Objective To explore the adverse event signals of children using macrolide drugs （azithromycin, clarithromycin, and erythromycin）, and provide reference for rational medicine use in clinical practice. Methods Data from children under 12 years old were extracted from the US FAERS database spanning from the first quarter of 2004 to the second quarter of 2023. The adverse drug reaction （ADR） signal mining for three macrolide antibiotics was conducted using the Reporting Odds Ratio （ROR） and Bayesian Confidence Propagation Neural Network （BCPNN） methods. Special emphasis was placed on analyzing and contrasting the differences in adverse events among the three drugs. Results A total of 1 615 reports for children under 12 years old were retrieved from the FAERS database, including 1 024 reports of azithromycin, 460 reports of clarithromycin, and 131 reports of erythromycin. Among azithromycin and erythromycin, there were more reports from boys than girls, while for clarithromycin, there were more reports from girls than boys. Oral administration was the most common route of administration for all three drugs. Regarding the outcome of adverse events reported, azithromycin and clarithromycin were primarily associated with other serious adverse events, whereas erythromycin was mainly associated with hospitalization and other serious adverse events. The number of adverse events reported decreased with increasing age, with a higher number of reports in the 0-3 age group. Using the ROR and BCPNN methods for signal detection, 86 signals were identified for azithromycin, 91 for clarithromycin, and 34 for erythromycin. These signals involved 22 System Organ Classes （SOCs）, with azithromycin mainly concentrated in skin and subcutaneous tissue disorders （n=21）, clarithromycin in gastrointestinal disorders （n=15）, and erythromycin in gastrointestinal disorders （n=8）. Twenty-four signals of moderate to high risk were detected, with 13 for azithromycin, 9 for clarithromycin, and 2 for erythromycin. Conclusion The adverse events induced by the three drugs with different risks in different systems. When clinically treating Mycoplasma pneumoniae pneumonia in children, the risk profiles of drugs in different systems should be considered, and personalized dosing should be implemented.

Objective:To investigate the prognostic value of deep learning-based automated quantification of tumor-stroma ratio (TSR) in patients undergoing neoadjuvant therapy (NAT) for breast cancer.Methods:Specimens were collected from 209 breast cancer patients who received NAT at Renmin Hospital of Wuhan University from October 2019 to June 2023. TSR levels in pre-NAT biopsy specimens were automatically computed using a deep learning algorithm and categorized into low stroma (TSR≤30%), intermediate stroma (TSR 30% to ≤60%), and high stroma (TSR>60%) groups. Residual cancer burden (RCB) grading of post-NAT surgical specimens was determined to compare the relationship between TSR expression levels and RCB grades. The correlation of TSR with NAT efficacy was analyzed, and the association between TSR expression and patient prognosis was further investigated.Results:There were 85 cases with low stroma (TSR≤30%), 93 cases with intermediate stroma (TSR 30% to ≤60%), and 31 cases with high stroma (TSR>60%). Different TSR expression levels showed significant differences between various RCB grades ( P<0.05). Logistic univariate and multivariate analyses showed that TSR was a risk factor for obtaining a complete pathological remission from neoadjuvant therapy for breast cancer when it was used as a continuous variable ( P<0.05); COX regression and survival analyses showed that the lower the percentage of tumorigenic mesenchyme was, the better the prognosis of the patient was ( P<0.05). Conclusions:The deep learning-based model enables automatic and accurate quantification of TSR. A lower pre-treatment tumoral stroma is associated with a lower RCB score and a higher rate of pathologic complete response, indicating that TSR can predict the efficacy of neoadjuvant therapy in breast cancer and thus holds prognostic significance. Therefore, TSR may serve as a biomarker for predicting therapeutic outcomes in breast cancer neoadjuvant therapy.

Objective:To investigate the prognostic value of deep learning-based automated quantification of tumor-stroma ratio (TSR) in patients undergoing neoadjuvant therapy (NAT) for breast cancer.Methods:Specimens were collected from 209 breast cancer patients who received NAT at Renmin Hospital of Wuhan University from October 2019 to June 2023. TSR levels in pre-NAT biopsy specimens were automatically computed using a deep learning algorithm and categorized into low stroma (TSR≤30%), intermediate stroma (TSR 30% to ≤60%), and high stroma (TSR>60%) groups. Residual cancer burden (RCB) grading of post-NAT surgical specimens was determined to compare the relationship between TSR expression levels and RCB grades. The correlation of TSR with NAT efficacy was analyzed, and the association between TSR expression and patient prognosis was further investigated.Results:There were 85 cases with low stroma (TSR≤30%), 93 cases with intermediate stroma (TSR 30% to ≤60%), and 31 cases with high stroma (TSR>60%). Different TSR expression levels showed significant differences between various RCB grades ( P<0.05). Logistic univariate and multivariate analyses showed that TSR was a risk factor for obtaining a complete pathological remission from neoadjuvant therapy for breast cancer when it was used as a continuous variable ( P<0.05); COX regression and survival analyses showed that the lower the percentage of tumorigenic mesenchyme was, the better the prognosis of the patient was ( P<0.05). Conclusions:The deep learning-based model enables automatic and accurate quantification of TSR. A lower pre-treatment tumoral stroma is associated with a lower RCB score and a higher rate of pathologic complete response, indicating that TSR can predict the efficacy of neoadjuvant therapy in breast cancer and thus holds prognostic significance. Therefore, TSR may serve as a biomarker for predicting therapeutic outcomes in breast cancer neoadjuvant therapy.

Apical microsurgery is accurate and minimally invasive, produces few complications, and has a success rate of more than 90%. However, due to the lack of awareness and understanding of apical microsurgery by dental general practitioners and even endodontists, many clinical problems remain to be overcome. The consensus has gathered well-known domestic experts to hold a series of special discussions and reached the consensus. This document specifies the indications, contraindications, preoperative preparations, operational procedures, complication prevention measures, and efficacy evaluation of apical microsurgery and is applicable to dentists who perform apical microsurgery after systematic training.
Microsurgery/standards* ; Humans ; Apicoectomy ; Contraindications, Procedure ; Tooth Apex/diagnostic imaging* ; Postoperative Complications/prevention & control* ; Consensus ; Treatment Outcome

Pulpotomy, which belongs to vital pulp therapy, has become a strategy for managing pulpitis in recent decades. This minimally invasive treatment reflects the recognition of preserving healthy dental pulp and optimizing long-term patient-centered outcomes. Pulpotomy is categorized into partial pulpotomy (PP), the removal of a partial segment of the coronal pulp tissue, and full pulpotomy (FP), the removal of whole coronal pulp, which is followed by applying the biomaterials onto the remaining pulp tissue and ultimately restoring the tooth. Procedural decisions for the amount of pulp tissue removal or retention depend on the diagnostic of pulp vitality, the overall treatment plan, the patient's general health status, and pulp inflammation reassessment during operation. This statement represents the consensus of an expert committee convened by the Society of Cariology and Endodontics, Chinese Stomatological Association. It addresses the current evidence to support the application of pulpotomy as a potential alternative to root canal treatment (RCT) on mature permanent teeth with pulpitis from a biological basis, the development of capping biomaterial, and the diagnostic considerations to evidence-based medicine. This expert statement intends to provide a clinical protocol of pulpotomy, which facilitates practitioners in choosing the optimal procedure and increasing their confidence in this rapidly evolving field.
Humans ; Calcium Compounds/therapeutic use* ; Consensus ; Dental Pulp ; Dentition, Permanent ; Oxides/therapeutic use* ; Pulpitis/therapy* ; Pulpotomy/standards*

Objective To investigate whether cisplatin induces tumor necrosis factor-α(TNF-α)secretion in human head and neck squamous cell carcinoma(HNSCC)cells to trigger RIP1/RIP3/MLKL-dependent necroptosis of the cells.Methods HNSCC cell lines HN4 and SCC4 treated with cisplatin(CDDP)or the combined treatment with CDDP and z-VAD-fmk(a caspase inhibitor)or Nec-1(a necroptosis inhibitor)for 24 h were examined for changes in cell viability using CCK8 assay and expressions of caspase-8 and necroptosis pathway proteins(RIP1/RIP3/MLKL)using Western blotting.The changes in migration of the cells were assessed with cell scratch assay,and the expressions of epithelial-mesenchymal transition(EMT)marker proteins N-cadherin,vimentin,and E-cadherin as well as the expressions of NF-κB(p65)and TNF-α were detected with Western blotting.Results The IC50 of cisplatin was 10 μg/mL in HN4 cells and 15 μg/mL in SCC4 cells.Cisplatin treatment significantly decreased the expressions of caspase-8,N-cadherin and vimentin and increased the expressions of E-cadherin,the necroptosis pathway proteins(RIP1/RIP3/MLKL),TNF-α,and NF-κB(p65),and these changes were obviously inhibited by treatment with Nec-1.Cisplatin stimulation also significantly lowered migration of the cells,and this inhibitory effect was strongly attenuated by Nec-1 treatment.Conclusion Cisplatin activates nuclear factor-κB signaling in HNSCCs to promote TNF-α autocrine and induce RIP1/RIP3/MLKL-dependent necroptosis,thus leading to inhibition of cell proliferation.

Objective:To investigate the association between body mass index (BMI) and the risk of chronic obstructive pulmonary disease (COPD).Methods:This study employed a single-center, cross-sectional design combined with online Mendelian randomization (MR) analysis. A total of 16 187 pieces of lung function data for COPD screening from the “Happy Breathing” project in the Jingzhou area between September 2021 and October 2023 were initially collected. Cases with missing questionnaire information, failed quality control, or isolated restrictive or small airway dysfunction were excluded, resulting in a final dataset of 3 999 cases, comprising 2 330 non-COPD and 1 669 COPD cases. Binary COPD status was set as the outcome variable, with BMI as the exposure variable. A smooth curve plot was used to depict the relationship between BMI and COPD prevalence; if non-linearity was observed, a two-piece linear regression model was employed to calculate threshold effects, adjusting for potential confounders such as age, sex, smoking history, biomass fuel exposure, and COPD awareness. Subsequently, online genome-wide association study (GWAS) data were utilized for MR analysis to explore any potential causal link between high BMI and COPD development.Results:Analysis of the “Happy Breathing” COPD screening data from the Jingzhou area revealed a nonlinear relationship between BMI and COPD risk. For BMI values <23.7 kg/m2, each 1 kg/m2 increase in BMI was associated with an 18% decrease in COPD risk ( OR=0.82, 95% CI: 0.79-0.85). However, for BMI >23.7 kg/m2, no significant association was found between increasing BMI and COPD risk ( OR=1.00, 95% CI: 0.96-1.05). MR analysis using online GWAS data suggested no potential causal relationship between high BMI and COPD occurrence, with both heterogeneity and pleiotropy tests yielding P>0.05. Conclusion:There may be a nonlinear relationship between BMI and the risk of COPD, with no apparent association between BMI and COPD risk for values above 23.7 kg/m2.

Objective To investigate whether cisplatin induces tumor necrosis factor-α(TNF-α)secretion in human head and neck squamous cell carcinoma(HNSCC)cells to trigger RIP1/RIP3/MLKL-dependent necroptosis of the cells.Methods HNSCC cell lines HN4 and SCC4 treated with cisplatin(CDDP)or the combined treatment with CDDP and z-VAD-fmk(a caspase inhibitor)or Nec-1(a necroptosis inhibitor)for 24 h were examined for changes in cell viability using CCK8 assay and expressions of caspase-8 and necroptosis pathway proteins(RIP1/RIP3/MLKL)using Western blotting.The changes in migration of the cells were assessed with cell scratch assay,and the expressions of epithelial-mesenchymal transition(EMT)marker proteins N-cadherin,vimentin,and E-cadherin as well as the expressions of NF-κB(p65)and TNF-α were detected with Western blotting.Results The IC50 of cisplatin was 10 μg/mL in HN4 cells and 15 μg/mL in SCC4 cells.Cisplatin treatment significantly decreased the expressions of caspase-8,N-cadherin and vimentin and increased the expressions of E-cadherin,the necroptosis pathway proteins(RIP1/RIP3/MLKL),TNF-α,and NF-κB(p65),and these changes were obviously inhibited by treatment with Nec-1.Cisplatin stimulation also significantly lowered migration of the cells,and this inhibitory effect was strongly attenuated by Nec-1 treatment.Conclusion Cisplatin activates nuclear factor-κB signaling in HNSCCs to promote TNF-α autocrine and induce RIP1/RIP3/MLKL-dependent necroptosis,thus leading to inhibition of cell proliferation.

Objective:To evaluate the effect of niraparib, the poly (ADP-ribose) polymerase (PARP) inhibitor, on the radiosensitivity of esophageal squamous cell carcinoma (ESCC) and to preliminarily investigate its mechanism.Methods:Human esophageal squamous cell carcinoma cells ECA-109 and KYSE-150 were divided into the control, niraparib, single irradiation, combined (niraparib+irradiation) groups. Cell proliferation was measured by CCK-8 assay. The changes of cell survival rate were detected by colony formation assay. The changes of cell cycle and apoptosis were analyzed by flow cytometry. The number of γH2AX foci was detected by immunofluorescence, and the expression levels of PARP-1, cleaved-PARP, RAD51, mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase 1 and 2 (ERK1/2) ] and p-MAPK (ERK1/2) proteins were determined by Western blot. All data were expressed as Mean±SD. Data between two groups conforming to normal distribution through the normality test were subject to independent sample t-test and multiple groups were analyzed using one-way ANOVA. Results:In human ESCC cells ECA-109 and KYSE-150, the proliferation of ESCC cells was significantly inhibited by niraparib combined with irradiation, and the values of average lethal dose (D 0), quasi-threshould dose(D q), survival fraction after 2 Gy irradiation (SF 2) in the combined group were decreased compared with those in the single irradiation group. The effect of irradiation alone on apoptosis of ECA-109 and KYSE-150 cells was limited. Compared to single irradiation group, irradiation combined with niraparib further increased the apoptosis rate in ESCC cells ( P=0.015, P=0.006). In ECA-109 cells, G 2/M phase arrest was significantly increased in combined group compared with irradiation alone group ( P<0.001). In ECA-109 cells, the number of γH2AX foci in combined group was higher than that in the single irradiation group after 2 h, and showed a significantly slower decay of γH2AX foci ( P<0.001). Moreover, niraparib combined with irradiation enhanced the radiation-induced cleavage of PARP-1 and down-regulated the expression of Rad51 and p-MAPK(ERK1/2). Conclusion:Niraparib can increase the radiosensitivity of esophageal cancer cells by inhibiting cell proliferation, promoting cell apoptosis, inhibiting the repair of DNA damage and regulating the MARK-ERK signaling pathway.

Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPARγ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPARγ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPARγ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.