Background: Advances in intensive care have markedly improved survival after severe brain injury, leading to a growing population of patients with prolonged disorders of consciousness (pDOC). Current management of pDOC remains largely supportive, and evidence-based neuromodulatory interventions are limited; moreover, existing guidelines provide insufficiently explicit recommendations regarding mechanisms of action and objective biomarkers of treatment response. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a potential noninvasive intervention; however, its modulatory effects on brain function in pDOC are not yet well characterized, and the paucity of integrative mechanistic evidence has constrained its translation into routine clinical practice. Objectives: Within a multimodal assessment framework, this study aims to systematically elucidate the neurobiological mechanisms by which taVNS modulates brain function and autonomic activity in patients with pDOC, and to evaluate its clinical potential to enhance levels of consciousness. Methods: In this randomized controlled trial, 60 patients with vegetative state/minimally conscious state will be enrolled and randomly allocated to a taVNS group, a transcutaneous nonauricular vagus nerve stimulation group (sham), or a control group (n = 20 per group) for a 4-week intervention. The primary outcome will be changes in the Coma Recovery Scale-Revised scores from baseline to weeks 1, 2, and 4 of treatment. Secondary outcomes will include functional brain activity assessed by electroencephalography and functional near-infrared spectroscopy, as well as autonomic modulation indexed by heart rate variability. Functional prognosis will be evaluated using the Glasgow Outcome Scale-Extended at the end of treatment and at a 6-month follow-up. Safety will be assessed by continuous monitoring and documentation of adverse events throughout the study period. Results and discussion: By integrating electroencephalography–functional near-infrared spectroscopy with heart rate variability, this study will characterize the effects of taVNS on functional brain networks and consciousness recovery in pDOC across complementary behavioral, electrophysiological, hemodynamic, and autonomic domains, while interrogating potential sources of clinical and neurobiological heterogeneity. The findings are expected to provide a mechanistic and evidence-based foundation for the mechanism-driven clinical implementation of taVNS and the optimization of stimulation protocols in pDOC. Clinical trial registration: International Traditional Medicine Clinical Trial Registry, ITMCTR20250021041, https://itmctr.ccebtcm.org.cn.

Ferroptosis has been shown to mediate the development of fibrosis. Polyphyllin VII (PP7), a bioactive component of Paris polyphylla, exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis. In this study, treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells (HSCs), which could be suppressed by a ferroptosis inhibitor. In addition, it promoted HSC ferroptosis by suppressing glutathione (GSH) peroxidase 4 (GPX4) and enhanced the expression of CX3C chemokine ligand 1 (CX3CL1). Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4. Notably, CX3CL1 directly interacted with GPX4, triggering HSC ferroptosis. The transcription factor hypermethylated in cancer 1 (Hic1), which binds to the Cx3cl1 promoter, increased the expression of CX3CL1. Its absence resulted in downregulation of CX3CL1, suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation. HIC1 was found to directly interact with PP7 at the GLY164 site. Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes. HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo. These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.

Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective To explore the application of cell block(CB)technology in the diagnosis of papillary thyroid carcinoma(PTC).Methods A total of 86 patients with thyroid nodules who were treated at Luoyang Central Hospital Affiliated to Zhengzhou University from February 2023 to December 2024 were retrospectively selected.Before the operation,all patients underwent ultrasound-guided fine needle aspiration biopsy.After the biopsy,the specimens were respectively subjected to cell smear(CS)and CB pathological examinations.Using postoperative pathology as the gold standard,the clinical application value of CS,CB,BRAFV600E gene detection,and combined detection in the preoperative diagnosis of PTC was evaluated.Results A total of 86 patients were included.Among them,42 cases were diagnosed as PTC by postoperative pathology,and 44 cases were benign lesions.The sensitivity(73.81％),specificity(97.73％),positive predictive value(96.88％),negative predictive value(79.63％),and accuracy(86.05％)of CB in the preoperative diagnosis of PTC were significantly higher than those of CS.The Kappa consistency test results showed that the consistency between CB pathological results and postoperative pathological results was better than that of CS.Receiver operating characteristic curve analysis indicated that the area under the curve(AUC)of CB was significantly higher than that of CS(0.858 vs.0.743,Z=2.391,P=0.017).Furthermore,the combination of CB and BRAFV600E gene detection further improved preoperative diagnostic performance,with a consistency with postoperative pathological results(Kappa=0.837)superior to other examination methods,and an AUC(0.918)significantly higher than other examination methods.Conclusion CB has significant clinical application value in the preoperative diagnosis of PTC,with diagnostic performance significantly superior to CS.Further combination with BRAFV600E gene detection can significantly improve preoperative diagnostic accuracy.

Objective:To summarize the clinical characteristics of elderly patients with stage Ⅰ diffuse large B-cell lymphoma (DLBCL) and analyze the factors associated with prognosis.Methods:A case series study was conducted by retrospectively collecting clinical data from patients aged over 60 years with newly diagnosed stage Ⅰ DLBCL across 20 medical centers in Jiangsu Province, China, between June 2010 and April 2023. The involved site, classification and treatment plan were summarized. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan-Meier method, and Cox regression model.Results:The study included 255 patients with a median age of 69 years, of whom 130 (51.0%) were male, 66 (25.9%) were aged ≥75 years and 26 (10.1%) had a high Charlson Comorbidity Index (CCI) score of ≥2. Extranodal involvement was observed in 163 (63.9%) patients, with the stomach (37.4%, 61/163), intestine (19.0%, 31/163), testes (11.0%, 18/163), and breast (7.4%, 12/163) being the most frequently affected sites. The non-germinal center B-cell (non-GCB) subtype was prevalent in 63.7% of patients (142/223), with no significant difference between the nodal and extranodal groups ( P=0.681). Furthermore, 73.9% (184/249) and 11.7% (29/249) of patients received the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and R-miniCHOP regimen, respectively. The overall 3-year PFS rate was 81.5%, and the 3-year OS rate was 85.6%. Patients aged ≥75 years ( HR=2.910, 95% CI 1.565-5.408, P=0.001) and/or with a CCI score ≥2 ( HR=2.324, 95% CI 1.141-4.732, P=0.020) had a significantly poorer PFS. Incorporating age ≥75 years and CCI score ≥2 into the stage-modified international prognostic index (sm-IPI) can better stratify the prognosis of elderly patients with stage Ⅰ DLBCL. The 3-year PFS rate was 48.7% in the high-risk group versus 85.7% in the low-risk group ( P<0.001). Conclusions:Our findings show that the elderly patients with stage Ⅰ DLBCL were predominantly characterized by extranodal involvement (particularly in the stomach and intestinal tract) and non-GCB subtype. Age ≥75 years and CCI ≥2 were identified as independent prognostic factors. The newly established sm-IPI-75-CCI incorporating these factors demonstrated superior prognostic discrimination compared to conventional risk assessment systems.

With the rapid evolution of medical information technology, internet hospitals had become an integral part of China′s healthcare service system and could play a unique role in multidisciplinary diagnosis and treatment (MDT). In 2023, Nanjing Drum Tower Hospital built a smart service platform for MDT based on its internet hospital under the design concept of " global collaboration, process re-engineering, and smart empowerment", and officially launched in November of the same year. The platform included a five-tier architectur: user interaction, application services, data management, system integration and infrastructure, and embeds functional modules such as consultation management, an AI-assisted engine and a workflow engine. This platform covered Nanjing Drum Tower Hospital Group members, implemented an online-offline integrated, end-to-end workflow (pre-intra-post consultation). It realized the integration and utilization of high-quality medical resources across regions and institutions, and improved the quality and efficiency of MDT. As of December 2024, the platform had covered 30 specialties and completed 75 MDT consultations. The consultation cycle had been shortened from the traditional MDT mode of 14.2 days to 2.4 days, effectively reducing the number of patients traveling to and from the hospital. This platform had expanded the business scope of internet hospitals, improved the utilization rate of medical resources, and could provide references for other public hospitals in China to optimize the MDT service mode.

Ferroptosis has been shown to mediate the development of fibrosis.Polyphyllin Ⅶ(PP7),a bioactive component of Paris polyphylla,exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis.In this study,treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells(HSCs),which could be suppressed by a ferroptosis inhibitor.In addition,it promoted HSC ferroptosis by suppressing glutathione(GSH)peroxidase 4(GPX4)and enhanced the expression of CX3C chemokine ligand 1(CX3CL1).Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4.Notably,CX3CL1 directly interacted with GPX4,triggering HSC ferroptosis.The transcription factor hypermethylated in cancer 1(Hic1),which binds to the Cx3cl1 promoter,increased the expression of CX3CL1.Its absence resulted in downregulation of CX3CL1,sup-pressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation.HIC1 was found to directly interact with PP7 at the GLY164 site.Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes.HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo.These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.

Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolu-tionizing drug discovery and treatment strategies.However,the links between in vitro and in vivo data are poorly understood,hindering a comprehensive understanding of the absorption,distribution,metabolism,and excretion(ADME)of PROTACs.In this work,14C-labeled vepdegestrant(ARV-471),which is currently in phase Ⅲ clinical trials for breast cancer,was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics(PK)by estab-lishing a physiologically based pharmacokinetics(PBPK)model.For in vitro-in vivo extrapolation(IVIVE),hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did.PBPK models,which were initially developed and validated in rats,accurately simulate ARV-471's PK across fed and fasted states,with parameters within 1.75-fold of the observed values.Human models,informed by in vitro ADME data,closely mirrored postoral dose plasma profiles at 30 mg.Furthermore,no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans.This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

Objective: To analyze the association between each regional fat mass and total body bone mineral density (BMD) in children and adolescents aged 7-17 years in Beijing, so as to provide theoretical basis and practical guidance for implementing interventions. Methods: From September to December 2020, a stratified cluster random sampling method was used to select 1 423 children and adolescents aged 7-17 years in Tongzhou District, Beijing. Dual energy X-ray absorptiometry (DXA) was employed to measure regional body composition and total body BMD. Multiple linear regression was used to analyze the association between regional fat mass and total body BMD. Results: The median (interquartile range) fat mass values for total body, upper limbs, abdomen, hips, and thighs were 13.51(8.84, 19.21), 1.59(1.08, 2.23), 0.73(0.39, 1.29), 2.32(1.46, 3.26), 5.29(3.59, 7.21)kg, respectively. After adjusting for covariates, the results of multiple linear regression analysis showed that total body fat mass (β=0.010), abdominal fat mass (β=-0.100), and hip fat mass (β=0.104) were significant associations with total body BMD (all P<0.01). Sexstratified analysis revealed that in boys, total body fat mass (β=0.008) and hip fat mass (β=0.058) were positively associated with BMD, while thigh fat mass (β=-0.038) showed a negative association with total body BMD (all P<0.05). In girls, total body fat mass (β=0.013), hip fat mass (β=0.163), and thigh fat mass (β=0.023) were positively associated with total body BMD, whereas abdominal fat mass (β=-0.196) showed a negative association with total body BMD (all P<0.05). Among children and adolescents with body fat percentage below the standard range, within the standard range and above the standard range, total body fat masses were positively associated with total body BMD (β=0.021, 0.016, 0.015); among children and adolescents with body fat percentage within the standard range while upper limb (β=-0.042), abdominal (β=-0.067), and thigh fat mass (β=-0.018) showed negative associations with total body BMD, and hip fat mass demonstrated a positive association with total body BMD (β=0.082) (all P<0.05). Conclusion Regional fat distribution is associated with total body BMD in children and adolescents, with the nature of these associations varying by sex and body fat percentage.