Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Exercise fatigue is a complex physiological and psychological phenomenon that includes peripheral fatigue in the muscles and central fatigue in the brain. Peripheral fatigue refers to the loss of force caused at the distal end of the neuromuscular junction, whereas central fatigue involves decreased motor output from the primary motor cortex, which is associated with modulations at anatomical sites proximal to nerves that innervate skeletal muscle. The central regulatory failure reflects a progressive decline in the central nervous system’s capacity to recruit motor units during sustained physical activity. Emerging evidence highlights the critical involvement of central neurochemical regulation in fatigue development, particularly through neurotransmitter-mediated modulation. Alterations in neurotransmitter release and receptor activity could influence excitatory and inhibitory signal pathways, thus modulating the perception of fatigue and exercise performance. Increased serotonin (5-HT) could increase perception of effort and lethargy, reduce motor drive to continue exercising, and contribute to exercise fatigue. Decreased dopamine (DA) and noradrenaline (NE) neurotransmission can negatively impact arousal, mood, motivation, and reward mechanisms and impair exercise performance. Furthermore, the serotonergic and dopaminergic systems interact with each other; a low 5-HT/DA ratio enhances motor motivation and improves performance, and a high 5-HT/DA ratio heightens fatigue perception and leads to decreased performance. The expression and activity of neurotransmitter receptors would be changed during prolonged exercise to fatigue, affecting the transmission of nerve signals. Prolonged high-intensity exercise causes excess 5-HT to overflow from the synaptic cleft to the axonal initial segment and activates the 5-HT1A receptor, thereby inhibiting the action potential of motor neurons and affecting the recruitment of motor units. During exercise to fatigue, the DA secretion is decreased, which blocks the binding of DA to D1 receptor in the caudate putamen and inhibits the activation of the direct pathway of the basal ganglia to suppress movement, meanwhile the binding of DA to D2 receptor is restrained in the caudate putamen, which activates the indirect pathway of the basal ganglia to influence motivation. Furthermore, other neurotransmitters and their receptors, such as adenosine (ADO), glutamic acid (Glu), and γ‑aminobutyric acid (GABA) also play important roles in regulating neurotransmitter balance and fatigue. The occurrence of central fatigue is not the result of the action of a single neurotransmitter system, but a comprehensive manifestation of the interaction between multiple neurotransmitters. This review explores the important role of neurotransmitters and their receptors in central motor fatigue, reveals the dynamic changes of different neurotransmitters such as 5-HT, DA, NE, and ADO during exercise, and summarizes the mechanisms by which these neurotransmitters and their receptors regulate fatigue perception and exercise performance through complex interactions. Besides, this study presents pharmacological evidence that drugs such as agonists, antagonists, and reuptake inhibitors could affect exercise performance by regulating the metabolic changes of neurotransmitters. Recently, emerging interventions such as dietary bioactive components intake and transcranial electrical stimulation may provide new ideas and strategies for the prevention and alleviation of exercise fatigue by regulating neurotransmitter levels and receptor activity. Overall, this work offers new theoretical insights into the understanding of exercise central fatigue, and future research should further investigate the relationship between neurotransmitters and their receptors and exercise fatigue.

Idiosyncratic drug-induced liver injury (IDILI) has long posed a challenging and pivotal concern in pharmaceutical research. The complex composition of traditional Chinese medicine (TCM) has introduced a bottleneck in current research, hindering the elucidation of the component basis associated with IDILI in TCM. Using Epimedii Folium (EF) and Psoraleae Fructus (PF) as illustrative examples, this study endeavors to establish an in vitro evaluation model, providing a high-throughput and preliminary assessment method for screening components related to TCM-induced IDILI. A TNF-α-mediated HepG2 susceptible model was first established in this study, with the focus on the index components present in EF and PF. The release of lactate dehydrogenase (LDH) in the cell supernatant served as the detection index. A concentration-toxicity response curve was constructed, and the hepatotoxic components of EF and PF were identified utilizing the synergistic toxicity index. The LDH results unveiled the hepatotoxic effects of bavachin, backuchiol, isobavachin, neobavaisoflavone, psoralidin, isobavachalcone, icarisid I, and icarisid II on both normal and susceptible cells, categorizing these 8 components as both direct hepatotoxicity components and idiosyncratic hepatotoxicity components. Bavachin and neobavaisoflavone exhibited no hepatotoxicity on normal cells but demonstrated significant effects on susceptible cells, designating them as potential idiosyncratic susceptible hepatotoxicity components. The study further delineated that 10 EF components and 3 PF components were direct immune-promoting hepatotoxicity components. Additionally, 14 idiosyncratic immune-promoting hepatotoxicity components were identified, encompassing 10 EF components and 4 PF components, with neobavaisoflavone, bavachinin, and isobavachin being potential idiosyncratic susceptible immune-promoting hepatotoxicity components. Synergistic toxicity index results indicated that 13 idiosyncratic immune-promoting hepatotoxicity components (except anhydroicaritin) combined with bavachin demonstrated synergistic hepatotoxicity on susceptible cells. Notably, 3 idiosyncratic susceptible immune-promoting hepatotoxicity components combined with bavachin exhibited synergistic hepatotoxicity, with neobavaisoflavone displaying the highest synergistic toxicity index and bavachinin the lowest. In summary, this methodology successfully screens hepatotoxic and immune-promoting hepatotoxic components in EF and PF, distinguishing the types of components inducing hepatotoxicity, evaluating the hepatotoxicity degree of each component, and elucidating the synergistic relationships among them. Importantly, these findings align with the characteristics of IDILI. The method provides an effective model tool for the fundamental research of TCM-related IDILI components.

Objective To investigate the long-term safety and effectiveness of withdrawal of hepatitis B immuneglobulin (HBIG) and/or nucleos(t)ide analogues (NAs) to prevent hepatitis B virus (HBV) reinfection in liver transplant recipients with hepatitis B-related diseases after successful vaccination. Methods Baseline data of 76 liver transplant recipients undergoing hepatitis B immune reconstitution after receiving hepatitis B vaccines were retrospectively analyzed. The vaccination and response, the follow-up results of respondents with HBIG and/or NAs withdrawal, and the reinfection of HBV after withdrawal of HBIG and/or NAs were analyzed. Results The time interval from liver transplantation to hepatitis B vaccination was 26 (20, 40) months. The time interval from vaccination to response was 15 (8,27) months. Initially, 76 recipients withdrew HBIG, and 36 recipients withdrew HBIG and NAs. During the follow-up, 12 of 76 recipients who withdrew HBIG resumed use of HBIG, and 16 of 36 recipients who withdrew HBIG and NAs resumed use of NAs. The withdrawal time of HBIG and NAs was 135 (98,150) and 133 (34,149) months, respectively. Sixteen respondents did not receive booster, and 36 respondents received boosters on a regular basis. The time interval between the first booster and HBIG withdrawal was 44 (11,87) months. No significant differences were observed in baseline data between the respondents with and without boosters (all P>0.05). During the follow-up, 9 recipients were lost to follow-up, 5 were re-infected with HBV, 3 died, and 1 recipient developed graft loss and underwent secondary liver transplantation. Among 5 recipients re-infected with HBV, 4 cases had virus mutation. Significant differences were found between re-infected and uninfected patients regarding withdrawal of NAs and hepatitis B e antigen (HBeAg) positive before transplantation (both P<0.05). Conclusions Long-term withdrawal of HBIG is feasible and safe for recipients with successful hepatitis B immune reconstitution after liver transplantation for hepatitis B-related diseases. Nevertheless, whether antiviral drugs can be simultaneously withdrawn remains to be validated.

Skeletal muscle injury is a common disease in clinical practice,and an in-depth understanding of its repair mechanisms is crucial for the development of effective therapeutic strategies.This paper focuses on the key role of TGF-β in skeletal muscle injury repair,introduces the diversity of its family members and signaling pathways,explores the expression and regulation part of TGF-β after skeletal muscle injury,analyzes its early expression dynamics and regulatory factors,and thoroughly investigates the effects of TGF-β on skeletal muscle repair,revealing its inflammatory regulation,cellular activation and proliferation as well as fibrosis.Key role.Special attention was paid to its mechanism of action in muscle regeneration and its regulatory mechanism at the cellular level.In addition,the potential clinical applications of TGF-β in the repair of skeletal muscle injury were discussed,and the development and application of it as a therapeutic target and modulator were explored.However,controversies and shortcomings still exist in the current study,such as the dual roles of TGF-β and the impact of individual differences on treatment.Future research directions should include digging deeper into the details of signaling pathways and biomarker discovery.By overcoming these challenges,the potential clinical application of TGF-β in skeletal muscle injury repair is expected to usher in new breakthroughs and provide patients with more individualized and effective treatment strategies.

Objective:To investigate the relationship between intramuscular adipose tissue index (IATI) calculated from computed tomography images at transverse process of the first lumbar and all-cause mortality in maintenance dialysis patients, and to provide a reference for improving the prognosis in these patients.Methods:It was a multicenter retrospective cohort study. The clinical data of patients who received maintenance hemodialysis or peritoneal dialysis treatment from January 1, 2017 to December 31, 2019 in 4 grade Ⅲ hospitals including Zhongda Hospital Affiliated to Southeast University, Taizhou People's Hospital Affiliated to Nanjing Medical University, Affiliated Hospital of Yangzhou University, and the Third Affiliated Hospital of Soochow University were retrospectively collected. IATI was calculated by low attenuation muscle (LAM) density/skeletal muscle density. The receiver-operating characteristic curve was used to determine the optimal cut-off value of IATI, and the patients were divided into high IATI group and low IATI group according to the optimal cut-off value. The differences of baseline clinical data and measurement parameters of the first lumbar level between the two groups were compared. The follow-up ended on December 23, 2022. The endpoint event was defined as all-cause mortality within 3 years. Kaplan-Meier survival curve and log-rank test were used to analyze the survival rates and the differences between the two groups. Multivariate Cox regression analysis models were used to analyze the association between IATI and the risk of all-cause mortality in maintenance dialysis patients. Multivariate logistic regression analysis model was used to analyze the influencing factors of high IATI.Results:A total of 478 patients were eligibly recruited in this study, with age of (53.55±13.19) years old and 319 (66.7%) males, including 365 (76.4%) hemodialysis patients and 113 (23.6%) peritoneal dialysis patients. There were 376 (78.7%) patients in low IATI (<0.42) group and 102 (21.3%) patients in high IATI (≥0.42) group. The proportion of age ≥ 60 years old ( χ2=24.746, P<0.001), proportion of diabetes mellitus ( χ2=5.570, P=0.018), fasting blood glucose ( t=-2.145, P=0.032), LAM density ( t=-3.735, P<0.001), LAM index ( t=-7.072, P<0.001), and LAM area/skeletal muscle area ratio ( Z=-9.630, P<0.001) in high IATI group were all higher than those in low IATI group, while proportion of males ( χ2=11.116, P<0.001), serum albumin ( Z=2.708, P=0.007) and skeletal muscle density ( t=12.380, P<0.001) were lower than those in low IATI group. Kaplan-Meier survival analysis showed that the 3-years overall survival rate of low IATI group was significantly higher than that in high IATI group (Log-rank χ2=19.188, P<0.001). Multivariate Cox regression analysis showed that IATI<0.42 [<0.42/≥0.42, HR(95% CI): 0.50 (0.31-0.83), P=0.007] was an independent protective factor of all-cause mortality, and age ≥60 years old [ HR (95% CI): 2.61 (1.60-4.23), P<0.001], diabetes mellitus [ HR (95% CI): 1.71 (1.06-2.78), P=0.029] and high blood neutrophil/lymphocyte ratio [ HR (95% CI): 1.04 (1.00-1.07), P=0.049] were the independent risk factors of all-cause mortality in maintenance dialysis patients. Stepwise Cox regression analysis showed that IATI<0.42 was still an independent protective factor of all-cause mortality in maintenance dialysis patients [<0.42/≥0.42, HR (95% CI): 0.45 (0.27-0.76), P=0.003]. Multivariate logistic regression analysis showed that low skeletal muscle density [ OR (95% CI): 0.84 (0.81-0.88), P<0.001] and high serum triglyceride [ OR (95% CI): 1.39 (1.07-1.82), P=0.015] were the independent influencing factors of IATI≥0.42. Conclusion:IATI<0.42 of the first lumbar level is an independent protective factor of all-cause mortality in maintenance dialysis patients. Localized myosteatosis within high-quality skeletal muscle may reduce the risk of all-cause mortality in these patients.

OBJECTIVE To establish a comprehensive platform for regional pharmaceutical care among Jiangxi provincial pediatric alliance to realize the management of pediatric hierarchical diagnosis and treatment, and improve the quality of pharmaceutical care. METHODS A unified diagnosis and treatment information standard and a knowledge base of children's rational drug use rules were established among the medical institutions of Jiangxi provincial pediatric alliance. On this basis, the medical records and drug use information of patients in various medical institutions in the region were uploaded to the chain in a structured manner in real time, and a comprehensive platform for regional pharmaceutical care was built. RESULTS The comprehensive platform for regional pharmaceutical care built based on blockchain technology could share medical resources and information among medical institutions, realize rational drug use management, remote prescription review, individualized drug use guidance, popular science education, government supervision, etc., and improve the quality of pharmaceutical care. CONCLUSION The comprehensive platform for regional pharmaceutical care among Jiangxi provincial pediatric alliance can help allocate high-quality medical resources (drug safety knowledge base and pediatric pharmacists) for primary medical institutions. Further more, it lays the foundation for government supervision at the same time ensuring children’s medication safety, which has great practical significance.

Objective To observe the pharmacokinetic effect of amoxicillin and clavulanate potassium tablets on amoxicillin in Chinese healthy subjects under fasting and high fat and high calorie diet.Methods 71 healthy subjects were given a single dose of amoxicillin potassium clavulanate tablets(0.375 g)on fasting or high fat diet,and venous blood samples were collected at different time points.The concentrations of amoxicillin in human plasma were determined by HPLC-MS/MS method,and the pharmacokinetic parameters were calculated by non-atrioventricular model using PhoenixWinNonlin 8.0 software.Results The main pharmacokinetic parameters of amoxicillin potassium clavulanate tablets after fasting and high fat diet were(5 105.00±1 444.00),(4 593.00±1 327.00)ng·mL-1,and postprandial-fasting ratio 89.40％,90％confidence interval(79.55％-100.19％);t1/2 were(1.52±0.16),(1.39±0.22)h;AUC0-t were(12 969.00±1 841.00),(11 577.00±1 663.00)ng·mL-1·h,and postdietary/fasting ratio 89.20％,90％confidence interval(83.92％-94.28％);AUC0-∞ were(13 024.00±1 846.00),(11 532.00±1 545.00)ng·mL-1·h,and postprandial-fasting ratio 88.60％,90％confidence interval(83.48％-93.50％).The median Tmax(range)were 1.63(0.75,3.00)and 2.50(0.75,6.00)h,respectively,and the Tmax of postprandial medication was delayed(P＜0.01).Conclusion Compared with fasting condition,amoxicillin Tmax was significantly delayed after high fat diet,while Cmax,AUC0-t and AUC0-∞ were not significantly changed,indicating that food could delay the absorption of amoxicillin,but did not affect the degree of absorption.