EncephalApp stroop test versus electronic number connection test-A for screening minimal hepatic encephalopathy in patients with liver cirrhosis: a comparative study.

OBJECTIVES: Minimal hepatic encephalopathy (MHE) is a common neuropsychiatric complication of liver cirrhosis. Both EncephalApp Stroop test (EncephalApp) and electronic number connection test-A (eNCT-A) are novel computerised psychometric tests for MHE screening. We aimed to compare the efficiency, convenience, accessibility, and acceptability of EncephalApp with that of eNCT-A for MHE screening in cirrhotic patients. METHODS: Ninety-five patients with hepatitis B-induced liver cirrhosis were included and respectively tested by the psychometric hepatic encephalopathy score (PHES), EncephalApp, and eNCT-A. Using PHES as the gold standard for MHE diagnosis, the efficiency of EncephalApp and eNCT-A for MHE screening were respectively analysed by the receiver operating characteristic (ROC) curve, and the areas under the ROC curve (AUROC) were compared. The convenience, accessibility, and acceptability of PHES, EncephalApp and eNCT-A were respectively evaluated by the 5-point Likert scale. RESULTS: Fifty-two (55%) of included cirrhotic patients were diagnosed with MHE. The EncephalApp had a sensitivity of 84.6%, a specificity of 74.4%, and an AUROC of 0.836. Meanwhile, the eNCT-A had a sensitivity of 78.8%, a specificity of 83.7%, and an AUROC of 0.845. No significant difference in AUROC was detected between the EncephalApp and eNCT-A (p = .453). Compared with the EncephalApp, the eNCT-A presented better convenience and higher acceptability in cirrhotic patients undergoing MHE screening (p = .019 and p < .001, respectively). CONCLUSIONS: As with the EncephalApp, the eNCT-A will be a potential home monitoring and point-of-care tool for cirrhotic patients at high risk of MHE.

Clinical efficiency of inhibitory control test for the diagnosis of minimal hepatic encephalopathy: A systematic review with meta-analysis.

AIM: Minimal hepatic encephalopathy (MHE) is a common neuropsychiatric complication of liver cirrhosis and portosystemic shunt. The inhibitory control test (ICT) is a novel computerized psychometric test for MHE diagnosis, but its efficiency has yet to be confirmed. This study aimed to systematically review the existing evidence concerning the ICT application and then evaluate the efficiency of ICT for MHE diagnosis in clinical practice. METHODS: A comprehensive search of published works was carried out to identify reports concerning the ICT for MHE diagnosis between January 2000 and December 2020. The pooled sensitivity, specificity, and diagnostic odds ratio of ICT for MHE diagnosis were calculated using a random or fixed effect model. The summary receiver operator characteristic (sROC) curve was constructed, and the area under the sROC curve was calculated. Metaregression and subgroup analyses were used to identify the source of heterogeneity. Publication bias was evaluated using the Deeks funnel plot asymmetry test. RESULTS: Twelve studies were included in this systematic review, and nine studies enrolling 1022 patients were included in the final meta-analysis. The ICT had a pooled sensitivity, specificity, and DOR of 83%, 64%, and 9, respectively. The area under the sROC curve was 0.79. The metaregression analysis indicated that different locations of studies (relative diagnostic odds ratio, 12.65; p = 0.02) were identified as the source of heterogeneity. No significant publication bias was observed. CONCLUSIONS: The ICT has a high sensitivity and moderate specificity for MHE diagnosis, and it can be used as a primary diagnostic method for MHE.

Purification of a Pd20-TNFα fusion protein that prevents liver metastasis of gastric cancer.

The specific binding peptide pd20 of gastric cancer cells with a high potential for liver metastasis was fused with human tumour necrosis factor (TNF) α, and a prokaryotic expression vector was established to express the pd20-TNFα fusion protein. After purification and identification, the preventive effects of the fusion protein on liver metastasis of gastric cancer were observed in mice. The whole gene synthesis method was used for pd20-TNFα fusion gene preparation, and a pd20-TNFα prokaryotic expression vector was constructed. The vector was induced and expressed in Escherichia coli BL21. The expression products were analysed and verified by SDS-PAGE electrophoresis and Western blot analysis. The Ni-NTA column method was used to purify the fusion protein, and the L929 cytotoxicity method was used to detect biological activity. Flow cytometry apoptosis experiments and invasion assays were performed to observe the effects of the fusion protein on apoptosis and metastasis of gastric cancer cells with high potential for liver metastasis. Thirty nude mice with liver metastasis of gastric cancer were established and then randomly divided into three groups of ten mice each. The Pd20-TNFα recombinant protein (1.2 × 10(6) U/kg day) or standard TNFα (1.2 × 10(6) U/kg day) saline was administered via tail vein injection for 7 consecutive days. The pathological changes in various organs of nude mice were observed 4 weeks later. The size of the gastric cancer, the incidence of liver metastasis and the number of liver metastases were measured and calculated. We successfully constructed a Pd20-TNFα recombinant plasmid and prepared the fusion protein. Detection of the pd20-TNFα protein by immunofluorescence showed a very strong expression in liver tissue, suggesting a targeting of the fusion protein to the liver. The L929 cytotoxicity assays showed that the pd20-TNFα fusion purified protein had a significant lethal effect on L929 cells, with a killing activity of up to 7.6 × 10(6) IU/ml. The apoptosis experiments showed that as the concentration of the fusion protein increased, the early gastric cancer cell apoptosis also increased, with the early apoptosis rate increasing from 5.99 % to 9.04 %. Cell invasion experiments showed that the purified pd20-TNFα fusion protein significantly inhibited the in vitro invasion of XGC9811-L cells, with the penetrating cells being significantly decreased compared with the control group per unit time (P < 0.01). Vector experiments showed that the pd20-TNFα recombinant protein group had significantly reduced cancer lesions and liver metastasis in nude mice compared with the control group. We successfully purified a pd20-TNFα fusion protein and confirmed that it had significant biological activity promoting early gastric cancer cell apoptosis, thereby inhibiting gastric cancer cell invasion.

Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis.

Minimal hepatic encephalopathy (MHE) is a frequent neurological and psychiatric complication of liver cirrhosis. The precise pathogenesis of MHE is complicated and has yet to be fully elucidated. Studies in cirrhotic patients and experimental animals with MHE have indicated that gut microbiota dysbiosis induces systemic inflammation, hyperammonemia, and endotoxemia, subsequently leading to neuroinflammation in the brain via the gut-liver-brain axis. Related mechanisms initiated by gut microbiota dysbiosis have significant roles in MHE pathogenesis. The currently available therapeutic strategies for MHE in clinical practice, including lactulose, rifaximin, probiotics, synbiotics, and fecal microbiota transplantation, exert their effects mainly by modulating gut microbiota dysbiosis. Microbiome therapies for MHE have shown promised efficacy and safety; however, several controversies and challenges regarding their clinical use deserve to be intensively discussed. We have summarized the latest research findings concerning the roles of gut microbiota dysbiosis in the pathogenesis of MHE via the gut-liver-brain axis as well as the potential mechanisms by which microbiome therapies regulate gut microbiota dysbiosis in MHE patients.

Krüppel-Like Factor 2 Is a Gastric Cancer Suppressor and Prognostic Biomarker.

Gastric cancer (GC) is a common digestive tract tumor. Due to its complex pathogenesis, current diagnostic and therapeutic effects remain unsatisfactory. Studies have shown that KLF2, as a tumor suppressor, is downregulated in many human cancers, but its relationship and role with GC remain unclear. In the present study, KLF2 mRNA levels were significantly lower in GC compared to adjacent normal tissues, as analyzed by bioinformatics and RT-qPCR, and correlated with gene mutations. Tissue microarrays combined with immunohistochemical techniques showed downregulation of KLF2 protein expression in GC tissue, which was negatively correlated with patient age, T stage, and overall survival. Further functional experiments showed that knockdown of KLF2 significantly promoted the growth, proliferation, migration, and invasion of HGC-27 and AGS GC cells. In conclusion, low KLF2 expression in GC is associated with poor patient prognosis and contributes to the malignant biological behavior of GC cells. Therefore, KLF2 may serve as a prognostic biomarker and therapeutic target in GC.

Endoscopic Ruler for varix size measurement: A multicenter pilot study.

BACKGROUND: We invented Endoscopic Ruler, a new endoscopic device to measure the size of varices in patients with cirrhosis and portal hypertension. AIM: To assess the feasibility and safety of Endoscopic Ruler, and evaluate the agreement on identifying large oesophageal varices (OV) between Endoscopic Ruler and the endoscopists, as well as the interobserver agreement on diagnosing large OV using Endoscopic Ruler. METHODS: We prospectively and consecutively enrolled patients with cirrhosis from 11 hospitals, all of whom got esophagogastroduodenoscopy (EGD) with Endoscopic Ruler. The primary study outcome was a successful measurement of the size of varices using Endoscopic Ruler. The secondary outcomes included adverse events, operation time, the agreement of identifying large OV between the objective measurement of Endoscopic Ruler and the empirical reading of endoscopists, together with the interobserver agreement on diagnosing large OV by Endoscopic Ruler. RESULTS: From November 2020 to April 2022, a total of 120 eligible patients with cirrhosis were recruited and all of them underwent EGD examinations with Endoscopic Ruler successfully without any adverse event. The median operation time of Endoscopic Ruler was 3.00 min [interquartile range (IQR): 3.00 min]. The kappa value between Endoscopic Ruler and the endoscopists while detecting large OV was 0.52, demonstrating a moderate agreement. The kappa value for diagnosing large OV using Endoscopic Ruler among the six independent observers was 0.77, demonstrating a substantial agreement. CONCLUSION: The data demonstrates that Endoscopic Ruler is feasible and safe for measuring the size of varices in patients with cirrhosis and portal hypertension. Endoscopic Ruler is potential to promote the clinical practice of the two-grade classification system of OV.

Altered gut microbiota is associated with sleep disturbances in patients with minimal hepatic encephalopathy caused by hepatitis B-related liver cirrhosis.

BACKGROUND: Sleep disturbances are prevalent in patients with minimal hepatic encephalopathy (MHE). This study aimed to evaluate the association between sleep disturbances and altered gut microbiota in patients with MHE caused by hepatitis B-related liver cirrhosis. RESEARCH DESIGN AND METHODS: Ninety-eight and 45 patients with MHE were included in exploration and validation cohorts, respectively. Sleep disturbances were assessed using the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Microbiota in fecal samples were analyzed via amplicon sequencing of bacterial 16S ribosomal RNA genes. RESULTS: The gut microbiomes of MHE patients with sleep disturbances were characterized by lower bacterial diversity and distinct bacterial composition. Relative abundances of Streptococcus salivarius and Veillonella were independent predictors of sleep disturbances in MHE patients and well-distinguished MHE patients with and without sleep disturbances in both the exploration and validation cohorts. Moreover, the relative abundances of S. salivarius were positively correlated with plasma ammonia levels, and functional modules associated with protein digestion and absorption and lipopolysaccharide biosynthesis were enriched in the microbiomes of MHE patients with sleep disturbances. CONCLUSIONS: Both S. salivarius and Veillonella were associated with sleep disturbances in patients with MHE caused by hepatitis B-related liver cirrhosis.

EncephalApp Stroop App predicts poor sleep quality in patients with minimal hepatic encephalopathy due to hepatitis B-induced liver cirrhosis.

BACKGROUND/AIM: A novel computerised Stroop test- EncephalApp Stroop App (EncephalApp) has good diagnostic validity for minimal hepatic encephalopathy (MHE) in cirrhotic patients. The Stroop test is correlated with sleep disturbances which are common, and severely affects health-related quality of life in cirrhotic patients with MHE. We evaluated the relationship between sleep quality and EncephalApp results in patients with MHE due to hepatitis B-induced liver cirrhosis. PATIENTS AND METHODS: We enrolled 180 adult patients with hepatitis B-induced cirrhosis. All patients were tested using the psychometric hepatic encephalopathy score (PHES) and EncephalApp. We analysed the diagnostic validity of EncephalApp for MHE using PHES as the gold standard for reference. The sleep quality of included patients was evaluated using the Pittsburgh Sleep Quality Index (PSQI). The predictive factors for poor sleep quality were analysed using backwards conditional stepwise logistic regression analysis. RESULTS: Ninety-eight patients (54.4%) were diagnosed with MHE by PHES. Receiver operating characteristic (ROC) curve analysis showed that the threshold value of EncephalApp for MHE diagnosis was 225.60 s. EncephalApp showed 85.2% sensitivity and 77.3% specificity for diagnosing MHE; the area under the ROC curve was 0.864. PSQI scores of cirrhotic patients with MHE were significantly lower than those without MHE (P < 0.05). Child Turcotte Pugh grades (Odds ratio [OR] = 2.11 [1.55-2.85], P < 0.01) and the total Off-time plus On-time of EncephalApp (OR = 4.14 [1.95-6.29], P < 0.01) were independent predictors of poor sleep quality in MHE patients. CONCLUSIONS: The total Off-time plus On-time of EncephalApp predicts poor sleep quality in patients with MHE due to hepatitis B-induced cirrhosis.

Potential targeted therapies for the inflammatory pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of acute and chronic liver dysfunction, and is characterized by a spectrum that ranges from mild neuropsychological disturbances to coma. Although ammonia plays a critical role in the pathogenesis of HE, the plasma concentrations of ammonia and manifest symptoms of HE are not always consistent in patients with HE. Recently, a substantial body of evidence has indicated that inflammation acts in concert with ammonia in the pathogenesis of HE. Meanwhile, emerging novel and potential therapeutic strategies, including N-acetylcysteine, hypothermia, minocycline, non-steroidal anti-inflammatory drugs, tumour necrosis factor-alpha antagonists and p38 inhibitors, have been reported to ameliorate systemic inflammation and neuroinflammation, improve or reverse neuropsychiatric manifestations, and prevent the onset and progression of HE in patients and/or animal models of acute or chronic liver failure. These results point to the possible therapeutic utility of decreasing inflammation in the treatment of HE, and translation of these experimental results to the clinic may provide novel and promising therapeutic approaches for patients with HE secondary to acute or chronic liver failure. This review will provide an overview of these potential targeted therapies in the prophylaxis and treatment of HE.