ObjectiveTo develop a predictive model and application for spontaneous passage of common bile duct stones using automated machine learning algorithms given the complexity of treatment decision-making for patients with common bile duct stones， and to reduce unnecessary endoscopic retrograde cholangiopancreatography （ERCP） procedures. MethodsA retrospective analysis was performed for the data of 835 patients who were scheduled for ERCP after a confirmed diagnosis of common bile duct stones based on imaging techniques in Changshu First People’s Hospital （dataset 1） and Changshu Traditional Chinese Medicine Hospital （dataset 2）. The dataset 1 was used for the training and internal validation of the machine learning model and the development of an application， and the dataset 2 was used for external testing. A total of 22 potential predictive variables were included for the establishment and internal validation of the LASSO regression model and various automated machine learning models. The area under the receiver operating characteristic curve （AUC）， sensitivity， specificity， and accuracy were used to assess the performance of models and identify the best model. Feature importance plots， force plots， and SHAP plots were used to interpret the model. The Python Dash library and the best model were used to develop a web application， and external testing was conducted using the dataset 2. The Kolmogorov-Smirnov test was used to examine whether the data were normally distributed， and the Mann-Whitney U test was used for comparison between two groups， while the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. ResultsAmong the 835 patients included in the study， 152 （18.20%） experienced spontaneous stone passage. The LASSO model achieved an AUC of 0.875 in the training set （n=588） and 0.864 in the validation set （n=171）， and the top five predictive factors in terms of importance were solitary common bile duct stones， non-dilated common bile duct， diameter of common bile duct stones， a reduction in serum alkaline phosphatase （ALP）， and a reduction in gamma-glutamyl transpeptidase （GGT）. A total of 55 models were established using automated machine learning， among which the gradient boosting machine （GBM） model had the best performance， with an AUC of 0.891 （95% confidence interval： 0.859‍ ‍—‍ ‍0.927）， outperforming the extreme randomized tree mode， the deep learning model， the generalized linear model， and the distributed random forest model. The GBM model had an accuracy of 0.855， a sensitivity of 0.846， and a specificity of 0.857 in the test set （n=76）. The variable importance analysis showed that five factors had important influence on the prediction of spontaneous stone passage， i.e.， were solitary common bile duct stones， non-dilated common bile duct， a stone diameter of <8 mm， a reduction in serum ALP， and a reduction in GGT. The SHAP analysis of the GBM model showed a significant increase in the probability of spontaneous stone passage in patients with solitary common bile duct stones， non-dilated common bile duct， a stone diameter of <8 mm， and a reduction in serum ALP or GGT. ConclusionThe GBM model and application developed using automated machine learning algorithms exhibit excellent predictive performance and user-friendliness in predicting spontaneous stone passage in patients with common bile duct stones. This application can help avoid unnecessary ERCP procedures， thereby reducing surgical risks and healthcare costs.

Objective To explore the association of working hours and shift work with occupational stress, fatigue accumulation, and depressive symptoms among primary community medical workers. Methods A total of 516 medical workers from five community medical service centers in Pudong New Area, Shanghai City, were selected as the research subjects using the convenience sampling method. The Core Scale of Occupational Stress Measurement, the Workers' Fatigue Accumulation Self-diagnosis Questionnaire, and the Patient Health Questionnaire were used to assess research subjects' occupational stress, fatigue accumulation, and depressive symptoms, respectively. Results Long working hours (>40 hours/week) were reported by 50.4% of workers among the research subjects, while shift works were reported by 16.9% of the workers. The detection rates of occupational stress, fatigue accumulation, and depressive symptoms were 26.6%, 41.7%, and 30.8%, respectively. Multivariate logistic regression analysis result revealed that, after adjusting for confounders such as age, sex, and education level, longer working hours were associated with higher risks of occupational stress, fatigue accumulation, and depressive symptoms (all P<0.05). Shift workers in community medical centers had higher risks of occupational stress, fatigue accumulation, and depressive symptoms compared with non-shift workers (all P<0.05). Conclusion Long working hours and shift work could increase the risks of occupational stress, fatigue accumulation, and depressive symptoms among community medical workers.

Objective To investigate the regulatory role of the programmed cell death protein 1 (PD-1) and its ligand programmed cell death protein ligand 1 (PD-L1) signaling on the subtypes and functions of natural killer (NK) cells at the maternal-fetal interface during the second trimester in mice following Toxoplasma gondii infection during the first trimester. Methods Twelve 6- to 8-week-old female mice of the C57BL/6J strain were divided into a control group and an infection group, of 6 mice in each group. On the 6.5th day of pregnancy (Gd6.5), each pregnant mouse in the infection group was intraperitoneally injected with 150 tachyzoites of the Toxoplasma gondii PRU strain, while mice in the control group were injected with an equal volume of physiological saline. On the 12.5th day of pregnancy (Gd12.5), uterus and placenta tissues were sampled from pregnant mice for pathological observations, and the mRNA expression levels of PD-1, PD-L1, and tumor necrosis factor-α (TNF-α) were quantified in uterus and placenta tissues. The PD-1 and DX5 expression was measured on NK cells at the maternal-fetal interface using flow cytometry. In addition, the in vitro JEG-3 trophoblast cells and NK-92MI cells co-culture system was established as the control group, and the addition of T. gondii tachyzoites in the co-culture system served as the infection group. The PD-1, PD-L1, and DX5 mRNA expression was quantified in cells using real-time fluorescence quantitative reverse transcription PCR (RT-qPCR) assay, and the TNF-α concentration was measured in the cell culture supernatant using enzyme-linked immunosorbent assay (ELISA). Results On Gd12.5, clear and intact cellular structures of placental decidual tissues were seen in pregnant mice in the control group, with no remarkable abnormal changes found in the uterine columnar epithelial cells, and inflammatory cell infiltration and blood stasis at varying degrees were found in uterine and placental tissues from pregnant mice in the infection group. The relative PD-1, PD-L1, and TNF-α mRNA expression was (1.004 ± 0.004), (1.001 ± 0.001), and (1.001 ± 0.001) in uterine tissues from pregnant mice in the control group and (2.480 ± 0.720), (3.355 ± 0.920), and (2.391 ± 0.073) in the infection group, respectively. The relative PD-1, PD-L1, and TNF-α mRNA expression was (1.007 ± 0.010), (1.006 ± 0.006), and (1.001 ± 0.001) in the uterine tissues in the control group and (6.948 ± 1.918), (3.225 ± 1.034), and (1.536 ± 0.150) in the infection group, respectively. The relative PD-1, PD-L1, and TNF-α mRNA expression was higher in both the uterine (t = 3.55, 4.43 and 33.02, all P values < 0.05) and placental tissues (t = 5.36, 3.72 and 6.18, all P values < 0.05) in the infection group than in the control group. Flow cytometry showed that the proportions of PD-1⁺ NK cells, PD-1⁺ DX5⁺ NK cells, and DX5⁺ NK cells were (12.200 ± 1.082)%, (9.373 ± 7.728)%, and (44.000 ± 4.095)% in uterine tissues from pregnant mice in the control group, and (21.733 ± 1.630)%, (18.767 ± 1.242)%, and (73.367 ± 0.611)% in the infection group, respectively. The proportions of PD-1⁺ NK cells, PD-1⁺ DX5⁺ NK cells, and DX5⁺ NK cells were (1.100 ± 0.510)%, (2.277 ± 1.337)%, and (96.167 ± 2.831)% in placental tissues from mice in the control group, and (26.867 ± 9.722)%, (23.433 ± 6.983)%, and (82.467 ± 2.248)% in the infection group, respectively. The proportions of PD-1⁺ NK cells (t = 8.45, P < 0.05) and DX5⁺ NK cells (t = 12.29, P < 0.05) were higher in uterine tissues from pregnant mice in the infection group than in the control group, and no significant difference was seen in the proportion of PD-1⁺ DX5⁺ NK cells (Z = -1.09, P > 0.05). The proportions of PD-1⁺ NK cells (t = 4.58, P < 0.05) and PD-1⁺ DX5⁺ NK cells (t = 5.15, P < 0.05) were higher in placental tissues from pregnant mice in the infection group than in the control group, while the proportion of DX5⁺ NK cells was lower in the infection group than in the control group (t = -6.56, P < 0.05). RT-qPCR assay revealed that the relative PD-1, PD-L1, and DX5 mRNA expression was (1.010 ± 0.005), (1.002 ± 0.003), and (1.001 ± 0.001) in the JEG-3 cells and NK92MI cells co-culture system and (3.638 ± 1.258), (0.397 ± 0.158), and (4.267 ± 1.750) in the control group, and ELISA measured that the TNF-α concentration was higher in the cell culture supernatant in the infection group [(22.056 ± 3.205) pg/mL] than in the control group [(12.441 ± 0.001) pg/mL] (t = 5.20, P < 0.05). The PD-1(t = 3.62, P < 0.05) and DX5 mRNA expression (t = 3.23, P < 0.05) was higher in the infection group than in the control group, and the PD-L1 mRNA expression was lower in the infection group than in the control group (t = -6.63, P < 0.05). Conclusions Following T. gondii infection, both PD-L1 expression and PD-1 expression on DX5⁺ NK cells at the maternal-fetal interface are upregulated in mice during the second trimester; however, the proportion of DX5⁺ NK cells decreases. These findings suggest that PD-1/PD-L1 signaling may suppress NK cell functions by modulating DX5⁺ NK cell subsets.

Delirium is a common cause and complication of hospitalization in the elderly and is associated with higher risk of future dementia and progression of existing dementia, of which 70% is Alzheimer's disease (AD). AD and delirium, which are known to be aggravated by one another, represent significant societal challenges, especially in light of the absence of effective treatments. The intricate biological mechanisms have led to numerous clinical trial setbacks and likely contribute to the limited efficacy of existing therapeutics. Artificial intelligence (AI) presents a promising avenue for overcoming these hurdles by deploying algorithms to uncover hidden patterns across diverse data types. This review explores the pivotal role of AI in revolutionizing drug discovery for AD and delirium from target identification to the development of small molecule and protein-based therapies. Recent advances in deep learning, particularly in accurate protein structure prediction, are facilitating novel approaches to drug design and expediting the discovery pipeline for biological and small molecule therapeutics. This review concludes with an appraisal of current achievements and limitations, and touches on prospects for the use of AI in advancing drug discovery in AD and delirium, emphasizing its transformative potential in addressing these two and possibly other neurodegenerative conditions.

OBJECTIVE To investigate the current situation of pharmaceutical management in compact medical consortium of Guangdong province， and to provide decision-making basis for promoting the high-quality construction and sustainable development of the provincial medical consortium. METHODS A self-designed questionnaire was used to select 50 compact medical consortiums in Guangdong province. The survey was answered by the heads of the pharmacy department of the general hospitals. The survey covered the basic scale of the consortium， the appointment of chief pharmacists， the implementation of pharmaceutical management and pharmaceutical care homogenization within the consortium， the difficulties in promoting the homogenization， and the expected provincial support. Descriptive statistical analysis was performed on the survey results. RESULTS A total of 50 questionnaires were collected， and the effective recovery rate was 100%. There were 16 chief pharmacists （32.00%） in charge of the pharmacy department of the general hospital in the medical consortium. Thirty-seven medical consortiums （74.00%） had established a drug supply support system within the consortium， 35 medical consortiums （70.00%） had carried out pharmaceutical management and coordination work within the medical consortium， 23 medical consortiums （46.00%） had established a clinical medication guidance system， 25 medical consortiums chenwenying2016@163.com （50.00%） had established a bidirectional communication mechanism， and only 8 medical consortiums （16.00%） had developed new models of pharmaceutical care. At present， the difficulties in promoting the homogenization of pharmaceutical management and pharmaceutical care within the medical consortium were mainly found in three aspects： the wide gap in management level of each member unit， the lack and uneven level of pharmaceutical personnel， and insufficient policy support and implementation. Most medical consortiums hoped that relevant departments could promote the homogenization of pharmaceutical work by holding special training courses or special supervision. CONCLUSIONS At present， the compact medical consortium in Guangdong province has achieved initial results in the implementation of the chief pharmacist system， the homogenization of pharmaceutical management and pharmaceutical care. However， it is still necessary to improve the coverage of chief pharmacist appointments in the medical consortium， implement the homogenization of pharmaceutical management， and accelerate the homogenization process of pharmaceutical care.

Objective To investigate the clinical manifestations,molecular genetics and gonadal pathol-ogy characteristics of patients with disorders of sex development(DSD),and to summarize the clinical experi-ence of identifying rare diseases from common symptoms.Methods The clinical data of 416 patients with DSD diagnosed and treated in the multidisciplinary center of DSD of Guangzhou Women and Children's Medical Cen-ter from May 2018 to August 2023 were retrospectively analyzed,summarized and discussed.Results Accord-ing to chromosome karyotype,416 cases of DSD were classified into three types:92 cases(22.1％)of abnormal sex chromosome karyotype,285 cases(68.5％)of 46,XY karyotype and 39 cases(9.4％)of 46,XX karyotype.Among the 92 patients with abnormal sex chromosome karyotype,59 cases were raised as males,18 cases(30.5％)complained of short penis with hypospadias and cryptorchidism.The most common karyotype was 45,X/46,XY(58 cases,63.0％).Among the 285 patients with 46,XY karyotype,238 cases were raised as males,and 63 cases(26.5％)complained of short penis and hypospadias;47 cases were raised as females,and 13 ca-ses(27.7％)complained of inguinal mass.A total of 216 patients with 46,XY karyotype were subjected to whole exome gene detection,and 155 cases(71.8％)were found to have molecular pathogenesis with the clinical phe-notype.Among the 39 patients with 46,XX karyotype,19 cases were raised as males,and 8 cases(42.1％)com-plained of short penis and hypospadias.In the 18 cases of gonad biopsy,17 cases showed testicular tissue in go-nads.Whole exome sequencing was performed in 14 cases.NR5A1 gene heterozygous mutation,SRY gene muta-tion and SOX3 gene mutation were found in 2 cases,respectively(14.3％).Twenty cases were raised as females,and 14 cases(70.0％)complained of clitoral hypertrophy.Gonad biopsy was performed in 8 cases,with 7 cases of ovotestis(87.5％)and 1 case of NR5A1 gene heterozygous mutation(14.3％).Conclusions The etiologies of DSD are complex and diverse,and the clinical manifestations are various,which can be manifested as hypospa-dias,micropenis,cryptorchidism and other common symptoms of the urinary system.Different etiologies have dif-ferent treatment options.Therefore,chromosome karyotype,molecular genetic testing and gonadal pathology can be used to clarify the cause of disease,especially for rare diseases,improve the detection rate,reduce the rate of missed diagnosis,and ensure reasonable treatment,especially sex selection.

Objective　To explore the clinical characteristics and drug resistance of Elizabethkingia meningoseptica (EM) nosocomial infection, so as to provide evidence for prevention of EM nosocomial infection and guiding the rational use of antibiotics. Methods　A retrospective study was conducted of 67 patients with EM infection in a tertiary hospital from January 2021 to December 2022. The infective characteristics and drug resistance were analyzed. Results　The cohort of 67 EM-infected patients was predominantly males aged ≥60 years, with the most frequent source being the first district of the intensive care unit (ICU), followed by the respiratory medicine and emergency department (19.40%, 13/67). The specimens were mainly isolated from respiratory tract (86.57%, 58/67), of which sputum accounted for 49.25% (33/67), and alveolar lavage fluid accounted for 37.31% (25/67). The majority of EM infections occurred in patients with pre-existing respiratory conditions (49.25%, 33/67), who generally experienced prolonged hospital stays and underwent invasive procedures, such as mechanical ventilation 94.03% (63/67), urinary catheterization (95.52%, 64/67), and central venous catheterization (97.01%, 65/67). Post-treatment, the improved rate of the 67 patients was 40.30% (27/67). Susceptibility testing demonstrated a high resistance rate of EM to cefoperazone-sulbactam, 98.39% (61/62), contrasted by significant susceptibility to compound trimethoprim-sulfamethoxazole (TMP-SMX)/cotrimoxazole, doxycycline, minocycline, and piperacillin-tazobactam, with susceptibility rates exceeding 90%. Conclusions　The patients infected with EM were almost elderly men with certain underlying diseases, experienced prolonged hospital stays, and had a history of invasive operations. The specimens of EM were mainly from Intensive Care Unit and isolated from respiratory tract. The strain showed high resistance to cefoperazone-sulbactam, whereas it remained highly susceptible to cotrimoxazole, doxycycline, minocycline and piperacillin-tazobactam, which may be considered as first-line treatment options.

AIM: To investigate the protective effect of eugenol against Fusarium solani(F.solani)-induced fungal keratitis(FK)in mice and to preliminarily explore possible underlying mechanisms.METHODS: A modified epifluorescence microscopy method was used to prepare the FK mouse model. An equal amount of DMSO(0.05%)was applied to the conjunctiva of the right eye of rats in the dimethyl sulfoxide(DMSO)group. The eugenol group was prepared by applying eugenol(160 μg/mL)to the conjunctival sac of the right eye of mice. The insulin-like growth factor-1(IGF-1)group was coated with the PI3K/AKT pathway activator IGF-1(10 nmol/mL)in the conjunctival sac of the right eye in addition to the administration of eugenol. The corneal morphology was observed under a slit-lamp microscope on days 1, 3, and 5 of inoculation with F.solani suspension, respectively. Hematoxylin eosin(HE)staining was used to assess corneal histopathological damage. The bacterial load of corneal tissue was determined. Enzyme-linked immunosorbent assay and Western blot were used to analyze the levels of inflammatory mediators interleukin-6(IL-6)and interleukin-1β(IL-1β)and the expression of PI3K/AKT pathway proteins.RESULTS: Eugenol treatment improved the morphological symptoms of keratitis and inflammatory response in FK mice, and reduced corneal pathologic tissue damage and fungal load. At 3 d after F.solani infection, corneal tissue IL-6 levels were significantly higher and IL-1β levels were significantly lower in the eugenol group compared with the DMSO group(both P<0.05); corneal tissue IL-6 levels were significantly higher and IL-1β levels were significantly lower in the eugenol group than in the IGF-1 group(both P<0.05). At 5 d after infection, both IL-6 and IL-1β levels in corneal tissue of the eugenol group were significantly lower than those of the DMSO and IGF-1 groups(P<0.05); compared with the DMSO group, the expression of p-PI3K and p-Akt in the corneal tissues of the eugenol group was significantly reduced(P<0.05); the expression of p-PI3K and p-Akt in corneal tissues was significantly lower in the eugenol group than that of the IGF-1 group(both P<0.05).CONCLUSION: Eugenol may attenuate F.solani-induced corneal inflammation by inhibiting the PI3K/AKT pathway, and it has a protective effect against F.solani keratitis in mice.

Objective:To design and evaluate the application value of intracavitary-interstitial brachytherapy (IC-ISBT) applicator template for locally advanced cervical cancer.Methods:MRI data of 100 patients with ⅡB-ⅣA stage cervical cancer (International Federation of Gynecology and Obstetrics 2018 staging system) before and after external beam radiation therapy (EBRT) admitted to Sun Yat-sen University Cancer Center from March 2019 to September 2020 were collected. The range of primary cervical lesions was retrospectively analyzed and compared. Based on the residual mass of patients, the corresponding high-risk clinical target volume (HR-CTV) was delineated, and the IC-ISBT applicator template was designed and initially applied to cervical cancer patients. Dosimetry analysis and efficacy evaluation were compared between the applicator template-guided ( n=37) and free-hand implantation groups ( n=63). Chi-square test or Fisher exact test was performed for categorical variables, and t-test or U-test for continuous variables. Results:The median distance between the residual tumor margin (clockwise 3, 6, 9, 12 o'clock) and the center of 100 patients with ⅡB-ⅣA stage cervical cancer after EBRT was 16.5, 14.0, 17.0 and 13.0 mm, respectively. The corresponding HR-CTV was superimposed to reconstruct the three-dimensional diagram, and the cylindrical IC-ISBT applicator template with mushroom-like head was designed and manufactured: the longest and shortest diameter of the head was 35 and 20 mm, respectively; the central channel was adapted to the uterine tube, the C1-C12 channels was arranged in inner circle, and the peripheral B1-B5 and A1-A4 pin channels were expanded bilaterally. In terms of dose coverage, there was no significant difference between the HR-CTV D 90% [(635.12±22.65) vs. (635.80±25.84) cGy], bladder D 2 cm3 [(473.79±44.78) vs. (463.55±66.43) cGy)], rectum D 2 cm3 [(396.99±73.54) vs. (408.00±73.94) cGy] and sigmoid colon D 2 cm3 [(293.07±152.72) vs. (311.31±135.77) cGy] between the template-guided and free-hand implantation groups (all P>0.05), but the HR-CTV D 98% was significantly higher [(544.78±32.07) vs. (536.78±32.04) cGy, P=0.007] and the rectum D 1 cm3 and D 0.1 cm3 were significantly lower [(438.62±69.65) vs. (453.97±67.89) cGy, P=0.016; (519.46±70.67) vs. (543.82±81.24) cGy, P=0.001] in the template-guided implantation group. In addition, there was no significant difference in the complete response rate between two groups (86% vs. 83%, P>0.05). Conclusions:This IC-ISBT applicator template is reasonably designed, and the therapeutic efficacy of the template-guided implantation is equivalent to that of free-hand implantation. The dose coverage of the target area meets the clinical demand with a better protection of the organs at risk. The applicator template has the potential to be widely used as a conventional template in clinical practice as the applicator-guided implantation is convenient to operate and repeat.

BACKGROUND:Inflammation and oxidative stress contribute to the barriers of regeneration in chronic wound.Oxymatrine has various biological activities,such as anti-oxidation,anti-inflammation and so on,which may have the potential effect of promoting wound healing. OBJECTIVE:To investigate the effect of oxymatrine on wound healing and the protective effect on H2O2-induced oxidative stress injury in human keratinoid cell line HaCaT cells. METHODS:(1)In vivo experiment:Hyaluronic acid methacryloyl hydrogels containing 0,0.05,0.1,0.2 g/L oxymatrine were prepared.A full-layer skin defect model with a diameter of 12 mm was made in the back of 75 diabetic mice and randomly divided into five groups for intervention,with 15 mice in each group.The wounds of the model group were bandaged and fixed.The wounds of the hydrogel group were covered with hyaluronic acid methacryloyl hydrogel.The wounds of the low-dose,moderate-dose and high-dose oxymatrine groups were covered with hyaluronic acid methacryloyl hydrogel containing 0.05,0.1,and 0.2 g/L oxymatrine,respectively,and then bandaged and fixed after light curing.Relevant indicators were detected within 14 days.(2)In vitro experiment:Human keratinocyte line HaCaT was divided into five groups.The normal group was cultured conventionally.H2O2 group and low-,moderate-and high-concentration oxymatrine groups were treated with H2O2 for 4 hours,and then the medium was replaced with medium containing 0,0.05,0.1,and 0.2 g/L oxymatrine,respectively,and the relevant indexes were detected after 24 hours of culture. RESULTS AND CONCLUSION:(1)In vivo experiment:Compared with the model group,the wound healing rate of mice in the hydrogel group had no significant change.The wound healing rate of mice in the low-,moderate-and high-dose oxymatrine group was increased at 7 and 14 days after treatment(P<0.05).Pathological observation of wound section 14 days after treatment showed that compared with the model group,the thickness of regenerated epidermal layer,the number of microvessels,and collagen deposition in the moderate-and high-dose oxymatrine groups were increased(P<0.05).Western blot assay analysis of wound samples 7 days after surgery showed that compared with the model group,the protein expressions of tumor necrosis factor α and interleukin 6 in the moderate-and high-dose oxymatrine groups were decreased(P<0.05).(2)In vitro experiment:CCK8 assay,EdU and Ki67 staining showed that compared with the H2O2 group,the cell proliferation ability of the moderate-and high-concentration oxymatrine groups was significantly increased(P<0.05).Compared with the H2O2 group,mitochondrial membrane potential was increased(P<0.05)and reactive oxygen species content was decreased(P<0.05)in the moderate-and high-concentration oxymatrine groups.Western blot assay results showed that compared with the H2O2 group,the expression levels of Nrf2 nuclear protein,Nrf2 total protein,HO-1 protein,and superoxide dismutase 1 protein were increased in the high-concentration oxymatrine group(P<0.05).(3)These findings confirm that oxymatrine can alleviate oxidative stress damage in HaCat cells and accelerate wound healing by upregulating the levels of Nrf2 and HO-1 protein.