Objective:To establish a decision tree model of pediatric complicated appendicitis (CA) based on Pediatric Appendicitis Score (PAS) combined with inflammatory indicators, and to evaluate its clinical application efficacy in pediatrics.Methods:The clinical data of 544 children diagnosed with appendicitis in Children′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2018 to December 2021 was retrospectively analyzed. According to postoperative pathology, the children were divided into uncomplicated appendicitis group and CA group. The independent risk factors of CA were screened by univariate and multivariate logistic regression analysis, and these parameters were included to establish the decision tree model. The accuracy of the decision tree model was verified by receiver operating characteristic (ROC) curve.Results:Binary logistic regression analysis indicated that the PAS, C-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR) were identified as independent risk factors for complicated appendicitis in children (all P<0.05). PAS, CRP and NLR were included as covariables to construct the decision tree model and binary logistic regression model for predicting CA. The decision tree demonstrated an overall accuracy of 79.2% with a sensitivity of 86.7% and specificity of 71.9%, and achieved an area under curve (AUC) of 0.821(95% CI: 0.786-0.857). The binary logistic regression model had a sensitivity of 79.6% and specificity of 69.1%, with an overall accuracy of 75.1% and achieved an AUC of 0.808(95% CI: 0.770-0.845). Conclusions:The decision tree model based on PAS score combined with CRP, NLR is a simple, intuitive and effective tool , which can provide pediatric emergency physicians a reliable basis for diagnosis of pediatric CA.

Objective To study the diagnostic value of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) combined with the new category of papanicolaou society of cytopathology in solid pancreatic lesions (SPL) rapid on-site evaluation (ROSE).Methods From February 2011 to October 2014,225 patients with SPL who underwent EUS-FNA and obtained the cytological diagnosis were enrolled.The lesions were finally diagnosed according to pathological results,imaging and follow-up data,and then the sensitivity,specificity,and accuracy of EUS-FNA in the diagnosis of SPL were calculated based on the new papanicolaou society of cytopathology terminology.Logistic stepwise regression analysis was performed to analyze the risk factors.Results Among 225 patients with SPL,96 cases (42.7％)had uncertain cytological diagnosis,17.3％ (39/225) could not be diagnosed,8.0％ (18/225) were atypical lesions,and 17.3％ (39/225) were suspicious malignant carcinomas.Among 129 cases (57.3％)with certain cytological diagnosis,15.1％ (34/225) were benign lesions,14.7％ (33/225) were tumors (benign or others) and 27.6％ (62/225) were malignant tumors.When atypical lesions were added into non-tumor lesions or tumor lesions,the sensitivity,specificity and accuracy of diagnosis were 87.3 ％,91.7％,88.2％,and 94.7％,72.2％,90.3％,respectively.Serum CA125≥14 kU/L (odds ratio (OR) =7.13,95％ confidence interval (CI) 2.02 to 25.22,P=0.002) and history of biliary disease (OR=3.85,95％CI 1.22 to 12.51,P=0.022) were two independent risk factors of pancreatic tumors.Conclusions Despite of a high percentage of uncertain cytological diagnosis,EUS-FNA still has high diagnostic value in SPL when combined with the new papanicolaou society of cytopathology terminology.Furthermore,serum CA125≥14 kU/L and history of biliary disease may help to diagnose pancreatic tumors.

Objective To evaluate the prevalence of full thickness rotator cuff tear in patients with proximal humeral fractures,and the relationships between different risk factors.Methods Data of 113 patients with proximal humeral fractures from January 2014 to January 2016 who underwent surgical treatment were retrospectively analyzed.The general characteristics of patients (age,sex,cause of injury) were recorded and the rotator cuff was evaluated preoperatively on MRI and explored intra-operatively.We calculated and compared the incidence rate of age,sex in patients with and without rotator cuff tear.And the incidence rate of rotator cuff tear in different types of fracture according to Neer classification was calculated.Results The full thickness ro tator cuff tear were indentified in 28 patients (24.8％),and 21 of them had been confirmed by MRI preoperatively.Statistical significant difference was found between patients with rotator cuff tear group (average of 75.11± 10.89 years old) and without rotator cuff tear group (64.68± 13.43) for the age of the patient.Full thickness rotator cuff tear was most common in Neer 3 GT fracture (33.3％,8/54),followed by Neer 2 GT (26.67％,4/15) and Neer 2 SN (17.65,6/34),however,no full thickness rotator was found in Neer 4 type fracture.There were 4 patients with total rotator cuff tear who had symptom of shoulder before the operation.The other 24 patients had no symptom of shoulder.Conclusion Patient age was found as a risk factor for full thickness rotator cuff tear in humeral proximal fractures with the rate of 24.8％.Full thickness rotator cuff tear was most common in Neer 3 GT fracture.

Objective: To investigate the clinical efficacy of arthroscopic irrigation combined with surgical debridement in the treatment of shoulder infection after arthroscopic rotator cuff repair. Methods: Data of 4 post-operative infected patients [(male 3 cases, female 1 case; 55 years (51-61 years)] after arthroscopic rotator cuff repair who underwent arthroscopic irrigation combined with surgical debridement from January 2016 to June 2019 were retrospectively analyzed. Less than 1 month after surgery, swelling, pain in the surgical area occurred and all patients had fever, abscess and sinus. Hematology and radiology were conducted immediately after admission. Antibiotic treatment was applied, and adjusted according to the culture results timely. All patients underwent arthroscopic irrigation combined with surgical debridement. Antibiotics continued accordingly after the operation. Blood routine, erythrocyte sedimentation rate, C-reactive protein, X-ray, etc. were rechecked regularly to evaluate the symptomatic relief of the infection and prognosis. Visual analogue scale (VAS) and American Shoulder and Elbow Surgeons (ASES) score were used to evaluate shoulder function during the pre-operative and post-operative follow-up period. Results: The surgery was successfully completed in all 4 patients. One was treated with VSD for vacuum suction and the wound was closed one week later. The results of microbial culture showed that 2 cases were Mycobacterium tuberculosis positive, 1 case Pseudomonas aeruginosa positive, and 1 case was Staphylococcus aureus positive. After treatment, the shoulder sinuses of all patients were healed, without swelling, pain, etc. The follow-up time was 3, 4, 32, and 33 months, respectively. There was no recurrence of infection until the latest follow-up. The joint mobility and scores were better than the situation of preoperative. The VAS score and ASES score of 2 patients with early debridement (< 1 month duration of infected symptoms) were respectively improved significantly from 5 and 40, 6 and 23 before operation to 1 and 80, 1 and 73 respectively at the latest follow up. The VAS score and ASES score of other 2 patients (> 6 months duration of infected symptoms) were respectively improved from 6 and 28, 6 and 32 to 1 and 62, 2 and 65 respectively. All patients were satisfied with the results. Conclusion Early arthroscopic irrigation combined with surgical debridement is an effective method to treat the post-operative infections after arthroscopic rotator cuff repair.

Acid-base dissociation constant (pK_a) is a key physicochemical parameter in chemical science, especially in organic synthesis and drug discovery. Current methodologies for pK_a prediction still suffer from limited applicability domain and lack of chemical insight. Here we present MF-SuP-pK_a (multi-fidelity modeling with subgraph pooling for pK_a prediction), a novel pK_a prediction model that utilizes subgraph pooling, multi-fidelity learning and data augmentation. In our model, a knowledge-aware subgraph pooling strategy was designed to capture the local and global environments around the ionization sites for micro-pK_a prediction. To overcome the scarcity of accurate pK_a data, low-fidelity data (computational pK_a) was used to fit the high-fidelity data (experimental pK_a) through transfer learning. The final MF-SuP-pK_a model was constructed by pre-training on the augmented ChEMBL data set and fine-tuning on the DataWarrior data set. Extensive evaluation on the DataWarrior data set and three benchmark data sets shows that MF-SuP-pK_a achieves superior performances to the state-of-the-art pK_a prediction models while requires much less high-fidelity training data. Compared with Attentive FP, MF-SuP-pK_a achieves 23.83% and 20.12% improvement in terms of mean absolute error (MAE) on the acidic and basic sets, respectively.

Prediction of the interactions between small molecules and their targets play important roles in various applications of drug development, such as lead discovery, drug repurposing and elucidation of potential drug side effects. Therefore, a variety of machine learning-based models have been developed to predict these interactions. In this study, a model called auxiliary multi-task graph isomorphism network with uncertainty weighting (AMGU) was developed to predict the inhibitory activities of small molecules against 204 different kinases based on the multi-task Graph Isomorphism Network (MT-GIN) with the auxiliary learning and uncertainty weighting strategy. The calculation results illustrate that the AMGU model outperformed the descriptor-based models and state-of-the-art graph neural networks (GNN) models on the internal test set. Furthermore, it also exhibited much better performance on two external test sets, suggesting that the AMGU model has enhanced generalizability due to its great transfer learning capacity. Then, a naïve model-agnostic interpretable method for GNN called edges masking was devised to explain the underlying predictive mechanisms, and the consistency of the interpretability results for 5 typical epidermal growth factor receptor (EGFR) inhibitors with their structure‒activity relationships could be observed. Finally, a free online web server called KIP was developed to predict the kinome-wide polypharmacology effects of small molecules (http://cadd.zju.edu.cn/kip).

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both

Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

Objective To investigate the prevalence of Echinococcus infections in small rodents around human residential areas in Yushu City, Qinghai Province in 2023, so as to provide insights into precision echinococcosis control. Methods One or two quadrats, each measuring 50 m × 50 m, were randomly assigned in Shanglaxiu Township and Longbao Township, Yushu City, Qinghai Province on June 2023, respectively, and 300 plate-type mouse traps, each measuring 12.0 cm × 6.5 cm, were assigned in each quadrat. Small rodents were captured during the period between 10 : 00 and 18 : 00 each day for 4 days. Then, all captured small rodents were identified and dissected, and liver specimens with suspected Echinococcus infections were subjected to pathological examinations. The Echinococcus cytochrome c oxidase 1 (cox1) gene was amplified using PCR assay, and the sequence of the amplified product was aligned to that was recorded in the GenBank to characterize the parasite species. In addition, a phylogenetic tree of Echinococcus was generated based on the cox1 gene sequence using the neighbor-joining method. Results A total of 236 small rodents were captured in Shanglaxiu and Longbao townships, Yushu City, including 65 Qinghai voles and 51 plateau pikas in Shanglaxiu Township, and 62 Qinghai voles and 58 plateau pikas in Longbao Township, and there was no significant difference in the constituent ratio of small rodents between the two townships (χ² = 0.294, P > 0.05). Seven plateau pikas and 12 Qinghai voles were suspected to be infected with Echinococcus by dissection, and pathological examinations showed unclear structure of hepatic lobules and disordered hepatocyte arrangement in livers of small rodents suspected of Echinococcus infections. PCR assay identified E. shiquicus DNA in 7 Qinghai voles, which were all captured from Shanglaxiu Township. Phylogenetic analysis showed that the cox1 gene sequence of Echinococcus in small rodents was highly homologous to the E. shiquicus cox1 gene sequence reported previously. Conclusion Plateau pika and Qinghai vole were predominant small rodents around human residential areas in Yushu City, Qinghai Province in 2023, and E. shiquicus infection was detected in Qinghai voles.