A review regarding the article 'Local versus General Anaesthesia for Transcatheter Aortic Valve Implantation (TAVI): A systematic review, meta-analysis, and trial sequential analysis of randomised and propensity-score matched studies'.

Transcatheter aortic valve implantation (TAVI) is a promising treatment strategy for high-risk surgical patients, and trials investigating its effectiveness in intermediate- and lower-risk patients are underway. Data are inconsistent regarding the superiority of using local anesthesia with conscious sedation alone versus general anesthesia (GA) as the anesthesia management of choice for elderly frail patients. Historically, TAVI procedure is performed under GA with transesophageal echocardiography. This approach gives operators stable hemodynamic control of the patient and helps decrease the risk of many of the operation's documented complications, including paravalvular leak and valve malpositioning. However, some studies have criticized the dependence of GA on mechanical ventilation and an increased need for catecholamine and/or vasopressor agents. Alternatively, to further capitalize on the minimally invasive nature of TAVI, some authors have advocated for the use of local anesthesia (LA) and/or conscious sedation approach, which would decrease procedure time, length of hospital stay, and minimize the need for postoperative inotropes. Ultimately and at present, the choice of anesthesia is based on the personal experience and preference of the Heart Team involved in the TAVI procedure, which will dictate the best possible management plan for each patient. Many patients currently undergoing TAVI are elderly and have multiple comorbidities, making their care complex. Anesthetic care is shifting from GA to sedation and regional block, but life-threatening complications are still relatively common and safety during planning and conduct of these procedures by the heart team, with the anesthesiologist at the center, is paramount.

A review regarding the article 'Effectiveness of mechanical circulatory support devices in reversing pulmonary hypertension among heart transplant candidates: A systematic review.'

Pulmonary hypertension (PH) with high pulmonary vascular resistance (PVR) is a very often diagnosed contraindication for orthotopic heart transplantation (OHT). It is a direct consequence of left ventricle failure characterized by high diastolic pressure obstructing the collection of blood from the pulmonary vessels. The occurrence of this situation grows with the increasing time of waiting for OHT, and with the progression of heart failure. Mechanical circulatory support (MCS) devices, particularly left ventricular assist devices (LVADs), have emerged as pivotal interventions for patients with fixed PH, offering a potential bridge to transplantation. The pathophysiological impact of PH in heart transplant candidates is profound, as it is associated with increased perioperative risk and heightened mortality post-transplantation. The selection of heart transplant candidates thus mandates a careful evaluation of PH, with an emphasis on distinguishing between reversible and fixed forms of the condition. Reversible PH can often be managed with medical therapies; however, fixed PH presents a more daunting challenge, necessitating more aggressive interventions like MCS. Patients are supported with LVADs until evidence of pulmonary afterload reversal is evident and then can be considered for heart transplantation. However, in those who are non-responders or have complications while being supported, their option for transplant is revoked. Despite these advancements, the heterogeneity of MCS devices and their mechanisms of action necessitates a nuanced understanding of their efficacy.

Akkermansia muciniphila improves gastric cancer treatment by modulating the immune microenvironment.

Background: Gut microbiota is pivotal in tumor occurrence and development, and there is a close relationship between Akkermansia muciniphila (AKK) and cancer immunotherapy. Methods: The effects of AKK and its outer membrane proteins on gastric cancer (GC) were evaluated in vitro and in vivo using cell counting kit-8 assay, flow cytometry, western blotting, ELISA, immunohistochemistry and immunofluorescence. Results: AKK outer membrane protein facilitated apoptosis of GC cells and exerted an immunostimulatory effect (by promoting M1 polarization of macrophages, enhancing expression of cytotoxic T-lymphocyte-related cytokines and suppressing that of Treg-related cytokines). Additionally, AKK and its formulation could inhibit tumor growth of GC and enhance the infiltration of immune cells in tumor tissues. Conclusion: AKK could improve GC treatment by modulating the immune microenvironment.

Akkermansia muciniphila (AKK) is a type of bacteria found in the human gut that is good for the immune system. We wanted to investigate the effect of AKK on cancer. We extracted a protein from AKK called Amuc. AKK and Amuc inhibited the growth of stomach cancer by encouraging the action of immune cells. AKK may therefore be able to treat stomach cancer.

Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2/GPX4 pathway.

Oxidative stress and lipid metabolism disorder caused by estrogen deficiency are regarded as the main causes of postmenopausal atherosclerosis, but the underlying mechanisms remain still unclear. In this study, ovariectomized (OVX) female ApoE-/- mice fed with high-fat diet were used to imitate postmenopausal atherosclerosis. The atherosclerosis progression was significantly accelerated in OVX mice, accompanied by the upregulation of ferroptosis indicators, including increased lipid peroxidation and iron deposition in the plaque and the plasma. While both estradiol (E2) and ferroptosis inhibitor ferrostatin-1 alleviated atherosclerosis in OVX mice, with the inhibition of lipid peroxidation and iron deposition, as well as the upregulation of xCT and GPX4, especially in endothelial cells. We further investigated the effects of E2 on ferroptosis in endothelial cells induced by oxidized-low-density lipoprotein or ferroptosis inducer Erastin. It was found that E2 exhibited anti-ferroptosis effect through antioxidative functions, including improving mitochondrial dysfunction and upregulating GPX4 expression. Mechanistically, NRF2 inhibition attenuated the effect of E2 against ferroptosis as well as the upregulation of GPX4. Our findings revealed that endothelial cell ferroptosis played a pivotal role in postmenopausal atherosclerosis progression, and the NRF2/GPX4 pathway activation contributed to the protection of E2 against endothelial cell ferroptosis.

Cigarette tar mediates macrophage ferroptosis in atherosclerosis through the hepcidin/FPN/SLC7A11 signaling pathway.

Despite the known promotional effects of cigarette smoking on progression of atherosclerosis (AS), tar as the most dominant toxic component in cigarette smoking has been little studied. Understanding the potential role and mechanisms of tar in AS may be a prerequisite for future reductions in cardiovascular morbidity and mortality. Male ApoE-/- mice were fed with high-fat diet and injected intraperitoneally with cigarette tar (40 mg/kg/day) for 16 weeks. The results showed that cigarette tar significantly promoted the formation of lipid-rich plaques with larger necrotic cores and less fibrous, and caused severe iron overload and lipid peroxidation in AS lesions. Moreover, tar significantly upregulated the expression of hepcidin and downregulated FPN and SLC7A11 of macrophages in AS plaques. Ferroptosis inhibitor (FER-1 and DFO) treatment, hepcidin-knockdown or SLC7A11-overexpression reversed above changes, thereby delaying the progression of atherosclerosis. In vitro, the use of FER-1, DFO, si-hepcidin, and ov-SLC7A11 increased cell viability and inhibited iron accumulation, lipid peroxidation and GSH depletion in tar treated macrophages. These interventions also inhibited the tar induced upregulation of hepcidin, and increased the expression of FPN, SLC7A11, and GPX4. Furthermore, NF-κB inhibitor reversed the regulatory effect of tar on hepcidin/FPN/SLC7A11 axis, and then inhibiting macrophage ferroptosis. These findings indicated that cigarette tar promotes atherosclerosis progression by inducing macrophage ferroptosis via NF-κB-activated hepcidin/FPN/SLC7A11 pathway.

A novel anti-atherosclerotic mechanism of quercetin: Competitive binding to KEAP1 via Arg483 to inhibit macrophage pyroptosis.

Natural antioxidants represented by quercetin have been documented to be effective against atherosclerosis. However, the related mechanisms remain largely unclear. In this study, we identified a novel anti-atherosclerotic mechanism of quercetin inhibiting macrophage pyroptosis by activating NRF2 through binding to the Arg483 site of KEAP1 competitively. In ApoE-/- mice fed with high fat diet, quercetin administration attenuated atherosclerosis progression by reducing oxidative stress level and suppressing macrophage pyroptosis. At the cellular level, quercetin suppressed THP-1 macrophage pyroptosis induced by ox-LDL, demonstrated by inhibiting NLRP3 inflammasome activation and reducing ROS level, while these effects were reversed by the specific NRF2 inhibitor (ML385). Mechanistically, quercetin promoted NRF2 to dissociate from KEAP1, enhanced NRF2 nuclear translocation as well as transcription of downstream antioxidant protein. Molecular docking results suggested that quercetin could bind with KEAP1 at Arg415 and Arg483. In order to verify the binding sites, KEAP1 mutated at Arg415 and Arg483 to Ser (R415S and R483S) was transfected into THP-1 macrophages, and the anti-pyroptotic effect of quercetin was abrogated by Arg483 mutation, but not Arg415 mutation. Furthermore, after administration of adeno associated viral vector (AAV) with AAV-KEAP1-R483S, the anti-atherosclerotic effects of quercetin were almost abolished in ApoE-/- mice. These findings proved quercetins suppressed macrophage pyroptosis by targeting KEAP1/NRF2 interaction, and provided reliable data on the underlying mechanism of natural antioxidants to protect against atherosclerosis.

Significance of Mannan Binding Lectin-Associated Serine Protease 2 in Urinary Extracellular Vesicles in IgA Nephropathy.

PURPOSE: Immunoglobulin A (IgA) nephropathy (IgAN) is a common chronic glomerulonephritis and the main cause of end-stage renal diseases. Recent evidence suggests that mannan binding lectin associated serine proteases 2 (MASP2) is related to IgAN; therefore, we investigated the expression and significance of MASP2 in serum and urinary extracellular vesicles (UEVs) in patients with IgAN. METHODS: Thirty-eight patients with IgAN and 17 healthy controls were enrolled in this study. UEVs were extracted by ultracentrifugation. The separation by ultra-high-speed centrifuge was verified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Candidate internal references (TSG101, CD9, flotillin, ß-actin and GAPDH) were identified by western blotting in the control group, and the expression of MASP2 in the UEVs was compared. The levels of MASP2 in the serum and UEVs in the IgAN and control groups were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: TEM and NTA results demonstrated that UEVs were successfully extracted. Western blotting results confirmed that TSG101 was suitable as an internal reference for this study. Compared with the control group, the IgAN group showed positive expression of MASP2. MASP2 levels in the UEVs, determined by ELISA, showed significant differences between IgAN and control groups, which were significantly positively correlated with the level of urinary microalbumin. CONCLUSIONS: The level of MASP2 in UEVs was related to IgAN and shows promise as a biomarker for evaluating the severity of renal injury and prognosis of IgAN, thereby helping to elucidate the role of MASP2 in the mannan-binding lectin pathway.

Effect of Recombinant Netrin-1 Protein Combined with Peripheral Blood Mesenchymal Stem Cells on Angiogenesis in Rats with Arteriosclerosis Obliterans.

This work was aimed to explore the effect of recombinant netrin-1 protein and peripheral blood mesenchymal stem cells (MSCs) on the angiogenesis ability of atherosclerosis. 28 Sprague Dawley (SD) rats were taken as research models. The arterial occlusion models were created by surgery and then divided into the saline control group (n =7), netrin-1 treatment group (n =7), MSCs treatment group (n =7), and netrin-1 + MSCs combined treatment group (n =7). The peripheral blood MSCs were extracted from the peritoneal cavity of diseased SD rats and cultured alone or in combination with netrin-1. The individually cultured MSCs and netrin-1 were locally injected into the ischemic tissues of SD rats. The Tarlov scoring was performed at the first, second, and third week of treatment, respectively. The expression of vascular endothelial growth factor (VEGF) was also measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the capillary density was measured by immunofluorescence staining. The mean maximum contractility of the gastrocnemius muscle in each group was determined in the third week after treatment. The Tarlov score of the netrin-1 + MSCs group was significantly higher than that of the control group (P < 0.05) at the second week. To the 4th week of treatment, the Tarlov score of the netrin-1 + MSCs group was highly increased compared to the netrin-1 group and the MSCs group (P < 0.05). The expression of VEGF in the treatment groups was greatly increased each week compared to the control group (P < 0.05). Compared with the netrin-1 and the MSCs groups, the VEGF was also notably increased in the netrin-1 + MSCs group (P <0.05). The capillary densities of the treatment groups were observably greater than that of the control group in the second and third weeks (P <0.05), while the capillary density in the netrin-1 + MSCs group was also significantly increased than those in the netrin-1 group and the MSCs group (P < 0.05). The mean maximum contractility of the netrin-1 + MSCs group was remarkably higher than that of the other groups (P < 0.05). The netrin-1 + MSCs group achieved the higher Tarlov score, higher VEGF expression, higher capillary density, and better muscle recovery than netrin-1 and MSCs treatments.

Quantitative CT imaging features for COVID-19 evaluation: The ability to differentiate COVID-19 from non- COVID-19 (highly suspected) pneumonia patients during the epidemic period.

OBJECTIVES: COVID-19 and Non-Covid-19 (NC) Pneumonia encountered high CT imaging overlaps during pandemic. The study aims to evaluate the effectiveness of image-based quantitative CT features in discriminating COVID-19 from NC Pneumonia. MATERIALS AND METHODS: 145 patients with highly suspected COVID-19 were retrospectively enrolled from four centers in Sichuan Province during January 23 to March 23, 2020. 88 cases were confirmed as COVID-19, and 57 patients were NC. The dataset was randomly divided by 3:2 into training and testing sets. The quantitative CT radiomics features were extracted and screened sequentially by correlation analysis, Mann-Whitney U test, the least absolute shrinkage and selection operator (LASSO) logistic regression (LR) and backward stepwise LR with minimum AIC methods. The selected features were used to construct the LR model for differentiating COVID-19 from NC. Meanwhile, the differentiation performance of traditional quantitative CT features such as lesion volume ratio, ground glass opacity (GGO) or consolidation volume ratio were also considered and compared with Radiomics-based method. The receiver operating characteristic curve (ROC) analysis were conducted to evaluate the predicting performance. RESULTS: Compared with traditional CT quantitative features, radiomics features performed best with the highest Area Under Curve (AUC), sensitivity, specificity and accuracy in the training (0.994, 0.942, 1.0 and 0.965) and testing sets (0.977, 0.944, 0.870, 0.915) (Delong test, P < 0.001). Among CT volume-ratio based models using lesion or GGO component ratio, the model combining CT lesion score and component ratio performed better than others, with the AUC, sensitivity, specificity and accuracy of 0.84, 0.692, 0.853, 0.756 in the training set and 0.779, 0.667, 0.826, 0.729 in the testing set. The significant difference of the most selected wavelet transformed radiomics features between COVID-19 and NC might well reflect the CT signs. CONCLUSIONS: The differentiation between COVID-19 and NC could be well improved by using radiomics features, compared with traditional CT quantitative values.

GSTM1 and GSTT1 Gene Polymorphisms with Gallbladder Carcinoma.

In order to explore the relationship between GSTM1 and GSTT1 gene polymorphisms and gallbladder cancer, so as to find a better treatment and prevention of gallbladder cancer and improve the treatment effect. In this paper, 247 patients with gallbladder cancer were selected for the experiment, including 187 male patients and 60 female patients. The total number of patients was randomly divided into two groups, namely the case group and the control group. The patients in normal condition and after treatment of tumor tissue and adjacent non-tumor tissue gene detection, and then through the logistic regression model to analyze the data. After the experiment, we found that the frequency ratio of GSTM1 and GSTT1 in gallbladder cancer patients before treatment was 57.33% and 52.37%, which was very high, which was very disadvantageous in gene detection. However, after treatment, the frequency of deletion of the two genes was 45.73% and 51.02%, which was significantly reduced. The reduced gene ratio is very beneficial to the observation of gallbladder cancer. Therefore, the surgical treatment of gallbladder cancer before the first drug after gene testing, in the understanding of various principles, will have twice the result with half the effort.

The protective effect of quercetin on macrophage pyroptosis via TLR2/Myd88/NF-κB and ROS/AMPK pathway.

AIMS: Pyroptosis is a pro-inflammatory form of programmed cell death, which plays a vital role in the development of inflammatory diseases. As a natural flavonoid, quercetin has been shown to possess anti-inflammatory activity, but its effects on macrophage pyroptosis is still unclear. Therefore, this study aims to investigate the effects of quercetin on macrophage pyroptosis and the underlying mechanism. MATERIAL AND METHODS: LPS/ATP treatment was used to induce THP-1 macrophage pyroptosis. Cell counting kit-8 (CCK-8) assay was used to evaluate cell viability. Scanning electron microscope (SEM) was used to detect cell morphology. Hoechst/propidium iodide (PI) staining and lactate dehydrogenase (LDH) assay were performed to evaluate the cell membrane integrity. The expression of key components and effectors of nod-like receptors3 (NLRP3) inflammasome were examined by real-time PCR and western blot. Immunofluorescence staining was used to detect reactive oxygen species (ROS) level and P65 nuclear translocation. KEY FINDINGS: Our results showed that quercetin prevented THP-1 macrophage pyroptosis by reducing the expression of NLRP3 and cleaved-caspase1, as well as IL-1ß and N-GSDMD in a concentration dependent manner. Quercetin suppressed NLRP3 inflammasome activation by inhibiting ROS overproduction. Moreover, quercetin inhibited the phosphorylation of P65 and its translocation from cytoplasm into nuclear. In addition, we found that quercetin suppressed the increase of TLR2/Myd88 and p-AMPK induced by LPS/ATP, while both TLR2 and AMPK agonist weakened the inhibitory effect of quercetin on the activity of NLRP3 inflammasome and alleviated the protective effect on macrophages pyroptosis. SIGNIFICANCE: Quercetin possesses a protective effect on macrophages pyroptosis via TLR2/Myd88/NF-κB and ROS/AMPK pathway.

Development of Time-Resolved Fluorescence Immunochromatographic Assays for Simultaneously Detecting Tylosin and Tilmicosin in Milk in Group-Screening Manner.

Tylosin and tilmicosin (T&T) residues in livestock products have received extensive attention from consumers. Time-resolved fluorescence immunochromatographic assay (TRFICA), as a fast, efficient and sensitive immunoassay method, has played an increasingly important role in the food safety field. Therefore, herein a quantitative and visual TRFICA was established for simultaneously detecting T&T in milk in a group-screening manner. Under the optimal conditions, the standard curve range of developed TRFICA based on the T&T was 1.87~7.47 ng/mL, and the half-maximal inhibition concentrations (IC50) were 4.06 ng/mL and 3.74 ng/mL, respectively. The limits of detection (LOD) of the TRFICA method were from 1.72 ng/mL to 1.39 ng/mL, and the visual cut-off values were 31.25 ng/mL and 62.50 ng/mL for T&T in milk, respectively. Moreover, the stability experiments showed that the strips could be stored at 4 °C for more than 6 months, the total detection time was less than 13 min, and the cross-reactivities (CRs) with related compounds were less than 0.1%, which concluded that the developed TRFICA method could be used in real milk sample detection.

The bonding variation of γ-TiAl during deformation.

To improve the ductility of γ-TiAl, the complicated interaction of Ti-Al chemical bonds, Al-Al covalent bonds, and Ti metallic bonds in the process of deformation should be evaluated. The electronic structure variation of γ-TiAl during deformation is investigated using first-principles calculation with the local energy schemes. The relative influence of these bonds on atomic stability is for the first time qualitatively evaluated by the combination of local energy schemes and Electron Localization Function (ELF) analysis. The discrepant influence pattern of some alloy elements on ductility is discussed based on the bonding analysis.

Modified EDTA selectively recognized Cu2+ and its application in the disaggregation of ß-amyloid-Cu (II)/Zn (II) aggregates.

The accumulation of the ß-amyloid (Aß) aggregates induced by Cu2+/Zn2+ in conjunction with toxicity is closely related to Alzheimer's disease (AD). Herein, we intended to improve the efficiency and selectivity of traditional chelator ethylenediaminetetraacetic acid (EDTA) combined with a fluorescent group 4-aminosalicylic acid (4-ASA)to acquire a novel potential chelator 4,4'-((2,2'-(ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(acetyl))bis(azanediyl))bis(2-hydroxybenzoic acid) (EDTA-ASA) capable of disaggregating Aß-Cu(II)/ Zn(II) aggregates. EDTA-ASA combines 4-ASA as fluorophore and multidentate amino nitrogen, hydroxyl and carboxyl groups to chelate Cu2+ from Aß-Cu (II) aggregates. The specific selectivity of EDTA-ASA towards Cu2+ in Tris-HCl buffer solution was investigated by fluorescence measurements. It exhibits high recognition towards Cu2+ with no significant interference of other competitive metal ions, which overcomes the deficiencies of EDTA. Importantly, the binding sites and binding mode for Cu2+ were clarified through DFT calculations. The thioflavin-T (ThT) fluorescence analyses and transmission electron microscopy (TEM) results have revealed EDTA-ASA exhibited an enhanced disaggregation capability on Aß-Cu (II)/Zn (II) aggregates in comparison to EDTA. The Cu2+ chelating affinity was sufficient for EDTA-ASA to sequester Cu2+ from Aß-Cu (II) aggregates.

Whole genome bisulfite sequencing of human spermatozoa reveals differentially methylated patterns from type 2 diabetic patients.

AIMS/INTRODUCTION: The incidence of type 2 diabetes mellitus is increasing worldwide, and it might partly cause metabolic disorder and type 2 diabetes mellitus susceptibility in patients' offspring through epigenetic modification. However, the underlying mechanisms remain largely unclear. Recent studies have shown a potential link between deoxyribonucleic acid methylation in paternal sperm and susceptibility to type 2 diabetes mellitus in offspring, so this article focuses on whether the whole-genome methylation profiles of spermatozoa in type 2 diabetes mellitus patients have changed. MATERIALS AND METHODS: We investigated the genome-wide deoxyribonucleic acid methylation profiles in spermatozoa by comparing eight individuals with type 2 diabetes mellitus and nine non-diabetic controls using whole-genome bisulfite sequencing method. RESULTS: First, we found that the proportion of methylated cytosine in the whole genome of the type 2 diabetes mellitus group was slightly lower than that of the control group. Interestingly, the proportion of methylated cytosines in the CG context decreased, and the proportion of methylated cytosines in the CHG context (H = A, T or C) increased in the type 2 diabetes mellitus group, but the proportion of methylated cytosines in the CHH context (H = A, T or C) barely changed. The methylated cytosines in the CG context were mainly distributed at the high methylated level, whereas methylated cytosines in the CHG context and methylated cytosines in the CHH context were mainly distributed at the low and middle methylated level in both groups. Second, functional enrichment analysis showed that differentially methylated genes played a significant role in nervous system development and cell metabolism. Finally, we identified 10 top type 2 diabetes mellitus-related differentially methylated genes, including IRS1, PRKCE, FTO, PPARGC1A, KCNQ1, ATP10A, GHR, CREB1, PRKAR1A and HNF1B. CONCLUSIONS: Our study provides the first evidence for deoxyribonucleic acid methylation reprogramming in spermatozoa of type 2 diabetes mellitus patients, and provides a new basis for explaining the complex mechanism of type 2 diabetes mellitus susceptibility in offspring.

Design of Novel Haptens and Development of Monoclonal Antibody-Based Immunoassays for the Simultaneous Detection of Tylosin and Tilmicosin in Milk and Water Samples.

In this work, a monoclonal antibody-based indirect competitive enzyme-linked immunosorbent assay (icELISA) was established to detect tylosin and tilmicosin in milk and water samples. A sensitive and specific monoclonal antibody was prepared by rational designed hapten, which was achieved by directly oxidizing the aldehyde group on the side chain of tylosin to the carboxyl group. Under the optimized conditions, the linear range of icELISA for tylosin and tilmicosin were 1.3 to 17.7 ng/mL and 2.0 to 47.4 ng/mL, with half-maximal inhibition concentration (IC50) values of 4.7 and 9.6 ng/mL, respectively. The cross-reactivity with other analogues of icELISA was less than 0.1%. The average recoveries of icELISA for tylosin and tilmicosin ranged from 76.4% to 109.5% in milk and water samples. Besides, the detection results of icELISA showed good correlations with HPLC-MS/MS. The proposed icELISA was satisfied for rapid and specific screening of tylosin and tilmicosin residues in milk and water samples.