ObjectivesTo investigate the molecular epidemiological characteristics of HIV-1 infection among men who had sex with men (MSM) in Taizhou City, Zhejiang Province, and to provide a scientific reference for acquired immune deficiency syndrome prevention and control efforts. MethodsThe research subjects were all newly reported MSM population in Taizhou City from 2020 to 2023. Blood samples without antiviral therapy were collected. The HIV-1 pol gene was amplified and sequenced, and the sequences were submitted to the Stanford University drug resistance database to identify the mutation sites and drug resistance. MEGA 11.0 software was used to analyze the nucleic acid sequences, construct phylogenetic tree, and calculate genetic distance of gene sequences. The molecular transmission network diagram of HIV-1 was constructed using Cytoscape_v3.10.1, and the influencing factors of network entry were analyzed by logistic regression. ResultsA total of 363 newly reported HIV-infected MSM patients were included, with a median age [M (P₂₅, P₇₅)] of 34 (26,47) years old. The majority had an educational level of junior high school or below (55.65%). A total of eight subtypes were found, mainly CRF07_BC and CRF01_AE. The primary drug resistance rate was 10.47% (38/363). The optimal molecular network gene distance was 0.019, with a network access rate of 42.70% (155/363), and a total of 47 molecular clusters were formed. Multivariate logistic analyses showed that compared with the CRF01_AE subtype, the clustering risk of CRF07_BC subtype was higher (OR=1.916, 95%CI: 1.191‒3.109), cases with drug resistance had a higher risk of cluster formation than those without drug resistance (OR=2.011, 95%CI: 1.006‒4.080), and recent infected patients had a lower risk of entering the largest molecular cluster than long-term infected patients (OR=0.376, 95%CI: 0.137‒0.928). ConclusionThe newly diagnosed infections among the MSM population are active in Taizhou City, Zhejiang Province, with a high level of primary drug resistance. Individuals carrying drug-resistant strains are more likely to cluster. Drug resistance monitoring should be strengthened to prevent further spread of drug-resistant strains in the network.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Negative logarithm of the acid dissociation constant (pK _a) significantly influences the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of molecules and is a crucial indicator in drug research. Given the rapid and accurate characteristics of computational methods, their role in predicting drug properties is increasingly important. Although many pK _a prediction models currently exist, they often focus on enhancing model precision while neglecting interpretability. In this study, we present GraFpK _a, a pK _a prediction model using graph neural networks (GNNs) and molecular fingerprints. The results show that our acidic and basic models achieved mean absolute errors (MAEs) of 0.621 and 0.402, respectively, on the test set, demonstrating good predictive performance. Notably, to improve interpretability, GraFpK _a also incorporates Integrated Gradients (IGs), providing a clearer visual description of the atoms significantly affecting the pK _a values. The high reliability and interpretability of GraFpK _a ensure accurate pK _a predictions while also facilitating a deeper understanding of the relationship between molecular structure and pK _a values, making it a valuable tool in the field of pK _a prediction.

Activity cliffs (ACs) are generally defined as pairs of similar compounds that only differ by a minor structural modification but exhibit a large difference in their binding affinity for a given target. ACs offer crucial insights that aid medicinal chemists in optimizing molecular structures. Nonetheless, they also form a major source of prediction error in structure-activity relationship (SAR) models. To date, several studies have demonstrated that deep neural networks based on molecular images or graphs might need to be improved further in predicting the potency of ACs. In this paper, we integrated the triplet loss in face recognition with pre-training strategy to develop a prediction model ACtriplet, tailored for ACs. Through extensive comparison with multiple baseline models on 30 benchmark datasets, the results showed that ACtriplet was significantly better than those deep learning (DL) models without pre-training. In addition, we explored the effect of pre-training on data representation. Finally, the case study demonstrated that our model's interpretability module could explain the prediction results reasonably. In the dilemma that the amount of data could not be increased rapidly, this innovative framework would better make use of the existing data, which would propel the potential of DL in the early stage of drug discovery and optimization.

Accurate prediction of drug-target interactions (DTIs) plays a pivotal role in drug discovery, facilitating optimization of lead compounds, drug repurposing and elucidation of drug side effects. However, traditional DTI prediction methods are often limited by incomplete biological data and insufficient representation of protein features. In this study, we proposed KG-CNNDTI, a novel knowledge graph-enhanced framework for DTI prediction, which integrates heterogeneous biological information to improve model generalizability and predictive performance. The proposed model utilized protein embeddings derived from a biomedical knowledge graph via the Node2Vec algorithm, which were further enriched with contextualized sequence representations obtained from ProteinBERT. For compound representation, multiple molecular fingerprint schemes alongside the Uni-Mol pre-trained model were evaluated. The fused representations served as inputs to both classical machine learning models and a convolutional neural network-based predictor. Experimental evaluations across benchmark datasets demonstrated that KG-CNNDTI achieved superior performance compared to state-of-the-art methods, particularly in terms of Precision, Recall, F1-Score and area under the precision-recall curve (AUPR). Ablation analysis highlighted the substantial contribution of knowledge graph-derived features. Moreover, KG-CNNDTI was employed for virtual screening of natural products against Alzheimer's disease, resulting in 40 candidate compounds. 5 were supported by literature evidence, among which 3 were further validated in vitro assays.
Alzheimer Disease/drug therapy* ; Biological Products/therapeutic use* ; Humans ; Neural Networks, Computer ; Machine Learning ; Drug Discovery/methods* ; Algorithms ; Drug Evaluation, Preclinical/methods*

ObjectiveTo analyze the failure of antiretroviral therapy (ART) and drug resistance characteristics among the newly reported HIV-infected patients in Taizhou City from 2020 to 2022. MethodsBlood samples, sociodemographic characteristics and ART information of the newly reported HIV-infected patients who received ART for ≥6 months in Taizhou City from 2020 to 2022 were collected for the detection of recent infections and HIV-1 genotypic drug resistance. Multivariate logistic regression analysis was used to analyze the influencing factors of treatment failure. The gene sequences of cases with failed ART were submitted to the HIV drug resistance database of Stanford University to determine the drug resistance mutation sites and drug resistance characteristics. ResultsAmong the 1 023 newly reported HIV-infected patients receiving ART, the median age （P₂₅，P₇₅） was 47 (33, 58) years, 81.4% were male, 66.4% (679/1 023) were infected through heterosexual transmission, 74.7% had a WHO clinical stage Ⅰ/Ⅱ, 62.2% had a baseline CD4 count of >200 cell·μL^-1, 94.4% (966/1 023) received an immediate ART, and 78.7% were long-term infected. Among the 66 patients with treatment failure (6.5%), the likelihood of treatment failure was lower in those with homosexual transmission (OR=0.39, 95%CI: 0.17‒0.84) and without history of sexually transmitted disease (STD) (OR=0.45, 95%CI: 0.24‒0.92), but higher in those with a baseline CD4 count of ≤200 cell·μL^-1, delayed ART (OR=3.19, 95%CI: 1.24‒7.52), and primary drug resistance (OR=4.69, 95%CI: 1.68‒11.89). Among the 36 HIV-infected patients with virological failure, 27 sequences were successfully amplified, with a successful amplification rate of 75.0% (27/36). The total drug resistance rate was 55.6% (15/27), of which the drug resistance rates of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 37.0% (10/27), 51.9% (14/27) and 3.7% (1/27), respectively. Among the NNRTIs, the degree of resistance to efavirenz and nevirapine was consistent, with a majority (51.9%) of highly drug-resistant. K103N and M184V were the most common mutation sites, but PIs mutations occured less frequently. A total of 8 genotypes of HIV-1 were detected, in which subtype CRF01_AE accounted for 37.0% (10/27), followed by CRF07_BC [14.8% (4/27)], CRF08_BC [14.8% (4/27)] and subtype C [14.8% (4/27)]. ConclusionDuring the period from 2020 to 2022, the newly reported HIV-infected individuals in Taizhou City were predominated by long-term infections. Immediate initiation of ART can reduce the risk of treatment failure in HIV-infected individuals. Virological treatment failures are primarily associated with resistance to NRTIs and NNRTIs. It is recommended to strengthen active detection and promptly initiate ART to minimize the occurrence of ART failure. Simultaneously, there is a need to intensify drug resistance detection targeted for those with treatment failure, so as to provide a scientific guidance for drug replacement.

Objective:To investigate the evidence-based practice of prevention and care of nasal and facial pressure injuries in patients with non-invasive positive pressure ventilation (NPPV) using the knowledge to action framework (KTA), and to explore its effectiveness.Methods:Using an evidence-based nursing approach, an evidence-based practice group was established to formulate a clinical problem, the literature from domestic and international databases were researched for relevant evidence, the evidence was introduced into clinical scenarios, an evidence-based practice plan was developed, and a strategy for applying the best evidence was constructed by conducting a baseline review of healthcare professionals and patients with NPPV, analyzing barriers and promoting factors, and making changes in clinical practice at the organizational level, the practitioner level, and the patient level. Purposive sampling method was used to select the healthcare staff of the cardiac surgical intensive care unit (CSICU) of the Shandong Provincial Hospital Affiliated to Shandong First Medical University, as well as the patients with NPPV admitted from October 1 to November 15, 2023 (pre-evidence-based practice) and November 16 to December 31 (post-evidence-based practice), as the subjects of the study. Through questionnaire analysis, the incidence of nasal and facial pressure injury of NPPV patients, the implementation rate of review indicators of medical staff, the score of the knowledge, belief and conduct of medical staff, and the compliance and comfort of patients before and after evidence-based practice were compared.Results:A total of 52 medical staff were included, aged (28.54±6.50) years old, with 3.00 (1.00, 12.75) years of working experience; 2 doctoral degree holders (3.85%), 4 master degree holders (7.69%), 46 bachelor degree holders (88.46%); 2 with senior title (3.85%), 17 with intermediate title (32.69%), and 33 junior titles (63.46%). Fifty patient questionnaires were collected before and after evidence-based nursing practice; the differences between before and after evidence-based practice in terms of gender, age, body weight, duration of ventilator usage, 24-hour bleeding and total bleeding were not statistically significant and were comparable. Compared with the pre-evidence-based practice, after carrying out the corresponding evidence-based nursing practice, the incidence of nasal and facial pressure injuries of NPPV patients decreased from 16.00% (8/50) to 4.00% (2/50, P < 0.05), the total implementation rate of review indicators of medical staff increased from 79.73% to 94.08% ( P < 0.01), and the total scores of knowledge, belief and conduct were significantly improved (141.96±13.88 vs. 114.65±19.72, P < 0.05), and compliance and comfort of patients were significantly improved (compliance score: 4.60±0.99 vs. 5.82±1.42, comfort score: 4.10±1.63 vs. 6.92±2.33, both P < 0.05]. Conclusion:The application of an evidence-based nursing approach to obtain evidence related to the prevention of nasal and facial pressure injuries in patients with NPPV can be used to guide clinical practice, significantly reducing the incidence of nasal and facial pressure injuries in such patients, improving the implementation rate of review indicators and the knowledge, belief, and conduct scores of medical staff, and enhancing compliance and comfort of NPPV patients.

Objective:To analyze the clinical characteristics of pediatric atypical hemolytic uremic syndrome (aHUS), and provide clinical experience for the diagnosis and treatment of aHUS in China.Methods:It was a single-center retrospective study. Fifteen aHUS children treated and having complete clinical data at Children's Hospital of Nanjing Medical University between December 31, 2017 and October 15, 2023 were enrolled to analyze the clinical features covering laboratory examinations, genetic testing results, and clinical manifestations. The children were classified based on genetic testing and complement factor H (CFH) antibody detection results to analyze the corresponding clinical characteristics.Results:Among the 15 aHUS patients. There were 8 males and 7 females. The onset age was 5.1 (0.7, 10.8) years old. All patients underwent genetic testing, with 9/15 of aHUS-related gene mutation, revealing 2 de novo mutations in complement factors-related genes. Among 11 patients screened for CFH antibody, 6 tested positive. C3 was detected in 14 patients , and C3 decreased in 9 patients. In laboratory examinations, there were notable decreases in red blood cell (RBC) count in 13 patients, platelet (PLT) count in 15 patients, hemoglobin (Hb) in 15 patients and estimated glomerular filtration rate (eGFR) in 14 patients. Blood urea nitrogen (BUN) and serum creatinine (Scr) were markedly elevated in 13 patients and 9 patients, respectively. Twelve patients exhibited elevated transaminase levels, and 14 patients exhibited elevated lactate dehydrogenase (LDH) levels. Clinically, 11 patients had triggers, and 4 patients had clear family histories. Common clinical features including anemia, thrombocytopenia, proteinuria and hematuria were in 15 patients. There were statistically significant differences in RBC count ( Z=-2.84, P=0.005), PLT count ( Z=-6.65, P<0.001), Hb ( t=-3.71, P=0.002), LDH ( Z=3.76, P=0.002), BUN ( Z=2.71, P=0.017), and eGFR ( Z=-3.65, P=0.003) before and after treatment except alanine transaminase, aspartate transaminase, Scr and complement C3 (all P>0.05). There were no significant differences in onset age, RBC count, PLT count, Hb, LDH, alanine transaminase, aspartate transaminase, Scr, BUN, eGFR, and C3 between aHUS-related gene mutation and non-mutation groups, and CFH antibody-positive and negative groups (all P>0.05). Conclusions:aHUS is marked by severity, and has diverse clinical manifestations. There are no significant differences in clinical presentation at admission between hereditary and acquired aHUS, highlighting the critical importance of genetic testing and complement-related factor detection in diagnosing aHUS etiology. The family history plays a supportive role in diagnosis of aHUS.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.