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BackgroundIt is unclear whether patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are allowed variable low levels of alcohol. This study aimed to evaluate the effect of mild-moderate alcohol consumption on the biochemical and histological characteristics of patients with MASLD.MethodsAlcohol consumption was assessed in 713 patients with steatotic liver disease (SLD) who underwent liver biopsy. Non-drinking, mild-moderate drinking, and excessive drinking were defined as 0 g/day, 1-20 g/day for women and 0 g/day, 1-30 g/day for men, respectively. Liver biopsies were scored according to the NASH CRN system.ResultsA total of 713 participants (median age 39.0 years and 77.1% male) with biopsy-proven SLD were enrolled, including 239 nondrinkers, 269 mild-moderate drinkers and 205 excessive drinkers. Excessive drinking was associated with increased risks for lobular inflammation and liver fibrosis compared to nondrinkers and mild-moderate drinkers. Compared with non-drinkers, mild-moderate drinkers had significantly lower odds for steatosis (OR = 0.60, 95% CI = 0.38–0.93, p = 0.025), hepatocellular ballooning (OR = 0.52, 95% CI = 0.29–0.91, p = 0.020) and fibrosis (OR = 0.50, 95% CI = 0.31–0.81, p = 0.005). However, in non-excessive drinkers with type 2 diabetes mellitus (T2DM), there was no association between mild-moderate alcohol consumption and liver fibrosis (OR = 0.562, 95% CI = 0.207–1.530, p = 0.257).ConclusionsMild-moderate alcohol consumption might be protective against liver fibrosis in MASLD patients, which is modified by the presence of T2DM. However, further longitudinal studies are needed to determine the effect of ongoing alcohol consumption on disease severity.

Background and aims To explore the incidence of alcohol-related hepatocellular carcinoma (HCC), evaluate possible synergisms between alcohol and well-known risk factors associated with HCC and establish a nomogram to predict alcohol-associated liver disease (ALD)-related HCC risk.Methods A database of 136 571 inpatients in the Fifth Medical Center of Chinese PLA General Hospital from 2002 to 2018 with chronic liver disease was established. Data were collected by medical records review. Multivariate logistic regression was used to identify the independent high-risk factors associated with HCC, and then were incorporated into a novel nomogram. Afterward, the new established model was validated using external cohort by receiver operating characteristic curves analysis. For external cohort, 1646 patients with ALD admitted to our hospital from 2019 to 2021 were included. ALD was diagnosed on the basis of a history of sustained heavy alcohol intake greater than 40 g/day for men and 20 g/day for women for >5 years, clinical evidence of liver disease and supporting laboratory abnormalities.Results Over the last 17 years, trends showed obviously increases in ALD. ALD-related HCC experienced a significant increase from 5.8% to 30.7%, whereas hepatitis B virus (HBV)-related HCC declined from 77.6% to 52.0%. In patients with ALD-related HCC (5119), 3816 (74.54%) cases had HBV infection, 493 (9.63%) cases had hepatitis C virus (HCV) infection, 71 (1.39%) cases were coinfected with both HBV and HCV, and 739 (14.44%) cases had neither HBV nor HCV infection. Drinking years (OR 1.009, 95% CI (1.000 to 1.017)), age (OR 1.060, 95% CI (1.051 to 1.069)), diabetes mellitus (OR 1.314, 95% CI (1.123 to 1.538)), HBV infection (OR 4.905, 95% CI (4.242 to 5.671)), liver cirrhosis (OR 4.922, 95% CI (3.887 to 6.232)) and male sex (OR 17.011, 95%CI (2.296 to 126.013)) were associated with increased risk of HCC in patients with ALD. A nomogram had a concordance index of 0.786 (95% CI 0.773 to 0.799) and had well-fitted calibration curves. These results were successfully validated both in the internal cohort and external cohort.Conclusion The prevalence of ALD and ALD-related HCC has been increased dramatically. The nomogram model established here with its high accuracy and easy-to-use features achieved an optimal prediction of HCC development in patients with ALD, which can help clinicians to develop an individualised and precise treatment strategy.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10−304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10−33; OR = 4.26) and rs7765379 (p = 5.08 × 10−18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

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.

The soil behind a wall is in a stress state with self-weight stress and horizontal stress as the main stress for the Rankine retaining wall with horizontal fill. However, there is a certain wall-soil friction and bonding force in practice. The friction and bonding force may cause the principal stress deflection in the fill near the retaining wall, and the classical Rankine earth pressure theory is not applicable for this case. In the current study, the principal stress deflection of the fill near the retaining wall is processed both by the rotation and by the analysis of the stress from the Mohr circle in the fill behind the wall. The active and passive earth pressures of the retaining wall filled with the cohesive soil is derived, considering the wall-soil friction and bonding force. The influences of the fill friction angle and the wall-soil friction angle on the earth pressures are analyzed. The examples are further used to compare the results from this study with those with the improved Coulomb method. The results show that the Rankine earth pressure is a special case of the formula presented in this study. With the increase of the wall-soil friction angle and internal friction angle, the passive earth pressures gradually increase. The active earth pressures decrease with the increase of the internal friction angle, and the decreasing rate gradually decreases. When the internal friction angle is small, the active earth pressures decrease continuously with the increase of the wall-soil friction angle, and the decreasing speed gradually decreases. When the internal friction angle is large, the active earth pressures first decrease and then increase with the increase of the wall-soil friction angle. The effect of the fill friction angle is more obvious than that of the wall-soil friction angle. Compared with the results from other methods, the active earth pressures obtained with this method are larger, but the passive earth pressure is smaller, and their differences increase with the increase in the wall-soil friction, especially when the cohesion is considered. Because the deflection of the principal stress in the soil on the back of the wall is more consistent with the actual situations, the results from this study will be more suitable to compute the earth pressure in practice.

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.

To determine the energy attenuation and energy reflection coefficients in layered foundation is the key factor to reveal the dynamic response characteristics of the high-speed railway foundation. Based on the foundation test model under the dynamic loading of the high-speed railway, the energy attenuation and energy reflection coefficients were introduced and the attenuation formulas of the vibration acceleration in the layered foundation were deduced. Five scale models of 1:1, 1:2, 1:5, 1:10 and 1:20 are established respectively by using Abaqus technique. The energy attenuation mechanism and interfacial energy reflection characteristics in the layered foundation were analyzed. Results show that it is appropriate to use vibration acceleration to characterize the propagation rule of the energy attenuation in the layered foundation. The size effect equations of the energy attenuation and energy reflection coefficients in the layered foundation are deduced and the size effect of the energy attenuation is revealed. Based on the nonlinear relationships among the energy attenuation coefficient, the model scale, the loading amplitude and the vibration frequency, the energy attenuation equation of the scale test model is constructed. The reliability of the theoretical and simulation results is verified by the scale test model. The conclusions obtained in this study can provide a reference for a similar engineering practice.

Currently, there are no satisfactory noninvasive methods for the diagnosis of fibrosis in patients with chronic drug-induced liver injury (DILI). Our goal was to develop an algorithm to improve the diagnostic accuracy of significant fibrosis in this population. In the present study, we retrospectively investigated the biochemical and pathological characteristics of consecutive patients with biopsy-proven chronic DILI, who presented at our hospital from January 2013 to December 2017. A noninvasive algorithm was developed by using multivariate logistic regression, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to diagnose significant fibrosis in the training cohort, and the algorithm was subsequently validated in the validation cohort. Totally, 1,130 patients were enrolled and randomly assigned into a training cohort (n = 848) and a validation cohort (n = 282). Based on the multivariate analysis, LSM, CHE, and APRI were independently associated with significant fibrosis. A novel algorithm, LAC, was identified with the AUROC of 0.81, which was significantly higher than LSM (AUROC 0.78), CHE (AUROC 0.73), and APRI (AUROC 0.68), alone. The best cutoff value of LAC in the training cohort was 5.4. When the LAC score was used to diagnose advanced fibrosis and cirrhosis stages, the optimal cutoff values were 6.2 and 6.7, respectively, and the AUROC values were 0.84 and 0.90 in the training cohort and 0.81 and 0.83 in the validation cohort. This study proved that the LAC score can contribute to the accurate assessment of high-risk disease progression and the establishment of optimal treatment strategies for patients with chronic DILI.

Background & Aims: Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent nonalcoholic fatty liver disease, characterized by inflammatory cell infiltration and hepatocellular damage. Mammalian target of rapamycin complex 1 (mTORC1) has been investigated extensively in the context of cancer, including hepatocellular carcinoma. However, the role of mTORC1 in NASH remains largely unknown. Methods: mTORC1 activity in macrophages in human mild and severe NASH liver was compared. Mice with macrophage-specific deletion of the regulatory-associated protein of mTOR (Raptor) subunit and littermate controls were fed a high-fructose, palmitate, and cholesterol diet for 24 weeks or a methionine- and choline-deficient diet for 4 weeks to develop NASH. Results: We report that in human beings bearing NASH, macrophage mTORC1 activity was lower in livers experiencing severe vs mild NASH liver. Moreover, macrophage mTORC1 disruption exacerbated the inflammatory response in 2 diet-induced NASH mouse models. Mechanistically, in response to apoptotic hepatocytes (AHs), macrophage polarization toward a M2 anti-inflammatory phenotype was inhibited in Raptor-deficient macrophages. During the digestion of AHs, macrophage mTORC1 was activated and coupled with dynamin-related protein 1 to facilitate the latter’s phosphorylation, leading to mitochondrial fission-mediated calcium release. Ionomycin or A23187, calcium ionophores, prevented Raptor deficiency–mediated failure of lysosome acidification and subsequent lipolysis. Blocking dynamin-related protein 1–dependent mitochondria fission impaired lysosome function, resulting in reduced production of anti-inflammatory factors such as interleukins 10 and 13. Conclusions: Persistent mTORC1 deficiency in macrophages contributes to the progression of NASH by causing lysosome dysfunction and subsequently attenuating anti-inflammatory M2-like response in macrophages during clearance of AHs. Keywords: mTORC1, NASH, Lysosome, Drp1

Chronic drug-induced liver injury (DILI), defined as DILI with persistent liver injury more than one year after the first onset by the latest European guidelines, is a notable challenge globally with big issues of defining causality and establishing effective treatment. About 20% of patients with DILI develop into chronic DILI. Chronic DILI manifests as persistent or repeated inflammatory or diminishing bile ducts, even progresses to cirrhosis and needs liver transplantation eventually. However, research on chronic DILI over the last decades is still lacking, and the incidence, phenotypes, mechanisms, risk factors, and treatment have not been fully understood. In this paper, we reviewed the definition of chronic DILI, updated clinical studies in terms of incidence, special manifestations, and promising risk factors of chronic DILI, along with the recent progress and challenges in glucocorticoid therapy.

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.

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

To investigate the mechanical properties and energy evolution characteristics of sandstone depending on the water contents and confining pressure, the uniaxial and triaxial tests were conducted. The test results show that the strain energy was stored in the sandstone samples at the prepeak stage, and that is suddenly released when the failure occurred, and energy dissipation is sharply increased at the postpeak stage. The damage and energy dissipation characteristics of the samples are observed clearly under the stepwise loading and unloading process. The critical strain energy and energy dissipation show a clear exponential relationship. The critical elastic energy decreases linearly as the water content increases. As the confining pressure increases, the critical elastic energy of the samples transforms from linear to exponential. The concept of energy enhancement factor is proposed to characterize the strengthening effect induced by the confining pressure on the energy storage capacity of the rock samples. The energy evolution of the sandstone samples is more sensitive to the confining pressure than that of the water content.

To reveal the performance of the stepped subsidence and the strong roof weighting during shallow coal mining, taking the fully mechanized mining face with large mining height in the Shendong mining area in China as the engineering background, theoretical analysis and numerical simulation were used to analyze the pressure-arching effect of the hanging roof blocks. Three typical pressure-arch models of the roof structure were proposed, such as the symmetrical pressure-arch of two key blocks, the step pressure-arch of multiple key blocks, and the rotative pressure-arch of multiple key blocks. Results indicate that the horizontal stress displays a nonlinear distribution at the abutments of the symmetrical pressure-arch, and there is a linear distribution of horizontal stress with a higher peak value at the midspan of the pressure-arch. The high horizontal stress at the arch abutment is necessary to form the rotative pressure-arch of multiple key blocks. The horizontal stress is relatively less at the arch abutment of the step pressure-arch structure. The main key block is easier to slide in this structure as the boundary horizontal stresses display the nonlinear distribution. The results are of instructive significance for roof weighting forecast and strata control during shallow horizontal mining for a thick coal seam.

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.

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.

Background. Over the last 20 years, the prevalence of hepatitis B virus (HBV) infection in China has decreased gradually due to the application of a national HBV vaccination program. In contrast, the prevalence of alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune liver disease, and drug-induced liver injury has markedly increased. Methods. We conducted a retrospective review of 82,562 hospitalized patients diagnosed with liver cirrhosis in Beijing 302 Hospital from 2002 to 2013. Results. The top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. The percentage of HBV cirrhosis decreased from 81.53% in 2002 to 66.0% in 2013, whereas the frequency of alcoholic cirrhosis increased from 3.34% in 2002 to 8.40% in 2013. Females (84.34%) accounted for the majority of cirrhotic patients with autoimmune liver diseases. Males accounted for 80.16% of HBV cirrhosis patients and 98.02% of alcoholic cirrhosis patients. Conclusion. In Beijing 302 Hospital, the top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. Over the last 12 years, the prevalence of HBV cirrhosis has decreased gradually, whereas that of alcoholic cirrhosis has increased significantly.

BACKGROUND: This study aimed to investigate the relationships of intrahepatic cccDNA with serum HBsAg and with HBV DNA in treatment-naive patients throughout acute and chronic HBV infection. METHODS: A total of 120 patients who had a liver biopsy were enrolled, including 19 with acute hepatitis B (AHB), and 101 patients with chronic HBV infection (CHB) of whom were 10 in immune-tolerant (IT) phase, 59 in immune-clearance (IC) phase, 8 in low-replicative (LR) phase, and 24 in HBeAg-negative hepatitis (ENH) phase. Intrahepatic cccDNA, serum HBsAg and serum HBV DNA levels were comparatively analyzed. RESULTS: The median intrahepatic cccDNA levels were 0.18 4.80, 3.81, 0.22 and 0.97 copies/cell for patients with AHB, CHB-IT, CHB-IC, CHB-LR, and CHB-ENH, respectively. In AHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg (r = 0.665, P = 0.003), as well as serum HBV DNA (r = 0.536, P = 0.022). In CHB patients, intrahepatic cccDNA was positively correlated with serum HBsAg in the IC phase (r = 0.392, P = 0.005), and with serum HBV DNA in the IC phase (r = 0.301, P = 0.036) and ENH phase (r = 0.588, P = 0.013). HBV replicative efficiency, defined as the ratio of serum HBV DNA to intrahepatic cccDNA, was obviously lower in AHB and CHB-LR patients than in CHB-IT, CHB-IC and CHB-ENH patients (0.70 and 0.53 vs. 1.12, 1.09 and 0.99, P