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Summary Background Angioplasty recanalisation is recommended as the first-line interventional procedure for Budd-Chiari syndrome, but subsequent restenosis is common. We aimed to test whether use of routine, non-selective stenting in angioplasty could improve patency and treatment efficacy with adequate safety in Budd-Chiari syndrome. Methods We did a randomised controlled trial, for which patients aged 18–75 years with Budd-Chiari syndrome with membranous obstruction or short-length stenosis (≤4 cm), and a Child-Pugh score of less than 13 were considered eligible. Patients were excluded if they had obstruction not amenable to angioplasty, were recommended to be treated with transjugular intrahepatic portosystemic shunt or liver transplantation, or had contraindications for angioplasty. Eligible patients were randomly assigned (1:1) to an angioplasty-only group or an angioplasty plus routine stenting group, with use of a web-based allocation system (Pocock and Simon's minimisation method, stratified by obstruction features and Child-Pugh score). Recanalisation procedures were done within 24 h of randomisation. The statistician and investigators responsible for data collection data and endpoint assessment were masked to group allocation. The primary outcome was the proportion of patients free of restenosis, analysed in the intention-to-treat population. The study is registered on ClinicalTrials.gov ( NCT02201485 ) and is completed. Findings Between July 28, 2014, and Sept 29, 2017, 88 (59%) of 150 screened patients were enrolled and assigned either the angioplasty-only group (n=45) or the angioplasty plus routine stenting group (n=43). During a median follow-up period of 27 months (IQR 19–41), the angioplasty plus routine stenting group had significantly higher proportion of patients free of restenosis (42 [98%] of 43 patients) than did the angioplasty-only group (27 [60%] of 45 patients; p Interpretation Routine stenting with angioplasty is superior to angioplasty alone for preventing restenosis in patients with Budd-Chiari syndrome with short-length stenosis and is safe to use as part of first-line invasive treatment. Further validation is needed in similar settings and other regions in which different characteristics of Budd-Chiari syndrome are more prevalent. Funding National Natural Science Foundation of China, National Key Technology R&D Programme, Optimised Overall Project of Shaanxi Province, Boost Programme of Xijing Hospital.

Summary Background The survival benefit of early placement of transjugular intrahepatic portosystemic shunts (TIPS) in patients with cirrhosis and acute variceal bleeding is controversial. We aimed to assess whether early TIPS improves survival in patients with advanced cirrhosis and acute variceal bleeding. Methods We did an investigator-initiated, open-label, randomised controlled trial at an academic hospital in China. Consecutive patients with advanced cirrhosis (Child-Pugh class B or C) and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy were randomly assigned (2:1) to receive either early TIPS (done within 72 h after initial endoscopy [early TIPS group]) or standard treatment (vasoactive drugs continued to day 5, followed by propranolol plus endoscopic band ligation for the prevention of rebleeding, with TIPS as rescue therapy when needed [control group]). Randomisation was done by web-based randomisation system using a Pocock and Simon's minimisation method with Child-Pugh class (B vs C) and presence or absence of active bleeding as adjustment factors. The primary outcome was transplantation-free survival, analysed in the intention-to-treat population, excluding individuals subsequently found to be ineligible for enrolment. This study is registered with ClinicalTrials.gov , number NCT01370161 , and is completed. Findings From June 26, 2011, to Sept 30, 2017, 373 patients were screened and 132 patients were randomly assigned to the early TIPS group (n=86) or to the control group (n=46). After exclusion of three individuals subsequently found to be ineligible for enrolment (two patients in the early TIPS group with non-cirrhotic portal hypertension or hepatocellular carcinoma, and one patient in the control group due to non-cirrhotic portal hypertension), 84 patients in the early TIPS group and 45 patients in the control group were included in the intention-to-treat population. 15 (18%) patients in the early TIPS group and 15 (33%) in the control group died; two (2%) patients in the early TIPS group and one (2%) in the control group underwent liver transplantation. Transplantation-free survival was higher in the early TIPS group than in the control group (hazard ratio 0·50, 95% CI 0·25–0·98; p=0·04). Transplantation-free survival at 6 weeks was 99% (95% CI 97–100) in the early TIPS group compared with 84% (75–96; absolute risk difference 15% [95% CI 5–48]; p=0·02) and at 1 year was 86% (79–94) in the early TIPS group versus 73% (62–88) in the control group (absolute risk difference 13% [95% CI 2–28]; p=0·046). There were no significant differences between the two groups in the incidence of hepatic hydrothorax (two [2%] of 84 patients in the early TIPS group vs one [2%] of 45 in the control group; p=0·96), spontaneous bacterial peritonitis (one [1%] vs three [7%]; p=0·12), hepatic encephalopathy (29 [35%] vs 16 [36%]; p=1·00), hepatorenal syndrome (four [5%] vs six [13%]; p=0·10), and hepatocellular carcinoma (four [5%] vs one [2%]; p=0·68). There was no significant difference in the number of patients who experienced other serious adverse events (ten [12%] vs 11 [24%]; p=0·07) or non-serious adverse events (21 [25%] vs 19 [42%]; p=0·05) between groups. Interpretation Early TIPS with covered stents improved transplantation-free survival in selected patients with advanced cirrhosis and acute variceal bleeding and should therefore be preferred to the current standard of care. Funding National Natural Science Foundation of China, National Key Technology R&D Program, Optimized Overall Project of Shaanxi Province, Boost Program of Xijing Hospital.

In this paper, the oblique water-entry impact of a vehicle with a disk cavitator is studied experimentally and numerically. The effectiveness and accuracy of the numerical simulation are verified quantitatively by the experiments in this paper and the data available in the literature. Then, the numerical model is used to simulate the hydrodynamic characteristics and flow patterns of the vehicle under different entry conditions, and the axial force is found to be an important parameter. The influences of entry angle, entry speed and cavitator area on the axial force are studied. The variation law of the force coefficient and the dimensionless penetration distance at the peak of the axial force are revealed. The research conclusions are beneficial to engineering calculations on the impact force of a vehicle with a disk cavitator over a wide range of water-entry parameters. Keywords: Vehicle, Oblique water entry, Impact force characteristics, Experimental and numerical analyses

Oncogenic protein farnesyltransferase (FTase) is a key enzyme responsible for the lipid modification of a large and important number of proteins including Ras, which has been recognized as a druggable target of diverse cancers. Here, we report a systematic scaffold-based analysis to investigate the affinity, selectivity and cross-reactivity of nonpeptide inhibitors across ontology-enriched, disease-associated FTase mutants, by integrating multiple similarity matching, binding affinity scoring and enzyme inhibition assay. It is revealed that nonpeptide inhibitors are generally insensitive to FTase mutations; many of them cannot definitely select for wild-type target over mutant enzymes. Therefore, off-target is observed as a common phenomenon for the untargeted consequence of targeted therapies with FTase inhibition. This is not unexpected if considering that the enzyme active site is highly conserved in composition, configuration and function. The off-target, on the one hand, causes nonpeptide inhibitors with adverse drug reactions and, on the other hand, makes the inhibitors as promising candidates for the new use of old drugs. To practice the latter, a number of unexpected mutant-inhibitor interactions involved in cancer signaling pathways are uncovered in the created profile, from which several nonpeptide inhibitors are identified as insensitive to a drug-resistant mutation. Structural analysis suggests that the inhibitor ligands can bind to the mutant active site in a similar manner with wild-type target, although their nonbonded interactions appear to be impaired moderately upon the mutation.

Background: Angioplasty recanalization is recommended as the first-line interventional treatment for Budd-Chiari syndrome (BCS). Despite its long-term patency is particularly significant for being indicative of disease resolution and correlating to ensuing treatment and patient outcome, restenosis of angioplasty is rather frequent. We therefore designed the current randomized controlled trial to test whether routine stenting in angioplasty for BCS can improve patency and treatment efficacy with adequate safety. Methods: Consecutive BCS patients amenable to recanalization were randomly assigned to angioplasty alone (AP) or with routine stent placement (AP+SP). Primary endpoint was restenosis. Secondary endpoints included symptom recurrence, procedure-related complications, hepatocellular carcinoma (HCC), liver function, and survival. Findings: From July 2014 to September 2017, 88 were enrolled and assigned to AP group (n=45) and AP+SP group (n=43). During a median follow-up of 27 months, AP+SP group has significantly lower restenosis incidence than AP group (4% vs. 40% at 3 years, log-rank p

The nonlinear and multi-factor-dependent characteristics of the hydrodynamic forces acting on the aft body of a supercavitating vehicle are investigated using computational fluid dynamics (CFD). The CFD model of natural supercavitating flow is first verified and validated upon the supercavitating flow around a cavitator in the shape of a circular disk. Then the model is used to simulate the supercavitating flows over a typical supercavitating vehicle model at different cavitation numbers σ and angles of attack (AOA) α. By analyzing the supercavitating flow patterns and hydrodynamic force curves, the hydrodynamic characteristics of the aft body and their forming mechanisms are revealed: (a) The normal force and pitch moment are mainly generated by the pressure difference between the windward side and leeward side of the cylinder section caused by asymmetrical reattaching of the supercavity. (b) The hydrodynamic coefficients depend on both σ and α nonlinearly. Free AOA αfr and critical AOA αcr are identified to model the nonlinearity of hydrodynamic force about AOA. (c) For the designated model, αfr and αcr depend on supercavitating flow patterns determined by σ. The simulation results and conclusions would be beneficial for more accurate dynamic modeling and control simulation for supercavitating vehicles.