Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Objective:To retrospectively analyze the clinical features and surgical efficacy of congenital cholesteatoma （CC） and acquired cholesteatoma （AC） in children. Methods:Clinical data of 169 children with middle ear cholesteatoma were reviewed in the Department of Otorhinolaryngology Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University from January 2010 to July 2020. The clinical characteristics, stages, surgical methods, and postoperative recurrence rates were analyzed and summarized. Results:The age distribution of enrolled children ranged from 2 to 14 years. The mean age of the CC group was （5.60±2.48） years compared with （6.45±2.48） years in the AC group, and the difference was statistically significant （P<0.05）. Preoperative hearing in the CC group was （40.06±13.52） dB HL, which was better than in the AC group at （48.40±13.84） dB HL （P<0.05）. The proportion of stage Ⅰ in the CC group was lower than that in the AC group according to EAONO/JOS staging （P<0.05）. The recurrence rate after primary surgery was 19.23% （10/52） in the CC group compared with 36.29% （45/124） in the AC group （P<0.05）. The mastoid retention rates after all operations were 28.85% （15/52） in the CC group and 5.65% （7/124） in the AC group （P<0.05）. Conclusion:Compared with congenital cholesteatoma, acquired cholesteatoma in children is more aggressive and has more complications, higher postoperative recurrence rate, and less possibility of mastoid retention. Early clinical detection and treatment are required, and canal wall-down tympanoplasty should be considered in surgery.
Humans ; Cholesteatoma, Middle Ear/congenital* ; Child ; Retrospective Studies ; Child, Preschool ; Adolescent ; Male ; Female ; Recurrence ; Cholesteatoma/congenital* ; Tympanoplasty ; Treatment Outcome

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Addressing the enduring challenge of evaluating traditional Chinese medicines (TCMs), the integrated evidence chain-based effectiveness evaluation of TCMs (Eff-iEC) has emerged. This paper explored its capacity through a demonstration study that evaluated the effectiveness evidence of six commonly used anti-hepatic fibrosis Chinese patent medicines (CPMs), including Biejiajian Pill (BP), Dahuang Zhechong Pill (DZP), Biejia Ruangan Compound (BRC), Fuzheng Huayu Capsule (FHC), Anluo Huaxian Pill (AHP), and Heluo Shugan Capsule (HSC), using both Eff-iEC and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. The recognition of these CPMs within the TCM academic community was also assessed through their inclusion in relevant medical documents. Results showed that the evidence of BRC and FHC received higher assessments in both Eff-iEC and GRADE system, while the assessments for others varied. Analysis of community recognition revealed that Eff-iEC more accurately reflects the clinical value of these CPMs, exhibiting superior evaluative capabilities. By breaking through the conventional pattern of TCMs effectiveness evaluation, Eff-iEC offers a novel epistemology that better aligns with the clinical realities and reasoning of TCMs, providing a coherent methodology for clinical decision-making, new drug evaluations, and health policy formulation.

N6-Methyladenosine (m6A) modification is a crucial post-transcriptional regulatory mechanism and the most abundant and highly conserved RNA epigenetic modification in eukaryotes. Previous studies have indicated the involvement of m6A modification in various tissue regeneration processes, including liver regeneration. Vir-like m6A methyltransferase associated protein (VIRMA) is an m6A methyltransferase with robust methylation capability. However, its role in liver regeneration remains poorly understood. In this study, we generated liver-specific Virma knockout mice using the Cre-loxP system and investigated the biological functions of VIRMA in liver regeneration using both the Associating Liver Partition and Portal vein Ligation for Staged Hepatectomy (ALPPS) mouse model and the carbon tetrachloride (CCl₄) mouse model. The expression level of VIRMA was rapidly up-regulated after ALPPS surgery and gradually down-regulated during liver repair. Virma deficiency significantly impaired liver regeneration capacity and disrupted cell cycle progression. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) analysis revealed that Shq1 is an effective downstream target of VIRMA-mediated m6A modification. The upregulation of Shq1 enhanced the proliferation ability of cells, which was attenuated by the specific AKT inhibitor ipatasertib. Supplementation of Shq1 in vivo alleviated the liver cell proliferation inhibition caused by Virma deficiency. Furthermore, the m6A-binding protein heterogeneous nuclear ribonucleoprotein a2b1 (HNRNPA2B1) enhanced the mRNA stability of Shq1. Mechanistically, Virma deficiency resulted in decreased m6A modification on Shq1 mRNA, leading to reduced binding ability of m6A-binding protein HNRNPA2B1 with Shq1, thereby decreasing the mRNA stability of Shq1 and reducing its protein expression level. Downregulation of Shq1 inhibited the PI3K/AKT pathway, thereby suppressing cell proliferation and cell cycle progression, ultimately impeding liver regeneration. In summary, our results demonstrate that VIRMA plays a critical role in promoting liver regeneration by regulating m6A modification, providing valuable insights into the epigenetic regulation during liver regeneration.

OBJECTIVES: To explore the efficacy of DSA-guided intrathecal drug delivery system combined with Zi Wu Liu Zhu Acupoint Therapy for management of cancer pain and provide reference for its standardized clinical application. Methods and. RESULTS: Recommendations were formulated based on literature review and expert group discussion, and consensus was reached following expert consultation. The consensus recommendations are comprehensive, covering the entire treatment procedures from preoperative assessment and preparation, surgical operation process, postoperative management and traditional Chinese medicine treatment to individualized treatment planning. The study results showed that the treatment plans combining traditional Chinese with Western medicine effectively alleviated cancer pain, reduced the use of opioid drugs, and significantly improved the quality of life and enhanced immune function of the patients. Postoperative follow-up suggested good treatment tolerance among the patients without serious complications. CONCLUSIONS The formulated consensus is comprehensive and can provide reference for clinicians to use DSA-guided intrathecal drug delivery system combined with Zi Wu Liu Zhu Acupoint Therapy. The combined treatment has a high clinical value with a good safety profile for management of cancer pain.
Humans ; Medicine, Chinese Traditional ; Cancer Pain/therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Drug Delivery Systems ; Pain Management/methods* ; China

Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.
Animals ; Female ; Mice ; CA1 Region, Hippocampal/metabolism* ; Cell Adhesion Molecules/metabolism* ; CRF Receptor, Type 1/metabolism* ; Memory Disorders/etiology* ; Mice, Inbred C57BL ; Nectins/genetics* ; Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors* ; Recognition, Psychology/physiology* ; Stress, Psychological/complications*