BACKGROUND:The incidence rate of chronic non-specific neck pain is high and the etiology is unknown.Myofascial pain and deep cervical flexor atrophy are the key factors.Extracorporeal shockwave therapy can improve microcirculation,relieve local pain,and delay the degenerative development of the cervical spine,while motion control training can significantly improve neck muscle strength and endurance and reduce neck pain.However,both methods have limited effectiveness when applied individually.OBJECTIVE:To explore the therapeutic efficacy of extracorporeal shock wave intervention combined with motion control training at the upper trapezius muscle on chronic non-specific neck pain.METHODS:Forty-two patients with chronic non-specific neck pain recruited from Shenyang Sport University were randomly divided into three groups:a shock wave group(n=14),in which extracorporeal shockwave intervention at the upper trapezius muscle was given for 10-15 minutes,once a week for 4 weeks;a training group(n=14),in which motion control training was given for 40-50 minutes,three times a week for 4 weeks;and a combination group(n=14),in which extracorporeal shockwave intervention at the upper trapezius muscle combined with motion control training was performed for 4 weeks.Patients were assessed for pain intensity,cervical spine function,upper trapezius muscle thickness,hemodynamic parameters,and serum interleukin 6 and tumor necrosis factor α levels before intervention,1 week and 4 weeks after intervention.RESULTS AND CONCLUSION:(1)Compared with the pre-intervention period,the visual analogue scale scores and neck disability index in the three groups were lower after 1 and 4 weeks of intervention(P＜0.05),and the visual analogue scale scores and neck disability index in the combination group were lower than those of the shock wave group and the training group(P＜0.05).(2)Compared with the pre-intervention period,the upper trapezius thickness increased in the training group and the combination group after 4 weeks of intervention(P＜0.05);the upper trapezius thickness was greater in the combination group than in the shock wave group and the training group after 4 weeks of intervention(P＜0.05).(3)The shock wave group and the combination group had an increase in the peak systolic velocity of the ascending segment of the transverse carotid artery(P＜0.05)and a decrease in the resistance index(P＜0.05)after 1 and 4 weeks of intervention,while the training group showed an increase in the peak systolic velocity of the ascending segment of the transverse carotid artery(P＜0.05)and a decrease in the resistance index(P＜0.05)after 4 weeks of intervention.The peak systolic velocity of the ascending segment of the transverse carotid artery in the combination group was higher(P＜0.05)and the resistance index was lower(P＜0.05)than those in the shockwave group and the training group after 1 and 4 weeks of intervention.(4)Compared with the pre-intervention period,the levels of interleukin 6 and tumor necrosis factor α were reduced in the shock wave and combination groups after 1 and 4 weeks of intervention(P＜0.05),and in the training group after 4 weeks of intervention(P＜0.05).After 1 and 4 weeks of intervention,the levels of interleukin 6 and tumor necrosis factor α were lower in the combination group than in the shock wave group and the training group(P＜0.05).To conclude,extracorporeal shock wave combined with motion control training for chronic non-specific neck pain significantly reduces pain and improves neck function,and the mechanism of action may be to promote the blood flow velocity at the trigger point,reduce blood flow resistance,reduce the serum levels of interleukin 6 and tumor necrosis factor α,and increase the thickness of the upper trapezius muscle.

Autoimmune hepatitis （AIH） is an immune-mediated chronic liver inflammatory disease with unknown pathogenesis， and intestinal barrier dysfunction is considered an important factor. Meanwhile， there are sex and age differences in the incidence rate of AIH， suggesting that hormone may be involved in regulation. On this basis， this article focuses on the association between estrogen， intestinal barrier， and immune homeostasis， systematically reviews the evidence that estrogen deficiency disrupts intestinal barrier homeostasis， and further summarizes the potential mechanism of estrogen in regulating the development and progression of AIH via intestinal barrier.

Background Prenatal exposure to fine particulate matter (PM_2.5) is closely associated with cortical damage and neuroinflammation in offspring. The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway is a key regulator of inflammation and may be subject to epigenetic regulation. Objective To investigate the role of cGAS-STING pathway activation in PM_2.5-induced cortical damage in offspring mice during pregnancy and the underlying epigenetic regulatory mechanisms. Methods Open field tests were used to assess depressive-like behavior in offspring mice. Morphological analysis was conducted to evaluate cortical damage and microglial activation in offspring brains. Real-time fluorescent quantitative PCR (RT-qPCR) and Western blot (WB) were performed to detect changes in the expression of key molecules in the cGAS-STING pathway in cortical tissue. A PM_2.5-induced microglial cell injury model was established in BV2 cells. Microglial activation was observed, cell viability was measured using the Cell Counting Kit-8 (CCK-8), and the expression levels of inducible nitric oxide synthase (iNOS) and key molecules in the cGAS-STING pathway were detected by RT-qPCR and WB. Bioinformatics analysis was performed to explore the epigenetic regulatory association between the STING signaling pathway and lysine-specific demethylase 5A (KDM5A). Changes in KDM5A mRNA and protein expression, as well as the protein level of histone H3 lysine 4 trimethylation (H3K4me3), were detected in an in vitro PM_2.5 injury model. Using small interfering RNA (siRNA) technology, the KDM5A gene was silenced in BV2 cells exposed to PM_2.5. The protein expression of H3K4me3 was detected to evaluate improvements in microglial activation, changes in inflammatory markers such as iNOS and mannose receptor (CD206), and alterations in the cGAS-STING pathway. Results Compared with the control group, the total distance of offspring mice in the PM_2.5 group was significantly reduced, and both the distance traveled and the time spent in the central area of the open field were significantly decreased (P<0.01, P<0.001), indicating depressive-like behavior in the offspring mice. Compared with the control group, the offspring mice in the PM_2.5 group exhibited disorganized cortical structure and significantly activated microglia (P<0.01), with significantly increased mRNA and protein levels of cGAS and STING (P<0.05, P<0.01, or P<0.001). The in vitro experiments demonstrated that the PM_2.5 treatment induced BV2 cells to polarize toward the M1 phenotype, exhibiting a distinct amoeboid morphology, with upregulated expression of the pro-inflammatory factor iNOS (P<0.05, P<0.01, or P<0.001) and activation of the cGAS-STING pathway (P<0.05, P<0.01). The analysis of RNA-seq data from KDM5A knockout cells revealed significantly downregulated STING expression, suggesting that KDM5A may activate the STING signaling pathway. The in vitro experiments further confirmed that the PM_2.5-treated BV2 cells exhibited significantly elevated mRNA and protein levels of KDM5A (P<0.01), while the H3K4me3 protein levels were markedly reduced (P<0.05). After silencing KDM5A in BV2 cells exposed to PM_2.5, compared with the PM_2.5+siNC group, the PM_2.5+siKDM5A group showed no obvious microglial activation and polarized toward the M2 phenotype, with significantly decreased expression levels of iNOS, cluster of differentiation 16 (CD16), and interleukin-1β (P<0.05, P<0.01), and significantly increased expression levels of anti-inflammatory factors CD206, YM1, and interleukin-10 (P<0.01, P<0.001). Meanwhile, the expression levels of cGAS and STING were also reduced (P<0.05, P<0.01). Conclusion KDM5A activates microglia through the cGAS-STING pathway, thereby contributing to PM_2.5-induced cortical damage in offspring mice during pregnancy.

Work-related musculoskeletal disorders (WMSDs) represent a significant occupational health challenge among healthcare professionals globally, posing substantial threats to physical and mental well-being as well as work sustainability. Adopting preventive behaviors—including ergonomic postural adjustments, optimized work-rest scheduling, proper use of protective and assistive equipment, and regular physical activity—is essential for mitigating the risk of WMSDs. Guided by the social ecological model, the review synthesized current evidence on the determinants of WMSDs preventive behaviors across four levels: intrapersonal characteristics, work environment conditions, interpersonal support, and policy/institutional factors. The findings suggest that higher educational attainment, favorable health-related behavioral patterns, optimized ergonomic work environments, adoption of supportive collaborative systems, strong organizational support, as well as policy safeguards facilitate preventive behavior adoption. Conversely, limited prevention-related knowledge, low risk perception, insufficient physical activity, excessive workload, lack of appropriate protective equipment, inadequate ergonomic training, a prevailing culture of presenteeism, and inadequate policy implementation constitute significant barriers. Multi-dimensional intervention strategies targeting these determinants are warranted to enhance preventive behaviors, reduce the risk of WMSDs, and strengthen occupational health protection for healthcare professionals.

AIM: To analyze changes in the anterior chamber angle structure in patients with implantable collamer lens with central-port(ICL V4c)implantation, and to investigate their associations with preoperative anterior segment anatomical parameters.METHODS: Retrospective case study. Patients with myopia or myopia combined with astigmatism who underwent ICL V4c implantation in the Refractive Surgery Center of the Department of Ophthalmology, the 2nd Affiliated Hospital of Harbin Medical University between July 2024 and November 2024 were recruited. Preoperative and postoperative uncorrected visual acuity, best-corrected visual acuity, intraocular pressure, anterior chamber angle(ACA), white-to-white distance(WTW), anterior chamber depth(ACD), angle to angle distance(ATA), horizontal sulcus-to-sulcus distance(HSTS), vertical sulcus-to-sulcus distance(VSTS),crystalline lens rise(CLR), pupil diameter(PD), iris thickness at 750 μm from the scleral spur(IT750),maximal iris thickness(ITM), iris curvature(I-Curv), and iris cross-sectional area(I-Area), angle opening distance(AOD750), thetrabecular-iris angle(TIA750)and the trabecular-iris space area(TISA750)in the temporal, nasal, superior, and inferior directions,as well as the vault at various postoperative time points were measured.RESULTS: The study involved 40 patients(79 eyes)with myopia or myopia combined with astigmatism who underwent ICL V4c implantation(10 males and 30 females)with the mean age of 24.73±3.79 y. Compared with preoperative measurements, at 1 mo postoperatively, the AOD750, TIA750, and TISA750 parameters at the four angles(temporal, nasal, superior, and inferior)all showed a significant reduction(P<0.01). Statistically significant differences in vault were observed at postoperative 1d(0.49±0.1), postoperative 1 wk(0.43±0.14), and postoperative 1 mo(0.41±0.14)(all P<0.001). Correlation analysis indicated that the postoperative state of the anterior chamber angle was jointly influenced by anterior chamber parameters(ACD, ATA, HSTS、VSTS), iris morphology(I-Area, IT750), pupil size(PD), and surgical factors(ICL size, early vault), and that the combination of influencing factors varied across different orientations. Regression analysis showed that ACD was positively correlated with all postoperative anterior chamber angle parameters(P<0.05). IT750 exhibited negative correlations with the temporal and inferior angles(P<0.05). I-Area was positively correlated with temporal AOD750 and TISA750(P<0.05), and PD had negative correlations with temporal TIA750 and nasal AOD750(P<0.05).CONCLUSION: Postoperative anterior chamber angle narrowing is a common phenomenon after ICL V4c implantation. The degree of change exhibits a significant correlation with multiple preoperative anterior segment anatomical parameters. Preoperative comprehensive assessment of ACD, PD, and IT750 may facilitate the evaluation of the risk of postoperative angle changes and the enhancement of surgical safety.

Objective: To explore the prevalence of bone defect and alveolar bone thickness changes in the mandibular incisors of untreated adults and post-orthodontic treatment adults, with the aim of providing strategies for preventing and managing alveolar bone defects during orthodontic treatment. Methods: This study was reviewed and approved by the Medical Ethics Committee. Clinical records, panoramic radiographs, cephalometric radiographs, and cone beam computed tomography (CBCT) images and informed consent were obtained for 150 untreated adults and 150 post-orthodontic adults. The untreated adults and post-orthodontic adults were respectively divided into three subgroups: skeletal ClassⅠ, Class Ⅱ and Class Ⅲ, with 50 cases per subgroup. Meanwhile, 60 cases with completeness of pre- and post-orthodontic data were enrolled from 150 post-orthodontic adults, including 20 cases each of skeletal ClassⅠ, Class Ⅱ, and Class Ⅲ. Cephalometric radiographs were imported into Dolphin software to measure skeletal parameters. CBCT images were imported into Mimics software to assess alveolar bone defects and to measure alveolar bone thickness of mandibular incisors among three groups: 150 untreated adult groups, 150 post-orthodontic groups and the pre- and post-treatment status of 60 patients selected from the latter group. Results: Untreated adult patients: the prevalence of labial dehiscence and fenestration in the mandibular incisors was higher than that on the lingual side among skeletal ClassⅠ, Ⅱ, and Ⅲ malocclusion patients, and there was a statistically significant difference in the alveolar bone thickness of the mandibular incisors among the three classes. Post-orthodontic treatment adults: for skeletal ClassⅠ and Ⅱ patients, the prevalence of lingual bone dehiscence in the mandibular incisors was significantly higher in the extraction groups than in the non-extraction groups; correspondingly, the lingual alveolar bone was also thinner in the extraction groups; Class Ⅱ non-extraction patients showed a higher prevalence of labial bone fenestration but a lower prevalence of lingual bone fenestration in mandibular incisors compared to Class Ⅱ extraction patients; the orthodontic-orthognathic combined treatment group showed significantly higher prevalence of labial/lingual bone dehiscence and thinner alveolar bone at multiple sites in the mandibular incisors compared to the camouflage group in skeletal Class Ⅲ patients. Comparison of mandibular incisor bone defects and thickness before and after orthodontic treatment in adult patients: in skeletal ClassⅠ and Ⅱ patients treated with premolar extraction and Class Ⅲ patients treated with orthodontic-orthognathic combined treatment, the lingual alveolar bone of mandibular incisors exhibited significant resorption and thinned after treatment, and this was accompanied by an increased prevalence of dehiscence; in non-extraction patients, ClassⅠ non-extraction patients showed thinning of the crestal-labial bone and apical-lingual bone, Class Ⅱ patients showed thinning of the crestal-labial bone and middle-labial bone of the mandibular incisors, along with an increased prevalence of dehiscence Conclusion In malocclusion adults, alveolar bone defects were already present in the mandibular incisors before orthodontic treatment. The alveolar bone defects and thickness in mandibular incisors among post-orthodontic adults were influenced by the treatment plan and Class of skeletal malocclusion.

ObjectiveTo investigate the mechanism by which Xiebai San regulates respiratory tract and intestinal mucosal immunity in rats with allergic asthma. MethodsForty male SD rats were randomly divided into four groups based on body weight: control group, model group, positive control group, and Xiebai San group. The model group, positive control group, and Xiebai San group were sensitized with ovalbumin to establish a rat model of allergic asthma. From day 21 (the aerosol challenge phase), each group received daily gavage interventions simultaneously: the positive control group was administered dexamethasone (0.068 mg/kg), the Xiebai San group received Xiebai San solution (2 g/mL, 11.3 mL/kg), while the control and model groups were given an equal volume of normal saline, once daily for 14 consecutive days. After euthanasia, lung and intestinal tissues were collected. Hematoxylin and eosin staining was used to observe histopathological changes. Transmission electron microscopy was employed to examine tissue ultrastructure. Immunohistochemistry was applied to detect the positive reaction areas of phosphatidyl-inositol 3-kinase (PI3K) and protein kinase B (Akt) proteins. Total protein and total RNA were extracted from lung and intestinal tissues, then the protein and mRNA expression levels of PI3K and Akt genes were detected by Western blotting and real-time quantitative PCR, respectively. ResultsHistopathological results showed alveolar emphysema accompanied by inflammatory cell infiltration, and intestinal mucosal injury with inflammatory cell infiltration in the model group as compared with the control group; the cellular structure of lung tissues was disrupted in the model group, with reduced organelles, while the ultrastructural lesions in the intestine were relatively mild. Compared with the model group, Xiebai San group exhibited milder pathological changes in lung tissues, with occasional alveolar wall damage and a small amount of inflammatory cell infiltration; the intestinal mucosal structure was improved, glands were arranged regularly, and pathological changes such as tissue loosening and inflammatory infiltration were alleviated; the cellular structure of lung tissues was relatively intact with reduced severity of lesions, and no ultrastructural pathological changes were observed in intestinal tissues. Immunohistochemistry and Western blotting results showed that compared with the control group, the specific positive reaction areas of PI3K and Akt in lung and intestinal tissues were significantly increased in the model group (all P<0.001); meanwhile, the protein expression levels of PI3K and Akt were significantly upregulated (all P<0.05). Compared with the model group, the positive area of Akt protein in lung tissue was significantly reduced in the Xiebai San group (P<0.001), and the positive area of PI3K in intestinal tissue was also significantly decreased (P<0.000 1). Additionally, the protein expression levels of PI3K and Akt in lung and intestinal tissues were significantly downregulated (all P<0.01). Real-time quantitative PCR results showed that compared with the control group, the mRNA expression levels of PI3K and Akt genes in lung and intestinal tissues were significantly elevated in the model group (all P<0.05). Compared with the model group, the mRNA expression levels of PI3K and Akt genes in lung and intestinal tissues were significantly reduced in the Xiebai San group (all P<0.05). ConclusionXiebai San exerts protective effects on rats with allergic asthma by inhibiting the expression of key nucleic acids and proteins in the PI3K-Akt signaling pathway in lung and intestinal tissues, improving the morphological structure of lung tissue, and maintaining intestinal mucosal integrity, and regulating intestinal mucosal immune function.

OBJECTIVE: To explore the genotype-phenotype correlation in a Chinese family with structural brain abnormalities due to variant of the TUBB gene. METHODS: A family undergoing prenatal diagnosis at Beijing Obstetrics and Gynecology Hospital in October 2024 was selected as the study subject. Clinical data were collected. Amniotic fluid sample was subjected to chromosomal copy number variation sequencing (CNV-seq). Trio whole-exome sequencing (Trio-WES) was carried out on the amniotic fluid and parental blood samples, and candidate variant was verified by Sanger sequencing. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2023-KY-076-01). RESULTS: Both prenatal ultrasound and fetal MRI showed deviation of brain midline, unilateral lateral ventriculomegaly, and bilateral gyral asymmetry. Trio-WES revealed that the fetus has harbored a maternally derived heterozygous missense variant of the TUBB gene [NM_178014.4: c.155A>G (p.N52S)]. Sanger sequencing confirmed that the woman and a previously terminated fetus both harbored the same variant. Both the proband and two fetuses exhibited similar neuroimaging abnormalities including midline deviation and asymmetrical gyri. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PM2_Supporting+PS2_Moderate+PS3). CONCLUSION The heterozygous c.155A>G (p.N52S) variant was the TUBB gene probably underlay the pathogenesis of the structural brain abnormalities in this family. Above findings have expanded the phenotypic spectrum associated with the variant and facilitated the prenatal diagnosis for this family.
Humans ; Female ; Pregnancy ; Prenatal Diagnosis ; Tubulin/genetics* ; Adult ; Brain/diagnostic imaging* ; Male ; Pedigree ; DNA Copy Number Variations/genetics* ; Exome Sequencing ; Genetic Association Studies ; Magnetic Resonance Imaging

ObjectiveTo investigate the regulatory effects of Huanglian Jiedutang （HLJDT） on immune cell migration， blood-brain barrier protection， and cellular functional recovery in a model of ischemic stroke. MethodsA transient middle cerebral artery occlusion （tMCAO） model was established in mice to induce ischemic stroke. Cerebral blood flow and neurological function were evaluated using laser speckle imaging and neurological deficit scoring. Histopathological damage in brain tissues was assessed by hematoxylin-eosin （HE） and Nissl staining. Mice were divided into a sham group， a model group， an HLJDT group， and a Ginkgo biloba extract （GBE） group. After one week of acclimatization， intragastric administration was initiated. The sham and model groups received normal saline， the HLJDT group received HLJDT at 1.82 g·kg^-¹， and the GBE group received GBE at 0.432 g·kg^-¹. Administration was continued for 5 consecutive days， and the tMCAO model was established after the final dose on day 6. Single-cell RNA sequencing was performed on brain tissues and peripheral immune cells. UMAP and odds ratio （OR） indices were used to analyze cell distribution. Differential expression analysis was conducted to evaluate the effects of HLJDT on endothelial cells， pericytes， and macrophages， combined with CellChat and decoupler to analyze cell-cell communication and transcription factor regulation. Finally， PCR and ELISA were used to validate the mRNA and protein expression of relevant genes. ResultsCompared with the sham group， the model group showed significantly increased neurological deficit scores （P<0.01） and significantly decreased cerebral blood flow （P<0.01）， accompanied by cortical structural disorder， aggravated cytoplasmic vacuolization， and increased numbers of Nissl bodies. Compared with the model group， both the HLJDT and GBE groups exhibited significantly reduced neurological deficit scores （P<0.01） and markedly improved cerebral blood flow （P<0.01）， along with amelioration of cortical structural disorder， alleviated cytoplasmic vacuolization， and reduced numbers of Nissl bodies. Single-cell analysis showed that HLJDT protected endothelial cells and pericytes by preventing their reduction， restored the expression of functional genes in these cells （e.g.， PECAM1 and NOS3）， and downregulated the expression of chemokines and adhesion-related factors （e.g.， CCL2 and CXCL2）. In macrophages， HLJDT reduced their recruitment to the central nervous system and downregulated the expression of chemokine receptors and inflammatory factors （e.g.， IL-6， CCR2， and CXCR2）. Cell-cell communication analysis further indicated that HLJDT， through the above mechanisms， alleviated damage to pericytes and endothelial cells， reduced their recruitment of macrophages， and decreased ligand-receptor interactions in chemokine signaling pathways （including CCL， CXCL， and CSF3） between pericytes/endothelial cells and macrophages， thereby preventing secondary injury. Compared with the sham group， the model group showed significantly upregulated mRNA expression levels of IL-1β， IL-6， TNF-α， CCL2， CXCL2， and CSF3 （P<0.01）， while mRNA expression levels of endothelial- and pericyte function-related genes （RGS5， PECAM1， VEGFB， and NOS3） were significantly downregulated （P<0.01）. In contrast， compared with the model group， the HLJDT and GBE groups exhibited significantly decreased mRNA expression levels of IL-1β， IL-6， TNF-α， CCL2， CXCL2， and CSF3 （P<0.01）， and significantly increased expression of RGS5， PECAM1， VEGFB， and NOS3 （P<0.01）. At the protein level， compared with the sham group， the model group showed significantly increased expression of IL-1β， IL-6， and TNF-α （P<0.01）， whereas these protein levels were significantly reduced in the HLJDT and GBE groups compared with the model group （P<0.01）. ConclusionHLJDT reduces neuronal damage in ischemic stroke by protecting endothelial cells and pericytes， while inhibiting their interaction with macrophages， thereby mitigating secondary injury in the central nervous system.

ObjectiveThis paper aims to analyze the variety characteristics and prescription patterns of marketed traditional Chinese patent medicines for treating abortion and provide references for new medicine development and clinical application. MethodsRelevant information of traditional Chinese patent medicines for treating abortion was systematically retrieved and collected. Microsoft Excel 2021 software was used to sort and statistically analyze the medicine syndrome types， quantity， market situation， and status of package inserts. Based on the Ancient and Modern Medical Case Cloud Platform （V2.3.9）， the medicine properties， flavors， meridian tropism， and medication characteristics of standardized prescriptions were analyzed. ResultsA total of 39 marketed traditional Chinese patent medicines for treating abortion in China were included. According to disease type， these medicines were categorized as therapeutic medicines for threatened abortion and recurrent spontaneous abortion. According to clinical function， they were categorized into three groups： fetus stabilization， blood nourishment， and adjunctive conditioning. They were also categorized into pre-pregnancy conditioning and post-pregnancy fetal maintenance by clinical intervention stage. Post-marketing research showed that only three products had undergone safety evaluations and one involved pharmacoeconomic research， indicating a general lack of standardized evidence-based data. Dosage forms were mainly pills and granules. Package insert analysis revealed that 15 products listed "contraindications"， while 28 included "precautions". Based on prescription inclusion and exclusion criteria， 25 products were selected for further analysis. Their therapeutic effects were mainly concentrated on "tonifying the kidney and spleen， replenishing Qi， and nourishing blood"， with core medicines including Paeoniae Radix Alba， Angelicae Sinensis Radix， and Atractylodis Macrocephalae Rhizoma. Most medicines were warm or neutral in nature， predominantly sweet and pungent in flavor， and mainly entered the spleen， liver， and kidney meridians. ConclusionTraditional Chinese patent medicines for treating abortion demonstrate clear clinical value. However， shortcomings remain， including insufficient post-marketing research， prescription homogeneity， and incomplete package inserts. Future efforts should establish a clinically value-oriented modern development pathway， strengthen safety surveillance and evidence evaluation， improve package inserts， and promote precision use to further enhance clinical value.