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Background There is growing recognition of natural history, complications, and outcomes of patients who develop non-acetaminophen (APAP) drug-induced acute liver failure (ALF). To clarify high-risk factors and develop a nomogram model to predict transplant-free survival (TFS) in patients with non-APAP drug-induced ALF. Methods Patients with non-APAP drug-induced ALF from 5 participating centers were retrospectively analyzed. The primary endpoint was 21-day TFS. Total sample size was 482 patients. Results Regarding causative agents, the most common implicated drugs were herbal and dietary supplements (HDS) (57.0%). The hepatocellular type (R ≥ 5) was the main liver injury pattern (69.0%). International normalized ratio, hepatic encephalopathy grades, the use of vasopressor, N-acetylcysteine, or artificial liver support system were associated with TFS and incorporated to construct a nomogram model (drug-induced acute liver failure-5, DIALF-5). The AUROC of DIALF-5 for 7-day, 21-day, 60-day, and 90-day TFS in the internal cohort were 0.886, 0.915, 0.920, and 0.912, respectively. Moreover, the AUROC of DIALF-5 for 21-day TFS had the highest AUROC, which was significantly higher than 0.725 of MELD and 0.519 of KCC (p p > 0.05). These results were successfully validated in the external cohort (147 patients). Conclusions Based on easily identifiable clinical data, the novel DIALF-5 model was developed to predict transplant-free survival in non-APAP drug-induced ALF, which was superior to KCC, MELD and had a similar prediction performance to ALFSG-PI but is more convenient, which can directly calculate TFS at multiple time points.

In recent years, cancer immunotherapy has made remarkable achievements. Immune checkpoint inhibitors (ICIs) have been used successfully in several types of cancer in the past decade. However, expanded indication and increased use of Immune checkpoint inhibitors have resulted in increased reports of toxicity called immune-related adverse events (irAEs). Due to the unique immunological characteristics of the liver, a hepatic immune-related adverse events has also been reported, which is usually termed Immune-mediated hepatitis (IMH). So far, it is generally considered that the mechanism of IMH induced by Immune checkpoint inhibitors is mainly the overactivation of T cells. It has been reported that the incidence of IMH ranges from 1% to 15%. Because of the lack of specific markers, a diagnosis of exclusion of IMH is critical. Although most IMH is mild and recoverable, several death cases have been reported, which has been increasingly concerned. This review summarizes the current understanding of the pathophysiology, epidemiology, diagnosis, management and prognosis of IMH caused by Immune checkpoint inhibitors. It also discusses the controversial issues in IMH, such as the role of liver biopsy, grading criteria, risk factors, rational treatment strategies with steroids, and the timing of Immune checkpoint inhibitors rechallenging, which may provide helpful information for IMH in future clinical practice.

When considering the friction and bonding force between the back of the retaining wall and the horizontal fill behind the wall, the principal stress of the soil element near the vertical back of the retaining wall is no longer vertical and horizontal but deflects to a certain extent. When the surface of the backfill becomes inclined, the principal stress of the soil behind the wall deflects in a more complicated way. In this paper, the cohesion of the soil element in the fill with an inclined surface is assumed, and the formulas for calculating the active and passive earth pressures of the retaining wall with inclined cohesive backfill are derived by rotating the principal stress of the soil element behind the wall. The proposed method is compared with the existing algorithm, and the influences of the inclination and the cohesion of the fill are analyzed. The results show that the proposed method is more universal. Both the active and passive earth pressures increase rapidly with the increase of the inclination of the fill. The active earth pressure and its horizontal component decrease with the increase of the cohesion of the fill, while the passive earth pressure and its horizontal component increase with the increase of the cohesion of the fill.

Aims Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis. Methods We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase. Results Among 62 patients with aspartate aminotransferase (AST) ≤ 50 U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST > 50 U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells. Conclusion Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed.

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease. ALDH2 gene mutations exist in about 8% of the world’s population, with the incidence reaching 45% in East Asia. The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde, facilitating the progression of other liver diseases, including non-alcoholic fatty liver diseases, viral hepatitis and hepatocellular carcinoma, through adduct formation and inflammatory responses. In this review, we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases, with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.

Aims: To develop, optimize, and validate a novel model using alanine aminotransferase (ALT) and total bilirubin (TB) dynamic evolution patterns in predicting acute liver failure (ALF) in drug-induced liver injury (DILI) patients.Methods: The demographics, clinical data, liver biopsy, and outcomes of DILI patients were collected from two hospitals. According to the dynamic evolution of ALT and TB after DILI onset, the enrolled patients were divided into ALT-mono-peak, TB-mono-peak, double-overlap-peak, and double-separate-peak (DSP) patterns and compared. Logistic regression was used to develop this predictive model in both discovery and validation cohorts.Results: The proportion of ALF was significantly higher in patients with the DSP pattern than in the ALT-mono-peak pattern and DOP pattern (10.0 vs. 0.0% vs. 1.8%,p < 0.05). The area under receiver operating characteristic curve (AUROC) of the DSP pattern model was 0.720 (95% CI: 0.682–0.756) in the discovery cohort and 0.828 (95% CI: 0.788–0.864) in the validation cohort in predicting ALF, being further improved by combining with international normalized ratio (INR) and alkaline phosphatase (ALP) (AUROC in the discovery cohort: 0.899; validation cohort: 0.958). Histopathologically, patients with the DSP pattern exhibited a predominantly cholestatic hepatitis pattern (75.0%, p < 0.05) with a higher degree of necrosis (29.2%, p = 0.084).Conclusion: DILI patients with the DSP pattern are more likely to progress to ALF. The predictive potency of the model for ALF can be improved by incorporating INR and ALP. This novel model allows for better identification of high-risk DILI patients, enabling timely measures to be instituted for better outcome.

Several models have been proposed to predict acute liver failure/death in patients with drug-induced liver injury (DILI), but the predictive performances of them have not been systematically compared. We aim to compare the current models for their predictive potency of mortality at DILI onset.DILI patients hospitalized at both Beijing Friendship Hospital and the Fifth Medical Center of PLA General Hospital were categorized into death/liver transplantation (LT) or survival without LT group. Predictive potency of 28-day, 90-day, 6-month and 12-month death/LT outcomes of Hy's Law, nHy's Law, Robles-Diaz Model, drug-induced liver toxicity (DrILTox ALF) Score, Model for End-stage Liver Disease (MELD) Score, and Ghabril Model was compared by Delong method.A total of 6.3% (83/1314) patients died or received LT within 12 months after DILI onset. The area under receiver operating characteristic of Hy's Law, nHy's Law, and Robles-Diaz Model was all lower than 0.750 for the prediction of within 12 months' mortality. DrILTox ALF Score, MELD Score and Ghabril Model showed better predictive potency of 28-day [0.896 (0.878-0.912), 0.934 (0.919-0.947), 0.935 (0.921-0.948), respectively], 90-day [0.883 (0.864-0.899), 0.951 (0.938-0.962), 0.952 (0.939-0.963), respectively], 6-month [0.820 (0.799-0.841), 0.905 (0.888-0.921) and 0.908 (0.891-0.923), respectively] and 12-month [0.801 (0.779-0.823), 0.882 (0.863-0.899) and 0.885 (0.866-0.902), respectively] mortality.Despite the difference of clinical characteristics and implicated-drug categories between China and industrialized countries, we demonstrate that MELD Score and Ghabril Model have the best predictive performance in the prediction of mortality within 12 months after DILI onset.

Background and aims The development of esophagogastric varices (EGV) is one of the most common complications in patients with Primary biliary cholangitis (PBC); yet, factors associated with their development have been poorly characterized. In this cohort, we aimed to investigate the clinical factors associated with EGV in patients with PBC. Methods: The cohort study included patients with PBC who received esophagogastroduodenoscopy screening and ursodeoxycholic acid (UDCA) therapy at baseline. Liver-related death and liver transplantation were assessed as the endpoint, liver transplantation-free survival rates were estimated by using Kaplan–Meier methods, and Cox regression analysis was performed to identify the potential risk factors of endpoint events for PBC with EGV. Results The 690 patients included in this study had a mean age of 57 years old and 553 (80.1%) were females, 13 (7.9%) in the 165 PBC with no liver cirrhosis and 400 (76.2%) in the 525 PBC with liver cirrhosis had signs of EGV, and 215 (31.2%) patients of the cohort had bleeding esophagogastric varices as the first presentation at diagnosis. The median (Interquartile range) follow-up period was 4.0 (2.0, 6.0) years. During the follow-up duration, 99 patients progressed to liver-related deaths, and 23 patients underwent liver transplantation. The 5-year cumulative LT-free survival was 88.20% (95% CI 83.7-92.7) in PBC without EGV, and 80.90% (95% CI 80.0-89.9), 80.30% (95% CI 69.7-90.9), 75.70% (95% CI 68.3-83.1) among PBC with small, medium and large-sized esophageal varices at baseline, respectively (p =0.002). The 10-year cumulative LT-free survival was 68.8% (95% CI 53.9-82.8) in PBC without EGV, and 54.2% (95% CI 36.4-72.0), 51.6% (95% CI 29.9-73.3), 62.1% (95% CI 49.2-75.0) among PBC patients with small, medium and large-sized esophageal varices at baseline, respectively (p=0.001). History of endoscopic therapy and UDCA biochemical responder with Paris criteria for PBC with EGV were associated with a statistically significant reduced risk of LT or death (p =0.001 and p=0.007).Conclusions Endoscopic therapy and a favorable biochemical profile of UDCA can prolong the LT-free survival of PBC patients with EGV, despite the presence of large-sized esophageal varices.

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To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI.Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase1.5× upper limit of normal or alkaline phosphatase1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort.Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.

Alcoholic liver disease (ALD) is a progressive liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Granulocytic myeloid‐derived suppressor cell (gMDSC) populations have been observed to expand in various liver diseases and to inhibit innate and adaptive immunity in patients with liver disease. However, the characteristics of gMDSCs in patients with ALD have not been studied. We studied 24 healthy controls (HCs) and 107 patients with ALD and found an accumulation of gMDSCs in the peripheral blood of patients with alcoholic liver cirrhosis (ALC). Furthermore, ALC patients with a poor prognosis displayed a significant increase in peripheral gMDSCs and showed an increased capacity for arginase I production compared to HCs. In contrast, plasma arginase I levels in ALC patients were negatively correlated with total bilirubin and international normalized ratio, two key parameters of liver damage. Importantly, gMDSCs accumulated in the livers of ALC patients, and the frequency of liver gMDSCs significantly correlated with that of peripheral gMDSCs. In addition, gMDSC enrichment in vitro significantly inhibited the function of natural killer (NK) cells, perhaps preventing the NK‐induced apoptosis of hepatic stellate cells. In summary, increased peripheral and intrahepatic gMDSC populations are present in patients with ALC and may contribute to enhancing the severity of liver cirrhosis.

We aimed to develop a prediction model based on the PIRO concept (Predisposition, Injury, Response and Organ failure) for patients with Hepatitis B Virus (HBV) related acute-on-chronic liver failure (ACLF). 774 patients with HBV related ACLF defined in the CANONIC study were analyzed according to PIRO components. Variables associated with mortality were selected into the prediction model. Based on the regression coefficients, a score for each PIRO component was developed, and a classification and regression tree was used to stratify patients into different nodes. The prediction model was then validated using an independent cohort (n = 155). Factors significantly associated with 90-day mortality were: P: age, gender and ACLF type; I: drug, infection, surgery, and variceal bleeding; R: systemic inflammatory response syndrome (SIRS), spontaneous bacteria peritonitis (SBP), and pneumonia; and O: the CLIF consortium organ failure score (CLIF-C OFs). The areas under the receiver operating characteristics curve (95% confidence interval) for the combined PIRO model for 90-day mortality were 0.77 (0.73–0.80). Based on the scores for each of the PIRO components and the cut-offs estimated from the classification and regression tree, patients were stratified into different nodes with different estimated death probability. Based on the PIRO concept, a new prediction model was developed for patients with HBV related ACLF, allowing stratification into different clusters using the different scores obtained in each PIRO component. The proposed model will likely help to stratify patients at different risk, defining individual management plans, assessing criteria for specific therapies, and predicting outcomes.

Alcoholic liver disease (ALD) is a complication that is a burden on global health and economy. Interleukin‐33 (IL‐33) is a newly identified member of the IL‐1 cytokine family and is released as an “alarmin” during inflammation. Soluble suppression of tumourigenicity 2 (sST2), an IL‐33 decoy receptor, has been reported as a new biomarker for the severity of systemic and highly inflammatory diseases. Here, we found the levels of plasma sST2, increased with the disease severity from mild to severe ALD. Importantly, the plasma sST2 levels in ALD patients not only correlated with scores for prognostic models (Maddrey's discriminant function, model for end‐stage liver disease and Child‐Pugh scores) and indexes for liver function (total bilirubin, international normalized ratio, albumin, and cholinesterase) but also correlated with neutrophil‐associated factors as well as some proinflammatory cytokines. In vitro, lipopolysaccharide‐activated monocytes down‐regulated transmembrane ST2 receptor but up‐regulated sST2 mRNA and protein expression and produced higher levels of tumour necrosis factor‐α (TNF‐α). By contrast, monocytes pretreated with recombinant sST2 showed decreased TNF‐α production. In addition, although plasma IL‐33 levels were comparable between healthy controls and ALD patients, we found the IL‐33 expression in liver tissues from ALD patients was down‐regulated at both RNA and protein levels. Immunohistochemical staining further showed that the decreased of IL‐33‐positive cells were mainly located in liver lobule area. These results suggested that sST2, but not IL‐33, is closely related to the severity of ALD. Consequently, sST2 could be used as a potential biomarker for predicting the prognosis of ALD.

To establish the movement relationship for the roof breaking under shallow mining conditions, the mechanical model of the roof rock beam was built, then the structure instability process of the roof rock beam was analyzed. The changing criterion of the vertical displacement was established and the relationship between the deflection and the rotary motion of roof block was determined. Regarding a mining face in Shangwan Mine, the responsing laws of the deflection and horizontal thrust of the roof rock beam were obtained through FLAC3D numerical analysis. The results show that the structure instability of the cracked roof rock beam depends on the interaction between the vertical load and the horizontal thrust. For the roof rock beam, when the vertical load keeps constant, the horizontal thrust fluctuating rises with increasing deflection. The horizontal thrust increases constantly with the deeper buried depth and the smaller span. Keywords: Shallow mining, Working face, Roof rock beam, Structure stability, Horizontal thrust

It is important to evaluate the deformation and failure of sandstone in the foundation engineering of coast, river bank and lake shore. While the deformation and failure of sandstone is a comprehensive result of energy release and dissipation, and energy release is the internal reason which leads to global failure of the sandstone. The experimental analysis is conducted on the character of energy revolution of the sandstone specimen by rating loading and unloading, and the catastrophe model is followed in analyzing elastic strain energy accumulation and release in rock deformation and failure. The index based on elastic energy release is proposed to assess the rock brittleness. It is found that increasing water content is to relieve energy release and catastrophe failure of the rock specimen, and weakening the capacity of elastic energy storage. The peak and residual values of elastic energy are raised as the confining pressure increases, and the post-peak released energy decreases progressively. The confining pressure strengthens energy storage and inhibits energy release of the rock specimen, and saturation of rock will weaken this inhibit effect. The brittleness index decreases with increasing confining pressure as the rock specimen transforming from brittle to ductile.

Para analizar los resultados de un anclaje completamente embutido en rocas unidas se efectuaron ensayos de doble cizallado y se llevo a cabo la deduccion analitica de la relacion entre la fuerza axial, la fuerza de cizallado y el desplazamiento de cizallado del anclaje completamente embutido usando el modelo mecanico simplificado. Finalmente se analizaron las sensitividades de los parametros influyentes del anclaje. Los resultados muestran que la fuerza de cizallado predomina en el ensayo de cizallado que la fuerza de cizallado es mucho mayor que la fuerza axial. La fuerza de cizallado del anclaje completamente embutido aumenta cuando el incremento del desplazamiento del cizallado aumenta y la curva que relaciona la fuerza de cizallado y el desplazamiento de cizallado puede ser simplificada a cinco pasos: fuerte aumento, ligera disminucion, suave aumento, suave disminucion y muy fuerte disminucion. Del mismo modo, las curvas de fuerza axial y de desplazamiento por cizallado pueden ser simplificadas a tres pasos: aumento estable, mantenimiento y fuerte disminucion. Los resultados de la simulacion muestran que el limite de tension de la resistencia a cizalla del anclaje es el factor mas significativo, la resistencia de las rocas unidas es el segundo y los parametros de la superficie unida tienen el ultimo efecto. Las conclusiones obtenidas en el estudio son de un valor teorico importante para la practica de ingenieria similar. Palabras clave: Ensayo de doble cizallado, Anclaje completamente embutido, Fuerza axial, Fuerza de cizallado, Simulacion numerica.

Background and Aims: Liver fibrosis is stage-dependently associated with non-alcoholic fatty liver disease (NAFLD) progression. The increased awareness of non-invasive diagnosis has led to the establishment of many fibrosis diagnosis models with various accuracies. We aimed to evaluate the diagnostic performance of nine clinical non-invasive fibrosis models in NAFLD and provide an optimal diagnostic method for advanced fibrosis by step layered combination of non-invasive models. Methods: 453 consecutive patients with biopsy-proven NAFLD were enrolled from three centers and were divided into study cohort and validation cohort randomly. Aspartate aminotransferase-to-platelet ratio index (APRI), BARD, FiB-4, FibroMeter NAFLD, Forns’ Index, Hui model, non-invasive Koeln-Essen- index (NIKEI), S Index and NAFLD fibrosis score (NFS) were calculated. The high area under the receiver operating characteristic curve (AUROC) models were stepwise combined for further diagnosing NAFLD advanced fibrosis. Results: All models had good performance with high negative predictive value (NPV) and specificity for diagnosing fibrosis, while positive predictive value (PPV) and sensitivity were low. APRI, BARD, FibroMeter NAFLD and NIKEI had higher AUROCs and their step layered combination for diagnosing advanced fibrosis showed high specificity, sensitivity, NPV and PPV up to 89.13%, 72.50%, 74.36%, and 88.17%, which also performed well in the validation cohort. Conclusions: APRI, BARD, FibroMeter NAFLD and NIKEI had better diagnostic accuracy, and could be preferred for diagnosing NAFLD fibrosis. The step layered combination of these models performed much better than each single scoring system for diagnosing advanced fibrosis, provides valuable reference for clinical practice and might be a potential substitution of liver biopsy.

Drug-induced liver injury (DILI), defined as liver injury caused by a drug and/or its metabolites, is a common clinical adverse drug reaction1, 2, 3, 4. This type of injury can cause acute liver failure and even death in severe cases5. DILI accounts for many drug warnings and is an important cause of failure in the clinical development of new drugs and new forms of traditional Chinese medicine (TCM). Thus, liver injury from drugs has attracted close attention from medical professionals, the pharmaceutical industry, and the general public6, 7, 8. For thousands of years, TCM has contributed to the prevention and treatment of disease, to the development of the Chinese nation, and to the quality of life of Chinese people. For many individuals, TCM remains an essential component of modern life. However, continuous improvements in monitoring adverse drug reactions/events (ADRs/ADEs), along with increased TCM use worldwide has frequently identified TCM-associated safety issues such as DILI9, 10. This situation imposes serious obstacles to the research and development of new, safe TCM drugs and the viability of TCM industries. Due to the lack of specific diagnostic indicators, an exclusion diagnosis of DILI has been commonly adopted, but this approach has shown a high rate of misdiagnosis. TCM DILI is often overlooked because of the pharmaceutical complexity of TCM, the limited basic information on the quantities of TCM components, as well as the increasingly common use of drug combinations. The causal relationship between liver injury and TCM is also difficult to clarify. In addition, potential TCM toxicity is often overlooked by the public since TCM preparations are commonly regarded as “natural, without toxic and side effects”. For these reasons and because developers and enterprises have paid insufficient attention to ADRs, the prevention and control of TCM safety risks is extremely difficult11. Therefore, the establishment of an objective and scientific technical system for assessing and identifying TCM DILI is needed. To this end, with strengthening the risk management of the entire drug life cycle as the main goal, the China Food and Drug Administration (CFDA)of China organized experts in related fields to develop the Guidance for Clinical Evaluation of Traditional Chinese Medicine-Induced Liver Injury. This task was accomplished by integrating the consensus of Chinese and international experts with research progress in the fields of medicine and pharmacy as well as in clinical and scientific research. This document aims to provide advice and assistance to relevant institutions and personnel in identifying the risk signals of TCM DILI; scientifically assess the causal relationship between patients׳ liver injury and TCM; effectively reduce misdiagnosis; fully evaluate the safety, risks and benefits of relevant TCM; and purposefully develop prevention and control measures for TCM DILI. These activities are needed to reduce the failure rate of new TCM drug research and development (R&D) and the risk of clinical use as well as to promote a viable TCM industry in China. This guide is designed for the evaluation of DILI and for risk control throughout the entire life cycle of TCM products, including the research and development stages of new drugs and post-marketing stage. It should also be used for TCM R&D, as well as by medical and regulatory agencies. Each drug marketing authority must carry the main responsibility for the product and not only strengthen the management of the entire lifecycle of the product but also take realistic and effective risk control measures to ensure the safety of public drug use. The TCMs (including ethnomedicines) in this guide consist of the TCM preparations that are being studied and those already on the market. This guide can be used as a reference for clinically used TCM decoctions and tablets, formulated TCM granules, TCM extract, homemade herbal medicines, TCM-containing health products and TCM health foods as well as relevant excipients. Many problems that urgently require in-depth study and solutions still exist in the field of TCM DILI. This guidance will be continuously revised and improved in accordance with research progress on TCM DILI and regulatory requirements.

Polygonum multiflorum (PM) is a well-known Chinese herbal medicine that has been reported to induce inflammation-associated idiosyncratic liver injury. This study aimed to identify the genetic basis of susceptibility to PM-drug-induced liver injury (PM-DILI) and to develop biological markers for predicting the risk of PM-DILI in humans. The major histocompatibility complex (MHC) regions of 11 patients with PM-DILI were sequenced, and all human leukocyte antigen (HLA)-type frequencies were compared to the Han-MHC database. An independent replication study that included 15 patients with PM-DILI, 33 patients with other DILI, and 99 population controls was performed to validate the candidate allele by HLA-B PCR sequence-based typing. A prospective cohort study that included 72 outpatients receiving PM for 4 weeks was designed to determine the influence of the risk allele on PM-DILI. In the pilot study, the frequency of HLA-B*35:01 was 45.4% in PM-DILI patients compared with 2.7% in the Han Chinese population (odds ratio [OR], 30.4; 95% confidence interval [CI], 11.7-77.8; P = 1.9 × 10-10 ). In the independent replication study and combined analyses, a logistic regression model confirmed that HLA-B*35:01 is a high-risk allele of PM-DILI (PM-DILI versus other DILI, OR, 86.5; 95% CI, 14.2-527.8, P = 1.0 × 10-6 ; and PM-DILI versus population controls, OR, 143.9; 95% CI, 30.1-687.5, P = 4.8 × 10-10 ). In the prospective cohort study, an asymptomatic increase in transaminase levels was diagnosed in 6 patients, representing a significantly higher incidence (relative risk, 8.0; 95% CI, 1.9-33.2; P < 0.02) in the HLA-B*35:01 carriers (37.5%) than in the noncarriers (4.7%). Conclusion: The HLA-B*35:01 allele is a genetic risk factor for PM-DILI and a potential biomarker for predicting PM-DILI in humans.

Para evaluar las caracteristicas mecanicas de anclado de una barra de acero con entalla transversal durante el ensayo de extraccion, se llevaron a cabo diferentes metodos complementarios, como pruebas de laboratorio, simulacion numerica y analisis teorico. Los resultados muestran que el bloque de anclado, durante el desarrollo de los ensayos de extraccion, presenta un modo de fallo por agrietamiento y que la curva de relacion fuerza de anclaje-desplazamiento, puede ser definida en cuatro pasos: fase de despegue, fase de avance, fase de agrietamiento y fase residual. Por eso la presentacion analitica y las expresiones obtenidas para la curva de relacion fuerza de anclaje-desplazamiento en los diferentes pasos se realizo usando un modelo de cilindro por elementos. Ademas, los resultados de la simulacion numerica verificaron que el bloque cara a la entalla transversal desarrollaba la fuerza en forma de cuna y que se destruyo mostrando un modo de fractura por agrietamiento. Se encontro que la fuerza de anclaje y bloque residual cara a la entalla transversal aumentaban durante los ensayos de extraccion con el incremento de la altura de la entalla. Estos resultados pueden facilitar una referencia basica para los disenos de refuerzo y la ingenieria practica de construccion. Palabras clave: Ensayo de extraccion, Barra con entalla transversal, Modelo de cilindro por elementos, Simulacion numerica.

Subjects in tunnels, being constrained by terrain and routes, entrances and exits to tunnels, usually stay in the terrain with slopes. Thus, it is necessary to carry out stability analysis by treating the tunnel slope as an entity. In this study, based on the Janbu slices method, a model for the calculation of the stability of the original slope-tunnel-bank slope is established. The genetic algorithm is used to implement calculation variables, safety coefficient expression and fitness function design. The stability of the original slope-tunnel-bank slope under different conditions is calculated, after utilizing the secondary development function of the mathematical tool MATLAB for programming. We found that the bearing capacity of the original slopes is reduced as the tunnels are excavated and the safety coefficient is gradually decreased as loads of the embankment construction increased. After the embankment was constructed, the safety coefficient was 1.38, which is larger than the 1.3 value specified by China’s standards. Thus, the original slope-tunnel-bank slope would remain in a stable state.

Organ-specific and systemic autoimmune diseases share numerous features and often coexist in the same patient. Autoimmune cholangitis/primary biliary cirrhosis and Sjogren syndrome represent paradigmatic examples of the common grounds of different autoimmunity phenotypes based on similarities in clinical manifestations and immunopathogenesis. In fact, primary biliary cirrhosis and Sjogren's syndrome have both been coined as an autoimmune epithelitis in which apoptosis may be in both cases the key element to explain the organ-specific immune-mediated injury against the biliary and exocrine gland epithelia, respectively. Further, growing evidence supports in both diseases the view that B cells, T cytotoxic cells, and T helper cells are involved in chronic inflammation, likely via the altered expression of pro-inflammatory cytokines. The presence of estrogen receptors on the biliary and exocrine gland epithelia has been advocated as a key to the female predominance encountered in primary biliary cirrhosis and Sjogren's syndrome. Sadly, despite available data, therapeutic approaches remain largely unsatisfactory and recent studies with mechanistic approaches (as in the case of B cell depletion with rituximab) have been of partial benefit only. Future studies should focus on new molecular tools (single-cell transcriptomics, microRNA, epigenetics) to provide unique insights into common mechanisms.

It is very important for mine production safety to ensure the stability of the tailings dam. Taking a flatland tailings pond as the background, a threedimensional computational model was built based on a tailings dam under mullock heap preloading condition. Considering the current operating water level conditions, a liquid-solid coupling analysis of the model was conducted.The deformation characteristics of the tailings dam were revealed during successive preloading at the front of the dam. The safety factor and the potential slide face of the tailings dam were calculated under different conditions using the strength reduction method. The results show that the tailings dam in its current condition is basically stable, but if the mullock heap continues to be heightened, the tailings dam will become unstable. Therefore, in order to limit the height of the mullock heap, establishing a monitor and early warning mechanism are put forward to ensure mine production safety.

In order to study the instability mechanism of the pressure-arch in the mining field under different dip angles of the coal seam, the structure mechanics model of the pressure-arch in the mining field was built based on a practical engineering. The moment, shear, and axial force at any section of the pressure-arch axis are obtained through the pressure-arch axis equation. It is concluded that the entire instability of the pressure-arch is caused by local damage and the failure models of local damage has three forms, namely tension-failure, shear-failure and compression-failure through the comprehensive analysis. The results show that with the increase of the dip angle of the coal seam, the failure modes of the pressure-arch change from compression-failure at the arch-waist and shear-failure at the skewbacks to shear-failure at the vault and tension-failure at the front of skewback. It is of meaningful to direct the engineering practice.

Only a subset of patients with excessive alcohol use develop alcoholic liver disease (ALD), though the exact mechanism is not completely understood. Once ingested, alcohol is metabolized by 2 key oxidative enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are 2 major ALDH isoforms, cytosolic and mitochondrial, encoded by the aldehyde ALDH1 and ALDH2 genes, respectively. The ALDH2 gene was hypothesized to alter genetic susceptibility to alcohol dependence and alcohol-induced liver diseases. The aim of this study is to determine the association between aldehyde dehydrogenase 2 (rs671) glu504lys polymorphism and ALD.ALDH2 genotyping was performed in 535 healthy controls and 281 patients with ALD.The prevalence of the common form of the single nucleotide polymorphism rs671, 504glu (glu/glu) was significantly higher in patients with ALD (95.4%) compared to that of controls (73.7%, P0.0001). Among controls, 23.7% had the heterozygous (glu/lys) genotype compared to 4.6% in those with ALD (odds ratio [OR] = 0.16, 95% CI: 0.09-0.28). The allele frequency for 504lys allele in patients with ALD was 2.3%, compared to 14.5% in healthy controls (OR = 0.13, 95% CI: 0.07-0.24).Patients with ALDH2 504lys variant were less associated with ALD compared to those with ALDH2 504glu using both genotypic and allelic analyses.

The new member of the IL-1 family, interleukin-33 (IL-33), participates in the progression of a variety of diseases through binding with its receptor ST2. Recently, much clinical evidence and experimental data have indicated that IL-33 is associated with various liver diseases. This review primarily addresses the relationship between IL-33 and several hepatic diseases. IL-33 can alleviate high-fat diet- (HFD-) induced hepatic steatosis and insulin resistance, and IL-33 acts as an alarmin, which quickly triggers the immune system to respond to virus invasion and toxic damage to the liver. However, when liver injury is chronic, IL-33 promotes Th2 reactions and hepatic stellate cell (HSC) activity, facilitating progression to liver fibrosis. The complicated functions of IL-33 should be considered before its clinical application.

Rock burst prediction method for coal mining is one of the worldwide challenging problems. Based on a high precision microseismic monitoring system consisting of nine geophones installed in Qixing Coal Mine in China, abundant microseismic events were detected through the continuous monitoring for 80 days. The potential high risk areas of rock burst were determined by analyzing the spatial and temporal distribution characteristics of microseismic events, which provides the basis for the early risk warning during the mining process. After a comprehensive analysis of the spatial and temporal evolution characteristics of the microseismic events, a prediction model for rock burst prediction was built based on the principles of seismology and rock mechanics by setting four indicators as prediction parameters, such as the average number of microseismic events N, the average released energy E, the decrease Δb of the seismological parameter b, and the potential maximum seismic magnitude M m. It was found that all the four prediction indicators are useful for predicting rock burst but they could vary greatly in efficiency in the practical engineering applications.

To evaluate mechanical performances of the transverse rib bar and reveal anchoring mechanism between the grout and steel bar, a series of pull-out tests were carried out, the numerical simulations and theoretical analysis of grout failure modes were also analyzed. Results show that the grout in front of the transverse rib display wedge-shape damage and the simulation results verify this damage forms. The formula of the effective transverse rib angle, the grout strength and anchorage force were derived based on elastic thick-wall cylinder theory. During the pull-out tests, the radial stress of the grout lagged the tangential stress reaching the ultimate tensile strength with the inner pressure increasing. The anchoring force of the transverse rib bar increases with the increase of the grout strength, and with the increase of the effective transverse rib angle. These conclusions provide the theoretical basis and technical support for the engineering practice.

Background and Aim Ursodeoxycholic acid (UDCA) treatment is an effective medical therapy for patients with primary biliary cirrhosis (PBC); however, 40% of PBC patients show an incomplete response to the UDCA therapy. This study aimed to investigate the safety and efficacy of umbilical cord-derived mesenchymal stem cell (UC-MSC) transfusion in PBC patients with an incomplete response to UDCA. Methods We conducted a single-arm trial that included seven PBC patients with a suboptimal response to UDCA treatment. UC-MSCs were first cultured, and then 0.5 × 106 cells/kg body weights were infused through a peripheral vein. UC-MSCs were given three times at 4-week intervals, and patients were followed up for 48 weeks. Primary outcomes were to evaluate the safety and feasibility of UC-MSC treatment, and secondary outcomes were to evaluate liver functions and patient's quality of life. Results No obvious side-effects were found in the patients treated with UC-MSCs. Symptoms such as fatigue and pruritus were obviously alleviated in most patients after UC-MSC treatment. There was a significant decrease in serum alkaline phosphatase and γ-glutamyltransferase levels at the end of the follow-up period as compared with baseline. No significant changes were observed in serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, prothrombin time activity, international normalized ratio, or immunoglobulin M levels. The Mayo risk score, a prognostic index, was also stable during the treatment and follow-up period. Conclusions UC-MSC transfusion is feasible and well tolerated in patients with PBC who respond only partially to UDCA treatment, thus representing a novel therapeutic approach for patients in this subgroup. A larger, randomized controlled cohort study is warranted to confirm the clinical efficacy of UC-MSC transfusion.

Kako bi se osigurala osnova za pojačanje konstrukcije i sigurnost izgradnje tunela s dvostrukim svodom, od teorijske i praktične vrijednosti je analizirati morfološku karakterizaciju, proces razvoja i asimetrični učinak tlačnog svoda u tunelu s dvostrukim svodom. Na temelju opisa graničnih parametara tlačnog svoda u tunelu s dvostrukim svodom, kao istraživački objekt uzet je tunel autoceste s dvostrukim svodom iskopan na dubini od 80 m, te je izrađen numerički proračunski model tunela s dvostrukim svodom uporabom FLAC3D, a potom je analiziran morfološki razvoj tlačnog svoda induciran iskopom korak-po-korak. Rezultati su pokazali da tlačni svod tunela s dvostrukim svodom pokazuje karakteristike asimetrične distribucije koja se postupno smanjuje od lijevog tunela ka desnom tunelu, da rasipanje energije deformacije tunela s dvostrukim svodom od lijevog tunela ka desnom tunelu ide od visokog do niskog, te da su nelinearne odzivne karakteristike u različitim sekvencama iskopa osjetljive na promjene u stanju naprezanja. Rezultatima je omogućena osnova za konstrukcije pojačane kamenom i sigurnost u izgradnji tunela s dvostrukim svodom., In order to provide a basis for the reinforcement design and construction safety of the double-arch tunnel, it is of theoretical and practical value to analyse the morphological characterization, the evolution process and the skewed effect of the pressure-arch in a double-arch tunnel. Based on the descriptions of the boundary parameters of the pressure-arch in a double-arch tunnel, taking the 80 m buried depth double-arch highway tunnel as the research object, the numerical calculation model of the double-arch tunnel was built by using FLAC3D, and then the morphological evolution of the pressure-arch induced by step-by-step excavation was analysed. The results showed that the pressure-arch of the double-arch tunnel displayed the skewed distribution characteristics which were gradually diminishing from the left tunnel to the right tunnel, the strain energy dissipation of the double-arch tunnel from the left tunnel to the right tunnel was from high to low, and the nonlinear response characteristics in different excavation sequences were sensitive to the changes of the stress state. The results provided a basis for the rock reinforcement design and safety construction of double-arch tunnel.

The study aimed to develop an effective method to quantitate HBV covalently closed circular DNA (cccDNA) using small section of formalin fixed paraffin-embedded (FFPE) liver biopsy.Plasmid-safe ATP-dependent DNase (PSAD)-treated samples were subjected to rolling circle amplification (RCA) prior to real-time PCR mediated by cccDNA-selective primers. Human beta-actin gene was used as a reference control.Compared to the classical method, i.e., PSAD digestion+real-time PCR, introduction of RCA increased the lower limit of detection for about 2 logs with good inter- and intra-assay reproducibility. HBV cccDNA was detected in 91.5% (119/130) of the FFPE samples. The cccDNA levels (copy/cell) between FFPE liver tissues and fresh frozen counterpart tissues were comparable. The median of cccDNA level in HBeAg-positive patients was higher than that in HBeAg-negative ones (52.60 vs. 31.25copies/cell, P0.01). Intrahepatic cccDNA level was positively correlated with intrahepatic HBV total DNA level, but not obviously correlated with serum HBV DNA or alanine aminotransferase levels.The method could sensitively and specifically quantitate intrahepatic HBV cccDNA in micro FFPE liver biopsy tissue for evaluation of HBV replication status in the liver.

Worldwide, hepatitis B virus (HBV) infection is one of the leading causes of chronic liver disease. Because HBV is not a cytopathogenic virus, host immune responses induced by viral persistence are generally thought to be responsible for the disease progression of chronic HBV infection.1 Generally, HBV-specific T cells were believed to play important roles in inducing hepatocellular damage during chronic HBV infection2,3; however, recent studies have shown that these cells often display functional impairment, such as T cell exhaustion by up-regulation of programmed death 1,4,5 T cell attrition through the B cell lymphoma 2 interacting mediator,6 and impaired T cell receptor signaling through the ζ-chain.7 T cell impairment is even more pronounced in the livers of patients with chronic hepatitis B (CHB) versus their blood.5 Furthermore, activated HBV-specific CD8 T cells are often found to be present in the livers of patients without evident liver immunopathology, whereas non–virus-specific lymphocytes have usually massively infiltrated the livers of patients with hepatocellular damage.8 A model of HBV-transgenic mice has further confirmed that non–virus-specific lymphocytes can exacerbate the liver inflammation initiated by virus-specific CD8 T cells.9,10 These findings suggest that non–virus-specific inflammatory cells infiltrating the liver may actively participate in HBV-associated liver pathogenesis. Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection.11 Recent studies have clearly suggested that NK cells may contribute to liver pathogenesis in rodent models12 and in patients with chronic hepatitis C virus (HCV) or HBV infection.13–16 Particularly during HCV infection, the viral infection results in an elevation of interferon-α (IFN-α) that subsequently polarizes NK cells toward cytolytic activity to induce liver injury.15 Emerging evidence indicates that during HBV infection, the early NK cell responses may lead to the initial control of the acute infection and allow the timely and efficient development of an adaptive immune response.17,18 However, if the virus persists, activated NK cells can mediate hepatocyte apoptosis by up-regulating tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in hepatitis B e antigen (HBeAg)–negative patients with hepatic flares14 and Fas ligand (FasL) in patients with HBV-associated acute-on-chronic liver failure.16 Although these studies have partially defined the role of NK cells in liver injury, NK cells may also use some other ligands to mediate liver injury in various disease progression phases of chronic HBV infection. In addition, recently available data about NK cells in CHB patients were primarily obtained from the peripheral compartments18,19; detailed information about the roles of NK cells in the liver pathogenesis of chronic HBV infection is scarce, especially for HBeAg-positive subjects. HBeAg-positive individuals with chronic HBV infection are generally divided into two groups: immune-tolerant (IT) carriers and immune-activated (IA) patients. The former group is characterized by minimal liver damage, normal alanine aminotransferase (ALT) levels, and active viral replication; the latter, generally after the IT phase, have increased liver injury and decreased viral replication.1,20 In this study, we comprehensively characterized the hepatic NK cells in these HBV-infected individuals and demonstrated that NK cell–mediated liver pathogenesis depended on an imbalanced cytokine milieu in the livers of these IA patients. Our findings may facilitate the rational development of immunotherapeutic strategies for enhancing viral control while limiting or blocking liver injury and inflammation.

Aims: This study attempts to characterize the feature of immunologically competent cells (ICCs) and evaluate its clinical implication in patients with acute-on-chronic liver failure (ACLF) in relation to chronic hepatitis B virus (HBV) infection. Methods: Circulating ICCs were examined in ACLF patients (n = 75), as well as in patients with hepatitis B (CHB, n = 31), CHB-related liver cirrhosis (LC, n = 36), and normal controls (NC, n = 30). Intrahepatic ICCs in some patients were further analyzed via immunohistochemical and flow cytometric assays. Results: Total lymphocytes, CD4+ T cells, CD8+ T cells, and NK cells in circulation were numerically lower in the ACLF and LC groups compared to the CHB and NC groups. Importantly, the number of these cells was significantly lower in non-surviving ACLF patients compared with surviving ACLF patients. In comparison to NC, ACLF patients displayed a significantly higher ratio of liver-infiltrating CD4+ T-cell frequency than its circulating counterpart, suggesting that the possiblility of the ICCs compartmentalization from the peripheral blood into the liver in ACLF. Immunohistochemical analysis showed that intrahepatic CD4+ cells, CD8+ cells, and CD56+ cells were significantly higher in the ACLF group compared with the other three groups, suggesting a stronger cellular immune response-mediated inflammation in ACLF group than other patient groups. Conclusions: The abnormal prevalence of circulating and intrahepatic ICCs possibly acts as an important factor that may drive the progression of HBV-related ACLF.

Interleukin-17 (IL-17)-producing CD4+ T cells (Th17)-mediated immune response has been demonstrated to play a critical role in inflammation-associated disease; however, its role in chronic hepatitis B virus (HBV) infection remains unknown. Here we characterized peripheral and intrahepatic Th17 cells and analyzed their association with liver injury in a cohort of HBV-infected patients including 66 with chronic hepatitis B (CHB), 23 with HBV-associated acute-on-chronic liver failure (ACLF), and 30 healthy subjects as controls. The frequency of circulating Th17 cells increased with disease progression from CHB (mean, 4.34%) to ACLF (mean, 5.62%) patients versus healthy controls (mean, 2.42%). Th17 cells were also found to be largely accumulated in the livers of CHB patients. The increases in circulating and intrahepatic Th17 cells positively correlated with plasma viral load, serum alanine aminotransferase levels, and histological activity index. In vitro, IL-17 can promote the activation of myeloid dendritic cells and monocytes and enhance the capacity to produce proinflammatory cytokines IL-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-23 in both CHB patients and healthy subjects. In addition, the concentration of serum Th17-associated cytokines was also increased in CHB and ACLF patients. Conclusion: Th17 cells are highly enriched in both peripheral blood and liver of CHB patients, and exhibit a potential to exacerbate liver damage during chronic HBV infection. (HEPATOLOGY 2009.)

Goals This study attempts to determine expressions of intrahepatic proinflammatory and anti-inflammatory cytokines and their secreting immunocytes to evaluate their roles in the pathogenesis of acute-on-chronic liver failure (ACLF) in chronically hepatitis B virus (HBV)-infected patients. Background ACLF generally affects patients with established, compensated chronic liver diseases who develop an acute deterioration in liver function. In China, HBV-associated ACLF patients account for more than 80% of ACLF patients owing to a high prevalence of chronic HBV infection. Clinical observation showed that the deterioration of this disease may correlate with host immune responses, but related underlying mechanism remains largely unknown. Study In situ expressions of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and their secreting CD4, CD8 T cells, and Kupffer cells (KCs) were analyzed in the livers of patients with ACLF, chronic hepatitis B (CHB), and normal controls (NC) using immunohistochemistry. Results Intrahepatic proinflammatory IFN-gamma and TNF-alpha expressions were markedly up-regulated in ACLF compared with CHB and NC. However, similar anti-inflammatory IL-10 expressions were observed in ACLF and CHB. IFN-gamma overexpression correlated significantly with increased CD4 and CD8 T-cell accumulation. TNF-alpha up-regulation also correlated significantly with increased KCs. Conclusions The imbalanced expression of proinflammatory and anti-inflammatory cytokines and increased accumulation of CD4, CD8 T cells, and KCs may contribute to immunopathogenesis in HBV-infected ACLF.

Background/Aims Functionally impaired dendritic cells (DCs) play important roles in suppressing host immune responses and facilitating viral persistence in chronic hepatitis B virus (HBV) infection. However, little is known regarding the status of intrahepatic DCs in HBV infection. Methods Based on availability, 11 recipient liver samples were obtained from acute-on-chronic hepatitis B liver failure (ACHBLF) patients who had undergone liver transplantation. The frequencies, phenotypes, and functions of intrahepatic DC subsets were analyzed. Results Both plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) extensively infiltrated the liver of the ACHBLF patients and expressed mature phenotypes therein. In particular, activated hepatic pDCs produced interferon (IFN)-α, which subsequently induced interleukin (IL)-12 and IL-10 production via toll-like receptor-9 ligation in liver-infiltrating lymphocytes cultured in vitro . However, blockade of IFN-α production significantly reduced the cytokine production of the LILs. Further, a significantly low frequency of peripheral pDCs and highly reduced IFN-α production were observed in a large cohort of the ACHBLF patients, particularly in the non-survivors. Moreover, a persistently upregulated expression of hepatic IFN-α-associated genes was observed in the ACHBLF patients during disease progression. Conclusions Activated pDCs accumulated in large numbers in the liver of the ACHBLF patients and regulated local immune responses in chronic HBV infection.