ObjectiveThis paper aims to find the identified and validated clinical biomarker data building upon a clinical study of early-phase phase Ⅱ and investigate the correlation analysis of Huanglian Jiedu Wan on syndrome improvement and clinical biomarkers in the treatment of "excess heat-toxicity" based on a machine learning model. Additionally， the effective prediction of clinical biomarker values for the main symptoms of the "excess heat-toxicity" syndrome was assessed. MethodsA total of 229 patients meeting the inclusion criteria for "excess heat-toxicity" syndrome were randomly divided into the Huanglian Jiedu Wan group and the placebo group. Syndrome score transition matrices were constructed for the Huanglian Jiedu Wan group and the placebo group based on three main symptoms of "excess heat-toxicity" syndrome， such as oral ulcers， sore throat， and gum swelling and pain. Data from the patients with these three syndromes were also integrated for an overall analysis. The corresponding syndrome score transition matrices were further constructed to visualize symptom change trends of the patients in the two groups via heatmaps. Based on the identified and validated clinical biomarkers related to inflammation， oxidative stress， and energy metabolism in the early phase， Spearman correlation analysis was employed to analyze and evaluate the associations between clinical biomarkers and syndrome improvement. Key clinical biomarkers reflecting the effect of Huanglian Jiedu Wan were screened through the comparison of differences between groups. An extreme gradient boosting （XGBoost） algorithm was used to develop a prediction model for main symptom classification， with classification performance evaluated through 10-fold cross-validation. Feature importance analysis was applied to identify variables with the greatest contribution to the prediction result. ResultsThe syndrome transition matrix results indicated that the Huanglian Jiedu Wan group showed a superior effect to the placebo group in improving oral ulcers， sore throat， and overall symptoms， with significant effects observed especially in sore throat and overall symptom analyses （P<0.01）. Spearman correlation analysis revealed that several clinical biomarkers positively correlated with "excess heat-toxicity" syndrome and its main symptom improvement， were also called "heat-related biomarkers"， including succinic acid， α-ketoglutaric acid， glycine， lactic acid， adenosine monophosphate （AMP）， tumor necrosis factor-α （TNF-α）， interferon-γ （IFN-γ）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， interleukin-10 （IL-10）， and so on. Conversely， clinical biomarkers negatively correlated with symptom severity， were also called "heat-clearing related biomarkers" after administration of Huanglian Jiedu Wan， including malic acid， fumaric acid， cis-aconitic acid， adrenocorticotropic hormone （ACTH）， IL-1β， IL-4， IL-8， succinic acid， and citric acid. The XGBoost classification model using all 52 biomarkers as variables achieved an average test accuracy of 0.754 and an average F1 score of 0.777. Feature importance analysis identified the scores of glutamic acid in saliva and IL-6 were the highest in all the variables， with importance scores of 0.081 and 0.080， respectively. After screening out 14 key variables and optimizing the parameters， model performance improved to an average accuracy of 0.758 and an F1 score of 0.798. Feature importance analysis further determined that the glutamic acid in saliva and IL-6 showed obvious changes after screening the variables， confirming the good syndrome prediction ability of the model constructed by these key clinical biomarkers. ConclusionThis study systematically elucidates the correlation between syndrome improvement and clinical biomarkers of Huanglian Jiedu Wan in the treatment of "excess heat-toxicity" syndrome. An XGBoost classification model based on key clinical biomarkers is successfully established， achieving effective prediction of the symptoms related to the "excess heat-toxicity" syndrome such as oral ulcers and sore throat and providing a new insight for objective identification of traditional Chinese medicine syndromes.

ObjectiveThis paper aims to find the identified and validated clinical biomarker data building upon a clinical study of early-phase phase Ⅱ and investigate the correlation analysis of Huanglian Jiedu Wan on syndrome improvement and clinical biomarkers in the treatment of "excess heat-toxicity" based on a machine learning model. Additionally， the effective prediction of clinical biomarker values for the main symptoms of the "excess heat-toxicity" syndrome was assessed. MethodsA total of 229 patients meeting the inclusion criteria for "excess heat-toxicity" syndrome were randomly divided into the Huanglian Jiedu Wan group and the placebo group. Syndrome score transition matrices were constructed for the Huanglian Jiedu Wan group and the placebo group based on three main symptoms of "excess heat-toxicity" syndrome， such as oral ulcers， sore throat， and gum swelling and pain. Data from the patients with these three syndromes were also integrated for an overall analysis. The corresponding syndrome score transition matrices were further constructed to visualize symptom change trends of the patients in the two groups via heatmaps. Based on the identified and validated clinical biomarkers related to inflammation， oxidative stress， and energy metabolism in the early phase， Spearman correlation analysis was employed to analyze and evaluate the associations between clinical biomarkers and syndrome improvement. Key clinical biomarkers reflecting the effect of Huanglian Jiedu Wan were screened through the comparison of differences between groups. An extreme gradient boosting （XGBoost） algorithm was used to develop a prediction model for main symptom classification， with classification performance evaluated through 10-fold cross-validation. Feature importance analysis was applied to identify variables with the greatest contribution to the prediction result. ResultsThe syndrome transition matrix results indicated that the Huanglian Jiedu Wan group showed a superior effect to the placebo group in improving oral ulcers， sore throat， and overall symptoms， with significant effects observed especially in sore throat and overall symptom analyses （P<0.01）. Spearman correlation analysis revealed that several clinical biomarkers positively correlated with "excess heat-toxicity" syndrome and its main symptom improvement， were also called "heat-related biomarkers"， including succinic acid， α-ketoglutaric acid， glycine， lactic acid， adenosine monophosphate （AMP）， tumor necrosis factor-α （TNF-α）， interferon-γ （IFN-γ）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， interleukin-10 （IL-10）， and so on. Conversely， clinical biomarkers negatively correlated with symptom severity， were also called "heat-clearing related biomarkers" after administration of Huanglian Jiedu Wan， including malic acid， fumaric acid， cis-aconitic acid， adrenocorticotropic hormone （ACTH）， IL-1β， IL-4， IL-8， succinic acid， and citric acid. The XGBoost classification model using all 52 biomarkers as variables achieved an average test accuracy of 0.754 and an average F1 score of 0.777. Feature importance analysis identified the scores of glutamic acid in saliva and IL-6 were the highest in all the variables， with importance scores of 0.081 and 0.080， respectively. After screening out 14 key variables and optimizing the parameters， model performance improved to an average accuracy of 0.758 and an F1 score of 0.798. Feature importance analysis further determined that the glutamic acid in saliva and IL-6 showed obvious changes after screening the variables， confirming the good syndrome prediction ability of the model constructed by these key clinical biomarkers. ConclusionThis study systematically elucidates the correlation between syndrome improvement and clinical biomarkers of Huanglian Jiedu Wan in the treatment of "excess heat-toxicity" syndrome. An XGBoost classification model based on key clinical biomarkers is successfully established， achieving effective prediction of the symptoms related to the "excess heat-toxicity" syndrome such as oral ulcers and sore throat and providing a new insight for objective identification of traditional Chinese medicine syndromes.

Background Work-related musculoskeletal disorders (WMSDs) are a major occupational health concern, particularly among workers exposed to adverse ergonomic conditions. Manganese production involves heavy physical demands, yet research on WMSDs among manganese workers remains limited. Objective To investigate the prevalence and influencing factors of WMSDs among manganese workers in a manganese enterprise in Guangxi. Methods A cross-sectional survey was conducted from May to June 2024 on workers at a manganese factory in Guangxi. The Chinese Musculoskeletal Disorders Questionnaire was used to collect information on demographic characteristics, distribution of musculoskeletal symptoms, and work-related exposures. χ² test was applied to compare differences in positive WMSDs rates across groups, and logistic regression analysis was performed to identify associated factors. Results A total of 1476 workers were enrolled in the study after pre-determined inclusion and exclusion criteria. The overall prevalence of WMSDs was 34.15%. The most commonly affected body regions were the lower back (17.28%), neck (16.67%), and shoulders (13.82%). The results of logistic regression analysis indicated that female, older age, and education level of college or above were associated with a higher risk of WMSDs (P<0.05). Awkward working postures were significantly associated with WMSDs in corresponding body regions; in particular, awkward postures of the neck, upper limbs, trunk, and lower limbs were related to an increased risk of WMSDs in multiple body sites (P<0.05). In addition, poor lighting conditions, high workplace temperature, frequent or sustained arm support during work, and high job demands were associated with an increased risk of overall or site-specific WMSDs (P<0.05). Conclusion The high prevalence of WMSDs among manganese workers is closely associated with demographic characteristics, working postures, and work environment and organizational factors. Targeted ergonomic interventions focusing on high-risk body regions and key ergonomic exposures are warranted to reduce the risk of WMSDs among manganese workers.

Objective To optimize the animal-free fermentation medium and fermentation conditions of pneumococcus, and make it suitable for fermentation production.MethodsThe orthogonal method was used to optimize the carbon source(glucose)(12. 5, 18. 75, 25 g/L), nitrogen source(soybean peptone)(30, 40, 50 g/L) and uracil(10, 20, 30 mg/L) concentrations of fermentation medium for type 1, 3, 5, 9N and 33F pneumococci, as well as fermentation culture conditions such as strain concentration(A_(694))(0. 2, 0. 4, 0. 6), fermentation temperature(35, 36, 37 ℃) and pH(6. 8, 7. 2, 7. 6).ResultsThe optimal fermentation medium compositions for pneumococcus were as follows: for type 1, soybean peptone at 50 g/L, initial glucose concentration at 18. 75 g/L, and uracil at 30 mg/L; the optimal fermentation conditions were A_(694)at 0. 6, temperature at 35 ℃,and pH at 7. 6. For type 3, the optimal medium consisted of soybean peptone at 30 g/L, initial glucose concentration at 12. 5 g/L,and uracil at 10 mg/L; the optimal fermentation conditions were A_(694)at 0. 6, temperature at 35 ℃, and pH at 7. 2. For type 5,the optimal medium comprised soybean peptone at 50 g/L, initial glucose concentration at 12. 5 g/L, and uracil at 20 mg/L;the optimal conditions were A_(694)at 0. 6, temperature at 36 ℃, and pH at 6. 8. For type 9N, the optimal medium consisted of soybean peptone at 50 g/L, initial glucose concentration at 18. 75 g/L, and uracil at 10 mg/L; the optimal conditions were A_(694)at 0. 6, temperature at 36 ℃, and pH at 7. 2. For type 33F, the optimal medium comprised soybean peptone at 50 g/L, initial glucose concentration at 12. 5 g/L, and uracil at 30 mg/L; the optimal conditions were A_(694)at 0. 4, temperature at 37 ℃, and pH at 6. 8.ConclusionThe optimized fermentation medium and fermentation conditions can be applied to the research and production of 24-valent pneumococcal polysaccharide vaccine.

OBJECTIVE: To investigate the prenatal manifestation and genetic basis for two fetuses suspected for Osteocraniostenosis (OCS). METHODS: Two fetuses undergoing invasive prenatal diagnosis at Cangzhou People's Hospital in April and August 2021 for short long bones and abnormal skull morphology were selected as the study subjects. Clinical data were collected and analyzed. Genomic DNA was extracted from amniotic fluid and peripheral blood samples of the two couples. Candidate variants were validated by Sanger sequencing. Literature was retrieved from CNKI, Wanfang Data Knowledge Service Platform and PubMed using keywords including "FAM111A gene", "gracile bone dysplasia", "FAM111A" and "osteocraniostenosis" from January 1, 2000 to June 30, 2025. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: K2020-049). RESULTS: Fetus 1 was found to have short limbs, abnormal skull morphology and shallow cerebral sulci. Fetus 2 showed short limbs, irregular skull halo, prominent forehead and bilateral frontal narrowing. Trio-WES revealed that fetus 1 has carried a heterozygous missense variant c.1582G>C (p.Asp528His) in exon 4 of the FAM111A gene, which was unreported previously. Fetus 2 has harbored a heterozygous in-frame deletion c.1020_1022delTTC (p.Ser343del) in exon 6 of the FAM111A gene, which has been recorded as likely pathogenic by the ClinVar and HGMD databases. Sanger sequencing confirmed that the parents of both fetuses were wild-type for the variant sites. A total of 9 previously reported patients with FAM111A-related gracile bone dysplasia/OCS from 4 publications were retrieved. The main clinical features included intrauterine growth restriction, hypomineralized skull, gracile long bones with narrow medullary cavities and characteristic facial anomalies, which were in large in keeping with the prenatal features of the two fetuses. CONCLUSION Both fetuses were diagnosed with FAM111A-related OCS based on the characteristic prenatal findings and identification of the FAM111A variants. Above finding expanded the phenotypic spectrum of FAM111A-associated disorders and provided clues for the prenatal diagnosis and genetic counseling.
Humans ; Female ; Pregnancy ; Prenatal Diagnosis ; Phenotype ; Fetus ; Male ; Bone Diseases, Developmental/genetics* ; Adult

OBJECTIVE To determine the contents of 15 components in Aurantii Fructus Immaturus from different origins （Citrus aurantium， C. junos， C. aurantium Linn.， C. sinensis Osb.， C. sinensis）， screen differential components， and provide references for the quality evaluation of Aurantii Fructus Immaturus. METHODS HPLC method was adopted to determine the contents of synephrine， N-methyltyramine， 5，7-dihydroxychromone-7-neohesperidoside， neoponcirin， narirutin， naringin， hesperidin， neohesperidin， naringenin， hesperetin， sinensetin， nobiletin， tangeretin， 5-demethylnobiletin， and auraptene in 46 batches of Aurantii Fructus Immaturus from different origins. The determination was performed on Waters Symmetry C18 column with mobile phase consisted of acetonitrile-0.1% formic acid （gradient elution） at the flow rate of 1.0 mL/min； column temperature was set at 40 ℃ ， detection wavelength was 284 nm， and sample injection volume was 5 μL. The differences between different origins of Aurantii Fructus Immaturus were analyzed by cluster analysis， principal component analysis （PCA） and orthogonal partial least squares-discriminant analysis （OPLS-DA）， and differential components were screened. RESULTS The linear relationships of the aforementioned 15 components were all good within the tested mass concentration ranges （all r＞0.999 0）. The RSDs for precision， stability （24 h）， and repeatability tests were all less than 2.00%. The average recovery rate ranged from 91.1% to 103.9% （all RSDs＜3.10%）. Cluster analysis， PCA， and OPLS-DA revealed that C. sinensis Osb. and C. sinensis were clustered into one category， while C. aurantium，C. junos and C. aurantium Linn. were clustered into another category. The variable importance projection values for neohesperidin， auraptene， naringin， neoponcirin， tangeretin， hesperidin， sinensetin， and 5，7-dihydroxychromone-7-neohesperidoside were all greater than 1. CONCLUSIONS In this study， the contents of 15 components in Aurantii Fructus Immaturus from different origins are determined， and 8 differential components， including neohesperidin， auraptene， naringin， and neoponcirin， are screened out.

AIM: To analyze the current status and influencing factors for insufficient hyperopia reserve in preschool children from Changzhi City, Shanxi Province, and to provide reference and basis for myopia prevention and control in this district.METHODS: A stratified cluster random sampling strategy was used to select 2 854 preschool children(5 708 eyes)from 29 child-care centers in Changzhi City between January and May 2024. Hyperopia reserve was assessed through measurements and questionnaire surveys. Totally 2 820 cases(5 640 eyes)were finally included, with 34 cases excluded(32 cases of uncooperativeness and 2 cases of distractibility). The univariate analysis and multivariate Logistic regression were performed to analyze the associated influencing factors of insufficient hyperopia reserve.RESULTS: A total of 580 preschool children with insufficient hyperopia reserve were detected, with an incidence of 20.57%. Logistic regression analysis revealed that male(OR=1.723, 95% CI: 1.419-2.093), maternal myopia(OR=2.210, 95% CI: 1.681-2.906), paternal myopia(OR=1.426, 95% CI: 1.059-1.921), myopia in both parents(OR=2.761, 95% CI: 2.110-3.612), preterm infants(OR=1.740, 95% CI: 1.294-2.342), the mean daily sleep duration <10 h(OR=1.272, 95% CI: 1.024-1.579), and the mean daily outdoor activity time <2 h(OR=1.222, 95% CI: 1.005-1.485)were risk factors for insufficient hyperopia reserve(all P<0.05). Conversely, using blackout curtains during the day and turning off lights at night(OR=0.598, 95% CI: 0.405-0.883)were identified to be protective factors(P<0.05).CONCLUSION: Sex, genetics, gestational age, sleep duration and environmental conditions, and outdoor activity time are potentially associated with insufficient hyperopia reserve in preschool children. Caregivers should prioritize the management of these risk factors to prevent the occurrence of myopia.

ObjectiveThis study aims to systematically evaluate the therapeutic effects of Huaihuasan on ulcerative colitis （UC） in the rats with the syndrome of dampness-heat in the large intestine and explore the potential mechanisms of action. MethodsA rat model of UC due to dampness-heat in the large intestine was successfully established by combining traditional Chinese medicine etiology with trinitrobenzenesulfonic acid （TNBS）/ethanol solution. Rats were randomly allocated into a normal group， a model group， a high-dose （10.58 g·kg^-1·d^-1） Huaihuasan group， a medium-dose （5.29 g·kg^-1·d^-1） Huaihuasan group， a low-dose （2.65 g·kg^-1·d^-1） Huaihuasan group， and a sulfasalazine （0.35 g·kg^-1·d^-1） group. The body weight changes and the diarrhea and bloody stool scores of the rats in each group were recorded. In addition， pathological changes of the colon tissue were observed to evaluate the therapeutic effects on the intestinal damage and inflammatory infiltration. Immunohistochemistry and real-time fluorescent quantitative PCR were employed to determine the expression levels of zonula occludens-1 （ZO-1） and Occludin in the colon tissue， the serum levels of interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α）， the expression of Toll-like receptor 4 （TLR4）， myeloid differentiation primary response 88 （MyD88）， and nuclear factor-κB p65 subunit （NF-κB p65） in the colorectum， and the mRNA levels of TLR4， MyD88， NF-κB p65， and IL-6 in the intestinal tissue. ResultsCompared with the model group， Huaihuasan effectively slowed down the trend of body weight loss （P<0.01）， mitigated diarrhea and bloody stool symptoms， reduce the disease activity index （DAI） （P<0.01）， restored the length of the colon （P<0.01）， and promoted the recovery of the colon tissue. The immunohistochemistry results showed that compared with the model group， Huaihuasan intervention promoted the expression of ZO-1 and Occludin （P<0.05）， reduced the serum levels of IL-6 and TNF-α （P<0.05， P<0.01）， and down-regulated the protein levels of TLR4， MyD88， and NF-κB p65 in the colon tissue （P<0.05， P<0.01） and the mRNA levels of TLR4， MyD88， NF-κB p65， and downstream IL-6 （P<0.05）. ConclusionHuaihuasan exerts significant therapeutic effects on UC due to dampness-heat in the large intestine by modulating the TLR4/NF-κB signaling pathway， reducing inflammatory mediator levels， and enhancing the intestinal barrier function. These findings provide theoretical support for the clinical application and mechanism study of Huaihuasan in the treatment of UC.

Autism spectrum disorder（ASD）is a multifactorial，pervasive neurodevelopmental disorder.As the morbidity rate of ASD in children increases year by year，feeding and eating behaviors，as an important and common clinical problem in children with ASD，are gaining more and more attention.Many children with ASD often have food selection issues，chewing problems，food allergy and related gastrointestinal symptoms，and even serious diseases such as eating disorders，which negatively impact on their growth and development.There are many factors affecting feeding and eating behavior problems in children with ASD，such as sensory processing，ritualistic eating behavior，gastrointestinal symptoms，age，and parenting pressure.There are also a variety of interventions that can help to improve feeding and eating behavior problems in children with ASD.Strengthening the understanding of these influencing factors and intervention treatment methods is beneficial for improving the quality of life in children with ASD.

Kawasaki disease（KD）is an acute systemic vasculitis primarily affecting small- and medium-sized arteries in children，with widespread inflammation as the major pathological hallmark. A subset of patients with KD exhibit resistance to high-dose intravenous immunoglobulin（IVIG）therapy，which significantly increases the risk of developing severe cardiovascular complications，particularly coronary artery lesions（CAL）. Interferon gamma-inducible protein 10（IP-10），a chemokine，exerts its biological functions by binding to its specific receptor，chemokine receptor 3（CXCR3）. In the relevant research on KD，the association between IP-10 and IP-10 gene polymorphism with KD has garnered significant attention from both domestic and international researchers. This article reviews the recent research progress on the relationship between IP-10，its gene polymorphism and KD，with the aim of providing references for the pathogenesis，prevention，treatment and prognosis of KD.