The philosophy of “treating disease before its onset” is a fundamental concept of traditional Chinese medicine (TCM), permeating its diagnostic and therapeutic framework, and is central to clinical practice. However, current TCM diagnostic and treatment models for the “pre-disease to disease” window period face several limitations, including the lack of comprehensive clinical parameters, difficulties in characterizing and integrating heterogeneous multimodal data, and insufficient dynamic precision in interventions and efficacy evaluations. To address these issues, guided by Professor Candong Li’s theory of TCM stateology, this study focuses on integrating objective multimodal data. It proposes a new model for personalized TCM diagnosis and treatment targeting the “pre-disease to disease” window period. This approach first proposes the idea of restructuring the conceptual framework of “symptom” and integrating multi-source heterogeneous data at macroscopic, mesoscopic, and microscopic levels to form a three-dimensional assessment indicator system. By integrating graph neural networks, convolutional neural networks, attention mechanisms, and knowledge graph-guided weight allocation, this approach enables collaborative representation, alignment, and fusion of multi-source data. Subsequently, it plans to construct a multimodal fusion model at both feature and decision levels, in order to establish mappings between indicators and TCM state elements, and to screen key indicators characterizing pathological evolution during the window period. Furthermore, it proposes a technical path for enhancing model interpretability using methods such as SHapley Additive exPlanations (SHAP) and Ablation-CAM++. Finally, with state assessment as the core, it proposes the concept of constructing a dynamic evaluation method for individualized diagnosis and treatment based on time-series data analysis using algorithms such as long short-term memory (LSTM) networks and gated recurrent units (GRUs). Moreover, a causal inference framework and semi-supervised learning strategies are introduced to enable quantitative evaluation of individual intervention effects and to provide interpretable therapeutic feedback, forming a complete technical path from data representation and fusion, weight adjustment, and interpretability analysis, to dynamic diagnosis feedback. This study aims to address deficiencies in the current TCM diagnosis and treatment model during the “pre-disease to disease” window period and to provide an operational framework for the clinical practice of TCM’s “treating disease before its onset”.

BACKGROUND: Pulse indicated continuous cardiac output (PiCCO) has largely replaced Swan-Ganz catheterization in shock patients. However, whether PiCCO monitoring can improve outcomes of shock patients, such as mortality, length of hospital stay, duration of mechanical ventilation, or laboratory parameters, remains unknown. METHODS: This retrospective cohort study included patients with shock in the intensive care unit (ICU) from January 2013 to January 2020. Patients were divided into PiCCO group and non-PiCCO group based on treatment with PiCCO monitoring or not. Demographic characteristics, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, quick Sequential Organ Failure Assessment (qSOFA) scores, 14-day mortality, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 0, 1, 3 and 7 days after onset of shock, duration of mechanical ventilation, length of hospital stay and hospitalization costs were compiled and analyzed using propensity score matching (PSM). RESULTS: Real-world analysis of 1,583 ICU patients suffering shock after propensity score matching revealed that 14-day mortality did not differ between PiCCO and non-PiCCO groups (36.2% vs. 32.6%, P=0.343). Duration of mechanical ventilation, hospital stay, and hospitalization costs were also similar between the two groups (P>0.05). No differences in changes of NT-proBNP levels on days 0, 1, 3, and 7 as compared to baseline were noted between the two groups (P>0.05). CONCLUSIONS: The results of our real-world indicate that PiCCO monitoring may not shorten the duration of mechanical ventilation, length of hospital stay, or reduce hospitalization costs, nor will it bring survival benefits to ICU patients suffering shock.

ObjectiveTo explore the effectiveness and potential mechanism of Shugan Jianpi Granules （疏肝健脾颗粒） combined with Chushi Zhiyang Ointment （除湿止痒软膏） in the treatment of atopic dermatitis with sleep disturbance of liver constraint and spleen deficiency syndrome. MethodsSixty-six patients with atopic dermatitis combined with sleep disturbance of liver constraint and spleen deficiency syndrome were randomly divided into 33 cases each in the treatment group and the control group. Both groups were treated with Chushi Zhiyang Ointment for external use. The treatment group additionally received Shugan Jianpi Granules orally， one dose per day； and the control group received cetirizine hydrochloride tablets orally， 10mg per day， taken before bedtime. Both groups were under the treatment for 4 weeks. Clinical effectiveness was evaluated after treatment， and the SCORing Atopic Dermatitis （SCORAD） index， pruritus visual analog scale （VAS） score， Insomnia Severity Index （ISI） score， and Pittsburgh Sleep Quality Index （PSQI） score were recorded before and after treatment， and serum levels of melatonin （MLT）， interleukin-4 （IL-4）， interleukin-6 （IL-6）， interleukin-13 （IL-13）， and tumor necrosis factor-α （TNF-α） were measured. The patients were also tested for blood routine， liver function and kidney function before and after treatment， and the occurrence of adverse events was also observed. ResultsThe total effective rate in the treatment group （90.63%， 29/32） was significantly higher than that in the control group （66.67%， 20/30， P＜0.05）. After the interventions， the scores for SCORAD， VAS， ISI， and PSQI， as well as the levels of IL-4， IL-6， IL-13， and TNF-α， were significantly reduced in both groups. In contrast， the MLT levels in treatment group significantly elevated compared to that before treatment （P＜0.05）. Comparing between the two groups after treatment， the scores of SCORAD， ISI， PSQI， and VAS， as well as the levels of serum IL-4 and IL-13 in the treatment group were significantly lower than those in the control group， while the MLT levels were markedly higher than that in the control group （P＜0.05 or P＜0.01）. There was no obvious abnormality in blood routine， liver function and kidney function in both groups when compared before and after treatment. The incidence rate of adverse reactions was 9.38% （3/32） in the treatment group and 13.33% （4/30） in the control group， and the difference between groups showed no statistical difference （P＞0.05）. ConclusionOn the basis of topical application of Chushi Zhiyang Ointment， the combined application of Shugan Jianpi Granules can significantly alleviate the degree of skin lesions and itching， and improve the quality of sleep in atopic dermatitis patients with sleep disturbance of liver constraint and spleen deficiency syndrome， and its mechanism may be related to regulating the immune balance， reducing the secretion of inflammatory factors， and elevating the level of MLT.

Objective:The purpose of this study was to investigate the diagnostic value and clinical significance of cochlear microphonics (CM) combined with otoacoustic emission (OAE) in patients with auditory neuropathy (AN).Methods:The study included patients who were diagnosed with bilateral AN and had CM originating from both sides. The CM amplitude, latency, duration and intensity-amplitude (I/O) function curve were recorded by CM test. According to whether the distortion product otoacoustic emissions (DPOAE) passed through, the patients were divided into three groups: bilateral OAE passed group (OAE PP Group), bilateral OAE failed group (OAE RR Group), and unilateral OAE passed through one side failed group (OAE PR Group). OAE was elicited by four or more frequencies of 750-8 000 Hz. The characteristics of CM and its related influencing factors were analyzed, and data were processed and analyzed by SPSS 26.0 software. Results:(1) A total of 256 patients (512 ears) with AN were enrolled, including 161 patients (322 ears) in OAE PP group, 32 patients (64 ears) in OAE PR group and 63 patients (126 ears) in OAE RR group. OAE failed in 30.9% of patients with AN. (2) When the stimulation intensity was 100 dB nHL, the CM amplitude of OAE passing ear (OAE P+CM P group) in AN patients aged 3 years was 0.43±0.17μV, which was significantly higher than that of OAE not passing ear (OAE R+CM P group) (0.29±0.15) μV ( t=4.876， P<0.001). The CM duration of the OAE P+CM P group was (5.18±1.04) ms, which was longer than that of the OAE R+CM P group at 4.60±1.12 ms ( P=0.005). The I/O function curve of OAE P+CM P group showed a nonlinear trend, while, that of OAE R+CM P group showed a linear trend. (3) In the OAE P+CM P group of AN patients, the amplitude of CM was negatively correlated with the onset age, test age, disease course, PTA, and ASSR threshold ( P<0.001), with correlation coefficients of r=-0.475, r=-0.519, r=-0.367, r=-0.374, and r=-0.494, respectively. In the OAE R+CM P group of AN patients, the amplitude of CM was negatively correlated with the onset age, test age, and ASSR threshold ( P<0.05), with correlation coefficients of r=-0.271, r=-0.240, and r=-0.287, respectively. Conclusions:Excluding patients with high-frequency steeply sloping hearing loss, when ABR is absent or abnormal and OAE is absent, CM detection can reduce the rate of missed diagnosis of AN. The analysis of CM amplitude and I/O function curve is helpful to determine the lesion site of AN patients, which is convenient for early diagnosis and effective intervention.

Objective: To investigate the environmental contamination of norovirus in nurseries and primary/secondary schools, so as to provide a scientific basis for effective prevention and control measures. Methods: A total of 483 external environmental samples were collected from 34 cluster outbreaks of norovirus gastroenteritis in kindergartens and primary/secondary schools in Linhai City from 2021 to 2024. Pathogen detection was conducted using a rapid nucleic acid extraction kit and realtime fluorescence RT-PCR, and the results were analyzed using the χ2 test or Fishers exact test. Results: Among the collected external environmental samples, the total positive rate of surface contamination was 13.66%. The positive rates in kindergartens and primary/secondary schools were 12.20% and 15.82%, respectively. In kindergartens, the five surfaces with the highest detection rates were desks/chairs (23.33%), toilet stool troughs (20.69%), urinal troughs (12.00%), washbasins/sinks (11.11%), and toilet mops (9.38%). In primary/secondary schools, the top five were toilet stool troughs (38.30%), urinal troughs (23.53%), toilet door handles (13.04%), toilet mops (12.50%), and drinking cups (11.11%). The difference in positive detection rates among different external environments in primary/secondary schools was statistically significant (Fishers exact probability test, P<0.01). The positive detection rate in sanitary toilets was higher than that in classroom environments (χ2=17.38), while the positive detection rate in classroom environments of kindergartens was higher than that in primary/secondary schools (χ2=5.42)(P<0.05). Conclusions Norovirus exhibits a high contamination rate in nurseries and schools, particularly in restroom areas. Strengthening sanitation and disinfection in highrisk environments, and improving hygiene awareness among children and staff, are essential for the effective prevent and control of norovirus.

OBJECTIVE To establish a quantitative analysis of multi-components by single-marker （QAMS） method for simultaneous determination of six flavonoids and two phenolic acids in Perilla frutescens leaves using scutellarin and rosmarinic acid as internal reference substances， and apply this method to determine the contents of eight components in 20 batches of P. frutescens leaves samples from different regions. METHODS Scutellarin served as the internal reference to calculate relative correction factors （RCFs） for scutellarin-7-O-diglucuronide， luteolin-7-O-diglucuronide， apigenin-7-O-diglucuronide， luteolin-7-O- β-D-glucuronide and apigenin-7-O-glucuronide. Rosmarinic acid was employed as the internal reference to determine the RCF for caffeic acid. The contents of the above flavonoids and phenolic acids were calculated with QAMS， and compared with the results of external standard method. RESULTS The eight analytes demonstrated excellent linearity within their respective concentration ranges （r≥0.999 0）. The mean recovery rates for spiked samples ranged from 95.60% to 102.15%， with relative standard deviations （RSDs） of 0.72% to 2.70% （n＝6）. The method exhibited good precision， repeatability， and stability （RSD＜2.50%， n＝6）. Variations in instruments， columns， column temperature， flow rate， and formic acid volume fraction had minimal impact on the RCFs （RSD＜3%， n＝3）. Comparison with the external standard method showed no significant differences in the content of each component across batches， except for caffeic acid in the ZS12 batch （absolute value of RE＜5%， n＝2）. The contents of six CARS-21） flavonoid components in P. frutescens leaves samples varied significantly across different geographic origins， while the content of total flavonoids showed no significant difference. In contrast， the contents of two phenolic acid components and total phenolic acid exhibited significant variation among samples from different regions. CONCLUSIONS The developed QAMS method can simultaneously determine the contents of six flavonoids and two phenolic acids in P. frutescens leaves. It is convenient for detection， highly accurate， and cost-effective. This method is suitable for the quality control of P. frutescens leaves， and the variation of flavonoid and phenolic acid content in samples from different regions provides a reference for the selection of optimal cultivation areas.

The identification and optimization of mutations in nanobodies are crucial for enhancing their thera-peutic potential in disease prevention and control.However,this process is often complex and time-consuming,which limit its widespread application in practice.In this study,we developed a work-flow,named Evolutionary-Nanobody(EvoNB),to predict key mutation sites of nanobodies by combining protein language models(PLMs)and molecular dynamic(MD)simulations.By fine-tuning the ESM2 model on a large-scale nanobody dataset,the ability of EvoNB to capture specific sequence features of nanobodies was significantly enhanced.The fine-tuned EvoNB model demonstrated higher predictive accuracy in the conserved framework and highly variable complementarity-determining regions of nanobodies.Additionally,we selected four widely representative nanobody-antigen complexes to verify the predicted effects of mutations.MD simulations analyzed the energy changes caused by these mu-tations to predict their impact on binding affinity to the targets.The results showed that multiple mu-tations screened by EvoNB significantly enhanced the binding affinity between nanobody and its target,further validating the potential of this workflow for designing and optimizing nanobody mutations.Additionally,sequence-based predictions are generally less dependent on structural absence,allowing them to be more easily integrated with tools for structural predictions,such as AlphaFold 3.Through mutation prediction and systematic analysis of key sites,we can quickly predict the most promising variants for experimental validation without relying on traditional evolutionary or selection processes.The EvoNB workflow provides an effective tool for the rapid optimization of nanobodies and facilitates the application of PLMs in the biomedical field.

Objective:To investigate the inpact of thyroid cancer-derived cancer-associated fibroblasts(CAF) autophagy on papillary thyroid cancer(PTC).Methods:CAF and normal fibroblasts were isolated from cancerous and adjacent normal thyroid tissues from four PTC patients. Expressions of fibroblast activation protein(FAP) and α-smooth muscle actin in cells were assessed. Conditioned medium of CAF and normal fibroblasts were prepared and used to culture PTC cells. The effects of CAF and normal fibroblasts on survival, proliferation, migration, invasion and iodine uptake of PTC cells were evaluated through cell proliferation assay, cell scratch assay, cell invasion assay, and cell iodine uptake assay. The autophagy level of CAF was also evaluated. Autophagy inhibition and activation were used to regulate the autophagy of CAF, and then their effects on PTC cell proliferation, migration and invasion were further evaluated. The in vivo effect of CAF autophagy on PTC xenograft tumor growth was evaluated.Results:CAF exhibited higher FAP expression and basal autophagy levels. PTC cells co-cultured with CAF-conditioned media showed enhanced proliferation, migration, invasion, and reduced iodine uptake. Autophagy inhibition reduced these effects, while autophagy activation further promoted them. In vivo, inhibiting CAF autophagy suppressed tumor growth.Conclusions:CAF promotes PTC cell malignancy through autophagy activation, enhancing proliferation, migration, and invasion while reducing iodine uptake.

Objective:To investigate the level of urinary serine protease(Corin) in early diabetic kidney disease(DKD) and its correlation with clinical stage.Methods:One hundred and seventy-three patients with type 2 diabetes mellitus(DM) from two tertiary A hospitals in Henan, diagnosed between April 2023 and December 2023 were selected as the research group, and 120 healthy subjects were selected as the control group. Basic clinical information and laboratory data were collected, and urinary Corin level was detected. DM patients were classified into G1-G5 stages based on estimated glomerular filtration rate(eGFR), and those in the early DKD stages(G1-G3) were further divided into A1-A3 subgroups based on urinary albumin/creatinine ratio(ACR). Spearman correlation analysis was performed to assess relationships between urinary Corin and other indicators, linear regression analysis identified factors influencing urinary Corin in early DKD patients, logistic regression analysis evaluated the risk factors for early DKD, and receiver operating characteristic(ROC) curve analysis determined the diagnostic value of urinary Corin in early DKD. Results:Urinary Corin levels were significantly higher in early DKD patients compared to healthy controls, with levels increasing as ACR rose( P<0.05). Urinary Corin was positively associated with serum creatinine( r=0.570), urea( r=0.458), cystatin C( r=0.693), ACR( r=0.616), urinary transferrin( r=0.448), urinary α1 microglobulin( r=0.507), urinary n-acetyl-β-D-glucosaminase( r=0.388) and A subgroup( r=0.692) while was negatively correlated with eGFR( r=-0.647), albumin( r=-0.312)(all P<0.05). eGFR was the only independent factor affecting urinary Corin. After adjusting for confounding factors in logistic regression analysis, urinary Corin was still an independent influencing factor for early DKD. ROC curve analysis indicated that urinary Corin had a diagnostic AUC of 0.842(95% CI 0.791-0.892, P<0.001), with a cut-off value of 2 226.04 pg/mL, sensitivity of 0.712, and specificity of 0.858 for early DKD diagnosis. Conclusions:Urinary Corin was elevated in early DKD patients and correlated with clinical stage. Urinary Corin is an independent factor of early DKD, and a reliable predictor of early DKD diagnosis.

Objective:To explore the feasibility and and clinical efficacy of lingual mucosa replacement ureteral stenosis repair and plasty for the treatment of long segment ureteral polyps.Methods:Clinical data of 3 patients (4 sides) with long-segment ureteral polyps admitted to the Second Hospital of Lanzhou University from October 2017 to October 2019 were retrospectively analyzed. Two cases were male and one case was female. The ages were22, 16, and 45 years old. Preoperative urologic ultrasound, CT urography and ureteroscopy were performed. The lesions were located on the left side in 3 cases and on the right side in 1 case; the stenosis was located in the middle and upper ureter; the length of the ureteral stenosis was 6, 7, 6, and 6 cm, respectively; and the preoperative blood creatinine was 72, 85, and 70 μmol/L, respectively. Three cases underwent ureteral stenosis repair and plasty with tongue mucosal substitution. During the operation, the ureter was fully exposed and longitudinally incised, polyps were removed, and 7.0-10.0 cm long and 1.5-2.0 cm wide lingual mucosa was harvested according to the length of the stenosis, and then the lingual mucosa was transplanted to the muscular layer and the inner surface of the sheath in the stenosed ureter, fixed with 6-0 thread until the muscular layer was rolled into shape and wrapped with a large omentum. All of them left one double-J tube in the ureter on the affected side. Perioperative results and complications were recorded. The patients' blood creatinine and anterior and posterior renal pelvic diameters were compared before and after treatment.Results:In our study, all three 4-sided surgeries were successfully completed without any serious intraoperative or postoperative complications (Clavien-Dindo score ≥ grade Ⅲ). Mean surgical. Time was (240.0±49.0) min, intraoperative bleeding was 50 ml, postoperative drain retention time was (6.3±2.5) d, and median postoperative hospitalization time was 6.5(3, 9)d. The double J-tube was removed at 3 months postoperatively, and renal function and imaging tests were reviewed. Because the postoperative follow-up results of patient 1 were missing, the mean value of blood creatinine in the other 2 patients was 73.0 μmol/L at 3 months postoperatively, which was significantly improved compared with the preoperative value of 58.2 μmol/L, and the difference was statistically significant ( P < 0.05). And the average value of anterior and posterior renal pelvic separation diameters of the other 2 patients after surgery was <5 mm, which was significantly improved compared with the preoperative value of 17.9 mm, but the difference was not statistically significant ( P>0.05).There was no restenosis in all 2 patients after surgery, and the intravenous urography showed that the ureter was patent after the surgery, and the degree of urinary obstruction did not aggravate. The group was followed up for 3 to 8 months (mean 4.7 months), and no recent complications have occurred so far. Conclusions:Lingual mucosa replacement ureteral stenosis repair and plasty for the treatment of ureteral polyps in the long segment has a high success rate and precise efficacy, and its operation is feasible.