OBJECTIVE To develop and validate interpretable machine learning models for predicting the risk of medication-related osteonecrosis of the jaw （MRONJ） and surgical outcomes， thereby providing quantitative support for MRONJ risk assessment and treatment decision-making.METHODS Two study cohorts were established. Cohort A adopted a nested case-control study design to develop a predictive model for the risk of MRONJ onset. Cohort B comprised patients with MRONJ from Cohort A who underwent surgical treatment and met the follow-up eligibility criteria， and employed a prospective follow-up cohort study design to develop a predictive model for the efficacy of MRONJ surgery. After missing-data processing， variable standardization， and encoding， predictive features were selected using the least absolute shrinkage and selection operator （LASSO） regression， and collinearity was assessed using the variance inflation factor （VIF）. Random Forest （RF）， eXtreme Gradient Boosting （XGB）， Multi-layer Perceptron （MLP）， Support Vector Machine （SVM）， and Gaussian Naive Bayes （NB） models were subsequently developed using the selected features. Hyperparameter optimization and internal performance evaluation were performed using two-level nested cross-validation repeated 20 times. In Cohort B， the synthetic minority over-sampling technique （SMOTE） was applied within the inner training folds to address class imbalance. Model performance was comprehensively evaluated using the receiver operating characteristic （ROC） curve， the precision-recall （PR） curve， calibration curve， and decision curve analysis （DCA）. Shapley additive explanations （SHAP） were used to quantify the relative contributions of individual clinical features to model predictions.RESULTS Seven clinical features， including alkaline phosphatase and tooth extraction， were retained for Cohort A； whereas eight clinical features， including age and duration of medication use， were retained for Cohort B. In Cohort A， the area under the ROC curve， the area under the PR curve， Brier score， sensitivity， and specificity of the RF model were 0.94， 0.92， 0.09， 0.92， and 0.85， respectively； the corresponding values in Cohort B were 0.93， 0.93， 0.12， 0.83， and 0.93， respectively. The results of calibration curves and DCA indicated that the RF models achieved favorable calibration and clinical net benefit， with VIF values for all variables below 5. SHAP visualization results showed that alkaline phosphatase， tooth extraction， and cumulative drug dose made substantial contributions to MRONJ risk prediction in Cohort A， whereas age， duration of medication use， and MRONJ stage contributed substantially to surgical outcome prediction in Cohort B.CONCLUSIONS The RF-based models for predicting MRONJ risk and surgical outcomes demonstrated good discrimination， accuracy of probabilistic predictions， and potential clinical utility during internal validation. These models may provide decision support for comprehensive MRONJ risk management and individualized clinical decision-making. However， external validation in independent， multicenter， and geographically diverse cohorts is still required.

OBJECTIVE To explore the characteristics and influential factors of pharmaceutical clinic service demands， providing evidence for optimizing pharmaceutical service models and facilitating pharmaceutical service models of pharmacist role transformation. METHODS A cross-sectional survey design was adopted， and 410 outpatient participants were selected from Fudan University Shanghai Cancer Center through convenience sampling for questionnaire administration from February to May 2025. Kano model was applied to analyze the demand attributes of 25 pharmaceutical services， while questionnaires were used to assess patients’ awareness and demand status. Subgroup analyses were conducted based on key demographic variables such as gender， age， educational attainment， and economic burdens， to SACA- systematically examine the differences in Kano attribute classification among patients in each subgroup. RESULTS The awareness rate of pharmaceutical outpatient services among patients was only 14.63%， yet those who were aware demonstrated a significantly higher demand rate for such services compared to those who were unaware （P＜0.001）. The demand for pharmaceutical clinic services exhibited a hierarchical characteristic： twelve items were identified as attractive attributes （e. g.， providing suggestions for more affordable treatment options， offering online consultation services， etc.）， five items as expected attributes （e.g.， having a good attitude and being able to patiently answer your questions， etc.）， three items as must-have attributes （e.g.， providing guidance on medication dosage and usage， providing guidance on medication precautions， etc.）， five items as indifferent attributes （e.g.， providing treatment plan recommendations based on the patient’s condition）. There were zero items classified as reverse attribute. Subgroup analysis revealed that female patients showed greater concern for “neat and clean attire of medical staff” than male patients （P＜0.001）； patients under 60 years of age demonstrated stronger demand for “providing treatment plan recommendations based on patients’ conditions” compared to patients aged 60 or above （P＝0.016）； those with below high school education placed greater emphasis on “providing guidance on medication precautions” compared to those with a high school education or above （P＝0.011）； patients with lower economic burdens exhibited stronger preferences for “neat and clean attire of medical staff ” （P＝0.002）. CONCLUSIONS The public awareness rate of pharmaceutical clinic services is considerably low； however， those who are aware of such services demonstrate significantly higher demand. The medication safety-related services and convenience-oriented demands should be prioritized in the development of pharmaceutical clinics. Moreover， the study also revealed that factors such as gender， age， educational level， and economic burdens exert significant influences on patients’ service demands.

ObjectiveTo explore the clinical safety of Feilike Mixture （FLK） in the real world. MethodsThe safety of all children who received FLK from 29 institutions in 12 provinces between January 21，2021 and December 25，2021 was evaluated through prospective centralized surveillance and a nested case control study. ResultsA total of 3 035 juveniles were included. There were 29 research centers involved，which are distributed across 12 provinces，including one traditional Chinese medicine （TCM） hospital and 28 general hospitals. The average age among the juveniles was （4.77±3.56） years old，and the average weight was （21.81±12.97） kg. Among them，119 cases （3.92%） of juveniles had a history of allergies. Acute bronchitis was the main diagnosis for juveniles，with 1 656 cases （54.46%）. FLK was first used in 2 016 cases （66.43%），and 142 juvenile patients had special dosages，accounting for 4.68%. Among them，92 adverse drug reactions （ADRs） occurred，including 73 cases of gastrointestinal system disorders，10 cases of metabolic and nutritional disorders，eight cases of skin and subcutaneous tissue diseases，two cases of vascular and lymphatic disorders，and one case of systemic diseases and various reactions at the administration site. The manifestations of ADRs were mainly diarrhea，stool discoloration，and vomiting，and no serious ADRs occurred. The results of multi-factor analysis indicated that special dosages （the use of FLK）［odds ratio （OR） of 2.642， 95% confidence interval （CI） of 1.105-6.323］，combined administration： spleen aminopeptide （OR of 4.978， 95%CI of 1.200-20.655），and reason for combined administration： anti-infection （OR of 1.814， 95%CI of 1.071-3.075） were the risk factors for ADRs caused by FLK. Conclusion92 ADRs occurred among 3 035 juveniles using FLK. The incidence of ADRs caused by FLK was 3.03%，and the severity was mainly mild or moderate. Generally，the prognosis was favorable after symptomatic treatment such as drug withdrawal or dosage reduction，suggesting that FLK has good clinical safety.

ObjectiveTo investigate the anti-Alzheimer's disease （AD） effect of Dipsacus asper（DA） in the Caenorhabditis elegans model， and decipher the underlying mechanism via the peroxisome proliferator-activated receptor α （PPARα）/transcription factor EB （TFEB） pathway. MethodsFirst， transgenic AD C. elegans individuals were assigned into the blank control， model， positive control （WY14643， 20 µmol·L^-1）， and low-， medium-， and high-dose （100， 200， and 400 mg·L^-1， respectively） DA groups. The amyloid β-42 （Aβ₄₂） formation in the muscle cells， the paralysis time， and the deposition of amyloid β-protein （Aβ） in the head were detected. The lysosomal autophagy in the BV2 cell model was examined by Rluc-LC3wt/G120A. The expression levels of lysosomal autophagy-related proteins LC3Ⅱ， LC3I， LAMP2， and TFEB were detected by Western blot. Real-time quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of autophagy-related genes beclin1 and Atg5 and lysosome-related genes LAMP2 and CLN2 downstream of PPARα/TFEB. A reporter gene assay was used to detect the transcriptional activities of PPARα and TFEB. Immunofluorescence was used to detect the fluorescence intensity of PPARα， and the active components of the ethanol extract of DA were identified by UPLC-MS. RCSB PDB， Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and Autodock were used to analyze the binding between the active components and PPARα-ligand-binding domain （LBD）. ResultsCompared with the model group， the positive control group and 200 and 400 mg·L^-1 DA groups showed prolonged paralysis time （P<0.05）， and all the treatment groups showed decreased Aβ deposition in the head （P<0.01）. DA within the concentration range of 50-500 mg·L^-1 did not affect the viability of BV2 cells. In addition， DA enhanced the autophagy flux （P<0.05）， up-regulated the mRNA levels of beclin1， Atg5， LAMP2， and CLN2 （P<0.05， P<0.01）， promoted the nuclear translocation of TFEB （P<0.05）， increased LAMP2 expression and autophagy flux （P<0.05， P<0.01）， and enhanced the transcriptional activities of PPARα and TFEB （P<0.01）. The positive control group and 200 and 400 mg·L^-1 DA groups showed enhanced fluorescence intensity of PPARα in the BV2 nucleus （P<0.01）. UPLC-MS detected nine known compounds of DA， from which 8 active components of DA were screened out. The docking results suggested that a variety of components in DA could bind to PPARα-LBD and form stable hydrogen bonds. ConclusionDA may reduce the pathological changes in AD by regulating the PPARα-TFEB pathway.

Objective Most patients with chronic insomnia depend on long-term medication， which may easily lead to a poor treatment outcome and adverse drug reactions， and transcranial alternating current stimulation （tACS）， as a noninvasive neuromodulation technique， can improve chronic insomnia. This study aims to investigate the clinical efficacy of tACS combined with pharmacotherapy in the treatment of chronic insomnia. Methods A total of 46 patients with chronic insomnia were enrolled and randomly divided into pharmacotherapy group with 20 patients and pharmacotherapy+tACS treatment group with 26 patients. The tACS electrodes were attached to the frontal region and the bilateral mastoids， with a frequency of 77.5 Hz and a current intensity of 15 mA， for 40 minutes each time， once a day for 10 consecutive days. The primary outcome measures were Pittsburgh Sleep Quality Index （PSQI） score and its improvement rate after 4 weeks， and the secondary outcome measures included the scores of Hamilton Depression Rating Scale （HAMD）， Hamilton Anxiety Rating Scale （HAMA）， Mini-Mental State Examination （MMSE）， and Montreal Cognitive Assessment （MoCA） and their improvement rates. Results Compared with the pharmacotherapy group， the pharmacotherapy+tACS treatment group had a significant reduction in PSQI score （P<0.05）， with an improvement rate of 37% and 21%， respectively， suggesting that the combined therapy had a better effect in improving sleep quality. The pharmacotherapy+tACS treatment group also had reductions in HAMA and HAMD scores， suggesting improvements in anxiety and depression symptoms， and there were no significant differences in MMSE and MoCA scores between the two groups. Conclusion Pharmacotherapy combined with tACS has a better effect than pharmacotherapy alone in improving sleep quality and anxiety and depression symptoms in patients with chronic insomnia， and therefore， it has good application prospects in clinical practice.

Objective:To analyze the current status of global clinical trial for botulinum toxin (BTX) drugs, and to provide a reference for BTX drug research priorities and trends.Methods:All registered BTX drug-related clinical trials from the inception of the platforms until December 2024 were retrieved from the International Clinical Trials Registry Platform (ICTRP) and the Center for Drug Evaluation (CDE) Clinical Trial Registration and Information Disclosure Platform of the National Medical Products Administration of China (referred to as the CDE Platform). The data were statistically analyzed using Excel 2021. The analysis was conducted from aspects such as registration volume and annual trend, distribution of conducting countries, drug type, study type and recruitment situation, and indications.Results:A total of 2 053 clinical trials related to BTX were included. The total number of registered trials showed an increasing trend year by year. The country with the largest number of clinical trials was the United States, with 571 trials, while China ranked third with 190 trials. Among the drug formulations, the injection form accounted for the highest proportion (99.02%, 2 033/2 053). A few new formulations included topical ointments, nasal sprays, and eye drops. In terms of drug serotypes and sources, the wild-type BTX-A projects accounted for a relatively high proportion (97.86%, 2 009/2 053), and also included a few wild-type BTX-B, wild-type BTX-E, recombinant BTX-AB, and recombinant BTX-A projects. In terms of research types, 90.4% (1 856/2 053) were intervention studies, 87.5% (1 796/2 053) of the clinical trials did not restrict gender, 90.7% (1 862/2 053) of the clinical trials recruited subjects covering adults, and 9.3% (191/2 053) of the clinical trials only recruited minors. The research indications covered various disciplines, such as skin beauty, neurology, urology, orthopedics, and ophthalmology. In recent years, the types of diseases registered for clinical trials had expanded significantly on the basis of the originally approved indications.Conclusion:Innovative directions in BTX drug research, including BTX drugs of different serotypes, recombinant BTX based on recombinant gene technology, BTX formulations for non-injectable delivery, and innovative areas of clinical application, are driving its continued clinical research.

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Autism Spectrum Disorder (ASD) is marked by early-onset neurodevelopmental anomalies, yet the temporal dynamics of genetic contributions to these processes remain insufficiently understood. This study aimed to elucidate the role of the Shank3 gene, known to be associated with monogenic causes of autism, in early developmental processes to inform the timing and mechanisms for potential interventions for ASD. Utilizing the Shank3B knockout (KO) mouse model, we examined Shank3 expression and its impact on neuronal maturation through Golgi staining for dendritic morphology and electrophysiological recordings to measure synaptic function in the anterior cingulate cortex (ACC) across different postnatal stages. Our longitudinal analysis revealed that, while Shank3B KO mice displayed normal neuronal morphology at one week postnatal, significant impairments in dendritic growth and synaptic activity emerged by two to three weeks. These findings highlight the critical developmental window during which Shank3 is essential for neuronal and synaptic maturation in the ACC.
Animals ; Nerve Tissue Proteins/metabolism* ; Mice, Knockout ; Dendrites/metabolism* ; Mice ; Synapses/metabolism* ; Gyrus Cinguli/metabolism* ; Male ; Mice, Inbred C57BL ; Autism Spectrum Disorder/genetics* ; Microfilament Proteins

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*