Chronic stress is a major risk factor for insomnia, yet the molecular mechanisms linking stress-induced gut dysbiosis and bile acid (BA) metabolism to circadian disruption remain poorly understood. A rat model of chronic unpredictable mild stress combined with modified multiple platform sleep deprivation was established. Sleep-wake patterns were assessed by PiezoSleep monitoring. Anxiety- and depression-like behaviors were evaluated using the open field test, elevated plus maze, and tail suspension test. Spatial memory was tested with the Morris water maze. Gut microbiota was profiled via 16S rRNA sequencing. Serum total BAs were measured by enzymatic cycling, and hypothalamic BA metabolites were quantified by targeted UPLC-MS/MS. The BA sequestrant cholestyramine was administered to evaluate therapeutic effects. To test BA sufficiency, a separate cohort received oral deoxycholic acid (DCA) for three days with subsequent sleep and molecular assessments. Model rats showed marked sleep loss, a reversed day/night sleep ratio, anxiety- and depression-like behaviors, and cognitive deficits. Their gut microbiota exhibited reduced Firmicutes along with increased Bacteroidetes and Proteobacteria. Serum total BAs and hypothalamic levels of deoxycholic acid were significantly elevated. This was accompanied by upregulation of TGR5, ERK, and CK1ε, depletion of nuclear PER2, and disrupted the rhythmic secretion of Clock and Bmal1. Cholestyramine lowered BA loads, restored PER2 nuclear localization, normalized the rhythmic gene expression of Clock and Bmal1, and reversed all behavioral and sleep abnormalities. Importantly, DCA alone phenocopied the core sleep, molecular, and circadian disturbances observed in the model rats. BA overload, especially DCA, drives circadian and sleep disturbances via the hypothalamic TGR5-ERK-CK1ε-PER2 pathway. BA sequestering represents a promising strategy for treating insomnia with comorbid negative emotional states.

In clinical research on TCM, RCT remains the key way to obtain evidence of causal effect. However, the implementation is often constrained by factors such as resource input, syndrome heterogeneity, and long-term outcome observation, so that single trials rarely provide sufficient support for clinical decision-making and entail higher trial-and-error costs. With the rapid accumulation of RWD in China and ongoing advances in causal inference and modeling methods internationally, there is an urgent need for a systematic methodological framework for TCM and other complex interventions that can shift part of this costly trial-and-error process from conventional clinical trial paths and expand the theoretical and technical space for efficacy evaluation of TCM. The concept of VEE was proposed and defined as a methodological framework that, when RCT cannot be adequately, promptly or widely conducted, or when existing trials cannot answer all key clinical questions, based on RWD, the virtual modeling techniques such as causal inference, digital-twin, and artificial intelligence was used to reconstruct intervention processes in a model space according to clinical trial logic and to simulate the causal effects of TCM interventions and their associated uncertainties. On this basis, a four-layer framework comprising a data foundation layer, causal identification layer, virtual modeling layer, and inferential application layer was constructed. The paper systematically clarified how VEE, under a target-trial perspective, integrated multi-source data, defined estimable effects, and reconstructed virtual disease courses and treatment pathways, and how it can be embedded into key sections such as trial question formulation, design optimization, result interpretation, and individualized decision-making, thereby providing methodological support to maximally reduce trial-and-error risk in physical clinical studies and to improve the clinical research efficiency and evidence continuity of TCM.

Background: Sepsis mortality is concentrated in Asia, Africa, and the Middle East. Trial activity has expanded beyond historically dominant regions, but whether this expansion has produced evidence aligned with burden, and comparable across regions, is unknown. Methods: In this cross-sectional analysis, we searched PubMed, Web of Science, Embase, and medRxiv from inception to Dec 31, 2025, for randomized trials of pharmacological interventions in sepsis or septic shock. Regional participant shares were compared with GBD 2021 sepsis mortality shares using participation-to-prevalence ratios (PPRs; <0·8 indicating underrepresentation) with bootstrap 95% CIs. Trial infrastructure, funding, therapeutic class, severity, and reporting were compared across regions. Findings: 197 trials (72 688 participants) were included. Asia & Oceania and Africa & the Middle East accounted for 76% of trials in 2021–25 versus 11% before 2000. Participant contributions nonetheless remained misaligned with mortality: Asia & Oceania contributed 26.2% of participants despite 42.2% of deaths (PPR 0.62 [95% CI 0.41–0.82]), and Africa & the Middle East 7.2% despite 29.9% (0.24 [0.13–0.38]), whereas western Europe and North America contributed 58.1% despite 9.6%. Trials in higher-burden regions were smaller, more often single-center, less often industry-funded, differed in therapeutic focus, had lower baseline APACHE II scores, and rarely reported race. Adults aged 70 years or older were underrepresented (0.68 [0.61–0.76]); women were underrepresented against a population benchmark but not against an intensive care benchmark. Interpretation: Geographic expansion alone has not produced a representative or readily transportable sepsis evidence base. Sustained multicenter trial capacity and transparent, region-specific reporting in high-burden settings are needed.

Introduction Sepsis patients with diabetes are at a high clinical risk. It is well reported that XueBiJing injection has good clinical benefit in sepsis individuals. However, there is no relevant report about the efficacy and safety of XBJ in sepsis patients with comorbid diabetes.Methods Data of two large randomized controlled clinical trials (XBJ-SAP (ChiCTR-TRC-13003534) and EXIT-SEP (NCT0323874)) were combined, and post hoc analyses were performed. Sepsis patients with diabetes were further divided into the XBJ-treated group and placebo group based on inclusion and exclusion criteria. The primary (28-day mortality) and secondary outcomes (mortality in the ICU and in the post-randomization hospital, acute physiology, and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score) were compared between the XBJ treatment and placebo groups in sepsis patients with the diabetes status at baseline. Moreover, the occurrence of adverse events (AEs) was also assessed.Results At the study baseline, a total of 378 sepsis patients (227 men [60.0%] and 151 women [40.0%]; mean [SD] age, 60.3 [11.1] years) were considered to have diabetes, of which 177 received XBJ and 201 received placebo administration. Among these sepsis patients with diabetes, the mortality at 28 days was significantly lower in the XBJ group than in the placebo group (29 of 173 patients [16.8%] vs. 56 of 198 patients [28.3%], P = 0.01), and the absolute risk difference was 11.5% (95% CI, 3.1%-19.9%). Furthermore, there was no difference in the overall incidence of adverse events (AEs) when XBJ was used (24.4% [42 of 172 patients] vs. 27.7% [54 of 195 patients].Discussion The present study underscores the pivotal role of XBJ in modulating the immune response among sepsis patients suffering from diabetes mellitus, exploring the positive effects of XBJ on sepsis patients with diabetes mellitus. The efficacy and safety of XBJ compared with those of the placebo were consistent with the overall trial findings, demonstrating that XBJ is efficacious in sepsis patients with diabetes and suggesting that there is no need for special safety precautions.Trial Registration Identifier ChiCTR-TRC-13003534 and NCT0323874.

Background The prevalence of diabetic cognitive impairment (DCI) is significant, some studies have shown that it is related to mitochondrial respiratory chain homeostasis, but the specific mechanism is not clear. 2-hydroxyisobutyric acid (2-HIBA) is a novel short-chain fatty acid with potential applications in the treatment of metabolic diseases because it can regulate mitochondrial disorders. Our aim was to explore a novel mechanism of action for 2-HIBA in the treatment of DCI in mitochondrial respiratory chain homeostasis. Methods Metabolic substances and differentially active metabolic pathways in the serum of diseased mice were identified based on multi-omics analysis. The nanoLC-Obitrap-MS technology was utilized to detect the content of selected small molecules with differential metabolic activity in the hippocampus and mitochondria of mice to evaluate their permeability through the blood-brain barrier (BBB) and outer mitochondrial membrane. A combination of behavioral, proteomic, and molecular biology approaches was used to explore specific regulatory mechanisms and identify potential pharmacological targets. Additionally, using techniques such as protein thermal shift, drug affinity responsive target stability (DARTS), hydrolase stability, and surface plasmon resonance (SPR) experiments, we demonstrated the direct binding effects of small molecule metabolites with protein targets. Results 2-HIBA was found to directly ameliorate cognitive dysfunction in db/db mice by penetrating the blood-brain barrier and reversing the decrease in the protein content of NADH dehydrogenase 3 (MT-ND3) in the hippocampus through direct binding to ND3. This action helps maintain the stability of NAD+/NADH and regulate the mitochondrial respiratory chain balance. Furthermore, a combined medication plant agonist of 2-HIBA can enhance the expression of MT-ND3, thereby improving cognitive dysfunction in mice. Conclusion MT-ND3 is a crucial target for improving diabetic cognitive dysfunction, and 2-HIBA can directly bind to the MT-ND3 protein to alleviate the functional impairment of the mitochondrial respiratory chain in mice to treat DCI.

Background:To explore the underlying mechanism and changes of anxiety and insomnia before and after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, we conducted an online cross-sectional survey. Methods:This is a cross-sectional study conducted in two phases: the first phase was from May to June 2020 (before vaccination) and the second phase was from June to August 2021 (after vaccination). In total, 2245 participants were enrolled before vaccination, and 7207 participants were enrolled after vaccination. Anxiety was measured using the Generalized Anxiety Disorder-7(GAD-7) Scale and insomnia using the Athens Insomnia Scale-8(AIS-8) Scale. Network analysis models were applied to examine the correlation between anxiety and insomnia. Furthermore, a network comparison test was performed to compare network characteristics before and after vaccination. Results:Our work showed that participants' anxiety and insomnia scores were lower after vaccination than before vaccination. Sense of well-being during the day (AIS6) in AIS remained high both before and after vaccination. The central intensity of premature wakefulness (AIS3), feeling afraid, and functioning (physical and mental) during the day (AIS7) decreased after vaccination, and the mediation between sense of well-being during the day (AIS6) and sleeping during the day (AIS8) increased significantly. Limitations:The study was a cross-sectional survey. The numbers of participants differed much in the two groups. Conclusions:The proportion of participants experiencing anxiety and insomnia decreased significantly after SARS-CoV-2 vaccination. Network analysis identified psychosis-related symptoms as key links between anxiety and insomnia. These findings suggest that targeted interventions focusing on daytime emotional regulation could improve mental health outcomes, guiding healthcare practices during public health crises.

Background: To analyze the correlation of glucose transporter 4 (GLUT4), leptin receptor (LEPR), and tumour necrosis factor-a (TNF-a) with endometrial receptivity (ER) in patients with polycystic ovarian syndrome (PCOS)induced infertility to provide clinical evidence for future diagnosis and treatment of PCOS-induced infertility. Methods: We prospectively enrolled 109 study subjects admitted to The Second Hospital Affiliated of Shandong University of Traditional Chinese Medicine from June 2020 to August 2023, including 42 patients with PCOS-induced infertility (research group), 35 nonpregnant patients with simple PCOS (control group), and 32 nonpregnant healthy women (normal group). GLUT4, LEPR, and TNF-a levels in the peripheral blood were detected in all participants, and their diagnostic value for PCOS in healthy women and PCOS-induced infertility in PCOS patients was analyzed. In addition, the endometrial thickness and endometrial blood flow pulsation index (PI) and resistance index (RI) of patients in the research group were measured. Furthermore, the correlation of GLUT4, LEPR, and TNF-a with ER was discussed. Results: GLUT4 was lower in the research group compared with the control and normal groups, while LEPR and TNFa were higher (P<0.05); the control group showed lower GLUT4 and higher LEPR and TNF-a levels than the normal group (P<0.05). The diagnostic sensitivity and specificity of GLUT4, LEPR, and TNF-a combined assay for PCOSinduced infertility in PCOS women were 88.57% and 75.00%, respectively, and those for PCOS in healthy women were 78.57% and 60.00%, respectively (P<0.05). In the research group, GLUT4 was positively correlated with endometrial thickness and negatively linked to RI and PI. At the same time, LEPR and TNF-a were negatively associated with endometrial thickness and positively correlated with RI and PI (P<0.05). Conclusions: GLUT4, LEPR, and TNF-a are closely related to ER in patients with PCOS-induced infertility, and their combined detection can effectively evaluate the occurrence of PCOS and PCOS-induced infertility.

OBJECTIVES:The growing popularity of herbal medicine (HM) underscores the need for high quality clinical trials to support its evidence-based integration. Pilot trials are essential for addressing methodological challenges in this field. This study evaluates the design quality, feasibility, and reporting of HM pilot trials, with a focus on their capacity to inform future full-scale studies. STUDY DESIGN AND SETTING:A comprehensive collection of HM pilot trials was conducted using PubMed, Web of Science, and Embase, based on predefined inclusion criteria. Data were extracted on trial characteristics, reporting quality, and progression to full-scale studies. To gather additional information on follow-up studies, authors of selected trials were contacted directly by email. Adherence to Consolidated Standards of Reporting Trials (CONSORT) guidelines for pilot trials was evaluated, and Poisson regression was applied to identify factors influencing reporting completeness. RESULTS:A total of 123 HM pilot trials were reviewed, predominantly from Asia (78.1%). Trials most commonly addressed respiratory (14.6%), nervous (14.6%), and reproductive systems (13.0%). Key gaps in reporting included feasibility assessments (13.1%), sample size rationale (47.2%), and randomization methods (35.8%). HM-specific details, including ingredient processing, quality control, and safety assessments, were inconsistently reported. Among the trials, 4 (3.3%) progressed to full-scale studies. Factors such as trial registration (incidence rate ratio (IRR) = 1.20, 95% CI: 1.11-1.30) and protocol publication (IRR = 1.16, 95% CI: 1.08-1.24) were positively associated with reporting completeness. Moreover, an analysis of the origin of HMs revealed that modern HM trials were 4.7 times more likely to progress to full-scale studies compared to traditional HM trials (odds ratio = 4.70, 95% CI: 0.37-252.91), although the result did not reach statistical significance (P = .300). CONCLUSION:HM pilot trials, as they stand, are not yet equipped to reliably guide full-scale studies. Core issues in methodological rigor, particularly in feasibility assessment, sample size justification, and randomization processes, limit their effectiveness and integration into evidence-based practice. A dedicated checklist that merges pilot study standards with the unique needs of HM trials is essential. PLAIN LANGUAGE SUMMARY:HM is increasingly used worldwide, but there are challenges in ensuring its effectiveness through clinical trials. This study aimed to evaluate the quality and reporting of pilot trials involving HM, which are smaller studies conducted before larger trials. Pilot trials are essential to identify potential issues in study design and ensure the reliability of future full-scale trials. We reviewed 123 trials from 21 countries and found that many lacked clear details on key aspects, such as sample sizes, randomization, and feasibility. These gaps make it difficult for pilot trials to reliably inform full-scale studies. Apart from this, the pilot trials reporting checklist did not include important details specific to herbal treatments, such as ingredient processing and quality control. In addition, only a few trials progressed to larger studies, often due to funding problems or other practical issues. Our study highlights the need for better reporting standards tailored to HM trials, with clear guidelines to address the unique aspects of herbal treatments. By improving the methodological rigor of pilot trials, we can ensure that HM becomes a more reliable and integral part of evidence-based health care.

Background:Whether the erector spinae plane block (ESPB) truly relieves pain after arthroscopic shoulder surgery (ASS) is still unsettled. We therefore examined whether ESPB sharpens post-operative pain control in these patients. Methods:We systematically searched the Cochrane Library, PubMed, Embase, and Web of Science for randomized controlled trials (RCTs) comparing ESPB with any comparator (no block, sham block, or alternative regional block) in patients undergoing ASS. The primary outcome was cumulative opioid consumption within the first 24 h postoperatively. Secondary outcomes included pain scores at rest and during movement, incidence of postoperative nausea and vomiting (PONV), time to first rescue analgesic request, and patient-reported satisfaction with analgesia. Results:Six RCTs comprised of 365 patients met inclusion criteria. ESPB did not reduce 24-h opioid consumption versus control (SMD -1.11; 95% CI -2.55 to 0.33; p = 0.13, I 2 = 96%). Pain scores were lower with ESPB at 2 h (SMD -0.83; 95% CI -1.30 to -0.37; p = 0.0005, I 2 = 35%) and 48 h (SMD -0.64; 95% CI -1.08 to -0.20; p = 0.004, I 2 = 95%), but not at 4 h. Furthermore, time to first rescue analgesic was prolonged by ESPB (SMD 4.04; 95% CI 0.77-7.31; p = 0.02, I 2 = 99%). However, ESPB did not reduce the rest and movement pain scores at 2 h (SMD -0.87; 95% CI -2.98 to 1.24; p = 0.42; I 2 = 97%; SMD -0.98; 95% CI -3.00 to 1.04; p = 0.34; I 2 = 97%) and 4 h (SMD -0.43; 95% CI -2.31 to 1.46; p = 0.66; I 2 = 97%; SMD -0.89; 95% CI -2.57 to 0.80; p = 0.30; I 2 = 96%), respectively. PONV and other adverse events were comparable. Subgroup analysis of single-injection ESPB also showed no opioid-sparing effect (SMD -1.46; 95% CI -3.21 to 0.30; p = 0.10, I 2 = 97%). Patient-reported satisfaction revealed no significant difference between ESPB and control group. Conclusion:The ESPB fails to reduce 24-h opioid consumption, pain scores at rest and movement at early stage, and the incidence of PONV. Nevertheless, it prolonged the time to first rescue analgesic without elevating the risk of adverse events. Systematic review registration:PROSPERO, registration number CRD 42023395027, https://www.crd.york.ac.uk/PROSPERO/view/CRD42023395027.

Myocardial markers and inflammatory factors have been identified as risk factors for the development of sepsis-induced cardiac dysfunction (SIC), the prognostic significance and clinical utility of utilizing a multi-index combined prognostic approach remain uncertain. Our objective was to establish a “risk score” utilizing clinical indexes to provide short-term prognostic insight for individuals with SIC. Utilizing Lasso regression and COX regression analysis, we identified a history of diabetes, CRP, and NT-proBNP on day 3 as independent risk factors for 28-day mortality in SIC patients. Specifically, the Cox regression analysis identified a hazard ratio of 24.74 (95

Background:This systematic review and meta-analysis assessed the analgesic efficacy of ultrasound-guided ESPB in metabolic surgery. Methods:A systematic literature search of PubMed, the Cochrane Library, Web of Science, and Embase was conducted from database inception to February 2025 to identify randomized controlled trials (RCTs) comparing ultrasound-guided erector spinae plane block (ESPB) with either no block, sham block, or alternative regional analgesic techniques in patients undergoing metabolic surgery. Primary outcomes included 24 h postoperative opioid consumption, while secondary outcomes encompassed pain scores, time to first analgesic requirement, postoperative nausea and vomiting, and patient satisfaction. Risk of bias was assessed using the Cochrane Risk of Bias Tool, and evidence quality was evaluated using GRADE. Results:Ten RCTs involving 729 patients were included. ESPB significantly reduced 24 h opioid consumption [mean difference (MD): -6.68; 95% CI: -10.75, -2.61; p = 0.001] and resting pain scores at 24 h [MD: -0.78; 95% CI: -1.10, -0.46; p < 0.00001]. Movement pain scores were also reduced to 6, 12, 24, and 48 h (p < 0.00001 for all). ESPB prolonged the time to first rescue analgesic [MD: 14.17; 95% CI: 5.50, 22.85; p = 0.001]. However, no significant differences were observed in PONV incidence or patient satisfaction scores. Conclusion:Ultrasound-guided ESPB is an effective and safe analgesic technique for metabolic surgery, significantly reducing opioid consumption and pain scores while delaying the need for rescue analgesics. Systematic review registration:PROSPERO 2025 CRD420251000358. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD420251000358.

ETHNOPHARMACOLOGICAL RELEVANCE:Qingrehuoxue (QRHX) granules, composed of 12 Chinese herbs, have been used for over 40 years to treat rheumatoid arthritis (RA) in China and show potential in protecting bone health. However, high-quality evidence on their effects is limited. AIM OF THE STUDY:To assess the effects of QRHX granules on bone marrow edema (BME) in active RA patients. MATERIALS AND METHODS:This multicenter, randomized, double-blind, placebo-controlled trial enrolled RA patients from 13 hospitals in China. Participants were randomly assigned in a 1:1 ratio to receive either QRHX granules (10 g, twice daily) plus methotrexate (MTX) or a placebo plus MTX for 24 weeks. The primary outcome was the change in MRI-assessed BME score at week 24. Secondary outcomes included changes in bone erosion scores, Disease Activity Score in 28 joints, and safety outcomes. RESULTS:A total of 204 patients (mean age, 48.77 years; SD, 11.96) were randomized to either the QRHX or placebo group. At week 24, the QRHX group showed a significantly greater reduction in BME scores compared to the placebo group (adjusted between-group difference, -2.50; 95 % CI, -4.76 to -0.25; P = 0.030). QRHX also significantly reduced bone erosion progression (adjusted between-group difference, -2.90; 95 % CI, -5.49 to -0.31; P = 0.030). Adverse events were rare and similar across both groups, with no deaths or life-threatening events. CONCLUSION:QRHX granules, combined with MTX, significantly reduced MRI-detected BME and slowed bone erosion in active RA, suggesting potential as a complementary treatment for bone protection in RA.

Background Mounting evidence indicates that the cerebral cortex is an important physiological system of emotional activity, and its dysfunction may be the main cause of stress. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), which initiates rapid signal transmission in the synapse before its reuptake into the surrounding glia, specifically astrocytes (ASTs). The astrocytic excitatory amino acid transporters 1 (EAAT1) and 2 (EAAT2) are the major transporters that take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with depression. Therefore, we hypothesized that the underlying antidepressant-like mechanism of Xiaoyaosan (XYS), a Chinese herbal formula, may be related to the regulation of astrocytic EAATs. Therefore, we studied the antidepressant mechanism of XYS on the basis of EAAT dysfunction in ASTs. Methods Eighty adult C57BL/6 J mice were randomly divided into 4 groups: a control group, a chronic unpredictable mild stress (CUMS) group, a Xiaoyaosan (XYS) treatment group and a fluoxetine hydrochloride (Flu) treatment group. Except for the control group, mice in the other groups all received chronic unpredictable mild stress for 21 days. Mice in the control and CUMS groups received gavage administration with 0.5 mL of normal saline (NS) for 21 days, and mice in the XYS and Flu treatment groups were administered dosages of 0.25 g/kg/d and 2.6 mg/kg/d by gavage. The effects of XYS on the depressive-like behavioral tests, including the open field test (OFT), forced swimming test (FST) and sucrose preference test (SPT), were examined. The glutamate (Glu) concentrations of the prefrontal cortex (PFC) were detected with colorimetry. The morphology of neurons in the PFC was observed by Nissl staining. The expression of glial fibrillary acidic protein (GFAP), NeuN, EAAT1 and EAAT2 proteins in the PFC of mice was detected by using Western blotting and immunohistochemistry. Quantitative real-time PCR (qPCR) was used to detect the expression of the GFAP, NeuN, EAAT1 and EAAT2 genes in the PFC of mice. Results The results of behavioral tests showed that CUMS-induced mice exhibited depressive-like behavior, which could be improved in some tests with XYS and Flu treatment. Immunohistochemistry and Western blot analysis showed that the protein levels of GFAP, NeuN, EAAT1 and EAAT2 in the PFC of CUMS mice were significantly lower than those in the control group, and these changes could be reversed by XYS and Flu. The results of qPCR analysis showed that the expression of GFAP, NeuN, EAAT1 and EAAT2 mRNAs in the PFC of CUMS mice was not significantly changed, with the exception of EAAT2, compared with that of the control group, while the expression of the above mRNAs was significantly higher in the XYS and Flu groups than that in the CUMS group. Conclusion XYS may exert antidepressant-like effects by improving the functions of AST and EAATs and attenuating glutamate-induced neuronal damage in the frontal cortex.

Acute lung injury (ALI) is a prevalent critical respiratory disease associated with high morbidity and mortality rates. Viola tianshanica Maxim has been traditionally employed in Uygur medicine for treatment of various respiratory diseases. Viola tianshanica Maxim extract (VTM) has strong anti-inflammatory and anti-oxidant properties, and its potential protective mechanism against ALI is worthy of further study. In this study, we investigated the protective effect of VTM on lipopolysaccharide (LPS)-induced ALI in mice and explored its underlying mechanisms involving NOD-like receptor protein 3 (NLRP3) inflammasome and Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. VTM was extracted from Viola tianshanica Maxim. Chemical compositions of VTM were identified by HPLC-HRMS/MS. The protective effect and molecular mechanisms of VTM on alleviating ALI were verified by hematoxylin-eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. A total of 13 chemical compositions were analyzed and identified from VTM, including esculetin, isoschaftoside, kaempferol-7-O-β-D-glucopyranoside, among others. VTM effectively alleviated ALI by reducing of the wet-to-dry weight (W/D) ratio, serum inflammatory cytokines PGE2 and LTB4 levels, and lung tissues IL-1β, IFN-γ, TNF-α and MCP-1 levels. VTM significantly decreased mRNA expressions of IL-6, TNF-α and MCP-1, inhibited MDA and MPO formation, and reversed SOD and GSH depletion. Meanwhile, VTM markedly improved histopathological changes, inhibited NLRP3 inflammasome activation by reducing the protein and mRNA expression levels of NLRP3, Caspase 1, GSDMD and IL-1β in lung tissues. Additionally, VTM mitigated oxidative stress in ALI by upregulating the protein and mRNA expression levels of Keap1, Nrf2 and HO-1 in lung tissues. Our findings indicated that pretreatment with VTM prevented LPS-induced ALI by regulating NLRP3 inflammasome and Nrf2 signaling pathway.

OBJECTIVE:To evaluate the impact of patient-centered care (PCC)-based personalized interventions on postoperative pain management and recovery outcomes in children undergoing adenotonsillectomy. METHODS:A single-center retrospective cohort study was conducted at a tertiary hospital from January 2023 to March 2025, involving 216 children aged 3-12 years. Participants were divided into a PCC intervention group (n = 108) and a routine care group (n = 108). The PCC protocol included individualized pain education, non-pharmacological interventions (cold therapy, distraction techniques), and family-involved decision-making. Data on pain scores (FLACC/FACES scales), analgesic use, hospitalization duration, and complications within 48 h postoperatively were extracted from electronic medical records. Group differences were analyzed using repeated-measures ANOVA, multivariate regression, and subgroup analyses. RESULTS:The PCC group demonstrated significantly lower pain scores at 6 h, 24 h, and 48 h compared to controls (all P < 0.001). Daily acetaminophen and ibuprofen doses were reduced by 19.2 % and 55 %, respectively (both P < 0.001). Median pain relief time was 2.6 h shorter in the PCC group (3.2 h vs. 5.8 h, P < 0.001). Hospitalization duration decreased by 5.5 h (18.5 h vs. 24.0 h, P < 0.001), and overall complication risk was reduced (OR = 0.31, P < 0.001). Subgroup analysis revealed greater benefits in children aged 3-6 years, with a 28.6 % shorter hospitalization (P < 0.001). CONCLUSION:PCC-based personalized interventions effectively alleviate postoperative pain, reduce analgesic dependence, and accelerate recovery, particularly in younger children. This model provides an evidence-based framework for optimizing pain management in pediatric ambulatory surgery.

Ethnopharmacological relevance Shenling Baizhu San (SLBZS) is a Traditional Chinese Medicine (TCM) formula composed of 10 medicinal herbs, historically used to strengthen the spleen, replenish qi, and alleviate fatigue-related symptoms. SLBZS originates from the 'Taiping Huimin Heji Ju Fang' of the Song Dynasty. Central fatigue (CF), a subtype of fatigue, is considered in TCM to be closely associated with spleen deficiency. However, there is currently a lack of research on SLBZS's therapeutic effects on CF and the pharmacological mechanisms underlying its potential benefits. Aim of the study This study aims to assess the effects of SLBZS on CF in rats induced by the Modified Multiple Platform Method (MMPM) and to elucidate the underlying mechanisms, focusing on mitochondrial biogenesis and SIRT1/PGC-1α pathway regulation. Materials and methods CF was induced in male Wistar rats using MMPM, involving intermittent sleep deprivation over 21 days. SLBZS was administered at low(LSLBZS), medium(MSLBZS), and high doses(HSLBZS). Chemical components of SLBZS were identified and quantified using Liquid Chromatography-Tandem Mass Spectrometry(LC-MS/MS). Behavioral tests evaluated physical performance, emotional state, and cognitive function, while serum biochemical markers, mitochondrial morphology, and the protein and gene expression levels of the SIRT1/PGC-1α pathway were analyzed to explore underlying mechanisms. Results A total of 141 main compounds in SLBZS were identified, comprising various components such as flavonoids, phenylpropanoids, terpenoids, among others. SLBZS significantly improved physical performance, alleviated negative emotions, and enhanced cognitive function in CF rats. Biochemically, SLBZS increased serum ATP levels and reduced fatigue-related markers. Mitochondrial analysis demonstrated that SLBZS reversed mitochondrial degeneration, increased mitochondrial number, and increased mtDNA copy number in the hippocampus. Furthermore, SLBZS upregulated SIRT1 /PGC-1α pathway expression at both the protein and gene levels in the hippocampus. Notably, the HSLBZS group demonstrated particularly pronounced effects. Conclusion SLBZS significantly alleviates CF symptoms enhances mitochondrial function via upregulating the SIRT1/PGC-1α pathway, positioning it as a promising alternative for CF management by addressing both its physiological and symptomatic aspects.

Background:The number of prediction models for diabetic foot ulcer (DFU) risk is increasing, but their methodological quality and clinical applicability are uncertain. We conducted a systematic review to assess their performance. Methods:We searched PubMed, Cochrane Library, and Embase databases up to 10 February 2024 and extracted relevant information from selected prediction models. The Prediction model Risk Of Bias ASsessment Tool (PROBAST) checklist was used to assess bias risk and applicability. All statistical analyses were conducted in Stata 14.0. Results:Initially, 13,562 studies were retrieved, leading to the inclusion of five development and five validation models from eight studies. DFU incidence ranged from 6% to 16.8%, with age and hemoglobin A1C (HbA1c) commonly used as predictive factors. All included studies had a high risk of bias, mainly due to disparities in population characteristics and methodology. In the meta-analysis, we observed area under the curve (AUC) values of 0.78 (95% CI [0.69-0.89]) for development models and 0.84 (95% CI [0.79-0.90]) for validation models. Conclusion:DFU risk prediction models show good overall accuracy, but there is a risk of bias. Adherence to the PROBAST checklist is crucial for improving their clinical applicability.

This study aimed to assess the effects of Anti-fatigue Decoction (AFD) against central fatigue by observing the behaviors and serological indicators of rats modeled by the modified multiple platform method (MMPM) after drug intervention. Grip strength measurements were used to evaluate the muscle strength of rats. The open field test was utilized to assess anxiety-like behavior, while the Morris water maze test was conducted to evaluate the memory function of the rats. Following the behavioral assessments, rat serum samples were collected to measure the concentrations of corticosterone (CORT) and lactic acid (LAC). The concentration of LAC was determined using the colorimetric method, while the concentration of CORT was measured using the enzyme-linked immunosorbent assay (ELISA) method. Compared to the blank control group, following MMPM modeling, rats exhibited significant reductions in grip strength and impaired ability to memory. The serum analysis revealed increased levels of LAC and CORT in the model group rats. AFD can noticeably reverse these adverse changes to a certain extent. These findings highlight the positive effects of AFD and coenzymeQ10 on physical and cognitive abilities and alterations in serum biomarker levels of central fatigue rats.

ImportancePrevious research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis.ObjectiveTo determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis.Design, Setting, and ParticipantsThe Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022.InterventionsThe patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days.Main Outcomes and MeasuresThe primary outcome was 28-day mortality.ResultsAmong the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group.Conclusions and RelevanceIn this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT03238742

Background: Though emerging evidence suggests a modulatory effect of sleep behaviors on gut microbiota, the dysbiosis of which is implicated in the development of fatty liver, whether and how microbial metabolism link sleep quality to hepatic steatosis remain obscure. Methods: Integrative analysis of metagenomics and metabolomics were performed in 1,384 community residents. Hepatic steatosis was evaluated, and sleep behaviors were collected through Pittsburgh Sleep Quality Index questionnaire. Findings: After adjustment for demographics, lifestyles and metabolic comorbidities, per standard deviation increment in the microbial score based on 14 selected species, mainly composed of butyrate producers, was associated with a 46% (OR: 0.54, 95%CI: 0.31 to 0.92) reduction in hepatic steatosis risk. Similarly, the combination of 16 microbial capacities, spanning pyruvate and glucose metabolism, was associated with 36% decreased risk for hepatic steatosis, independent of major confounders. Collectively, the panel of selected species and microbial functions mediated up to 23.8% and 14.5% of the total effect of sleep quality on hepatic steatosis. Moreover, decreased cinnamoylglycine, hippuric acid and salicylaldehyde, resulting from suppressed intestinal gluconeogenesis, functioned as three main effectors of gut microbiota mediating the deteriorating effect of poor sleep quality on haptic steatosis. Interpretation: Microbial metabolism is functionally involved in the modulatory effect of sleep quality on hepatic lipid accumulation. Gut microbiota may be a promising therapeutic target for alleviating the detrimental effect of poor sleep quality on hepatic steatosis. Funding: Guangzhou Science and Technology Project, Guangdong Natural Science Foundation, Distinguished Young Scholars of the National Natural Science Foundation of China, and the National Natural Science Foundation of China.Declaration of Interest: None.Ethical Approval: This study was approved by the Ethics Committee of School of Public Health, Sun Yat-Sen University (L2017-001) and was in accordance with the principles of the Declaration of Helsinki. Participants were recruited from a community healthcare center in Chashan Town (Guangdong, China). All participants provided written informed consents before their participation in the study.