Small-Diameter Transjugular Intrahepatic Portosystemic Shunt versus Endoscopic Variceal Ligation Plus Propranolol for Variceal Rebleeding in Advanced Cirrhosis.

Background Some studies have shown that transjugular intrahepatic portosystemic shunt (TIPS) placement within 72 hours of admission improves survival in patients at high risk who present with acute variceal bleeding. However, the role of small-diameter covered TIPS in the secondary prophylaxis of variceal bleeding is still debatable. Purpose To compare the efficacy of 8-mm TIPS and endoscopic variceal ligation (EVL) plus propranolol in the prevention of variceal rebleeding among participants with advanced cirrhosis. Materials and Methods Between June 2015 and December 2018, participants admitted to the hospital for variceal bleeding were considered for enrollment in this randomized controlled trial (ClinicalTrials.gov). Participants with Child-Pugh class B or C cirrhosis were randomly assigned to receive an 8-mm covered TIPS or EVL and propranolol. The primary end point was recurrent variceal bleeding assessed using Kaplan-Meier curve analysis. Secondary end points included survival and overt hepatic encephalopathy (HE) assessed using Kaplan-Meier curve analysis. Results A total of 100 participants were enrolled, with 50 randomly assigned to the EVL plus propranolol group (median age, 54 years; IQR, 45-60 years; 29 male, 21 female) and 50 randomly assigned to the TIPS group (median age, 49 years; IQR, 43-56 years; 32 male, 18 female). The median follow-up period was 43.4 months. In the TIPS group, variceal rebleeding risk was reduced compared with variceal rebleeding risk in the EVL plus propranolol group (hazard ratio [HR], 0.31; 95% CI: 0.14, 0.69; P = .008), but the incidence of overt HE was higher in the TIPS group (30.0% vs 16.0%, P = .03). No differences in survival were observed between the two groups (1-year survival: TIPS, 98.0%; EVL plus propranolol, 92.0%; 3-year survival: TIPS, 94.0%; EVL plus propranolol, 85.7%; HR, 0.52; 95% CI: 0.19, 1.42; P = .22). Conclusion When compared with EVL plus propranolol, 8-mm TIPS led to reduced variceal rebleeding but did not impact overall survival in participants with Child-Pugh class B or C cirrhosis. Clinical trial registration no. NCT02477384 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Barth in this issue.

Fabrication of a Large-Area Flexible Scintillating Membrane for High-Resolution X-ray Imaging Using an AIEgen-Functionalized Metal-Organic Framework.

With the growing demand for X-ray imaging, especially for three-dimensional objects with curved surfaces, a large-area flexible X-ray imaging membrane based on scintillating materials becomes the focus of vigorous investigation. Among the developed scintillators, metal-organic frameworks (MOFs) featuring tunable photophysical properties and marked luminescence stability hold great promise for serving as ideal X-ray scintillators. Here, we report a flexible composite scintillating membrane with superior imaging performance. The membrane is achieved by embedding an aggregation-induced emission (AIE) luminogen (AIEgen, H4ETTC)-functionalized MOF scintillator (Y-PCN-94) into a polymer matrix (PDMS). Notably, Y-PCN-94 exhibits a strong AIE effect under both ultraviolet (UV) light and X-ray irradiation, which is also the first time that the AIE effect was observed in the MOF system under an ionizing radiation field. This also gives the material promising radioluminescence properties, such as a low X-ray detection limit (1.6 µGy s-1) and high imaging resolution (>14.3 lp mm-1), which can be mainly attributed to the combination of the AIE effect and strong X-ray stopping power. This work demonstrates that incorporating AIEgens into MOFs or other frameworks can offer an alternative approach for producing high-performance X-ray scintillators.

MELD 3.0 Score for Predicting Survival in Patients with Cirrhosis After Transjugular Intrahepatic Portosystemic Shunt Creation.

BACKGROUND AND AIMS: The selection of appropriate candidates for transjugular intrahepatic portosystemic shunt (TIPS) is important and challenging. To validate the Model for End-Stage Liver Disease (MELD) 3.0 in predicting mortality in patients with cirrhosis after TIPS creation. METHODS: A total of 855 consecutive patients with cirrhosis from December 2011 to October 2019 who underwent TIPS placement were retrospectively reviewed. The prognostic value of the MELD 3.0, MELD, MELD-Na, Child-Pugh and FIPS score was assessed using Harrell's C concordance index (c-index). The Hosmer-Lemeshow test was used to test the goodness of fit of all models and the calibration plot was drawn. RESULTS: The c-index of the MELD 3.0 in predicting 3-month mortality was 0.727 (0.645-0.808), which were significantly superior to the MELD (0.663 [0.565-0.761]; P = 0.015), MELD-Na (0.672 [0.577-0.768]; P = 0.008) and FIPS (0.582 [0.477-0.687]; P = 0.015). The Child-Pugh score reached c-indices of 0.754 (0.673-0.835), 0.720 (0.649-0.792), 0.705 (0.643-0.766) and 0.665 (0.614-0.716) for 3-month, 6-month, 1-year, and 2-year mortality, respectively, which seems comparable to MELD 3.0. A MELD 3.0 of 14 could be used as a cut-off point for discriminating between high- and low-risk patients. The MELD 3.0 could stratify patients with Child-Pugh grade B (log-rank P < 0.001). The Child-Pugh score could stratify patients defined as low risk by MELD 3.0 (log-rank P < 0.001). CONCLUSIONS: The MELD 3.0 was significantly superior to the MELD, MELD-Na and FIPS scores in predicting mortality in patients with cirrhosis after TIPS creation.

Highly efficient ozone elimination by metal doped ultra-fine Cu2O nanoparticles.

Nowadays, ozone contamination becomes dominant in air and thus challenges the research and development of cost-effective catalyst. In this study, metal doped Cu2O catalysts are synthesized via reduction of Cu2+ by ascorbic acid in base solutions containing doping metal ions. The results show that compared with pure Cu2O, the Mg2+ and Fe2+ dopants enhance the O3 removal efficiency while Ni2+ depresses the activity. In specific, Mg-Cu2O shows high O3 removal efficiency of 88.4% in harsh environment of 600,000 mL/(g·hr) space velocity and 1500 ppmV O3, which is one of the highest in the literature. Photoluminescence and electron paramagnetic spectroscopy characterization shows higher concentration of crystal defects induced by the Mg2+ dopants, favoring the O3 degradation. The in-situ diffuse reflectance Fourier transform infrared spectroscopy shows the intermediate species in the O3 degradation process change from O22- dominant of pure Cu2O to O2- dominant of Mg-Cu2O, which would contribute to the high activity. All these results show the promising prospect of the Mg-Cu2O for highly efficiency O3 removal.

Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells.

Ras-Erk MAPK signaling controls many of the principal pathways involved in metazoan cell motility, drives metastasis of multiple cancer types and is targeted in chemotherapy. However, its putative roles in immune cell functions or in infections have remained elusive. Here, using primary dendritic cells (DCs) in an infection model with the protozoan Toxoplasma gondii, we show that two pathways activated by infection converge on Ras-Erk MAPK signaling to promote migration of parasitized DCs. We report that signaling through the receptor tyrosine kinase Met (also known as HGF receptor) contributes to T. gondii-induced DC hypermotility. Furthermore, voltage-gated Ca2+ channel (VGCC, subtype CaV1.3) signaling impacted the migratory activation of DCs via calmodulin-calmodulin kinase II. We show that convergent VGCC signaling and Met signaling activate the GTPase Ras to drive Erk1 and Erk2 (also known as MAPK3 and MAPK1, respectively) phosphorylation and hypermotility of T. gondii-infected DCs. The data provide a molecular basis for the hypermigratory mesenchymal-to-amoeboid transition (MAT) of parasitized DCs. This emerging concept suggests that parasitized DCs acquire metastasis-like migratory properties that promote infection-related dissemination.

Endoscopic Cyanoacrylate Injection Versus Balloon-Occluded Retrograde Transvenous Obliteration for Prevention of Gastric Variceal Bleeding: A Randomized Controlled Trial.

BACKGROUND AND AIMS: The optimal treatment for gastric varices (GVs) is a topic that remains open for study. This study compared the efficacy and safety of endoscopic cyanoacrylate injection and balloon-occluded retrograde transvenous obliteration (BRTO) to prevent rebleeding in patients with cirrhosis and GVs after primary hemostasis. APPROACH AND RESULTS: Patients with cirrhosis and history of bleeding from gastroesophageal varices type 2 or isolated gastric varices type 1 were randomized to cyanoacrylate injection (n = 32) or BRTO treatment (n = 32). Primary outcomes were gastric variceal rebleeding or all-cause rebleeding. Patient characteristics were well balanced between two groups. Mean follow-up time was 27.1 ± 12.0 months in a cyanoacrylate injection group and 27.6 ± 14.3 months in a BRTO group. Probability of gastric variceal rebleeding was higher in the cyanoacrylate injection group than in the BRTO group (P = 0.024). Probability of remaining free of all-cause rebleeding at 1 and 2 years for cyanoacrylate injection versus BRTO was 77% versus 96.3% and 65.2% versus 92.6% (P = 0.004). Survival rates, frequency of complications, and worsening of esophageal varices were similar in both groups. BRTO resulted in fewer hospitalizations, inpatient stays, and lower medical costs. CONCLUSIONS: BRTO is more effective than cyanoacrylate injection in preventing rebleeding from GVs, with similar frequencies of complications and mortalities.

Liver stiffness by two-dimensional shear wave elastography for screening high-risk varices in patients with compensated advanced chronic liver disease.

OBJECTIVES: To investigate the usefulness of the criteria with liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT) for ruling out high-risk varices in patients with compensated advanced chronic liver disease (cACLD). METHODS: A total of 661 patients with cACLD had successfully undergone 2D-SWE and endoscopy screening. We analyzed risk factors for the presence of high-risk varices and compared proportions of patients who were spared endoscopy when used the predicting criteria with LS (ranged from 16 to 25 kPa) and PLT (ranged from 80 × 109/L to 150 × 109/L). RESULTS: PLT, albumin, LS were found to be independent predictors of high-risk varices. The LS values for ruling out and ruling in high-risk varices were 14.0 kPa and 24.8 kPa, respectively. When the Baveno VI criteria LS < 20 kPa and PLT > 150 × 109/L were used, the high-risk varices miss rate was 2.1%, while the saved endoscopy rate only was 19.2%. The new criteria that LS < 16 kPa and PLT > 100 × 109/L saved 30.4-34.6% endoscopy with 0-3.2% high-risk varices miss rate in the subgroup analysis stratified according to the types of underlying liver disease. CONCLUSIONS: The Baveno VI criteria can be applied to LS measurement by 2D-SWE. The new criteria that LS < 16 kPa and PLT > 100 × 109/L could be a potential model to spare more endoscopy screening with < 5% high-risk varices miss rate. KEY POINTS: • LS measured by 2D-SWE is reliable predictive factor for predicting all-size varices and high-risk varices in patients with compensated advanced chronic liver disease. • LS measured by 2D-SWE < 16 kPa and PLT > 100 × 109 /L, which can spare more endoscopy than Baveno VI criteria with < 5% high-risk varices miss rate. • The Baveno VI criteria can be applied to LS measurement by 2D-SWE.

Use of an Intrahepatic Arterial Targeting Wire for Guiding Portal Vein Puncture During TIPS Creation in Patients With Obliterative Portal Vein Thrombosis.

Obtaining portal vein access is a challenging step in TIPS creation, particularly in patients with portal vein thrombosis (PVT). We report the use of an intrahepatic arterial targeting wire to provide a target for portal vein puncture in 20 patients with cirrhosis and complete obliterative PVT who underwent TIPS placement. Technical success rate of TIPS placement was 90% (18/20). The median number of punctures was three. No severe complication occurred.

Transjugular intrahepatic portosystemic shunt for the treatment of portal hypertensive biliopathy with cavernous transformation of the portal vein: a case report.

BACKGROUND: Portal hypertensive biliopathy (PHB) was caused by anatomical and functional abnormalities in the intrahepatic and extrahepatic bile ducts secondary to portal hypertension. Currently, there is no consensus regarding to the optimal treatment for PHB. Transjugular intrahepatic portosystemic shunt (TIPS) is the treatment choice for the management of symptomatic PHB, however, it could be very difficult in patients with PHB and cavernous transformation of portal vein. CASE PRESENTATION: We report a case of PHB, successfully managed with TIPS. A 23-year-old man with liver cirrhosis presented with jaundice. Magnetic resonance cholangiopancreatography (MRCP) showed multiple tortuous hepatopetal collateral vessels compressing the common bile duct (CBD) and leading to the dilated proximal bile duct. He was diagnosed with PHB and treated with TIPS. A guidewire was inserted into the appropriate collateral vessel through transsplenic approach to guide intrahepatic puncture and TIPS was performed successfully. After the operation, portal vein pressure decreased and the symptoms of biliary obstruction were relieved significantly. In addition, the patient showed no jaundice at a follow-up of one year. CONCLUSIONS: For PHB patients presenting for cavernous transformation of the portal vein, which precludes the technical feasibility of TIPS, a combined transjugular/transsplenic approach could be an alternative option.

[Efficacy Analysis of Transcatheter Arterial Embolization in Acute Non-Variceal Upper Gastrointestinal Bleeding].

Objective: To evaluate the safety and effectiveness of transcatheter arterial embolization (TAE) in the treatment of acute non-variceal upper gastrointestinal bleeding (ANVUGIB), and to guide clinical practice and continue to optimize diagnosis and treatment strategies. Methods: This retrospective study included 266 patients who underwent angiography due to ANVUGIB between March 2016 and March 2021. Data on the positive rate of angiography, the technical success rate and clinical success rate of TAE, and the rebleeding rate and the all-cause mortality within 30 days after TAE treatment were collected, and the influencing factors relevant to the above events were analyzed accordingly. Results: All 266 patients completed angiography--the positive rate of angiography was 54.1% (144/266), the total technical success rate was 97.3% (217/223), the clinical success rate was 73.1% (155/212), and the rebleeding rate and all-cause mortality within 30 days were 26.9% (57/212) and 16.1% (35/217), respectively. This study found that shock index>1 ( OR=5.950; 95% CI: 1.481-23.895; P=0.012), computed tomography angiography (CTA) positive result ( OR=6.813; 95% CI: 1.643-28.252; P=0.008) and interval<24 h ( OR=10.530; 95% CI: 2.845-38.976; P<0.001) were independent predictors of positive angiography. Shock index>1 ( OR=2.544; 95% CI: 1.301-4.972; P=0.006) and INR>1.5 ( OR=3.207; 95% CI: 1.381-7.451; P=0.007) were independent risk factors for rebleeding. Patients with postoperative bleeding ( OR=3.174; 95% CI: 1.164-8.654; P=0.024) and patients with rebleeding after embolization ( OR=34.665; 95% CI: 11.471-104.758; P<0.001) had a higher risk of death within 30 days. Conclusion: TAE is safe and effective in the treatment of ANVUGIB. Patients with shock index>1 and positive CTA are more likely to be angiographic positive, and should undergo angiography as early as possible after bleeding. In addition, rebleeding after embolization deserves high attention.

Development and Validation of an Easy-to-Use Risk Scoring System for Screening High-Risk Varices in Patients with HBV-Related Compensated Advanced Chronic Liver Disease.

BACKGROUND: A large portion of patients with compensated advanced chronic liver disease (cACLD) do not have varices or only have low risk varices. AIMS: To create and validate an easy-to-use risk scoring system to identify high-risk varices (HRV) and spare esophagogastroduodenoscopy (EGD) in patients with hepatitis B virus (HBV)-related cACLD. METHODS: In total, 334 patients with HBV-related cACLD who had undergone routine laboratory tests and ultrasound examination were enrolled. Multivariate logistic regression analysis was used to determine which variables were the independent risk factors for the presence of HRV, so as to establish the scoring system for screening HRV. The criteria were tested in a training cohort with 221 patients and validated in a validation cohort with 113 patients. RESULTS: In the training cohort, the prevalence of HRV was 29.5%. Albumin (ALB) [OR 0.83; 95% confidence index (CI) 0.77-0.90; P < 0.0001], platelet count (PLT) (OR 0.96, 95% CI 0.96-0.99; P < 0.0001) and portal vein diameter (OR 1.40; 95% CI 1.15-1.71; P = 0.001) were independent risk factors for the presence of HRV. The negative predictive value was > 95%, when albumin-platelet-portal vein diameter varices scores (APP score) were < 0.24. One hundred twenty-five of 221 (56.6%) patients met an APP score < 0.24 with a 4.8% HRV miss rate. In the validation cohort, 59 of 113 (51.3%) patients met the APP score < 0.24 with a 1.7% HRV miss rate. CONCLUSIONS: APP score is a potential model for safely screening HRV and sparing EGDs in patients with HBV-related cACLD.

Prognostic Factors for Acute Transjugular Intrahepatic Portosystemic Shunt Occlusion Using Expanded Polytetrafluoroethylene-Covered Stent.

BACKGROUND: The expanded polytetrafluoroethylene (ePTFE)-covered stent has been widely used in the transjugular intrahepatic portosystemic shunt (TIPS) procedure. However, the epidemiologic data of acute TIPS occlusion (ATO) and the underlying mechanisms are scarce. AIMS: The purpose of this study was to evaluate the incidence and prognostic factors for ATO within 1 week in TIPS recipients using ePTFE-covered stents. METHODS: We identified 222 patients who underwent ePTFE-covered TIPS creation for complications of portal hypertension between June 2015 and June 2017 at a large tertiary center. Medical records and TIPS procedure data were retrospectively reviewed, and the influence of these variables on ATO was assessed by multivariate logistic regression analysis. RESULTS: TIPS technical success was achieved in 219 patients (98.6%). Two patients were excluded due to missing data, leaving 217 patients for final analysis. ATO occurred in nine patients (4.1%). Blood flow was restored by balloon angioplasty (n = 4), additional stent insertion (n = 4), and parallel TIPS (n = 1). In multivariable logistic regression, intrastent stenosis (HR 43.871; 95% CI 3.816, 504.373; P = 0.002), previous splenectomy (HR 26.843; 95% CI 2.106, 342.124; P = 0.011), and stent shortening in the hepatic vein (HR 11.54; 95% CI 1.021, 130.416; P = 0.048) were demonstrated as independent significant risk factors for ATO. CONCLUSIONS: These findings suggest that the intrastent stenosis, previous splenectomy, and stent shortening in the hepatic vein are vital prognostic factors for ATO in TIPS recipients. Individualized post-TIPS management strategy was required.

[Role of Hemostatic Clips as Guidance during Transcatheter Arterial Embolization in Patients with Peptic Ulcer Bleeding after Endoscopic Treatment Failure].

OBJECTIVE: To investigate the feasibility and clinical efficacy of transcatheter arterial embolization using hemostatic clips as the guidance in the patients with peptic ulcer bleeding after endoscopic treatment failure. METHODS: From February 2009 to October 2018, 33 patients with peptic ulcer bleeding who were treated with transcatheter arterial embolization after endoscopic treatment failure were included in the study. Clinical success rate, 30-d mortality rate and complication rate were observed. RESULTS: According to Forrest grading of ulcer bleeding on endoscopy, 8 patients (24.2%) were defined as Ⅰa, 14 patients (42.5%) Ⅰb, 4 patients (12.1%) Ⅱa, and 7 patients (21.2%) Ⅱb. There were 8 patients not given endoscopic treatment due to poor vision. In 25 patients who received endoscopic treatment, 7 patients did not achieve primary endoscopic hemostasis and 18 patients had re-bleeding despite successful primary hemostasis. The mean interval time from endoscopic treatment failure to transcatheter arterial embolization was (35.42±67.54) h. All patients underwent arterial angiography, and 18 patients with positive angiographic findings were treated with embolization. Among the 15 patients with negative angiographic findings, hemostatic clip could be observed fluoroscopically in 8 patients and used as guidance for embolization. Prophylactic embolization was performed in 4 out of 7 patients without visualization of clip fluoroscopically. The clinical success rates in negative angiographic findings patients with and without clip guidance were 75.0% and 28.6% respectively. The clinical success rate with positive angiographic findings was 66.7%. The overall clinical success rate and 30-d mortality rate were 60.0% and 20.0% respectively. No complication related to embolization was observed. CONCLUSION: The preliminary clinical study demonstrates that transcatheter arterial embolization with the guidance of clips is effective and safe for patients with peptic ulcer bleeding after endoscopic treatment failure.

Comparison of transjugular intrahepatic portosystemic shunt (TIPS) alone and combined with embolisation for the management of cardiofundal varices: a retrospective study.

OBJECTIVES: To assess the efficacy of transjugular intrahepatic portosystemic shunt (TIPS) with and without adjunctive embolisation in managing cardiofundal varices bleeding. METHODS: The retrospective study comprised 82 patients (54 men; mean age 53.9 years; mean Model of End-stage Liver Disease score 9.3) with cardiofundal varices bleeding who underwent TIPS creation from 2011 to 2015. Variceal rebleeding, the outflow tracts of varices, overt hepatic encephalopathy (HE) and post-procedure varices patency were assessed. RESULTS: Gastrorenal shunt was present in 92.7% of patients (n = 76). Embolisation was performed in 67.1% of patients (n = 55). The 1- and 2-year variceal rebleeding rates in the TIPS combined with embolisation group were significantly lower than those in the TIPS alone group (3.8% and 13.4% vs 13.0% and 28.0%, respectively; p = 0.041). No significant differences between the two groups were found in the cardiofundal varices patency, overt HE or survival (p > 0.05). CONCLUSIONS: The results suggest that TIPS combined with embolisation can reduce the risk of variceal rebleeding for patients with cardiofundal varices. KEY POINTS: • TIPS combined with embolisation reduces the risk of rebleeding in treating cardiofundal varices. • TIPS combined with embolisation could not completely occlude cardiofundal varices. • TIPS combined with embolisation could not prevent the development of hepatic encephalopathy.

Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization.

Pathological observations show that cancer cells frequently invade the surrounding stroma in collective groups rather than through single cell migration. Here, we studied the role of the actin-binding protein Girdin, a specific regulator of collective migration of neuroblasts in the brain, in collective cancer cell migration. We found that Girdin was essential for the collective migration of the skin cancer cell line A431 on collagen gels as well as their fibroblast-led collective invasion in an organotypic culture model. We provide evidence that Girdin binds to ß-catenin that plays important roles in the Wnt signaling pathway and in E-cadherin-mediated cell-cell adhesion. Girdin-depleted cells displayed scattering and impaired E-cadherin-specific cell-cell adhesion. Importantly, Girdin depletion led to impaired cytoskeletal association of the ß-catenin complex, which was accompanied by changes in the supracellular actin cytoskeletal organization of cancer cell cohorts on collagen gels. Although the underlying mechanism is unclear, this observation is consistent with the established role of the actin cytoskeletal system and cell-cell adhesion in the collective behavior of cells. Finally, we showed the correlation of the expression of Girdin with that of the components of the E-cadherin complex and the differentiation of human skin cancer. Collectively, our results suggest that Girdin is an important modulator of the collective behavior of cancer cells.

hnRNP G prevents inclusion on the HPV16 L1 mRNAs of the central exon between splice sites SA3358 and SD3632.

HPV16 late L1 mRNAs encode a short central exon that is located between HPV16 3'-splice site SA3358 and HPV16 5'-splice site SD3632. While SA3358 is used to produce both HPV16 early mRNAs encoding the E6 and E7 oncogenes, and late mRNAs encoding E4, L1 and L2, SD3632 is used exclusively to produce late L1 mRNA. We have previously identified an 8-nucleotide regulatory RNA element that is required for inclusion of the exon between SA3358 and SD3632 to produce L1 mRNAs at the expense of mRNAs polyadenylated at the HPV16 early polyadenylation signal pAE. Here we show that this HPV16 8-nucleotide splicing enhancer interacts with hnRNP G. Binding of hnRNP G to this element prevents inclusion of the exon between SA3358 and SD3632 on the HPV16 late L1 mRNAs. We concluded that hnRNP G has a splicing inhibitory role and that hnRNP G can control HPV16 mRNA splicing.