WITHDRAWN: Comparison of second-generation cryoballoon ablation and quantitative radiofrequency ablation guided by ablation index for atrial fibrillation.

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Site-specific metastases of gallbladder adenocarcinoma and their prognostic value for survival: a SEER-based study.

BACKGROUND: Gallbladder cancer is a rare but highly malignant cancer, which often progresses to a metastatic stage when diagnosed because of its asymptomatic manifestation. In this study, we intended to analyze the prognostic value of metastatic gallbladder adenocarcinoma (GBA) with site-specific metastases. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, GBA patients diagnosed with metastases between 2010 and 2016 were selected to identify the prognosis according to the isolated metastatic sites, including liver, lung, bone, brain and distant lymph nodes (DL). Kaplan-Meier methods were used for survival comparisons and multivariable Cox regression models were constructed to find out independent factors that associated with survival. RESULTS: Data from 1526 eligible patients were extracted from the SEER database. Among the patients, 788 (51.6%) had isolated liver metastases, 80 (5.2%) had isolated distant nodal involvement, 45 (2.9%) had isolated lung metastases, 21 (1.4%) had isolated bone metastases, 2 (0.1%) had isolated brain metastases and 590 (38.7%) had multiple metastases. No significant survival difference was shown between patients with single or multisite metastases (P > 0.05). Patients with isolated lung or DL metastases had significant better survival outcomes than those with isolated bone metastases (P < 0.05). Multivariate analysis showed that performing surgery at primary site, receiving chemotherapy were associated with better OS and CSS for patients with isolated liver or DL metastases. CONCLUSIONS: The study showed that different metastatic sites affect survival outcomes in metastatic GBA patients. Highly selected subset of patients with liver or DL metastases might benefit from surgery at primary site.

A Refined Composite Multivariate Multiscale Fluctuation Dispersion Entropy and Its Application to Multivariate Signal of Rotating Machinery.

In the fault monitoring of rotating machinery, the vibration signal of the bearing and gear in a complex operating environment has poor stationarity and high noise. How to accurately and efficiently identify various fault categories is a major challenge in rotary fault diagnosis. Most of the existing methods only analyze the single channel vibration signal and do not comprehensively consider the multi-channel vibration signal. Therefore, this paper presents Refined Composite Multivariate Multiscale Fluctuation Dispersion Entropy (RCMMFDE), a method which extracts the recognition information of multi-channel signals with different scale factors, and the refined composite analysis ensures the recognition stability. The simulation results show that this method has the characteristics of low sensitivity to signal length and strong anti-noise ability. At the same time, combined with Joint Mutual Information Maximisation (JMIM) and support vector machine (SVM), RCMMFDE-JMIM-SVM fault diagnosis method has been proposed. This method uses RCMMFDE to extract the state characteristics of the multiple vibration signals of the rotary machine, and then uses the JMIM method to extract the sensitive characteristics. Finally, different states of the rotary machine are classified by SVM. The validity of the method is verified by the composite gear fault data set and bearing fault data set. The diagnostic accuracy of the method is 99.25% and 100.00%. The experimental results show that RCMMFDE-JMIM-SVM can effectively recognize multiple signals.

Phosphorylation of Yes-associated protein impairs trophoblast invasion and migration: implications for the pathogenesis of fetal growth restriction†.

Fetal growth restriction (FGR) is a condition in which a newborn fails to achieve his or her prospective hereditary growth potential. This condition is associated with high newborn mortality, second only to that associated with premature birth. FGR is associated with maternal, fetal, and placental abnormalities. Although the placenta is considered to be an important organ for supplying nutrition for fetal growth, research on FGR is limited, and treatment through the placenta remains challenging, as neither proper uterine intervention nor its pathogenesis have been fully elucidated. Yes-associated protein (YAP), as the effector of the Hippo pathway, is widely known to regulate organ growth and cancer development. Therefore, the correlation of the placenta and YAP was investigated to elucidate the pathogenic mechanism of FGR. Placental samples from humans and mice were collected for histological and biomechanical analysis. After investigating the location and role of YAP in the placenta by immunohistochemistry, we observed that YAP and cytokeratin 7 have corresponding locations in human and mouse placentas. Moreover, phosphorylated YAP (p-YAP) was upregulated in FGR and gradually increased as gestational age increased during pregnancy. Cell function experiments and mRNA-Seq demonstrated impaired YAP activity mediated by extracellular signal-regulated kinase inhibition. Established FGR-like mice also recapitulated a number of the features of human FGR. The results of this study may help to elucidate the association of FGR development with YAP and provide an intrauterine target that may be helpful in alleviating placental dysfunction.

Trophoblastic proliferation and invasion regulated by ACTN4 is impaired in early onset preeclampsia.

Successful pregnancy requires normal placentation, which largely depends on the tight regulation of proliferation, invasion, and migration of trophoblast cells. Abnormal functioning of trophoblast cells may cause failure of uterine spiral artery remodeling, which may be related to pregnancy-related disorders, such as preeclampsia. Here, we reported that an actin-binding protein, α-actinin (ACTN)4, was dysregulated in placentas from early onset preeclampsia. Moreover, knockdown of ACTN4 markedly inhibited trophoblast cell proliferation by reducing AKT membrane translocation. Furthermore, E-cadherin regulated ACTN4 and ß-catenin colocalization on trophoblast cell podosomes, and ACTN4 down-regulation suppressed the E-cadherin-induced cell invasion increase via depolymerizing actin filaments. Moreover, loss of ACTN4 recapitulated a number of the features of human preeclampsia. Therefore, our data indicate that ACNT4 plays a role in trophoblast function and is required for normal placental development.-Peng, W., Tong, C., Li, L., Huang, C., Ran, Y., Chen, X., Bai, Y., Liu, Y., Zhao, J., Tan, B., Luo, X., Wang, H., Wen, L., Zhang, C., Zhang, H., Ding, Y., Qi, H., Baker, P. N. Trophoblastic proliferation and invasion regulated by ACTN4 is impaired in early onset preeclampsia.

Characterization of gut microbiota associated with clinical parameters in intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that specifically occurs in pregnancy. Elevated levels of liver transaminases aspartate aminotransferase, alanine aminotransferase and serum bilirubin levels are common biochemical characteristics in ICP. The disorder is associated with an increased risk of premature delivery and stillbirth. The characterization of the potential microbiota in ICP could go a long way in the prevention and treatment of this pregnancy disease. METHODS: A total of 58 patients were recruited for our study: 27 ICP patients and 31 healthy pregnant subjects with no ICP. The V3 and V4 regions of the 16S rDNA collected from fecal samples of both diseased and control groups were amplified. 16S rRNA gene amplicon sequencing was then performed on gut microbiota. Sequencing data were analyzed and the correlation between components of microbiota and patient ICP status was found. Related metabolic pathways, relative abundance and significantly different operational taxonomic units (OTUs) between ICP and controls were also identified. RESULTS: Elevated levels of total bile acid, ALT, AST, Dbil and Tbil were recorded or observed in ICP subjects as compared to the control. Gut microbiota in pregnant women was dominated by four major phyla and 27 core genera. PCoA analysis results indicated that there was no significant clustering in Bray-Curtis distance matrices. Our results showed that there was a correlation between specific OTUs and measured clinical parameters of pregnant women. Comparison at the different taxonomy levels revealed high levels of abundance of Blautia and Citrobacter in ICP patients. At the family level, Enterobacteriaceae and Leuconostocaceae were higher in ICP patients. 638 KEGG Orthologs and 138 pathways significantly differed in the two groups. PLS-DA model with VIP plots indicated a total of eight genera and seven species were key taxa in ICP and control groups. CONCLUSIONS: Our research indicated that although there was no significant clustering by PCoA analysis, patients with ICP have increased rare bacteria at different phylogenetic levels. Our results also illustrated that all 638 KEGG Orthologs and 136 in 138 KEGG pathways were less abundant in ICP patients compared to the controls.

Granulocyte colony-stimulating factor attenuates myocardial remodeling and ventricular arrhythmia susceptibility via the JAK2-STAT3 pathway in a rabbit model of coronary microembolization.

BACKGROUND: Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. Understanding the underlying mechanisms could improve its management. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME. METHODS: Forty male rabbits were randomized into four groups (n = 10 each): Sham, CME, G-CSF, and AG490 (a JAK2 selective inhibitor). Rabbits in the CME, G-CSF, and AG490 groups underwent left anterior descending (LAD) artery catheterization and CME. Animals in the G-CSF and AG490 groups received intraperitoneal injection of G-CSF and G-CSF + AG490, respectively. The ventricular structure was assessed by echocardiography. Ventricular electrical properties were analyzed using cardiac electrophysiology. The myocardial interstitial collagen content and morphologic characteristics were evaluated using Masson and hematoxylin-eosin staining, respectively. RESULTS: Western blot and immunohistochemistry were employed to analyze the expressions of Cx43, G-CSF receptor (G-CSFR), JAK2, and STAT3. The ventricular effective refractory period (VERP), VERP dispersion, and inducibility and lethality of ventricular tachycardia/fibrillation were lower in the G-CSF than in the CME group (P < 0.01), indicating less severe myocardial damage and arrhythmias. The G-CSF group showed higher phosphorylated-Cx43 expression (P < 0.01 vs. CME). Those G-CSF-induced changes were reversed by A490, indicating the involvement of JAK2. G-CSFR, phosphorylated-JAK2, and phosphorylated-STAT3 protein levels were higher in the G-CSF group than in the AG490 (P < 0.01) and Sham (P < 0.05) groups. CONCLUSION: G-CSF might attenuate myocardial remodeling via JAK2-STAT3 signaling and thereby reduce ventricular arrhythmia susceptibility after CME.

Telmisartan reduces atrial arrhythmia susceptibility through the regulation of RAS-ERK and PI3K-Akt-eNOS pathways in spontaneously hypertensive rats.

Telmisartan is an angiotensin II receptor blocker that displays unique PPAR-γ modulating activity. PPAR-γ agonists have been shown to decrease susceptibility to atrial fibrillation through their antioxidant and antiapoptotic effects. The aim of this study was to determine whether telmisartan would have a greater effect on susceptibility to atrial arrhythmia in a hypertensive rat model than valsartan, which is a traditional angiotensin II receptor blocker. In this study, spontaneously hypertensive rats were treated with 10 mg·(kg body mass)(-1)·d(-1) telmisartan (TEL group), 10 mg·(kg body mass)(-1)·d(-1) valsartan (VAL group), or vehicle (saline; SHR group) for 4 weeks. Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. After 4 weeks of treatment, we performed echocardiographic assessment, electrophysiological analysis, histological evaluation, and Western blot analysis. Telmisartan decreased systolic blood pressure to a similar extent as valsartan. Relative to the WKY controls, atrial arrhythmia susceptibility was significantly increased in the SHR group, and was significantly decreased by both telmisartan and valsartan, albeit to a greater extent with telmisartan. Arrhythmogenic atrial remodeling, including enlargement of the left atrium, myocyte hypertrophy, interstitial fibrosis, and myocyte apoptosis, was observed in the SHR group, and was accompanied by activated RAS-ERK signaling and suppressed PI3K-Akt-eNOS signaling. The results suggest that telmisartan reduced susceptibility to atrial arrhythmia to a greater extent than valsartan, ameliorated atrial remodeling, and reversed imbalances in the RAS-ERK and PI3K-Akt-eNOS pathways.

NET-targeted nanoparticles for antithrombotic therapy in pregnancy.

Pulmonary embolism caused by deep vein thrombosis (DVT) is a major contributor to maternal morbidity and mortality. There is still an unmet need for safe and effective treatment options for DVT during pregnancy. Recent research has shown that neutrophil extracellular trap (NET) formation plays a very vital role in thrombosis. We created nanoparticles surface-modified by neutrophil elastase (NE)-binding peptide that can target activated neutrophils specifically in vitro and in vivo. Prussian blue nanoparticles (PB NPs) designed in the core scavenges abnormally elevated reactive oxygen species (ROS) in the vascular microenvironment and acts as a photothermal agent to mediate photothermal therapy (PTT) to damage fibrin network structure. Based on the data we have included, this noninvasive therapeutic approach is considered safe for both mothers and the fetus. Furthermore, our findings indicate that this therapeutic approach has a significant alleviation effect on intrauterine growth restriction caused by maternal thrombosis.

Comparison of Second-Generation Cryoballoon Ablation and Quantitative Radiofrequency Ablation Guided by Ablation Index for Atrial Fibrillation.

We compared the efficacy and complication rates of quantitative radiofrequency ablation guided by ablation index (RFCA-AI) with those of second-generation cryoballoon ablation (CBA-2). Consecutive patients (n = 230) with symptomatic atrial fibrillation (AF) undergoing a first ablation CBA-2 (92 patients) or RFCA-AI (138 patients) procedure were enrolled in this study. The late recurrence rate in the CBA-2 group was higher than that in the RFCA-AI group (P = .012). Subgroup analysis showed the same result in patients with paroxysmal AF (PAF) (P = .039), but no difference was found in patients with persistent AF (P = .21). The average operation duration in the CBA-2 group (85 [75-99.5] minutes) was shorter than that in the RFCA-AI group (100 [84.5-120] minutes) (P < .0001), but the average exposure time (17.36(13.87-22.49) vs 5.49(4.00-8.24) minutes) in the CBA-2 group and X-ray dose (223.25(149.15-336.95) vs 109.15(80.75-168.7) mGym) were significantly longer than those in RFCA-AI group (P < .0001). Multivariate logistic regression analysis showed that left atrial diameter (LAD), early recurrence, and methods of ablation (cryoballoon ablation) were independent risk factors for late recurrence after AF ablation. Early recurrence of AF and LAD were independent risk factors for predicting late recurrence after AF ablation.

Influence of ABC stroke score on late recurrence of paroxysmal atrial fibrillation following radiofrequency catheter ablation.

BACKGROUND: In this study we investigated the impact of ABC stroke score on the recurrence of paroxysmal atrial fibrillation (PAF) following radiofrequency catheter ablation (RFCA). METHODS: A total of 132 patients with PAF who underwent RFCA from October 2018 to September 2019 were included in this study. During the first phase of this study the patients were categorized into two groups based on late recurrence of atrial fibrillation after RFCA. In the second phase, the patients were further divided into two groups based on whether their ABC stroke score was ≥ 6.5. RESULT: The univariate analysis indicated that the risk factors for late recurrence of PAF included early recurrence, ABC stroke score, CHA2DS2-VASc score, and NT-proBNP (P < 0.05). Cox multivariate regression analysis revealed that ABC stroke score (P = 0.006) and early recurrence (P = 0.000) were independent predictors of late recurrence, and ABC stroke score ≥ 6.5 was a risk for predicting recurrence of PAF after RFCA with a sensitivity of 66.7% and specificity of 65.7%. After the completion of the 1:1 matching, the univariate Cox analysis indicated that an elevated score of ABC stroke (≥ 6.5) was an independent predictor of late recurrence of PAF (HR = 2.687, 95% CI: 1.036-6.971, P = 0.042). However, using an ABC stroke score cut off at 6.4 predicted the recurrence of atrial tachyarrhythmia with 85% sensitivity and 58.5% specificity. CONCLUSION: An ABC stroke score ≥ 6.4 is a predictor for late recurrence of PAF after RFCA.

Removal of pristine and aged microplastics from water by magnetic biochar: Adsorption and magnetization.

Adsorption is an efficient and eco-friendly removal technique for small pristine microplastics in water. However, small pristine microplastics are not representative of those large microplastics in natural water with different aging levels. Whether the adsorption technique is effective in removing large aged microplastics from water remained unknown. To this end, the removal efficiency of large polyamide (PA) microplastics with different aging time by magnetic corncob biochar (MCCBC) was evaluated under different experimental conditions. After treated by heated-activated potassium persulfate, the physicochemical properties of PA have changed dramatically, as evidenced by rough surface, decreased particle size and crystallinity, and increased oxygen-containing functional groups, which enhanced with aging time. These changes promoted the combination of aged PA and MCCBC, thereby resulting in a higher removal efficiency of aged PA (~97 %) than that of pristine ones (~25 %). It is supposed that the adsorption process was a result of complexation, hydrophobic interaction, and electrostatic interaction. Increased ionic strength inhibited the removal of both pristine and aged PA, and neutral pH conditions favored PA removal. Furthermore, particle size played a great role in the removal of aged PA microplastics. When the particle size of aged PA was smaller than 75 µm, their removal efficiency was significantly increased (p < 0.01). The small PA microplastics were removed by adsorption, whereas the large ones were removed by magnetization. These research findings highlight magnetic biochar as promising technique for removing environmental microplastics.

Downregulation of CLDN1 impairs trophoblast invasion and endovascular trophoblast differentiation in early-onset preeclampsia.

INTRODUCTION: To investigate the role of claudin-1 (CLDN1) in trophoblast invasion and endovascular trophoblast (enEVT) differentiation in early-onset preeclampsia (EOPE). METHODS: The expression and localization of CLDN1 in normal (n = 18) and EOPE (n = 20) placental tissues were detected by immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction (qRT‒PCR) and Western blotting. Next, invasion, migration and tube formation assays were performed to explore the involvement of CLDN1 in trophoblast invasion and enEVT differentiation in trophoblast cell lines (HTR8/SVneo). Then, invasion and enEVT markers were analyzed via Western blotting and qRT‒PCR, respectively. Finally, we established an EOPE mouse model to detect the Cldn1 protein level. RESULTS: CLDN1 expression was significantly decreased in EOPE placental tissues. Knockdown of CLDN1 suppressed HTR8/SVneo cell invasion, migration and the ability to penetrate the endothelial tube. Conversely, overexpression of CLDN1 promoted trophoblast invasion and the ability to invade the endothelial tube. Inhibition of CLDN1 decreased the protein expression of VIM and SNAIL along with downregulating IL1B and PECAM1 mRNA levels, while overexpression of CLDN1 gave the opposite results. In the EOPE mouse model, we found a decrease in Cldn1 expression in EOPE mouse placentas. DISCUSSION: These results suggest that the downregulation of CLDN1 in trophoblast cells is involved in the pathogenesis of early-onset preeclampsia by affecting trophoblast invasion and enEVT differentiation.

Release characteristics and toxicity assessment of micro/nanoplastics from food-grade nonwoven bags.

Micro/nanoplastic (M/NP) contamination in food has become a global concern. Food-grade polypropylene (PP) nonwoven bags, which are widely used to filter food residues, are considered environmentally friendly and nontoxic. However, the emergence of M/NPs has forced us to re-examine the use of nonwoven bags in cooking as plastic contact with hot water leads to M/NP release. To evaluate the release characteristics of M/NPs, three food-grade PP nonwoven bags of different sizes were boiled in 500 mL water for 1 h. Micro-Fourier transform infrared spectroscopy and Raman spectrometer confirmed that the leachates were released from the nonwoven bags. After boiling once, a food-grade nonwoven bag can release 0.12-0.33 million MPs (>1 µm) and 17.6-30.6 billion NPs (<1 µm), equivalent to a mass of 2.25 - 6.47 mg. Number of M/NPs released is independent of nonwoven bag size; however, it decreases with increasing cooking times. M/NPs are primarily produced from easily breakable PP fibers, and they are not released into the water at once. Adult zebrafish (Danio rerio) were cultured in filtered distilled water without released M/NPs and in water containing 14.4 ± 0.8 mg L-1 released M/NPs for 2 and 14 days, respectively. To evaluate the toxicity of the released M/NPs on the gills and liver of zebrafish, several oxidative stress biomarkers (i.e., reactive oxygen species, glutathione, superoxide dismutase, catalase, and malonaldehyde) were measured. The ingestion of the released M/NPs by zebrafish induces oxidative stress in the gills and liver, depending on the exposure time. Food-grade plastics, such as nonwoven bags, should be used with caution in daily cooking because they release large amounts of M/NPs when heated, which can threaten human health.

Effects of biochar on the phytotoxicity of polyvinyl chloride microplastics.

Polyvinyl chloride microplastics (PVC-MPs) are toxic to crops, resulting in economic losses during agricultural production. Owing to its strong adsorption capacity, biochar can effectively remove MPs from water. It is presumed that biochar can alleviate the phytotoxicity of PVC-MPs. To verify this hypothesis, the effects of different concentrations of corncob biochar (CCBC) on the phytotoxicity of PVC-MPs were investigated using hydroponic experiments. The results showed that PVC-MPs attached to lettuce roots substantially inhibited the growth and quality of lettuce. The tested CCBC adsorbed the PVC-MPs. At appropriate concentrations, CCBC alleviated the inhibitory effect of PVC-MPs on lettuce yield; however, it decreased some quality indicators. The single PVC-MPs induced oxidative damage to lettuce, as demonstrated by the increased hydrogen peroxide (H2O2) and malondialdehyde (MDA) content. Addition of CCBC considerably decreased the contents of H2O2 and MDA in the lettuce shoots but increased the H2O2 content in the roots. These findings indicate that CCBC may alleviate the adverse effects caused by PVC-MPs to the lettuce shoots but aggravate the toxic effects on the lettuce roots. This study provides a basis for understanding the removal of the phytotoxicity of MPs.

Responses of cherry radish to different types of microplastics in the presence of oxytetracycline.

Croplands have become a hotspot for antibiotic and microplastic (MP) pollution. However, little is known regarding their combined effects on crops. In this study, the individual and combined effects of oxytetracycline (OTC) and three MPs (i.e., polypropylene (PP), polyamide (PA), and polyvinylchloride (PVC)) on cherry radish were investigated using pot experiments. Individually, OTC (50 mg kg-1), PA (2%, w/w), and PP (2%, w/w) induced negligible effects on cherry radish biomass and the root/shoot ratio. However, PVC (2%, w/w) significantly inhibited cherry radish growth; that is, its shoot and root fresh weight decreased by 46.2% and 81.1%, respectively. In the combined exposure groups, OTC alleviated the adverse effects of PVC on the cherry radish leaf number and shoot fresh weight. This was linked to that OTC increased the content of photosynthetic pigments. Superoxide dismutase activity in cherry radish roots was inhibited to different extents in all treatment groups except for the PA and PVC treatments. Malondialdehyde (MDA) content in cherry radish roots increased in all treatment groups, suggesting that both OTC and MPs caused oxidative damage to cherry radish root cells, therefore inhibiting cherry radish root growth. However, the presence of OTC non-significantly changed the effects of MPs on cherry radish roots. Irrespective of OTC presence, MPs induced a reduction in the root/shoot ratio of cherry radish, suggesting that the inhibitory effect of MPs on cherry radish roots was stronger than that on shoots. These findings contribute to the evaluation of the phytotoxicity of antibiotics and MPs in soil-vegetable systems.

Electrocardiogram Parameters That Affect the Success Rate of Radiofrequency Ablation in Patients with Outflow Tract Ventricular Premature Complexes.

Objectives: The objectives of this study are to assess the efficacy of radiofrequency catheter ablation (RFCA) in patients with outflow tract (OT) ventricular premature complexes (VPCs) and to explore the electrocardiographic (ECG) features of initially successful procedures. Methods: Based on the outcome of ablation, 154 consecutive patients with OT-VPCs who underwent RFCA from January 2017 to December 2019 were divided into two groups. The rate of successful procedures and the ECG features were analyzed and compared between the two groups. Results: The highest success rate was found in patients with VPCs from the right ventricular outflow tract (RVOT), and the lowest success rate was evident among patients with complexes from both the RVOT and the left ventricular OT (LVOT). The patients with successful procedures (136) reflected a lower pseudo delta wave ratio (16.2% vs. 44.4%, P < 0.01), a smaller R-wave amplitude in lead V1 (V1) (0.23 ± 0.24 mV vs. 0.35 ± 0.44 mV, P < 0.05), shorter intrinsicoid deflection time in lead V2 (V2) (44.00 ± 18.33 ms vs. 57.41 ± 20.67 ms, P < 0.01), a shorter RS duration in V2 (93.67 ± 21.33 ms vs. 106.93 ± 18.76 ms, P < 0.01), and smaller R/S-waveratios in V2. Furthermore, multivariate analysis demonstrated that RS duration in V2 was above 109.17 ms and R/S ratio in V2 was above 0.28, forecasting a failed procedure. Conclusions: The ECG predictors of failed ablation were characterized by RS duration and R/S ratio in V2.

Population Pharmacokinetics of Rivaroxaban in Chinese Patients with Non-Valvular Atrial Fibrillation: A Prospective Multicenter Study.

BACKGROUND AND OBJECTIVE: Rivaroxaban is a novel oral anticoagulant widely used for thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF). The present study aimed to develop a population pharmacokinetic (PPK) model for rivaroxaban in Chinese patients with NVAF. METHODS: We performed a prospective multicenter study. The plasma concentration of rivaroxaban was directly detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and indirectly by rivaroxaban-calibrated chromogenic anti-Xa assay (STA®). Gene polymorphisms were detected by MassARRAY single nucleotide polymorphism genotyping technology. Nonlinear mixed-effects modeling was used to develop the PPK model for rivaroxaban in patients with NVAF, and we simulated the steady-state rivaroxaban exposures under different dosing strategies in different covariate levels. RESULTS: A total of 150 patients from five centers were recruited, including 263 plasma concentrations detected by HPLC-MS/MS, 2626 gene polymorphisms, and 131 plasma concentrations detected by anti-Xa assay. In our study, an oral one-compartment model was used to describe the pharmacokinetics of rivaroxaban in patients with NVAF. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 5.79 L/h (relative standard error [RSE] 4.4%) and 51.5 L (RSE 5.0%), respectively. Covariates in the final model included creatinine clearance, total bilirubin, rs4728709, and body weight. The simulation results showed that in the 15 mg once-daily dosing regimen, in most instances the maximum plasma concentration at steady state (Cmax,ss) and trough plasma concentration at steady state (Cmin,ss) were in the target range for different covariate levels. When patients were administered rivaroxaban 15 or 20 mg once daily, the Cmax,ss and Cmin,ss in the different bodyweight levels were also in the target range. For patients with the ABCB1 rs4728709 mutation, the Cmin,ss in the 10, 15, and 20 mg once-daily dosing regimens were lower than the target range. The anti-Xa assay was highly linearly correlated with the HPLC-MS/MS method [y = 1.014x - 2.4648 (R2 = 0.97)]. CONCLUSIONS: Our study was the first multicenter PPK model for rivaroxaban in Chinese patients with NVAF (Alfalfa-RIVAAF-PPK). The study found that 15 mg once daily may be suitable as the principal rivaroxaban dose for Chinese patients with NVAF. For patients with the rs4728709 mutation, it may be necessary to examine insufficient anticoagulation. We found that the rivaroxaban-calibrated chromogenic anti-Xa assay and HPLC-MS/MS method were highly linearly correlated. Prospective studies with larger sample sizes and real-world studies are needed for further verification.

Synthesis and antifungal activity of novel sulfone derivatives containing 1,3,4-oxadiazole moieties.

A series of new sulfone compounds containing 1,3,4-oxadiazole moieties were synthesized. The structures of these compounds were confirmed by spectroscopic data (IR, ¹H- and ¹³C-NMR) and elemental analyses. Antifungal tests indicated that all the title compounds exhibited good antifungal activities against eight kinds of plant pathogenic fungi, and some showed superiority over the commercial fungicide hymexazol. Among them, compounds 5d, 5e, 5f, and 5i showed prominent activity against B. cinerea, with determined EC50 values of 5.21 µg/mL, 8.25 µg/mL, 8.03 µg/mL, and 21.00 µg/mL, respectively. The present work demonstrates that sulfone derivatives such as 5d containing a 1,3,4-oxadiazole moiety can be used as possible lead compounds for the development of potential agrochemicals.

Radiofrequency catheter ablation combined with spironolactone in the treatment of atrial fibrillation: A single-center randomized controlled study.

At present, the question of whether radiofrequency ablation (RFA) combined with spironolactone can reduce the levels of plasma angiotensin II (AngII) and aldosterone (ALD) in patients with atrial fibrillation (AF) and reduce the recurrence of AF has not been reported. HYPOTHESIS: The present study evaluates the effect of spironolactone as an ALD antagonist on the short-term and long-term recurrence of AF after RFA. A total of 203 patients were enrolled in the present study, with 102 patients in the spironolactone therapy group (Group PVI/SP) and 101 patients in the control group (Group PVI alone). The AngII and ALD levels and the size of the left atrium in patients with AF were observed in order to evaluate the relationship between the combination therapy of spironolactone with RFA and the success rate in AF treatment. After therapy, the levels of AngII (52.8 vs. 64.3 pg/ml, p < .001), ALD (45.7 vs. 60.6 pg/ml, p = .016), and N-terminal of B-type natriuretic peptide (NT-proBNP) (73.5 vs. 110 pg/ml, p = .016), along with the size of the left atrium (35.8 vs. 37.2 mm, p = .007), were all significantly lower in Group PVI/SP compared with Group PVI alone. The cumulative AF-free survival rate was higher in Group PVI/SP than in Group PVI alone after treatment (85.3% vs.73.3%, p = .033). In RFA combined with spironolactone treatment, spironolactone can directly antagonize the effects of ALD and AngII and the recurrence of AF and improve left ventricular function.