Adverse drug reactions （ADRs） refer to harmful or unintended reactions unrelated to the intended purpose of medication administration， which can lead to various issues such as accelerated disease progression and prolonged hospitalization. Traditional ADRs monitoring systems （such as spontaneous reporting systems） suffer from limitations such as low reporting rates and inconsistent data quality， which hinder the early prevention and control of ADRs. With the rapid development of information technology， machine learning has emerged as a powerful tool for management and decision-making of ADRs by leveraging its strengths in feature extraction and dynamic temporal pattern analysis. By reviewing relevant literature at home and abroad in recent years， this paper summarizes the progress in the application of machine learning for ADRs prediction. It is found that machine learning has gradually been applied to the early warning and risk prediction of ADRs in target organs such as the kidneys， liver， heart and bone marrow （such as acute kidney injury， drug-induced liver injury， and so on）. Although machine learning demonstrates significant application potential in the field of ADRs prediction， it still faces limitations such as inadequate quality control of clinical data， lack of standardized criteria for model performance evaluation， insufficient model interpretability and difficulties in clinical translation. In the future， the development trend of machine learning in the field of ADRs prediction should follow a “technology-validation-integration” pathway to systematically promote the practical implementation of models.

The connotation of "treat heat with cold" and "disperse fire constraint" differs， and under the guidance of these two principles， there are variations in the selection of acupoints， choice of needles， and manipulation techniques in clinical acupuncture. "Treat heat with cold" is used to clear and drain heat pathogens， while "disperse fire constraint" focuses on diffusing and dissipating fire from constraint. When both fire constraint and internal heat coexist， treatment should combine both "dispersing the fire" and "cooling the heat". In clinical acupuncture， for clearing heat and draining heat pathogens， acupoints on Governor vessel （督脉） and Yangming （阳明经） channel are commonly selected， with Jing-well points， Ying-spring points and He-sea points. To diffuse and dissipate fire constraint， acupoints on the Taiyang （太阳） and Shaoyang （少阳） channels are usually chosen， with Jing-river points and Ashi points as the primary options. In terms of needle choice， for heat syndrome， filiform needles， three-edged needles， and cupping are often used for clearing heat and resolving toxins； for fire constraint syndrome， moxibustion and fire needles are employed to expel fire from the body. Regarding manipulation techniques， draining method can be used in both conditions， with heat syndrome requiring shallow needling and quick removal， while fire constraint syndrome requiring deeper and longer retention of needles， having an emphasis on hand pressure coordination and smooth qi flow. In clinical practice， it is essential to distinguish the presence of "constraint" and the depth of the disease location to appropriately combine "dispersing fire" and "cooling heat".

ObjectiveTo explore the visual attention distribution across different lateral facial profiles and analyze the influence of observer gender and professional background on aesthetic evaluation， providing an aesthetic basis for the design of clinical orthodontic treatment. MethodsEye-tracking technology was employed to record the gaze paths of 136 subjects （orthodontists， non-orthodontic dentists， and non-medical professionals） when evaluating three types of male and female lateral profiles （convex， straight， and concave）. A questionnaire survey was conducted using a visual analog scale （VAS）. Data differences and the consistency between eye-tracking and questionnaire results were analyzed through t-tests， analysis of variance （ANOVA）， and Kappa coefficient analysis. ResultsThe questionnaire scores for straight profiles were significantly higher than those for convex and concave profiles （P<0.05）. Eye-tracking revealed that subjects primarily focused on the eye and nasal regions （P<0.001）， followed by the mouth. However， orthodontists showed no significant difference in attention between the mouth and eye-nasal areas （P>0.05）. Additionally， gender differences were notable. Female observers prioritized the mouth （P<0.05）， while male observers paid later attention to the oral-buccal region. The forehead and chin rapidly attracted attention during the initial evaluation phase， particularly in female concave profiles （P<0.05）. Eye-tracking data demonstrated high consistency with questionnaire results （κ=0.868）. ConclusionThis study， utilizing eye-tracking technology， finds that the eye and nasal regions are the core focus areas for aesthetic evaluation of lateral profiles. Gender differences result in distinct gaze preferences （males emphasize the nose， while females emphasize the eyes）， whereas orthodontists focus more on the lips and forehead. As aesthetic baselines， the forehead and chin， with their profile characteristics， should be prioritized in treatment. This research provides a basis for developing personalized orthodontic plans and establishing aesthetic consensus between clinicians and patients.

ObjectiveTo investigate the effects of atorvastatin （ATV） on the proliferation and differentiation of rat bone marrow mesenchymal stem cells （BMSCs）， periodontal ligament stem cells （PDLSCs）， and dental pulp stem cells （DPSCs） in vitro， and to validate the regulatory effect of ATV on periodontal bone formation and tooth movement using a rat orthodontic tooth movement （OTM） model. MethodsThe effects of ATV on the proliferation and osteogenic/odontogenic differentiation of rat BMSCs， PDLSCs， and DPSCs were assessed in vitro. CCK-8 assay was used to detect the proliferation of the three types of cells. Alkaline phosphatase （ALP） staining and Alizarin Red staining were employed to evaluate osteogenic differentiation capacity. Western blot was used to detect the expression of osteogenesis-related proteins ［collagen type I （COL-I）， Runt-related transcription factor 2 （Runx2）， bone morphogenetic protein-2 （BMP-2）， osteocalcin （OCN）］ and the odontogenesis-related protein dentin sialophosphoprotein （DSPP） in BMSCs， PDLSCs and DPSCs. An OTM rat model was established， with rats randomly assigned to an ATV gavage group and a control group. The ATV gavage group received daily oral administration of ATV at a dose of 20 mg/kg， while the control group received an equal volume of solvent by gavage. Tooth movement distance was measured via Micro-CT on days 7， 14， and 21. Histomorphology of periodontal tissues was observed using Hematoxylin and Eosin （HE） staining and Masson staining. The gene and protein expression levels of osteogenic markers （BMP-2， Runx2， OCN） on the tension side of the first molar were detected by qRT-PCR and immunohistochemistry， respectively. ResultsATV at concentrations of 1×10⁻⁶ mol/L and 1×10⁻⁷ mol/L significantly promoted the proliferation and osteogenic/odontogenic differentiation of BMSCs， PDLSCs， and DPSCs， manifested as enhanced ALP activity， increased mineralized nodule formation， and up-regulated expression of osteogenic/odontogenic proteins COL-I， Runx2， BMP-2， OCN， and DSPP （P<0.001）. In the OTM model， compared with the control group， the ATV gavage group showed a significant reduction in tooth movement distance （P<0.05）， enhanced osteogenic activity in periodontal tissues， and significantly increased gene （P<0.001） and protein （P<0.05） expression of BMP-2， Runx2， and OCN on the tension side of the first molar. ConclusionATV enhances periodontal osteogenesis by promoting osteogenic/dentinogenic differentiation， thus inhibiting tooth movement.

Objective: To investigate the clinical efficacy and safety of pudendal nerve modulation (PNM) in the treatment of female pudendal neuralgia (PN)，so as to promote the clinical application of this technique. Methods: A retrospective analysis was conducted on 20 female PN patients who failed conservative treatment at Gongli Hospital during Nov.2020 and Oct.2023.All patients underwent simultaneous PNM and sacral nerve modulation (SNM) with the assistance of 3D printing navigation.Dual-stage test electrodes for PNM and SNM were implanted，followed by alternate therapeutic trial for each modality.Secondary conversion rates and longitudinal outcomes，including visual analogue score (VAS)，patient health questionnaire-9 (PHQ-9)，and quality of life (QoL) scores were compared preoperatively，post-stage Ⅰ，and at 3，6，and 12 months post-stage Ⅱ. Results: All operations were successful.After the trial phase，the secondary conversion rate for PNM was significantly higher than that for SNM; 16 patients (16/20，80%) chose the second-phase PNM implantation surgery，3 (3/20，15%) chose second-phase SNM implantation，and 1 (1/20，5%) had electrodes removed due to ineffective results from both trials.Further assessment revealed that the improvements in VAS，PHQ-9，and QoL scores for PNM patients were significantly better than those for SNM patients after the first phase of surgery and at 3，6 and 12 months after the second-phase conversion (P<0.05).No complications such as electrode migration or infection were observed during the follow-up of 12-15 months. Conclusion: PNM provides more effective relief of pain symptoms and improvements in depressive states for female PN patients compared to SNM.With the assistance of 3D printing navigation，the operation is simple and safe，and offers stable therapeutic effects.It is worthy of clinical promotion and application.

Diabetic retinopathy(DR)is one of the most common and severe microvascular complications in diabetic patients and has become one of the leading causes of blindness worldwide. With the continuous rise in the prevalence of diabetes, in-depth exploration of the pathogenesis of DR and effective intervention measures is of great clinical significance. The mechanistic target of rapamycin(mTOR), as a protein kinase, is widely involved in cellular processes such as growth, metabolism, and autophagy. Research indicates that the mTOR signaling pathway plays a crucial regulatory role in the pathological progression of DR, and its abnormal activity can disrupt retinal cell autophagy function, thereby accelerating cellular damage and disease progression. Autophagy, as an important regulatory mechanism for cellular homeostasis, maintains cellular functional balance by clearing damaged organelles and protein aggregates. This article provides a systematic review of the structural and functional aspects of the mTOR signaling pathway, the molecular regulatory mechanisms of autophagy, and their roles in retinal pathological changes. By summarizing current research findings, the article aims to clarify the key regulatory role of the mTOR-autophagy axis in DR, providing theoretical support for elucidating the molecular pathogenesis of DR and offering potential targets and research directions for developing novel targeted therapeutic strategies, thereby holding significant scientific and clinical value.

OBJECTIVE: To observe the effects of Tongdu Tiaoshen acupuncture (for unblocking the obstruction in the governor vessel and regulating the spirit) on depression-like behavior and the hippocampal Endophilin A1/reactive oxygen species (ROS) pathway in the chronic unpredictable mild stress (CUMS) model rats, and explore the mechanism of this therapy for depression. METHODS: Forty-eight male SD rats of SPF grade were randomly divided into a normal group (n=12) and a modeling group (n=36). In the modeling group, CUMS was performed to establish depression model. The successfully-modeled rats were randomized into a model group, a Tongdu Tiaoshen acupuncture group (referred to as the acupuncture group), and a fluoxetine group, with 12 rats in each group. In the acupuncture group, "Baihui" (GV20), "Shenting" (GV24), "Shuigou" (GV26) and "Dazhui" (GV14) were stimulated with acupuncture. This intervention measure was delivered once a day, continuously for 6 days; it was discontinued on day 7 and was completed in 28 days. In the fluoxetine group, intragastric administration was done with fluoxetine solution (2.1 mg/kg), once a day, and for 28 consecutive days. Before and after modeling, and after intervention completion, the body mass, sucrose preference rate and the total distance of movement and the boxes of horizontal crossing in the open field experiment were observed in each group. After intervention, using HE staining, the hippocampal neuron morphology was observed; using Nissl staining, the hippocampal Nissl body number was counted. The hippocampal mitochondria was observed under transmission electron microscopy. The average fluorescence intensity of ROS in hippocampal was determined using flow cytometry. With Western blot method, the protein expression of Endophilin A1, growth associated protein 43 (GAP-43), and brain-derived neurotrophic factor (BDNF) in hippocampal was detected; and with RT-qPCR method, the mRNA expression of Endophilin A1, GAP-43, and BDNF was recorded. Using the immunofluorescence, the average fluorescence intensity of Endophilin A1, GAP-43, and BDNF in hippocampal tissue was determined. RESULTS: Compared with the normal group, in the model group, the body mass, sucrose preference rate, and the total distance of movement and the boxes of horizontal crossing in the open field experiment decreased (P<0.01); the hippocampal neuronal structure was unclear, the matrix was relatively loose, and the number of Nissl body decreased (P<0.01); mitochondrial structure was disarranged, the outer membrane was ruptured, mitochondrial cristae was irregular or missed; the average fluorescence intensity of ROS in hippocampal tissue, the protein and mRNA expression and the average fluorescence intensity of Endophilin A1 in hippocampal tissue increased (P<0.01), while the protein and mRNA expression of GAP-43 and BDNF and its average fluorescence intensity decreased (P<0.01). Compared with the model group, the acupuncture group and the fluoxetine group showed the increase in body mass, sucrose preference rate, the total distance of movement and the boxes of horizontal crossing in the open field experiment (P<0.05, P<0.01); the hippocampal neuronal structure became relatively clear, the matrix was relatively dense, and the number of Nissl body was elevated (P<0.01); mitochondrial structure got normal and disarranged slightly, the average fluorescence intensity of ROS in hippocampal tissue, the protein and mRNA expression and the average fluorescence intensity of Endophilin A1 in hippocampal tissue were reduced (P<0.01), while the protein and mRNA expression of GAP-43 and BDNF and the average fluorescence intensity rose (P<0.01, P<0.05). Compared with the fluoxetine group, the acupuncture group presented the increase in the average fluorescence intensity of ROS, the protein expression and the average fluorescence intensity of Endophilin A1, the protein expression of GAP-43 and the mRNA expression of BDNF (P<0.01, P<0.05), and the decrease of the protein expression and the average fluorescence intensity of BDNF, the mRNA expression of Endophilin A1, and the average fluorescence intensity of GAP-43 (P<0.01, P<0.05). CONCLUSION Tongdu tiaoshen acupuncture alleviates depression-like behaviors in CUMS model rats and protects hippocampal neurons, which may be related to suppressing Endophilin A1/ROS signaling pathway and attenuating oxidative stress reactions.
Animals ; Male ; Hippocampus/metabolism* ; Acupuncture Therapy ; Rats, Sprague-Dawley ; Rats ; Depression/psychology* ; Humans ; Reactive Oxygen Species/metabolism* ; Disease Models, Animal ; Acupuncture Points

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Metastatic dissemination is the major cause of death from breast-cancer (BC). Fusobacterium nucleatum (F.n) is widely enriched in BC and has recently been identified as one of the high-risk factors for promoting BC metastasis. Here, with an experimental model, we demonstrated that intratumoral F.n induced BC aggressiveness by transcriptionally activating Epithelial-mesenchymal transition-associated genes. Therefore, the F.n may be a potential target to prevent metastasis. Given the fact that cancer-associated fibroblasts (CAFs) are abundant in BC and located near blood vessels, we report an optogenetic system that drives CAF to in situ produce human antibacterial peptide LL37, with the characteristics of biosafety and freely intercellular trafficking, for depleting intratumoral F.n, leading to a 72.1% reduction in lung metastatic nodules number without affecting the balance of the systemic flora. Notably, mild photothermal treatment was found that could normalize CAF, contributing to synergistically inhibiting BC metastasis. In addition, the system can also simultaneously encode a gene of TNF-related apoptosis-inducing ligand to suppress the primary tumor. Together, our study highlights the potential of local elimination of tumor pathogenic bacteria to prevent BC metastasis.

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.