Clinical data on the efficacy and safety of tenofovir alafenamide fumarate (TAF) in chronic hepatitis B (CHB) patients with suboptimal response to entecavir (ETV) are limited. This study was designed to investigate the efficacy and safety of switching to TAF in CHB patients with low-level viremia (LLV). CHB patients with LLV who received ETV treatment for more than 52 weeks were divided into TAF group (n = 104) and ETV group (n = 395). Propensity score matching (PSM) was performed to adjust for baseline differences in age between the two groups. The outcomes included complete virological response (CVR) at weeks 12 and 24, normalization rates of aminotransferase (ALT) and aspartate aminotransferase (AST), and renal function and blood lipid levels. Compared with the ETV group, the TAF group had significantly higher rates of CVR at week 12 and week 24 in both the raw cohort and the PSM cohort (all P < 0.05). In the PSM cohort, the superiority of TAF over ETV in achieving CVR remained statistically significant at both time points (all P < 0.05). ALT and AST normalization rates were also significantly greater in the TAF group than in the ETV group at week 24 (all P < 0.05). No significant differences in creatinine (Cr) levels or estimated glomerular filtration rate (eGFR) were observed between week 24 and baseline in the raw cohort. No significant changes in blood lipid levels were detected in the TAF group at week 24 (all P > 0.05). Switching to TAF may be beneficial for patients with LLV after prolonged ETV therapy, as it is associated with a significantly higher rate of CVR. No lipid metabolism-related disorders were observed following the switch to TAF.
To investigate the specific biological mechanisms by which Haikun Shenxi capsule (HKSX) alleviates renal fibrosis (RF), with a particular focus on the interplay between gut microbiota regulation and host metabolic modulation. Methods The therapeutic effects of HKSX were evaluated using a unilateral ureteral obstruction (UUO) mouse model. The therapeutic effects of HKSX were evaluated using a unilateral ureteral obstruction (UUO) mouse model. Untargeted metabolomic analyses were performed on serum and fecal samples to identify metabolic changes. Gut microbiota composition was assessed via 16S rRNA sequencing. Renal injury and fibrosis were evaluated by histopathological examination and by measuring the expression of fibrotic markers, including α-smooth muscle actin (α-SMA) and type I collagen (collagen I). HKSX modulates metabolic homeostasis by regulating the concentrations of pyruvic acid and ornithine in mouse serum and feces. These alterations affect key pathways, including the pentose phosphate pathway, tricarboxylic acid (TCA) cycle, and amino acid metabolism, contributing to the restoration of metabolic equilibrium. Concurrently, 16S rRNA sequencing revealed that HKSX improved the gut microbiota composition by increasing microbial diversity and increasing the abundance of beneficial bacteria, particularly Akkermansia. Moreover, HKSX alleviated UUO-induced renal damage and suppressed the expression of α-SMA and collagen I. These findings provide strong evidence that HKSX exerts its renoprotective effects through bidirectional regulation of gut microbiota and host metabolism. The integration of traditional Chinese medicine (TCM) with modern systems biology offers fresh perspectives for developing improved natural therapies for RF and related metabolic disorders.
Cancer cells exhibit metabolic reprogramming, most notably the Warburg effect, which underscores their heightened dependency on glucose uptake facilitated by glucose transporters (GLUTs). While targeting GLUTs holds promise for disrupting tumor metabolism, monotherapeutic inhibition often leads to compensatory resistance mechanisms, metabolic plasticity, and dose-limiting toxicity. This review comprehensively examines the rationale and mechanisms underlying combined strategies that integrate GLUT inhibitors with conventional chemotherapy, targeted therapy, immunotherapy, and radiotherapy. Such combinations exploit synthetic lethality, reverse immunosuppression, enhance DNA damage, and overcome adaptive resistance. We also discuss emerging approaches such as isoform-specific inhibitors, nanocarrier-based delivery, and artificial intelligence-guided combination design to improve selectivity and efficacy. Finally, we highlight key translational challenges and discuss how cross-disease insights into GLUT biology may inform the safety, selectivity, and therapeutic design of cancer-directed GLUT-targeted combination strategies.
This study aimed to investigate the efficacy and safety of Jiannao Tongluo (JNTL) granules in patients with convalescent cerebral infarction and to explore the underlying mechanisms. A randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted from November 2024 to November 2025. A total of 110 eligible patients were randomly assigned at a 1:1 ratio to receive either JNTL granules or placebo control for 12 weeks on the basis of standard secondary prevention and comprehensive rehabilitation. The primary outcome was the variation in the Montreal Cognitive Assessment (MoCA) score. The secondary outcomes included the Vascular Dementia Assessment Scale-Cognitive Subscale (VaDAS-cog), Mini-Mental State Examination (MMSE), Fugl-Meyer Assessment (FMA), modified Barthel index (MBI), and TCM symptom score (SYM), which were measured at baseline and at weeks 4, 12, and 24. Serum inflammatory factors (hs-CRP, IL-6, IL-1β, TNF-α, and SAA) and neurotrophic factors (BDNF and VEGF) were measured at baseline and week 12. The activation of the cerebral cortex was evaluated by functional near-infrared spectroscopy (fNIRS) at baseline and week 12. Safety was monitored throughout the trial. A total of 97 patients (48 in the JNTL granule group and 49 in the control group) completed the trial, for a dropout rate of 11.8
To investigate whether nuclear receptor coactivator 1 (NCOA1) participates in the pathogenesis of diabetic kidney disease (DKD) by modulating extracellular matrix (ECM) production in mesangial cells (MCs), and to explore the underlying molecular mechanism. The rat glomerular MCs and streptozotocin-induced DKD mouse models were employed. NCOA1 expression was evaluated under both normal and high-glucose conditions. The functional role of NCOA1 was assessed via plasmid-mediated overexpression in high-glucose treated MCs. Integrin alpha 5 (ITGA5) expression was examined in vivo and in vitro, and its regulatory relationship with NCOA1 was investigated. Furthermore, siRNA-mediated knockdown of ITGA5 was performed to determine its necessity in high-glucose driven ECM overproduction. NCOA1 was abundantly expressed in resting MCs but markedly downregulated upon high-glucose stimulation. Plasmid-driven overexpression of NCOA1 significantly attenuated high-glucose induced ECM protein synthesis. Notably, ITGA5 expression was substantially elevated in the glomerular mesangium of DKD mice and in high-glucose exposed MCs, and this upregulation was negatively governed by NCOA1. Functionally, ITGA5 silencing effectively abrogated the excessive matrix production provoked by high glucose, phenocopying the protective effect of NCOA1 overexpression. NCOA1 protects against high-glucose induced mesangial expansion in DKD, at least partially, through negative regulation of ITGA5. These findings identify the NCOA1/ITGA5 axis as a potential therapeutic target for counteracting glomerular fibrosis in DKD.
Migraine is among the most prevalent neurological disorders and can affect people’s daily activities because of high- and long-lasting pain intensity attacks. The available dosage forms, such as oral and parenteral formulations, can enhance patients’ symptoms but still have poor side effects, bioavailability, or dosing difficulty. As a result, there is an urgent need to find other novel drug delivery systems (DDSs) to treat migraine. The intranasal (IN) route was investigated as an alternative pathway to deliver therapeutic molecules directly to the brain, bypassing the blood–brain barrier (BBB) and hepatic first-pass metabolism. Nanocarriers facilitate drug transportation regardless of their lipophilicity, resulting in more efficient drug absorption and bioavailability. They also effectively contribute to brain targeting, which maximizes the therapeutic effect of drugs. This review discusses the efficacy of nanocarriers loaded with antimigraine agents and delivered by the IN route in the management of migraine. In preclinical studies, nanocarriers such as liposomes, ethosomes, nanostructured lipid carriers, and many others have been used to enhance brain targeting. Studies have focused on obtaining high results for brain pharmacokinetics, such as drug targeting efficiency (DTE) and direct transport percentage (DTP). This leads to better drug accumulation and a rapid onset of action. Despite the proven success of preclinical studies on the delivery of migraine drugs loaded with nanocarriers through the IN route, there is still a shortage in translating this success into the clinical stage.
To develop and internally validate an interpretable machine-learning model using routine precollection variables to predict mononuclear cell (MNC) collection efficiency (CE) during leukapheresis for CAR-T manufacturing. This retrospective study included 206 consecutive patients who underwent leukapheresis between 2022 and 2025. Candidate variables were screened with Pearson correlation, Boruta, recursive feature elimination, and variance-threshold filters. Six supervised algorithms were trained with nested cross-validation, using an inner fivefold loop for tuning and an outer tenfold loop repeated three times for performance estimation. Bootstrap resampling (1000 iterations) generated confidence intervals, and SHAP analysis was used for interpretation. Extreme gradient boosting (XGBoost) showed the best continuous prediction performance, with an R2 of 0.67 (95
To evaluate the associations between transcription factor (TF)-defined molecular lineages and the clinical characteristics of pituitary neuroendocrine tumors (PitNETs). A retrospective cohort analysis was performed in 274 patients who underwent extra-pseudocapsular transsphenoidal resection. Tumors were classified by TF-defined lineage and invasion grade (0–3) and Knosp score. Group differences were tested, and predictors of gross total resection (GTR) were examined using hierarchical multivariable logistic regression. TF-defined lineage classification improved diagnostic precision. Among tumors with an immunonegative hormone profile, 74.7
To investigate the feasibility of 2D convolutional neural networks (CNNs) in the automatic classification of anterior talofibular ligaments (ATFLs) on MR images. A total of 560 transverse T2-weighted MR images of the ATFL were collected from Center A, and 96 from Center B; manual segmentation of the ATFL was performed. The ATFL segmentation model was trained on YOLO11 and was validated on images from Center B. The dice similarity coefficient (DSC) between manual and automatic segmentation was calculated. A total of 1,103 T2-weighted MR images of the ATFL were further collected from Center C and divided into three groups: normal, partial, and total tear, and ATFL was automatically segmented for all the images. The 2D ResNet model was then trained for ATFL classification. Finally, the segmentation model and classification model were applied to 420 images from Center D. The median DSC for the YOLO11 segmentation model was 0.95. For Center D data, the automatic workflow achieved an accuracy of 92.6
Sepsis is a dysregulated response of the host to infection that can lead to life-threatening organ dysfunction and remains a leading cause of mortality. Early recovery of impaired organ function is crucial for the outcomes of sepsis. Electroacupuncture (EA) is a promising adjunctive therapy for sepsis, but no study has focused on the efficacy of EA for organ dysfunction. This study aimed to investigate the efficacy and safety of EA in improving organ dysfunction among intensive care unit (ICU) patients with sepsis. In this single-center, randomized, sham-controlled clinical trial, an adaptive sample size of 154–500 patients diagnosed with sepsis will be included. Eligible patients will be randomly assigned to receive EA or sham EA treatment at a 1:1 ratio using block randomization. Patients in the two groups will receive 6 consecutive sessions of 30-min EA or sham EA treatment, with the initial acupuncture treatment being completed within 24 h after randomization. The primary outcome is the change in the total score of the Sepsis-Related Sequential Organ Failure Assessment (SOFA) on day 7 after randomization compared with baseline. Secondary outcomes include changes in the SOFA score and related serological outcomes, mortality, ICU-free days, hospital-free days and organ support-free days from baseline to day 28. Statistical analyses will be performed on a full analysis set (FAS) and a per-protocol set (PPS). We expect the findings of this trial to provide evidence that the use of EA as an adjunctive therapy to ICU treatment can promote the recovery of organ function and other outcomes in sepsis patients. ClinicalTrials.gov identifier: NCT06666946. Registered on 28 October 2024.
Previous studies have confirmed the opioid-sparing and analgesic properties of perioperative esmolol, yet relevant clinical evidence specifically focusing on patients with ischemic heart disease (IHD) remains scarce, and the spinal nociceptive mechanism underlying esmolol-induced pain relief has not been fully elucidated. This study aimed to investigate the association between perioperative esmolol administration and early postoperative opioid demand in IHD patients undergoing elective non-cardiac surgery, and further explore the role of spinal 5-hydroxytryptamine (5-HT)/5-HT2B signaling in incisional pain using a female rat plantar incision model. For the clinical retrospective cohort, eligible IHD patients were divided into esmolol-exposed and non-exposed groups balanced via 1:1 propensity score matching. The primary outcome was cumulative 24-h postoperative opioid consumption converted to intravenous morphine equivalents (IME); secondary endpoints included early Numeric Rating Scale (NRS) pain scores, opioid-related adverse events and perioperative cardiovascular safety indicators. In animal experiments, intrathecal esmolol or selective 5-HT2B antagonist RS127445 was delivered to the female rats with plantar incision, followed by detection of mechanical withdrawal thresholds and spinal 5-HT/5-HT2B expression. After matching, 52 patients were included in each group. Perioperative esmolol was associated with a 3.0 mg reduction in 24 h IME (mean difference [MD] = −3.0, 95
Emerging evidence suggests the involvement of the renin-angiotensin system (RAS) in the pathogenesis and progression of autoimmune dermatological diseases. In a small exploratory study, we investigated angiotensin-converting enzyme (ACE) activity in blood obtained from male probands with psoriasis vulgaris (n = 4) and atopic dermatitis (AD, n = 5). The degradation capacity of dabsylated synthetic bradykinin (DBK) with and without inhibition was determined using a thin-layer chromatography (TLC)-based neuropeptide reporter assay. We observed a significantly reduced capacity for cleavage of DBK in psoriasis patients compared with that in AD patients and controls. In patient samples, the variation in the measured values was generally greater than that in healthy controls. We could not confirm the increased ACE activity in the circulation in psoriasis patients reported by others, likely because of different study designs and detection methods. We did not include samples of female patients and focused on younger men to avoid hormonal effects and minimize age-related factors. This preliminary study of the hypothesis-generating nature lacks power, but it certainly adds a question to the current view of the role of ACE in psoriasis. Treatments targeting specific components of the RAS could ameliorate inflammatory responses; thus, research in this area is becoming increasingly important.
Hysterectomy significantly increases the risk of pelvic organ prolapse (POP). However, the underlying molecular changes remain unclear. The aim of this study was to elucidate potential molecular associations by comparing single-cell transcriptomic profiles of vaginal tissues from postmenopausal women across three groups: normal controls, POP patients with an intact uterus, and post-hysterectomy POP patients. A single-cell transcriptomic dataset of prolapsed vaginal tissues was used to analyze genes that were differentially expressed between fibroblasts and macrophages in the two prolapse types. Key transcriptional regulators of myofibroblast differentiation were identified. Cell subtypes were identified, and macrophage polarization states were assessed to evaluate immune responses in different POP subtypes. Post-hysterectomy POP patients exhibited impaired myofibroblast differentiation, downregulated expression of wound-healing genes, and disrupted extracellular matrix (ECM) remodeling. In contrast, uterus-intact POP patients showed stronger immune activation, enhanced fibroblast‒macrophage crosstalk, and upregulated expression of genes related to leukocyte-mediated immunity. Key transcriptional regulators were linked to myofibroblast differentiation. Macrophage profiling revealed predominant M2 polarization in post-hysterectomy patients, indicating a potential compensatory response to biomechanical instability, whereas uterus-intact POP patients maintained more active immune responses. This study revealed that hysterectomy alters vaginal homeostasis through ECM disorganization, impaired wound healing, and macrophage reprogramming. Our findings highlight distinct molecular changes in fibroblasts and macrophages between uterus-intact POP patients and post-hysterectomy POP patients, advancing the understanding of POP pathogenesis.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality rates. While previous studies have focused primarily on the epidemiological and clinical aspects of SFTS, indicators of renal injury at admission have received limited attention. We retrospectively analyzed 260 patients with SFTS admitted to the study hospital between April 1, 2023, and July 18, 2024, who were classified into the survival group (n = 163) and death group (n = 97) on the basis of 28-day prognosis. Renal-related data were collected upon admission. Univariate and multivariate Cox regression analyses were used to identify independent predictors, and a nomogram was constructed. Receiver operating characteristic (ROC) curves and calibration curves were used to assess the discrimination and calibration of the model. Kaplan–Meier curves were used to assess the cumulative survival rate of patients with these risk factors. External validation was conducted in 40 patients with SFTS who were admitted to an affiliated branch hospital during the same period. The 28-day mortality rate was 37.3
A significant gap exists in medical support for organ transplant patients during out-of-hours (OOH). General large language models (LLMs), affected by AI hallucinations, are unsuitable for complex post-transplant care. We built the first post-transplant AI agent based on LLMs to address these issues. We constructed a specialized “post-transplant AI agent” (named Doctor Xiao Yi) and conducted a mixed-methods study comparing it to a hospital-wide general AI agent (named Nan Xiao Yi). Data included 20,176 real-world logs (June–December 2025) and a cross-sectional survey of 152 transplant patients. We examined patterns of use over time, the types of questions raised, and the factors influencing patient behavior. Unlike Nan Xiao Yi, Doctor Xiao Yi remained active during OOH, with a peak at 4:00 AM (P < 0.001). The general agent handled admin tasks like appointments, while the specialist agent provided clinical support such as diet, symptoms, and medication. Survey found 60.5
Transpapillary therapy remains a critical treatment modality for main pancreatic duct (MPD) injury after acute necrotizing pancreatitis. This study aimed to verify the factors linked to the technical success of transpapillary drainage by endoscopic retrograde cholangiopancreatography (ERCP) in managing MPD injury, and the impact of technical success on tube duration and overall survival. A retrospective analysis was conducted on patients who underwent ERCP for MPD injuries following acute pancreatitis from May 2019 to April 2021. Univariate and multivariate logistic regression analyses were employed to identify factors associated with successful treatment. Kaplan–Meier curves were used to analyze the impact of technical success on tube duration and overall survival. We included 63 patients in whom MPD opacification was achieved (43 technical successes and 20 failures). The technical success group had a significantly higher proportion of patients whose interval from onset of acute pancreatitis to endoscopic transpapillary drainage (IOP) was less than 90 days (58.14
Bone morphogenetic proteins (BMPs) are bone-derived osteokines that regulate energy metabolism and combat obesity by promoting brown adipocyte differentiation. BMP4, BMP7, BMP8B, and BMP9 are highly expressed in osteoblasts and bone matrix, from which they are released into circulation. They act as endocrine factors that induce brown adipogenesis, increase mitochondrial biogenesis, and increase thermogenesis via conserved signaling pathways (Smad, MAPK, and PGC1α). Concurrently, these BMPs maintain skeletal homeostasis and mediate crosstalk between bone and metabolic organs, including adipose tissue and the hypothalamus, thereby regulating appetite and energy balance. Preclinical studies have confirmed that BMP-based interventions can increase energy expenditure, improve insulin sensitivity, and alleviate obesity-related complications. However, clinical translation remains hindered by adverse effects, short half-lives, and obesity-induced BMP resistance. This review first elucidates the peripheral and central regulatory mechanisms of BMPs in energy metabolism, clarifies the subtype-specific metabolic effects of major BMPs, further evaluates their therapeutic potential against obesity and metabolic syndrome, and finally analyzes the core obstacles to clinical implementation and corresponding solution strategies.
BackgroundPeptic ulcer disease (PUD) represents an ongoing global public health concern and is responsible for significant illness and mortality. Despite considerable advancements in medical therapy, the distribution and overall burden of PUD vary substantially across different regions and population segments worldwide. This research provides a comprehensive analysis of the global PUD burden, examining trends from 1990 to 2021 and forecasting patterns until 2050. The findings of this research, which use the most up-to-date epidemiological data available, are significant for epidemiology and disease management.MethodsWe leveraged data from the Global Burden of Disease (GBD) 2021 study, which covers 195 countries and territories. Our analysis assessed key metrics of disease impact, including disability-adjusted life years (DALYs), mortality rates, incidence and prevalence data, years lived with disability (YLDs), and years of life lost (YLLs). We calculated age-standardized rates (ASRs) to allow for consistent comparisons across populations. Temporal changes were quantified using estimated annual percentage changes (EAPCs) derived from linear regression. Furthermore, we applied hierarchical cluster analysis to investigate regional patterns in the PUD burden. These methods were chosen because of their robustness and ability to provide a comprehensive understanding of the global burden of PUD.ResultsPUD was responsible for an estimated 6.06 million DALYs in 2021 (ASR: 71.56 per 100,000). This burden increased substantially with advancing age, peaking among individuals aged 80 and above. Compared with females, males had higher DALY rates (ASR: 87.02 vs 57.05 per 100,000) and considerably higher mortality rates. Regions with low and low-middle sociodemographic index (SDI) presented the highest ASRs (e.g., 178.38 per 100,000 in low-SDI areas). The highest DALY rates were observed in South Asia and parts of sub-Saharan Africa. Between 1990 and 2021, the global DALY ASR decreased markedly (EAPC: -2.96), though absolute DALY numbers remained elevated in populous, low- to middle-SDI regions. Model-based projections (exponential smoothing and ARIMA), assuming the continuation of recent trends, suggest that ASRs may continue to decline through 2050.ConclusionsOver the past three decades, the global age-standardized burden of PUD has markedly decreased. However, significant challenges remain, particularly for older adults, males, and individuals in low-SDI areas, such as South Asia and sub-Saharan Africa. Although forecasts suggest further reductions in ASRs, the overall burden, influenced by population changes, underscores the crucial need for ongoing, targeted prevention and control efforts. This should prioritize Helicobacter pylori detection and eradication, safer NSAID use with gastroprotection in high-risk patients, and improved access to timely diagnosis and emergency care for ulcer complications in low-SDI regions. These efforts should focus on high-risk groups and regions to ensure equitable progress and should be a priority for all healthcare professionals, researchers, and public health policymakers.
