynamics simulations. The dissolution and diffusion processes of the DMC/MeOH azeotropes system in the MMM were simulated, and the surface-silylated silica (A-SiO2) with relatively better performance was screened. Based on the simulation results, A-SiO2/PDMS-PTFE MMMs were prepared by the coblending method, and the pervaporation separation performance of MMM membranes for DMC/MeOH azeotropes with different A-SiO2 loadings was investigated. When the A-SiO2 loading was 15 wt %, the separation factor of DMC/MeOH azeotropes at 50 °C was 4.74 and the flux was 1178 g m-2 h-1, which was consistent with the expected results of the simulation. The MMMs showed good stability in pervaporation over a period of up to 120 h. This study demonstrates that molecular simulations can provide a viable means for pretest screening and validation of experimental mechanisms, and to a certain extent, guide the design and optimization of pervaporation membranes.

Polystyrene nanobeads exacerbate chronic colitis in mice involving in oxidative stress and hepatic lipid metabolism.

BACKGROUND: Nanoplastics (NPs) are omnipresent in our lives as a new type of pollution with a tiny size. It can enter organisms from the environment, accumulate in the body, and be passed down the food chain. Inflammatory bowel disease (IBD) is a nonspecific intestinal inflammatory disease that is recurrent and prevalent in the population. Given that the intestinal features of colitis may affect the behavior and toxicity of NPs, it is imperative to clarify the risk and toxicity mechanisms of NPs in colitis models. METHODS AND RESULTS: In this study, mice were subjected to three cycles of 5-day dextran sulfate sodium (DSS) exposures, with a break of 7 to 11 days between each cycle. After the first cycle of DSS exposure, the mice were fed gavagely with water containing 100 nm polystyrene nanobeads (PS-NPs, at concentrations of 1 mg/kg·BW, 5 mg/kg·BW and 25 mg/kg·BW, respectively) for 28 consecutive days. The results demonstrated that cyclic administration of DSS induced chronic inflammation in mice, while the standard drug "5-aminosalicylic acid (5-ASA)" treatment partially improved colitis manifestations. PS-NPs exacerbated intestinal inflammation in mice with chronic colitis by activating the MAPK signaling pathway. Furthermore, PS-NPs aggravated inflammation, oxidative stress, as well as hepatic lipid metabolism disturbance in the liver of mice with chronic colitis. CONCLUSION: PS-NPs exacerbate intestinal inflammation and injury in mice with chronic colitis. This finding highlights chronically ill populations' susceptibility to environmental hazards, which urgent more research and risk assessment studies.

Bibliometric analysis of the inflammatory mechanism in aortic disease.

BACKGROUND: In view of the key role of inflammation in the pathogenesis of aortic disease, we visually analyzed the research hotspots of inflammatory mechanism in aortic disease in this work through the method of bibliometrics from the Web of Science (WOS) Core database over the past three decades. METHODS: A visual bibliometric network of research articles on inflammatory mechanisms in aortic disease was obtained from VOSviewer and Citespace based on the WOS Core Collection. RESULTS: A total of 1278 documents from January 1990 to February 2021 were selected for analysis. The United States and China had the highest percentage of articles, comprising 34.01% and 24.92% of articles worldwide, respectively. Harvard University has published the most articles in this field, followed by the University of Michigan and Huazhong University of Science and Technology. The top 3 research hotspots were atherosclerosis, oxidative stress, and macrophages. The journal with the most articles in this area was Arteriosclerosis Thrombosis and Vascular Biology, followed by Atherosclerosis and PLOS One. The research trend on inflammatory mechanisms in the aortic system has 5 distinct directions: (1) atherosclerosis, NF-κB, expression, smooth muscle cell, and oxidative stress; (2) coronary artery disease, C-reactive protein, risk factors, endothelial dysfunction, and aortic stenosis; (3) abdominal aortic aneurysm, matrix metalloproteinases, macrophage, and pathogenesis; (4) cholesterol, metabolism, low-density lipoprotein, gene expression, and a therosclerotic lesions; and (5) calcific aortic valve disease, interstitial cells, calcification, and stenosis. CONCLUSIONS: Inflammatory mechanism research has shown a tendency to rise gradually in the aortic field. Numerous studies have explored the role of inflammatory responses in aortic disease, which may increase the risk of endothelial dysfunction (aortic fibrosis and stiffness) and induce plaque formation. Among them, NFκB activation, nitric-oxide synthase expression, and oxidative stress are particularly essential.

Reconsideration and surgical technique report of root repair management of acute Stanford type A aortic dissection.

Currently, there is a lack of expert consensus and clinical guidelines about the treatment strategy for aortic roots in patients with acute Stanford type A aortic dissection with aortic sinuses less than 45 mm in diameter and without combined connective tissue disorder. The physiological aortic sinus plays a key role in the protection of the aortic valve and cardiac function. Thus, we invented a "watching without dealing with" technique of aortic root repair to preserve the aortic sinus as much as possible. This technique could simplify the operation and improve the patient's prognosis, which is worth learning and promoting.

Peptide-Engineered Fluorescent Nanomaterials: Structure Design, Function Tailoring, and Biomedical Applications.

Fluorescent nanomaterials have exhibited promising applications in biomedical and tissue engineering fields. To improve the properties and expand bioapplications of fluorescent nanomaterials, various functionalization and biomodification strategies have been utilized to engineer the structure and function of fluorescent nanomaterials. Due to their high biocompatibility, satisfied bioactivity, unique biomimetic function, easy structural tailoring, and controlled self-assembly ability, supramolecular peptides are widely used as versatile modification agents and nanoscale building blocks for engineering fluorescent nanomaterials. In this work, recent advance in the synthesis, structure, function, and biomedical applications of peptide-engineered fluorescent nanomaterials is presented. Firstly, the types of different fluorescent nanomaterials are introduced. Then, potential strategies for the preparation of peptide-engineered fluorescent nanomaterials via templated synthesis, bioinspired conjugation, and peptide assembly-assisted synthesis are discussed. After that, the unique structure and functions through the peptide conjugation with fluorescent nanomaterials are demonstrated. Finally, the biomedical applications of peptide-engineered fluorescent nanomaterials in bioimaging, disease diagnostics and therapy, drug delivery, tissue engineering, antimicrobial test, and biosensing are presented and discussed in detail. It is helpful for readers to understand the peptide-based conjugation and bioinspired synthesis of fluorescent nanomaterials, and to design and synthesize novel hybrid bionanomaterials with special structures and improved functions for advanced applications.

Letter to the Editor: Admission Values of Plasma Biomarkers Predict the Short-Term Outcomes in Acute Aortic Dissection.

Not applicable.

Hydrogeochemistry Assessment of Shallow Groundwater and Human Health Threats in the Northwestern Ordos Basin, China.

Groundwater is the main sources of water supply for drinking purposes in the Ordos Basin in the northwestern part of China. In order to sustain and protect the quality of groundwater resources, shallow groundwater samples were collected and analyzed to identify the hydrogeochemical characteristics, and to evaluate health risk to human. Cluster analysis showed that the 134 groundwater samples were divided into three classes (i.e., class 1, class 2, class 3). The groundwater types are mostly characterized by SO4-Cl type and SO4 type, mixed HCO3 type. The primary natural mechanisms controlling the chemical compositions are water-rock interaction and evaporation-precipitation. The extremely high concentrations of sulfate could be caused by contamination from pyrite or from infiltration of sulfate from inorganic fertilizers or from wastewater discharges. Results of the assessment of the health risks for ingestion of Cl-, NO3-, F-, Cr, and As in drinking water indicated that the total health risks are beyond the US EPA acceptable level of 10-6 per year for consumption of groundwater sourced from all three cluster classes. The highest risks were for ingestion of arsenic and chromium in groundwater. The highest total risks to adults and children were 1.51 × 10-5 and 2.45 × 10-2 (class 1), 4.12 × 10-4 and 8.98 × 10-3 (class 2), 3.06 × 10-3 and 5.49 × 10-2 (class 3), respectively. The study showed that there is a high risk of health problems among the residents of the Ordos Basin in China that are ingesting contaminated drinking water, with the health risks to children higher than the risks to adults.

Recent advances in the fabrication, functionalization, and bioapplications of peptide hydrogels.

Self-assembled peptide-based nanomaterials have exhibited wide application potential in the fields of materials science, nanodevices, biomedicine, tissue engineering, biosensors, energy storage, environmental science, and others. Due to their porous structure, strong mechanical stability, high biocompatibility, and easy functionalization, three-dimensional self-assembled peptide hydrogels revealed promising potential in bio-related applications. To present the advances in this interesting topic, we present a review on the synthesis and functionalization of peptide hydrogels, as well as their applications in drug delivery, antibacterial materials, cell culture, biomineralization, bone tissue engineering, and biosensors. Specifically, we focus on the fabrication methods of peptide hydrogels through physical, chemical, and biological stimulations. In addition, the functional design of peptide hydrogels by incorporation with polymers, DNA, protein, nanoparticles, and carbon materials is introduced and discussed in detail. It is expected that this work will be helpful not only for the design and synthesis of various peptide-based nanostructures and nanomaterials, but also for the structural and functional tailoring of peptide-based nanomaterials to meet specific demands.

Baicalein attenuates vinorelbine-induced vascular endothelial cell injury and chemotherapeutic phlebitis in rabbits.

Chemotherapy is one of the major strategies for cancer treatment. Several antineoplastic drugs including vinorelbine (VRB) are commonly intravenously infused and liable to cause serious phlebitis. The therapeutic drugs for preventing this complication are limited. In this study, the mechanism of baicalein (BCN) was investigated on VRB-induced phlebitis in vivo and vascular endothelial cell injury in vitro. Treatment with BCN obviously attenuated vascular endothelial cell loss, edema, inflammatory cell infiltration and blood clots, and reduced the serum levels of TNF-α, IL-1ß, IL-6 and ICAM-1 in the rabbit model of phlebitis induced by intravenous injection of VRB compared with vehicle. Further tests in vitro demonstrated that BCN lessened VRB-induced endothelial cell apoptosis, decreased intracellular ROS levels, suppressed phosphorylation of p38 and eventually inhibited activation of NF-κB signaling pathway. And these effects could be reversed by p38 agonist P79350. These results suggested that BCN exerted the protective effects against VRB-induced endothelial disruption in the rabbit model of phlebitis via inhibition of intracellular ROS generation and inactivation of p38/NF-κB pathway, leading to the decreased production of pro-inflammatory cytokines. Thus, BCN could be used as a potential agent for the treatment of phlebitis.

Micafungin compared with caspofungin for the treatment of febrile episodes in neutropenic patients with hematological malignancies: A retrospective study.

BACKGROUND: Invasive fungal infections are associated with morbidity and mortality in neutropenia secondary to hematological malignancies. Empirical antifungal agents are used to reduce their consequences. Caspofungin is the only echinocandin approved for this indication. Micafungin was compared with caspofungin for the treatment of patients with hematological malignancies and prolonged neutropenia. METHODS: A retrospective cohort study was conducted involving patients who had hematological malignancies with profound neutropenia for a minimum of 10 days, and received empirical micafungin or caspofungin for a minimum of five days, between April 2005 and November 2009. Successful outcome was based on a composite end point: survival for a minimum of seven days following antifungal cessation, successful treatment of baseline fungal infection, absence of adverse events and absence of breakthrough fungal infection. Fungal infections were defined according to revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG) criteria, with modification of the diagnostic imaging criteria. RESULTS: Micafungin had similar overall success to caspofungin (60.4% [29 of 48] versus 57.3% [47 of 82], respectively; P=0.729). Survival was higher in the micafungin group compared with the caspofungin group (100% [48 of 48] versus 89% [73 of 82]; P=0.02). No baseline invasive fungal infections were identified in the micafungin group, compared with three proven infections treated successfully with caspofungin (3.7%; P=0.18). Three proven breakthrough infections were observed in the micafungin group (three of 48 [27.3%]) compared with none in the caspofungin group (zero of 82; P=0.02). CONCLUSION: Micafungin has similar efficacy to caspofungin as empirical antifungal therapy in febrile neutropenic patients with hematological malignancies. Verification of these results in a prospective trial is warranted.

HISTORIQUE: Les infections fongiques invasives s'associent à la morbidité et à la mortalité en cas de neutropénie secondaire à un cancer hématologique. Les antifongiques empiriques sont utilisés pour en réduire les conséquences. La caspofongine est la seule échinocandine approuvée pour cette indication. La micafongine lui a été comparée pour traiter des patients atteints d'un cancer hématologique et d'une neutropénie prolongée. MÉTHODOLOGIE: Les chercheurs ont mené une étude de cohorte rétrospective auprès de patients atteints d'un cancer hématologique et d'une neutropénie profonde pendant au moins dix jours et qui avaient reçu de la micafongine ou de la caspofongine empirique pendant au moins cinq jours entre avril 2005 et novembre 2009. Les résultats positifs se fondaient sur un paramètre ultime composite : survie au moins sept jours après l'arrêt de l'antifongique, résolution de l'infection fongique de départ, absence d'effets indésirables et de percée de l'infection fongique. Les infections fongiques étaient définies conformément aux critères des définitions révisées de maladie fongique invasive de l'Organisation européenne de recherche sur le traitement du cancer et l'Invasive Fungal Infections Cooperative Group et du National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG), avec la modification aux critères d'imagerie diagnostique. RÉSULTATS: La micafongine fonctionnait de manière similaire à la caspofongine (60,4 % [29 sur 48] plutôt que 57,3 % [47 sur 82], respectivement; P=0,729). La survie était plus élevée dans le groupe sous micafongine que sous caspofongine (100 % [48 sur 48] plutôt que 89 % [73 sur 82]; P=0,02). Aucune infection fongique invasive n'a été constatée au départ dans le groupe prenant de la micafongine, mais trois infections démontrées traitées à la caspofongine (3,7 %; P=0,18) l'ont été. Trois percées d'infections démontrées été observées dans le groupe prenant de la micafongine (trois sur 48 [27,3 %]), mais aucune dans celui prenant de la caspofongine (zéro à 82; P=0,02). CONCLUSION: La micafongine a une efficacité similaire à celle de la caspofongine comme thérapie antifongique empirique chez les patients neutropéniques fébriles atteints d'un cancer hématologique. Il faudra vérifier ces résultats dans un essai prospectif.

Polysaccharides from Eucommia ulmoides Oliv. leaves alleviates alcohol-induced mouse brain injury and BV-2 microglial dysfunction.

Acute alcohol intoxication is a harmful clinical condition characterized by behavioral and neurological symptoms, for which few effective therapies are available at present. Dysfunction of microglial BV-2 cells has been reported to be associated with acute alcohol-induced brain injuries. In the present study, the protective effects of Eucommia ulmoides Oliv. leaves polysaccharides (EULP) on acute alcoholic brain injury and microglial dysfunction were investigated. 14-day pretreatment of EULP significantly attenuated neurobehavioral deficit and neurotransmitter damage in the brain tissue of mice caused by acute alcohol exposure. Additionally, EULP regulated the metabolic disorder of brain tissue. Consistently, it was shown that EULP pretreatment significantly improved alcohol-induced phagocytosis decrease, oxidative stress and inflammation in BV-2 cells. Therefore, EULP may be proposed and employed as a potential therapeutic agent for alcohol-induced brain damage.

Long-term outcomes of extensive thoracoabdominal aortic aneurysm repair utilizing normothermic iliac perfusion: A retrospective cohort study with 10-year single-center experience.

BACKGROUND: Normothermic iliac perfusion has been increasingly utilized for TAAA repair; however, the long-term outcomes in large samples are lacking. This study was designed to assesses the perioperative and long-term results of thoracoabdominal aortic repair using normothermic iliac perfusion. METHODS: We retrospectively analyzed 156 patients having Crawford extent II or III thoracoabdominal aortic aneurysm replacement with normothermic iliac perfusion from 2012 to 2022. Primary endpoints were composite adverse events and long-term survival, which encompassed 30-day mortality, persistent stroke, persistent paraplegia, and acute renal failure needing continuous dialysis. The cohort was divided into two subgroups based on the use of selective visceral and cold renal perfusion techniques. RESULTS: The combined adverse event rate was 14.1%. Specific rates were: 30-day mortality (4.5%), persistent stroke (1.9%), persistent paraplegia (4.5%), and renal failure requiring persistent dialysis (3.2%). The median follow-up time was 67 months. Overall survival rates at 1, 3, 5, 7, and 10 years were 91.6%, 90.0%, 85.4%, 77.6%, and 69.7%, respectively. Subgroup analysis showed the visceral and renal perfusion group had a significantly reduced adverse event incidence compared to the nonperfusion group (6.5% vs. 19.1%, P=0.026). Multivariable logistic regression analysis confirmed selective visceral and cold renal perfusion techniques as protective factors against postoperative adverse events (OR 0.30, 95%CI 0.09-0.94; P=0.038). Multivariable Cox regression analysis identified age ≥50 years (HR 2.63, 95%CI 1.10-6.27; P=0.029) and NYHA grade ≥III (HR: 3.20, 95% CI: 1.04-9.87; P=0.043) as independent risk factors predicting overall survival. CONCLUSIONS: Normothermic iliac perfusion is a feasible option for thoracoabdominal aortic repair with cost benefits and simpler management, and selective visceral and cold renal perfusion techniques may further improve its safety and effectiveness. However, enhanced vigilance and meticulous care are essential, particularly for elderly patients and those with cardiac insufficiency.

Clinical neuromodulatory effects of deep brain stimulation in disorder of consciousness: A literature review.

BACKGROUND: The management of patients with disorders of consciousness (DOC) presents substantial challenges in clinical practice. Deep brain stimulation (DBS) has emerged as a potential therapeutic approach, but the lack of standardized regulatory parameters for DBS in DOC hinders definitive conclusions. OBJECTIVE: This comprehensive review aims to provide a detailed summary of the current issues concerning patient selection, target setting, and modulation parameters in clinical studies investigating the application of DBS for DOC patients. METHODS: A meticulous systematic analysis of the literatures was conducted, encompassing articles published from 1968 to April 2023, retrieved from reputable databases (PubMed, Embase, Medline, and Web of Science). RESULTS: The systematic analysis of 21 eligible articles, involving 146 patients with DOC resulting from acquired brain injury or other disorders, revealed significant insights. The most frequently targeted regions were the Centromedian-parafascicular complex (CM-pf) nuclei and central thalamus (CT), both recognized for their role in regulating consciousness. However, other targets have also been explored in different studies. The stimulation frequency was predominantly set at 25 or 100 Hz, with pulse width of 120 µs, and voltages ranged from 0 to 4 V. These parameters were customized based on individual patient responses and evaluations. The overall clinical efficacy rate in all included studies was 39.7%, indicating a positive effect of DBS in a subset of DOC patients. Nonetheless, the assessment methods, follow-up durations, and outcome measures varied across studies, potentially contributing to the variability in reported efficacy rates. CONCLUSION: Despite the challenges arising from the lack of standardized parameters, DBS shows promising potential as a therapeutic option for patients with DOC. However, there still remains the need for standardized protocols and assessment methods, which are crucial to deepen the understanding and optimizing the therapeutic potential of DBS in this specific patient population.

Protective role of AT(2) and B(1) receptors in kinin B(2)-receptor-knockout mice with myocardial infarction.

AT(2)Rs [AngII (angiotensin II) type 2 receptors] contribute to the cardioprotective effects of angiotensin II receptor blockers, possibly via kinins acting on the B(1)R (B(1) receptor) and B(2)R (B(2) receptor). Recent studies have shown that a lack of B(2)R up-regulates B(1)R and AT(2)R; however, the pathophysiological relevance of such an event remains unclear. We hypothesized that up-regulation of AT(2)R and B(1)R compensates for the loss of B(2)R. Blockade of AT(2)R and/or B(1)R worsens cardiac remodelling and dysfunction following MI (myocardial infarction) in B(2)R(-/-) (B(2)-receptor-knockout mice). B(2)R(-/-) mice and WT (wild-type) controls were subjected to sham MI or MI and treated for 4 weeks with (i) vehicle, (ii) a B(1)R-ant (B(1)R antagonist; 300 µg/kg of body weight per day), (iii) an AT(2)R-ant [AT(2) receptor antagonist (PD123319); 20 mg/kg of body weight per day], or (iv) B(1)R-ant+AT(2)R-ant. B(2)R(-/-) mice had a greater MCSA (myocyte cross-sectional area) and ICF (interstitial collagen fraction) at baseline and after MI compared with WT controls. Cardiac function and increase in macrophage infiltration, TGFß(1) (transforming growth factor ß(1)) expression and ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation post-MI were similar in both strains. Blockade of AT(2)R or B(1)R worsened cardiac remodelling, hypertrophy and dysfunction associated with increased inflammation and ERK1/2 phosphorylation and decreased NO excretion in B(2)R(-/-) mice, which were exacerbated by dual blockade of B(1)R and AT(2)R. No such effects were seen in WT mice. Our results suggest that, in the absence of B(2)R, both B(1)R and AT(2)R play important compensatory roles in preventing deterioration of cardiac function and remodelling post-MI possibly via suppression of inflammation, TGFß(1) and ERK1/2 signalling.

Nonlinear Mechanical Property of 3D Braided Composites with Multi-Types Micro-Distortion: A Quantitative Evaluation.

A new alternative calculation procedure is developed to quantify the effect of yarn distortion characteristics on the mechanical properties of three-dimensional (3D) braided carbon/resin composites. Firstly, the multi-type yarn distortion characteristics factors including path, cross-section shape and cross-section torsion effects are described based on the stochastic theory. Then, the multiphase finite element method is employed to overcome the complex discretization in traditional numerical analysis, and the parametric studies including multi-type yarn distortion and different braided geometrical parameters on the resulting mechanical properties are performed. It is shown that the proposed procedure can simultaneously capture the yarn path and cross-section distortion characteristics caused by the mutual squeeze of component materials, which is difficult to characterize by experimental methods. In addition, it is found that even small distortions of yarn may significantly affect the mechanical properties for 3D braided composites, and the 3D braided composites with different braiding geometric parameters will show different sensitivity to the distortion characteristics factors of yarn. The procedure, which could be implemented into commercial finite element codes, is an efficient tool for the design and structural optimization analysis of a heterogeneous material with anisotropic properties or complex geometries.

Alcohol induces apoptosis and autophagy in microglia BV-2 cells.

Alcohol (ethanol) has proven to be toxic to nearly all organs, with the brain being one of the principal targets. As one of the important components of the brain's blood-brain barrier (BBB) and central nervous system, the state of microglia may be associated with some symptoms of alcohol intoxication. In the present study, microglia BV-2 cells were exposed to various concentrations of alcohol for 3 or 12 h, imitating different stages of drunkenness after alcohol use, respectively. From the perspective of the autophagy-phagocytosis axis, our findings show that alcohol alters autophagy levels or promotes apoptosis in BV-2 cells. The current study adds to the understanding of the action mechanisms of alcohol neurotoxicity. We anticipate that this study will increase public awareness of alcohol's negative effects and contribute to the creation of novel alcoholism treatment approaches.

Comparison of Safety and Effectiveness of Local or General Anesthesia after Transcatheter Aortic Valve Implantation: A Systematic Review and Meta-Analysis.

It remains controversial to choose anesthesia for transcatheter aortic valve implantation (TAVI). A meta-analysis of cohort studies was conducted to assess the efficacy and safety of local anesthesia (LA) compared to general anesthesia (GA) in TAVI. All relevant studies published from 1 January 2002, to 31 June 2022, were searched in Ovid, PubMed, Embase, Web of Science, and Cochrane Library. A total of 34 studies involving 23,480 patients were included in the meta-analysis. TAVI with LA was associated with a significant reduction in hospital stay [WMD = −2.48, 95% CI (−2.80, −2.16), p < 0.00001], operative [WMD = −12.25, 95% CI (−13.73, −10.78), p < 0.00001] and fluoroscopy time [WMD = −3.30, 95% CI (−5.40, −1.19), p = 0.002], and an increased risk of acute kidney injury [OR = 1.31, 95% CI (1.01, 1.69), p = 0.04] and a reduced incidence of major bleeding [OR = 0.59, 95% CI (0.46, 0.75), p < 0.0001] and the use of cardiovascular drugs [OR = 0.17, 95% CI (0.05, 0.57), p = 0.004]. No differences were found between LA and GA for 30-day mortality, procedural success rate, myocardial infarction, permanent pacemaker implantation, paravalvular leak, shock, and cerebrovascular events. Overall, 4.4% of LA converted to GA. Based on current evidence, our results suggested that LA strategies reduced hospital stay, operative time, fluoroscopy time, cardiovascular drug consumption, and major bleeding rates in patients undergoing TAVI but led to increased acute kidney injury rates. Further studies and randomized trials are required to verify the presented findings and to identify patients who might benefit from LA.

The impact of antiplatelet therapy on the descending thoracic aorta fate and long-term prognosis of extensive repaired type A aortic dissection.

OBJECTIVES: To evaluate the impact of antiplatelet therapy on the long-term descending thoracic aorta (DTA) fate and prognosis of extensive repaired type A aortic dissection (TAAD). METHODS: 1147 eligible TAAD patients from January 2010 to December 2019 were stratified into non-antiplatelet (n = 754) and antiplatelet groups (n = 393). The primary end points were overall survival, and DTA remodelling, including false lumen (FL) thrombosis and aortic redilation. The secondary end points were DTA reintervention or rupture and major bleeding events (MBEs). RESULTS: The 5-year overall survival rates were 95.6% and 94.3% in the non-antiplatelet and antiplatelet groups (P = 0.53), respectively. In the stent covering segment, the 1-year FL complete thrombosis rates were 92.1% and 92.4% in the non-antiplatelet and antiplatelet groups (P = 0.27), respectively, while in the stent uncovering segment, the 5-year FL complete thrombosis rates were 47.1% and 56.5% in the non-antiplatelet and antiplatelet groups (P = 0.12), respectively. Antiplatelet therapy was not an independent predictor of aortic redilation at the pulmonary artery bifurcation (ß±SE = -0.128 ± 0.203, P = 0.53), diaphragm (ß±SE = 0.143 ± 0.152, P = 0.35) or coeliac artery (ß±SE = 0.049 ± 0.136, P = 0.72) levels. With death as a competing risk, the cumulative incidences of DTA reintervention or rupture at 5 years were 4.6% and 4.0% in the non-antiplatelet and antiplatelet groups (sHR = 0.85, 95% CI, 0.49∼1.19; P = 0.58), respectively, and the 5-year cumulative incidences of MBEs were 2.1% and 2.3% in the non-antiplatelet and antiplatelet groups (sHR = 0.82, 95% CI, 0.56∼2.67; P = 0.62), respectively. CONCLUSIONS: Antiplatelet therapy did not impact long-term DTA FL thrombosis, redilation, reintervention or rupture, MBEs or overall survival on extensive repaired TAAD. Thus, antiplatelet therapy can be administered as indicated on extensive repaired TAAD.

Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1.

ANG II type 2 receptors (AT(2)R) elicit cardioprotective effects in part by stimulating the release of kinins; however, the mechanism(s) responsible have not been fully explored. We demonstrated previously that overexpression of AT(2)R increased expression of prolylcarboxypeptidase (PRCP; a plasma prekallikrein activator) and release of bradykinin by mouse coronary artery endothelial cells (ECs). In the present study we hypothesized that the AT(2)R-stimulated increase in PRCP is mediated by the tyrosine phosphatase SHP-1, which in turn activates the PRCP-dependent prekallikrein-kallikrein pathway and releases bradykinin. We found that activation of AT(2)R using the specific agonist CGP42112A increased SHP-1 activity in ECs, which was blocked by the AT(2)R antagonist PD123319. Activation of AT(2)R also enhanced conversion of plasma prekallikrein to kallikrein, and this effect was blunted by a small interfering RNA (siRNA) to SHP-1 and abolished by the tyrosine phosphatase inhibitor sodium orthovanadate. Treating cells with a siRNA to PRCP also blunted AT(2)R-stimulated prekallikrein activation and bradykinin release. Furthermore, blocking plasma kallikrein with soybean trypsin inhibitor (SBTI) abolished AT(2)R-stimulated bradykinin release. These findings support our hypothesis that stimulation of AT(2)R activates a PRCP-dependent plasma prekallikrein pathway, releasing bradykinin. Activation of SHP-1 may also play an important role in AT(2)R-induced PRCP activation.