Assessment of visual function in blind mice and monkeys with subretinally implanted nanowire arrays as artificial photoreceptors.

Retinal prostheses could restore image-forming vision in conditions of photoreceptor degeneration. However, contrast sensitivity and visual acuity are often insufficient. Here we report the performance, in mice and monkeys with induced photoreceptor degeneration, of subretinally implanted gold-nanoparticle-coated titania nanowire arrays providing a spatial resolution of 77.5 µm and a temporal resolution of 3.92 Hz in ex vivo retinas (as determined by patch-clamp recording of retinal ganglion cells). In blind mice, the arrays allowed for the detection of drifting gratings and flashing objects at light-intensity thresholds of 15.70-18.09 µW mm-2, and offered visual acuities of 0.3-0.4 cycles per degree, as determined by recordings of visually evoked potentials and optomotor-response tests. In monkeys, the arrays were stable for 54 weeks, allowed for the detection of a 10-µW mm-2 beam of light (0.5° in beam angle) in visually guided saccade experiments, and induced plastic changes in the primary visual cortex, as indicated by long-term in vivo calcium imaging. Nanomaterials as artificial photoreceptors may ameliorate visual deficits in patients with photoreceptor degeneration.

Lenvatinib with or without Concurrent Drug-Eluting Beads Transarterial Chemoembolization in Patients with Unresectable, Advanced Hepatocellular Carcinoma: A Real-World, Multicenter, Retrospective Study.

Introduction: Lenvatinib is the first-line treatment for advanced hepatocellular carcinoma (HCC). We aimed to compare the clinical outcomes of lenvatinib plus drug-eluting beads transarterial chemoembolization (DEB-TACE) versus lenvatinib alone in real-world practice. Methods: This retrospective analysis included 142 consecutive patients who received lenvatinib plus DEB-TACE and 69 patients who received lenvatinib alone as first-line treatment from 15 Chinese academic centers from November 2018 to November 2019. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria, and safety profiles were compared between the two groups. Results: The median OS and PFS were significantly longer in the combined therapy group than in the monotherapy group in whole cohort (median OS, 15.9 vs. 8.6 months, p = 0.0022; median PFS, 8.6 vs. 4.4 months, p < 0.001) and after propensity score matching analysis (median OS, 13.8 vs. 7.8 months, p = 0.03; median PFS, 7.8 vs. 4.5 months, p = 0.009). Moreover, the treatment option was an independent prognostic factor for OS and PFS with adjustment based upon baseline characteristics (adjusted hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.36-0.78, p = 0.001, and adjusted HR: 0.42, 95% CI: 0.30-0.60, p < 0.001, respectively) and propensity score (adjusted HR: 0.52, 95% CI: 0.36-0.76, p = 0.001, and adjusted HR: 0.46, 95% CI: 0.33-0.64, p < 0.001, respectively). Moreover, a greater ORR was observed in the combined group (ORR: 46.48% vs. 13.05%, p < 0.001). Furthermore, the most common adverse events (AEs) were elevated aspartate aminotransferase (54.9%) and fatigue (46.4%) in the lenvatinib plus DEB-TACE group and lenvatinib group, respectively. Most AEs were mild-to-moderate and manageable. Conclusions: With well-tolerated safety, lenvatinib plus DEB-TACE was more effective than lenvatinib monotherapy in improving OS, PFS, and ORR. Thus, it may be a promising treatment for advanced HCC. Future prospective studies confirming these findings are warranted.

Optimal time point of response assessment for predicting survival is associated with tumor burden in hepatocellular carcinoma receiving repeated transarterial chemoembolization.

OBJECTIVES: Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. METHODS: A total of 1549 eligible treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score ≤ 7, and performance status score ≤ 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was ≤ 6, > 6 but ≤ 12, and > 12, respectively. RESULTS: Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). CONCLUSIONS: ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden. KEY POINTS: • This is the first study utilizing individual patient data to comprehensively analyze the surrogacy of ORR with a long follow-up period. • Optimal timing of ORR assessment for predicting survival should be tailored according to tumor burden. • For patients with low and intermediate tumor burden, initial ORR is optimal for its timeliness upon similar sensitivity with best ORR. For patients with high tumor burden, best ORR has optimal sensitivity.

Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS.

Background & Aims: Hepatic encephalopathy (HE) is a major complication after transjugular intrahepatic portosystemic shunt (TIPS) and is primarily influenced by the gut microbiota. We aimed to evaluate alterations in the microbiota after TIPS and the association between such alterations and HE. Methods: We conducted a prospective longitudinal study of 106 patients with cirrhosis receiving TIPS. Faecal samples were collected before and after TIPS, and the gut microbiota was analysed by 16S ribosomal RNA sequencing. Results: Among all patients, 33 developed HE (HE+ group) within 6 months after TIPS and 73 did not (HE- group), and 18 died during follow-up. After TIPS, the autochthonous taxa increased, whereas the potential pathogenic taxa decreased in the HE- group, and the autochthonous taxon Lachnospiraceae decreased in the HE+ group. Furthermore, synergism among harmful bacteria was observed in all patients, which was weakened in the HE- group (p <0.001) but enhanced in the HE+ group (p <0.01) after TIPS. Variations of 5 autochthonous taxa, namely, Coprococcus, Ruminococcus, Blautia, Ruminococcaceae_uncultured, and Roseburia, were negatively correlated with the severity of HE. Notably, increased abundances of Coprococcus and Ruminococcus were protective factors against HE, and the incidences of HE in patients with improved, stable, and deteriorated microbiota after TIPS were 13.3, 25.9, and 68.2%, respectively. Higher total bilirubin level, Child-Pugh score, model for end-stage liver disease score, Granulicatella, and Alistipes and lower Subdoligranulum before TIPS were the independent risk factors for death. Conclusions: Alterations in gut dysbiosis were negatively related to the occurrence and severity of post-TIPS HE, and the pre-TIPS microbiota were associated with death, suggesting the gut microbiota could be a promising potential biological target for screening suitable patients receiving TIPS and prevention and treatment of post-TIPS HE. Lay summary: Alterations in the gut microbiota after transjugular intrahepatic portosystemic shunt (TIPS) and the relationship between such alterations and post-TIPS hepatic encephalopathy (HE) remain unclear. We therefore performed this study and found that after TIPS, restoration of the gut microbiota, mainly characterised by expansion of autochthonous taxa, depletion of harmful taxa, and weakening of synergism among harmful bacteria, was inversely related to the occurrence and severity of post-TIPS HE.

Maximizing Performance of a Hybrid MnO2/Ni Electrochemical Actuator through Tailoring Lattice Tunnels and Cation Vacancies.

Electrochemical actuators play a key role in converting electrical energy to mechanical energy. However, a low actuation stress and an unsatisfied strain response rate strongly limit the extensive applications of the actuators. Here, we report hybrid manganese dioxide (MnO2) fabricated by introducing ramsdellite (R-MnO2) and Mn vacancies into birnessite (δ-MnO2) nanosheets, which in situ grew on the surface of a nickel (Ni) film, forming a hybrid MnO2/Ni actuator. The actuator demonstrated a rapid strain response of 0.88% s-1 (5.3% intrinsic strain in 6 s) and a large actuation stress of 244 MPa owing to the special R-MnO2 with a high density of sodium ion (Na+)-accessible lattice tunnels, Mn vacancies, and also a high Young's modulus of the hybrid MnO2/Ni composite. Besides, the cyclic stability of the actuator was realized after 1.2 × 104 cycles of electric stimulation under a frequency of 0.05 Hz. The finding of the novel hybrid MnO2/Ni actuator may provide a new strategy to maximize the actuating performance evidently through tailoring the lattice tunnel structure and introducing cation vacancies into electrochemical electrode materials.

Corrigendum: Large-Area Photoreceptor Degeneration Model in Rabbits by Photocoagulation and Oxidative Stress in the Retina.

[This corrects the article DOI: 10.3389/fnins.2021.617175.].

Large-Area Photoreceptor Degeneration Model in Rabbits by Photocoagulation and Oxidative Stress in the Retina.

Photocoagulation is used for the treatment of retinal ischemic disease. However, due to the invasive nature of photocoagulation and variety of melanin concentrations between individuals, it is challenging to avoid damaging the adjacent photoreceptors and inducing several side effects. Previous studies indicate the role of laser power, duration, and spot size on retinal lesions, but the effect of interspot distance of the laser pulses needs to be considered in panretinal photocoagulation. In this study, we examine different parameters of photocoagulation on lesions of the retina in rabbit, finding that the lesion level of the outer nuclear layer of the retina depended on the pulse duration and laser spot size, and decreasing interspot distance could completely abolish the photoreceptor layer. The degeneration of the photoreceptor by photocoagulation occurred in 24 h and was not restored afterward. We then conducted panretinal photocoagulation in rabbit and found that oxidative stress was decreased in the inner nuclear layer of the retina, and pupillary light reflex and ERG signals were impaired. Our study could provide a rabbit model to explore the mechanism of photoreceptor degeneration and therapies for the side effects after photocoagulation.

Insights into the mechanism regulating the differential expression of the P28-OMP outer membrane proteins in obligatory intracellular pathogen Ehrlichia chaffeensis.

Ehrlichia chaffeensis causes human monocytic ehrlichiosis (HME), which is one of the most prevalent, life-threatening emerging infectious zoonoses. The life cycle of E. chaffeensis includes ticks and mammals, in which E. chaffeensis proteins are expressed differentially contributing to bacterial survival and infection. Among the E. chaffeensis P28-OMP outer membrane proteins, OMP-1B and P28 are predominantly expressed in tick cells and mammalian macrophages, respectively. The mechanisms regulating this differential expression have not been comprehensively studied. Here, we demonstrate that the transcriptional regulators EcxR and Tr1 regulate the differential expression of omp-1B and p28 in E. chaffeensis. Recombinant E. chaffeensis Tr1 bound to the promoters of omp-1B and p28, and transactivated omp-1B and p28 promoter-EGFP fusion constructs in Escherichia coli. The consensus sequence of Tr1 binding motifs was AC/TTATA as determined with DNase I footprint assay. Tr1 showed a higher affinity towards the p28 promoter than the omp-1B promoter as determined with surface plasmon resonance. EcxR activated the tr1 expression in response to a temperature decrease. At 37°C low level of Tr1 activated the p28 expression. At 25°C high level of Tr1 activated the omp-1B expression, while repressing the p28 expression by binding to an additional site upstream of the p28 gene. Our data provide insights into a novel mechanism mediated by Tr1 regulating E. chaffeensis differential gene expression, which may aid in the development of new therapeutics for HME.

Long-term survival prediction for transjugular intrahepatic portosystemic shunt in severe cirrhotic ascites: assessment of ten prognostic models.

OBJECTIVES: Patients with severe cirrhotic ascites have poor prognosis, yet individual patient survival varies greatly. Therefore, suitable prognostic models can be helpful in clinical decision making. The aim of this study was to evaluate and compare the performance of 10 scores in predicting transplant-free survival (TFS) after transjugular intrahepatic portosystemic shunt (TIPS) in severe cirrhotic ascites. METHODS: Two hundred eighty consecutive cirrhotic patients with severe ascites undergoing TIPS between March 2006 and December 2017 were retrospectively screened and included from nine tertiary Chinese centers, consisting of 123 patients with refractory ascites and 157 with recurrent ascites. Discriminatory ability of these models was further assessed in the whole cohort and subgroups. RESULTS: TFS rates of all 280 patients were 75.4, 65.7, and 53.6% at 6-month, 1-year, and 2-year follow-up, respectively. Compared with other prognostic systems, the integrated model for end-stage liver disease (iMELD, incorporating serum sodium and age) showed optimal performance in predicting 6-month, 1-year, and 2-year TFS. Cutoffs were determined according to c-index and were used to stratify patients into three strata presenting significantly different TFS for short-term and long-term: iMELD < 32, ≥32 but <38 and ≥38 (log-rank P < 0.001). CONCLUSIONS: The iMELD score proved to be the best prognostic model in predicting TFS in patients with severe cirrhotic ascites receiving TIPS. Meanwhile, the model could stratify patients in three strata to help guiding clinical practice.

Exploratory Analysis to Identify Candidates Benefitting from Combination Therapy of Transarterial Chemoembolization and Sorafenib for First-Line Treatment of Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Observational Study.

INTRODUCTION: The benefits of combining transarterial chemoembolization (TACE) and sorafenib (TACE-S) over TACE alone for treatment of unresectable hepatocellular carcinoma (HCC) remain controversial. Yet, such populations are heterogeneous in terms of baseline characteristics. OBJECTIVE: To investigate the predictors of survival benefits from added sorafenib and identify the potential candidates for TACE-S. METHODS: This multicenter observational study was conducted in 17 Chinese tertiary hospitals for patients with unresectable, liver-confined HCC. Eligible patients with performance status score of ≤1 and Child-Pugh score of ≤7 were treated with TACE or TACE-S. Interactions between treatment and baseline variables were evaluated to find indicators for survival benefits, based on which the patients were stratified. Multivariate models adjusted for baseline characteristics or propensity score were used to compare overall survival (OS) and time to tumor progression (TTP). RESULTS: From January 2009 to December 2015, 1,719 consecutive patients received TACE (n = 1,406) or TACE-S (n = 313). Although TACE-S compared with TACE improved TTP (adjusted hazard ratio [HR] 0.75, p = 0.008), no difference in OS was observed (adjusted HR 0.87, p = 0.090). Nevertheless, the tumor burden (sum of maximum diameter of largest tumor [cm] and tumor number) and albumin-bilirubin (ALBI) score independently predicted the survival benefits from added sorafenib (interaction p< 0.001). For patients with either moderate tumor burden (7-13) or low ALBI score (no more than -2.8) defined as candidates, TACE-S prolonged OS (adjusted HR 0.73, p = 0.003) and TTP (adjusted HR 0.72, p = 0.014) compared to TACE alone, whereas its superiority disappeared in non-candidates. CONCLUSIONS: Not all unresectable HCC patients but those with moderate tumor burden or low ALBI score achieve survival benefits from TACE-S compared with TACE alone. Future randomized controlled trials focusing on the subset are warranted.

Different dendritic domains of the GnRH neuron underlie the pulse and surge modes of GnRH secretion in female mice.

The gonadotropin-releasing hormone (GnRH) neurons exhibit pulse and surge modes of activity to control fertility. They also exhibit an unusual bipolar morphology comprised of a classical soma-proximal dendritic zone and an elongated secretory process that can operate as both a dendrite and an axon, termed a 'dendron'. We show using expansion microscopy that the highest density of synaptic inputs to a GnRH neuron exists at its distal dendron. In vivo, selective chemogenetic inhibition of the GnRH neuron distal dendron abolishes the luteinizing hormone (LH) surge and markedly dampens LH pulses. In contrast, inhibitory chemogenetic and optogenetic strategies targeting the GnRH neuron soma-proximal dendritic zone abolish the LH surge but have no effect upon LH pulsatility. These observations indicate that electrical activity at the soma-proximal dendrites of the GnRH neuron is only essential for the LH surge while the distal dendron represents an autonomous zone where synaptic integration drives pulsatile GnRH secretion.

Validation of the six-and-twelve criteria among patients with hepatocellular carcinoma and performance score 1 receiving transarterial chemoembolization.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended for patients with intermediate hepatocellular carcinoma (HCC) according to treatment guidelines. However, a large number of patients with advanced HCC also receive TACE in clinical practice, especially for those with liver-confined HCC and Eastern Cooperative Oncology Group score (ECOG) 1. In view of previous studies, such patients have different prognoses from advanced HCC patients with macrovascular invasion or extrahepatic spread; therefore, patients with ECOG 1 alone might be classified into the intermediate stage and benefit from TACE treatment, but a study particularly focusing on such patients and exploring the effectiveness of TACE therapy is lacking. AIM: To investigate treatment outcomes of TACE in HCC patients with ECOG 1 alone and propose a specific prognostic model. METHODS: Patients from 24 Chinese tertiary hospitals were selected in this nationwide multicenter observational study from January 2010 to May 2016. Overall survival (OS) was estimated using Kaplan-Meier curves and compared by the log-rank test. Multivariate Cox regression was used to develop the potential prognostic models. The discriminatory ability of the models was compared and validated in various patient subgroups. The individual survival prediction for six-and-twelve (6&12) criteria, defined as the algebraic sum of tumor size (cm) and tumor number, was illustrated by contour plot of 3-year survival probability and nomogram. RESULTS: A total of 792 eligible patients were included. During follow-up, median OS reached 18.9 mo [95% confidence interval (CI): 16.9-21.0]. Three independent multivariate analyses demonstrated that tumor size, tumor number, α-fetoprotein level, albumin-bilirubin grade and total bilirubin were prognostic factors of OS (P < 0.05). The previously proposed 6&12 criteria was comparable or even better than currently proposed with the highest predictive ability. In addition, the 6&12 criteria was correlated with OS in various subgroups of patients. The patients were stratified into three strata with score ≤ 6, > 6 but ≤ 12, and > 12 with different median OS of 39.8 mo (95%CI: 23.9-55.7), 21.1 mo (95%CI: 18.4-23.8) and 9.8 mo (95%CI: 8.3-11.3), respectively (P < 0.001). CONCLUSION: TACE is effective for advanced HCC patients with ECOG 1 alone, and the 6&12 criteria may help with clinical decision-making.

Comparison between Child-Pugh Score and albumin-bilirubin grade in patients treated with the combination therapy of transarterial chemoembolization and sorafenib for hepatocellular carcinoma.

BACKGROUND: Albumin-Bilirubin (ALBI) grade has been proposed for the evaluation of liver function in hepatocellular carcinoma (HCC). The combination therapy of transarterial chemoembolization (TACE) and sorafenib is widely used for HCC patients with preserved liver function; our study aimed to investigate and compare the discriminating values of ALBI grade and Child-Pugh score in overall survival (OS). METHODS: A total of 173 HCC patients with preserved liver function (Child-Pugh A) were enrolled. The prognostic values of OS for ALBI grade and Child-Pugh score were separately investigated. RESULTS: In multivariate analyses, both ALBI grade and Child-Pugh score could significantly stratify the patients with different OS [adjusted hazard ratio (HR) 2.15 and 1.48, P<0.001 and P=0.035 for ALBI grade and Child-Pugh score]. In addition, time-dependent ROC analysis demonstrated that the ALBI grade had a better discriminatory ability than Child-Pugh score in predicting survival, especially for long-term outcomes. According to the subgroup analyses, the ALBI grade remained significant in more patient subsets and was more consistent than Child-Pugh score for the prediction of OS. CONCLUSIONS: ALBI grade was better than Child-Pugh score in stratifying prognosis for HCC patients with preserved liver function (Child-Pugh A) and treated by the combination therapy of TACE and sorafenib.

Validation and evaluation of clinical prediction systems for first and repeated transarterial chemoembolization in unresectable hepatocellular carcinoma: A Chinese multicenter retrospective study.

BACKGROUND: The treatment outcome of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) varies greatly due to the clinical heterogeneity of the patients. Therefore, several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE (re-TACE). AIM: To investigate the correlations between prognostic systems and radiological response, compare the predictive abilities, and integrate them in sequence for outcome prediction. METHODS: This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016. The Hepatoma Arterial-embolization Prognostic (HAP) score system and its modified versions (mHAP, mHAP2 and mHAP3), as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival (OS) prediction for first TACE. The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART (assessment for re-treatment with TACE) and ABCR (alpha-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh and Response) systems for post re-TACE survival (PRTS). RESULTS: All the prognostic systems were correlated with radiological response achieved by first TACE, and the six-and-twelve criteria exhibited the highest correlation (Spearman R = 0.39, P = 0.026) and consistency (Kappa = 0.14, P = 0.019), with optimal performance by area under the receiver operating characteristic curve of 0.71 [95% confidence interval (CI): 0.68-0.74]. With regard to the prediction of OS, the mHAP3 system identified patients with a favorable outcome with the highest concordance (C)-index of 0.60 (95%CI: 0.57-0.62) and the best area under the receiver operating characteristic curve at any time point during follow-up; whereas, PRTS was well-predicted by the ABCR system with a C-index of 0.61 (95%CI: 0.59-0.63), rather than ART. Finally, combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo, compared with non-candidates with a median PRTS of 20.0 mo (log-rank test P < 0.001). CONCLUSION: Radiological response to TACE is closely associated with tumor burden, but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.

Exogenous GM3 ganglioside inhibits atherosclerosis via multiple steps: A potential atheroprotective drug.

Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. A significant increase in ganglioside GM3 content generally happens in atherosclerotic plaques causing a GM3-enriched microenvironment. It remains unclear whether the GM3-enriched microenvironment influences atherogenesis. This study sought to answer the question by investigating exogenous GM3 effects on multiple steps involved in atherogenesis. First, the physicochemical properties of native low-density lipoprotein (LDL) and LDL enriched with exogenous GM3 (GM3-LDL) were characterized by dynamic laser scattering, atomic force microscopy, and agarose gel electrophoresis. Then, electrophoretic mobility, conjugated diene and malondialdehyde production, and amino group blockage of GM3-LDL/LDL were measured to determine LDL oxidation degrees and cellular recognition/internalization of GM3-LDL/GM3-oxLDL were detected via confocal microscopy and flow cytometry. Subsequently, influences of exogenous GM3 addition on the monocyte-adhering ability of endothelial cells and on lipid deposition in macrophages were investigated. Finally, exogenous GM3 effect on atherogenesis was evaluated using apoE-/- mice fed a high-fat diet. We found that exogenous GM3 addition increased the size, charge, and stability of LDL particles, reduced LDL susceptibility to oxidation and its cellular recognition/internalization, impaired the monocyte-adhering ability of endothelial cells and lipid deposition in macrophages. Moreover, exogenous GM3 treatment also significantly decreased blood lipid levels and atherosclerotic lesion areas in atherosclerotic mice. The data imply that exogenous GM3 had an inhibitory effect on atherogenesis, suggesting a protective role of a GM3-enriched microenvironment in atherosclerotic plaques and implying a possibility of exogenous GM3 as an anti-atherosclerotic drug.

Angioplasty with versus without routine stent placement for Budd-Chiari syndrome: a randomised controlled trial.

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<0·0001). In the survival analysis, 3-year restenosis-free survival was 96·0% (95% CI 88·6-100·0) in the routine stenting group versus 60·4% (46·4-78·7) in the angioplasty-only group (log-rank p<0·0001). The hazard ratio for restenosis was 0·04 (95% CI 0·01-0·31) in favour of routine stenting, with an absolute risk reduction of 35·6% (95% CI 24·2-55·0). Two (5%) patients in the angioplasty plus routine stenting group and one (2%) patient in the angioplasty-only group died during follow-up. One (2%) patient from the angioplasty plus routine stenting group had puncture site haematoma, which was not related to stenting. No stent fracture or migration occurred. Anticoagulation-related adverse events occurred in five (11%) patients from angioplasty alone group and five (12%) patients from angioplasty plus routine stenting group. 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.

Development of a prognostic score for recommended TACE candidates with hepatocellular carcinoma: A multicentre observational study.

BACKGROUND & AIMS: Previous prognostic scores for transarterial chemoembolization (TACE) were mainly derived from real-world settings, which are beyond guideline recommendations. A robust model for outcome prediction and risk stratification of recommended TACE candidates is lacking. We aimed to develop an easy-to-use tool specifically for these patients. METHODS: Between January 2010 and May 2016, 1,604 treatment-naïve patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh A5-B7 and performance status 0 undergoing TACE were included from 24 tertiary centres. Patients were randomly divided into training (n = 807) and validation (n = 797) cohorts. A prognostic model was developed and subsequently validated. Predictive performance and discrimination were further evaluated and compared with other prognostic models. RESULTS: The final presentation of the model was "linear predictor = largest tumour diameter (cm) + tumour number", which consistently outperformed other currently available models in both training and validation datasets as well as in different subgroups. The thirtieth percentile and the third quartile of the linear predictor, namely 6 and 12, were further selected as cut-off values, leading to the "six-and-twelve" score which could divide patients into 3 strata with the sum of tumour size and number ≤6, >6 but ≤12, and >12 presenting significantly different median survival of 49.1 (95% CI 43.7-59.4) months, 32.0 (95% CI 29.9-37.5) months, and 15.8 (95% CI 14.1-17.7) months, respectively. CONCLUSIONS: The six-and-twelve score may prove an easy-to-use tool to stratify recommended TACE candidates (Barcelona Clinic Liver Cancer stage-A/B) and predict individual survival with favourable performance and discrimination. Moreover, the score could stratify these patients in clinical practice as well as help design clinical trials with comparable criteria involving these patients. Further external validation of the score is required. LAY SUMMARY: There is currently no prognostic model specifically developed for recommended or ideal transarterial chemoembolization (TACE) candidates with hepatocellular carcinoma, despite these patients being frequently identified as the best target population in pivotal randomized controlled trials. The six-and-twelve score provides patient survival prediction, especially in ideal candidates of TACE, outperforming other currently available models in both training and validation sets, as well as different subgroups. With cut-off values of 6 and 12, the score can stratify ideal TACE candidates into 3 strata with significantly different outcomes and may shed light on risk stratification of these patients in clinical practice as well as in clinical trials.

Hand-foot-skin reaction of grade ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC.

Background & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time-dependent receiver operating characteristic curves, the development of a hand-foot-skin reaction ≥ grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43-0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58-0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib-related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half.

Nanowire arrays restore vision in blind mice.

The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, we develop artificial photoreceptors based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 µm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. Our study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices.

In situ AFM imaging of apolipoprotein A-I directly derived from plasma HDL.

BACKGROUND AND AIMS: The major apolipoproteins of plasma lipoproteins play vital roles in the structural integrity and physiological functions of lipoproteins. More than ten structural models of apolipoprotein A-I (apoA-I), the major apolipoprotein of high-density lipoprotein (HDL), have been developed successively. In these models, apoA-I was supposed to organize in a ring-shaped form. To date, however, there is no direct evidence under physiological condition. METHODS: Here, atomic force microscopy (AFM) was used to in situ visualize the organization of apoA-I, which was exposed via depletion of the lipid component of plasma HDL pre-immobilized on functionalized mica sheets. RESULTS: For the first time, the ring-shaped coarse structure and three detailed structures (crescent-shaped, gapped "O"-shaped, and parentheses-shaped structures, respectively) of apoA-I in plasma HDL, which have the ability of binding scavenger receptors, were directly observed and quantitatively measured by AFM. The three detailed structures probably represent the different extents to which the lipid component of HDL was depleted. Data on lipid depletion of HDL may provide clues to understand lipid insertion of HDL. CONCLUSIONS: These data provide important information for the understanding of the structure/maturation of plasma HDL. Moreover, they suggest a powerful method for directly visualizing the major apolipoproteins of plasma lipoproteins or the protein component of lipoprotein-like lipid-protein complexes.