The interest in covalent drugs has resurged in recent decades, spurring the development of numerous specialized computational docking tools to facilitate covalent ligand design and screening. Herein, we present CarsiDock-Cov, a new paradigm distinguishing itself as the first deep learning (DL)-guided approach for covalent docking. CarsiDock-Cov retains the core components of its non-covalent predecessor, leveraging a DL model pretrained on millions of docking complexes to predict protein-ligand distance matrices, along with a dedicated-designed geometric optimization procedure to convert these distances into refined binding poses. Additionally, it incorporates several key enhancements specifically tailored to optimize the protocol for covalent docking applications. Our approach has been extensively validated on multiple public datasets regarding the docking and screening of covalent ligands, and the results indicate that our approach not only achieves comparably improved applicability compared to its non-covalent predecessor, but also exhibits competitive performance against various state-of-the-art covalent docking tools. Collectively, our approach represents a significant advance in covalent docking methodology, offering an automated and efficient solution that shows considerable promise for accelerating covalent drug discovery and design.

OBJECTIVE To know about the working mode and human resource status of pharmacy intravenous admixture services （PIVAS） in national medical institutions. METHODS Through questionnaire survey， the national PIVAS was invited to fill out questionnaire and statistical analysis was performed on the effective sample data related to PIVAS working mode and human resources in the questionnaire. RESULTS In this study， 761 PIVAS from 722 medical institutions of 29 provinces were involved in the questionnaire survey， with 471 valid questionnaires for working mode and 441 valid questionnaires for human resources survey. In terms of working mode， among 471 PIVAS， 292 PIVAS （62.0%） were in pharmacist-alone mode， and 176 PIVAS （37.4%） were in pharmacist-nurse cooperative mode； there was no significant difference in the types of medical orders received by PIVAS between these two working modes except for the other medical orders （P＞0.05）. In terms of human resource setting， among 441 PIVAS， the average number of total staff of single PIVAS was 24（16，33）， including 11（6，19） pharmacists， 7（2，13） nursing staff， and 3（1，5） workers； there was a statistically significant difference in the number of personnel among three groups （P＜ 0.01）. The per capita income of PIVAS respondents in 2019 was [7.9（4.8，10.7）]×104 yuan， and in 2021 it was [8.8（5.8，11.7）]× 104 yuan， with an increase of 9.0% compared to 2019. The difference between the two groups was statistically significant （P＜ 0.01）. CONCLUSIONS Medical institutions’ PIVAS in China had not fully implemented the pharmacist-alone work model， and some medical institutions had chosen a pharmacist-nurse cooperative mode. It is suggested that relevant departments formulate corresponding qualification requirements and training standards for nursing personnel as soon as possible based on sufficient research on PIVAS’s demand for nursing professionals.

OBJECTIVE To know about the pharmacy intravenous admixture charge and operation balance of pharmacy intravenous admixture services （PIVAS） in national medical institutions. METHODS Using questionnaire survey method， the national PIVAS leaders were invited to fill in the questionnaire， investigation and statistical analysis of the drug dispensing charge standard and the income and expenditure situations of PIVAS nationwide were conducted. RESULTS A total of 761 PIVAS completed the questionnaire， among which 466 PIVAS （61.2%） had already started implementing pharmacy intravenous admixture charge， mainly in tertiary hospitals. The charge standards for chemotherapy drugs and parenteral nutrition solutions were relatively high， while the standards for packaged drugs were the lowest， with differences in charge standards among provinces（P＜0.05）. Among the 25 provinces that reported annual drug preparation fee revenue， Hubei had the highest revenue in both 2019 and 2021. In 2019， the number of PIVAS with a balance of payments was more than that of PIVAS with an imbalance of payments， but the number of PIVAS with an imbalance of payments in 2021 exceeded the number of PIVAS with a balance of payments （P＜0.05）； among them， eight provinces were unbalanced in 2019 and 2021， such as Tianjin， Chongqing， Guizhou， etc. CONCLUSIONS PIVAS charge standards of the surveyed medical institutions in all provinces are not unified. It is suggested to improve the charge standard further， formulate the charge adjustment cycle， and promote a sustainable development of PIVAS.

The amount of data generated by the human experience in medical cases of classic formulas is large and the research value is high， but how to extract valuable information from these massive data is an important problem of researches on classical formulas. It is concluded that there are many problems in the current study of human experience in classical formulas， such as large amount of data， uneven quality， weak extrapolation and clinical application， which seriously affected the evidence strength of human experience in classical formulas and the contribution to experience accumulation and theoretical support. Therefore， from the structural perspective of the research questions， this paper proposed the research ideas of human experience in medical cases of classic formulas： firstly， according to the characteristics of traditional Chinese medicine （TCM） cases， based on the PICO model， which refers parti-cipants （P）， intervention （I）， comparisons （C）， and outcomes （O）， a TCM medical record evaluation tool in line with the evidence-based concept was constructed to evaluate the quality of medical cases； secondly， constructing a standardized database of human experience in classical formulas and using data mining algorithms to explore the deep relationship hidden in human experience； finally， the clinical value evaluation is carried out to verify the effectiveness of the diagnosis and treatment rules of classical formulas to achieve clinical transformation.

Objective:To investigate whether IL-7-secreting oncolytic herpes simplex virus(HSV)could activate CD8+T cells and inhibit the growth of hepatocellular carcinoma.Methods:The expression of IL-7 was detected by Western blot.The in vitro cleavage of tumor cells by tumor oncolytic virus HSV and HSV-IL-7 were detected by crystal violet staining.The tumor inhibition ability of HSV-IL-7 and HSV were detected in subcutaneous transplanted tumor model.Levels of IL-7,IFN-γ and TNF-α in serum and tumor tissues were determined by ELISA.The infiltration of CD8+T cells in tumor tissues was detected by immunohistochemistry.Flow cytometry was used to detect Granzyme B secretion in CD8+T cells infiltrated by tumor.Results:Tumor cells infected with HSV-IL-7 expressed high level of IL-7.Both HSV and HSV-IL-7 can effectively lyse B16-F10,CT-26 and H22 tumor cell lines in a dose-dependent manner in vitro.HSV-IL-7 could significantly inhibit the growth of H22 hepatoma cells in vivo(P<0.01)and prolong the survival time of tumor-bearing mice(P<0.001).HSV-IL-7 could significantly increase the IL-7 content in tumor sites(P<0.000 1),and effectively increase the number of tumor infiltrating CD8+T cells(P<0.001).HSV-IL-7 significantly enhanced Granzyme B secretion of tumor-infiltrating CD8+T cells and IFN-γ and TNF-α in tumor tissues(P<0.000 1).Conclusion:HSV-IL-7 has well tumor inhibition activity in vivo and in vitro.It also can activate the anti-tumor activity of CD8+T cells in vivo by secreting IL-7,inhibit tumor growth and prolong the survival time of tumor-bearing mice.

Objective:To investigate the effects of low-frequency and high frequency repetitive transcranial magnetic stimulation (rTMS) combined with levodopa and benserazide hydrochloride on mild cognitive impairment in patients with Parkinson disease (PD).Methods:Totally 90 PD patients with mild cognitive impairment who visited from January 2020 to June 2022 were included , and they were divided into a simple drug group ( n=30), drug+ low-frequency group ( n=30), and drug+ high-frequency group ( n=30) according to the order of admission.The patients in the simple drug group were treated with oral levodopa and benserazide hydrochloride, while the patients in drug+ low-frequency and drug+ high-frequency groups were treated with low-frequency or high-frequency rTMS on the basis of oral levodopa and benserazide hydrochloride.Montreal cognitive assessment(MoCA), digital span (DS), Chinese auditory learning test (CALT), the judgment of line orientation test (JLOT) and verbal fluency test (VFT) were used to evaluate the cognitive function of patients before and after 4 weeks of treatment.SPSS 26.0 was used for statistical analysis.The paired t-test was used for intra-group comparison before and after treatment, while one-way ANOVA was used for inter-group comparison. Results:There were no significant differences in MoCA, DS anterograde, DS backward, CALT immediate recall, CALT delayed recall, JLOT, and VFT scores among patients in the simple drug group before and after 4 weeks of treatment( t=-1.157, -0.648, -0.215, -0.290, -0.154, -0.782, -0.960, all P>0.05). After 4 weeks of treatment, MoCA, DS anterograde, DS backward, CALT immediate recall, CALT delayed recall, JLOT and VFT scores in drug+ low-frequency group and drug+ high-frequency group were higher than before treatment (drug+ low frequency group: t=-16.357, -11.379, -7.999, -11.805, -16.624, -15.996, -17.241, all P<0.05; drug+ high-frequency group: t=-25.198, -13.971, -13.904, -25.831, -26.382, -20.108, -15.643, all P<0.05). There were no statistically significant differences in the scores of MoCA, DS anterograde, DS backward, CALT immediate recall, CALT delayed recall, JLOT and VFT among the three groups before treatment (all P>0.05). After treatment, there were statistically significant differences in the scores of MoCA, DS anterograde, DS backward, CALT immediate recall, CALT delayed recall, JLOT and VFT among the three groups (simple drug group : (20.37±1.96), (4.37±1.19), (2.80±0.55), (6.93±1.70), (5.17±1.09), (15.50±2.69), (10.73±1.55); drug+ low-frequency group: (23.83±2.32), (5.87±0.94), (3.87±0.73), (9.17±1.74), (8.13±1.50), (20.77±2.19), (13.30±1.73); drug+ high-frequency group: (27.17±1.64), (6.73±1.01), (4.80±0.81), (11.20±2.06), (10.03±1.54), (25.17±3.14), (15.87±2.05)) (all P<0.05). Further analysis showed that both the drug+ low-frequency and drug+ high-frequency groups had higher scores than the simple drug group, and the drug+ high-frequency group had higher scores than the drug+ low-frequency group(all P<0.05). Conclusion:The combination of drug+ low-frequency or drug+ high-frequency rTMS and drug therapy can help improve cognitive function in patients with PD, and the efficacy of drug+ high-frequency rTMS may be more significant, which provides a new therapeutic idea for clinical treatment of patients with PD.

Objective:To explore the clinical efficacy of areola approach endoscopic thyroidectomy (AET) and gasless axillary approach endoscopic thyroidectomy (GAET) in the treatment of papillary thyroid carcinoma (PTC) patients.Methods:A total of 96 PTC patients from the Thyroid Surgery Department of Linyi People’s Hospital from May. 2019 to May. 2022 were selected and randomly divided into 48 patients using a random number table method. The areola group received AET, while the armpit group received GAET. The surgical situation, postoperative recovery, relevant biochemical indicators [white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), parathyroid hormone (PTH), blood calcium] before and after surgery, postoperative pain level, discomfort level, neck function, and complications were compared between the two groups.Results:The surgical time and extubation time of the armpit group were (125.71±15.73) minutes and (3.12±0.53) days, respectively, which were shorter than those of the areola group (137.94±20.02) minutes and (3.48±0.46) days. The intraoperative bleeding volume was (14.19±4.16) mL, which was less than that of the areola group (22.65±7.39) mL, and the number of lymph nodes cleaned was 5.06±1.02, which was more than that of the areola group (4.23±1.14) ( P<0.05) ; there was no significant difference in postoperative drainage volume and hospital stay between the two groups ( P>0.05) ; Peripheral blood WBC in the armpit group on the 1st and 3rd day after surgery [ (5.69±0.15) ×10 9/L, (5.52±0.14) ] ×10 9/L, ESR [ (8.21±0.55) mm/h, (7.64±0.60) mm/h], CRP [ (10.06±1.78) ng/L, (8.93±1.33) ng/L] were lower than those in the areola group [ (5.83±0.21) ×10 9/L, (5.70±0.23) ×10 9/L, (8.87±0.74) mm/h, (8.19±0.68) mm/h, (12.45±1.90) ng/L, (10.45±1.50) ng/L] ( P<0.05). There was no significant difference in the levels of the above biochemical indicators 5 days after surgery ( P>0.05). There was no significant difference in peripheral blood PTH and calcium levels between the two groups on the 1st, 3rd, and 5th postoperative days ( P>0.05). The pain level [ (3.25±0.32) scores, (2.53±0.27) scores, (1.82±0.22) scores] and discomfort level [ (6.85±0.71) scores, (5.24±0.66) scores, (3.51±0.57) scores] in the axillary group were lower than those in the areola group [ (3.78±0.40) scores, (2.89±0.34) scores, (2.06±0.26) scores, (7.46±0.84) scores, (6.09±0.73) scores, (4.16±0.60) scores] on the 1st, 3rd, and 5th postoperative days ( P<0.05). The neck flexion, lateral flexion, and extension range of motion in the axillary group on the 3rd day after surgery were (33.16±3.09) °, (27.63±2.57) °, and (30.44 2.73) °, respectively, which were greater than those in the areola group[ (30.08±2.76) °, (25.14±2.30) °, and (27.98±2.54) °], and the swallowing disorder index was (30.16±4.97) points lower than the (34.83±4.13) points in the areola group ( P<0.05). The incidence of complications in the axillary group was 4.17% (2/48), lower than the 16.67% (8/48) in the areola group. Conclusion:GAET treatment for PTC patients can improve the effect of lymph node dissection, reduce the degree of surgical trauma, postoperative pain and discomfort, accelerate early postoperative recovery of neck function, and reduce complications.

Objective To explore the interventional mechanism of Bufei Yishen formula on chronic obstructive pulmonary disease from pathway level.Methods Macrophage inflammatory model was established by LPS stimulation.Based on gene set enrichment analysis(GSEA)method,macrophage inflammation related pathways were screened,and normalized enrichment score(NES)was used to identify pathways that were reversed by traditional Chinese medicine treatment,revealing the interventional mechanism of Bufei Yishen formula and its compatibility.Results The NES of Bufei Yishen formula was-1377.23,among which the NES of Bushen compatibility was-485.07,that of Huoxue was-351.86,Huatan was-303.71,and Yiqi was-236.59.There were 213 significantly disturbed pathways reversed after the intervention of Bufei Yishen formula,among which there were 184 reversed pathways for Huoxue compatibility,147 reversed pathways for Bushen,134 reversed pathways for Huatan,133 reversed pathways for Yiqi,and the reversal rate was 75.41%,60.25%,54.92%,54.51%,respectively.90 pathways,including TGF-β production,were significantly reversed in the four compatibilities.Positive regulation of cytokine production involved in inflammatory response etc were specifically reversed pathways for compatibility.Conclusion The intensity of Bufei Yishen formula that reversed macrophage-inflammatory related pathways was in order of Bushen,Huoxue,Huatan and Yiqi compatibility.And the number of pathways that could be reversed by the compatibility of Bufei Yishen formula was Huoxue,Bushen,Huatan and Yiqi.Bufei Yishen formula could regulate the common and specific reversal pathways of the compatibilities to intervene the inflammatory response.

Objective To provide some evidence for early empirical treatment of infections caused by Pseudanonas aeruginosa(PA)and establish a certain foundation for further studies on its resistance mechanisms.Analyzed the resistance rate of PA and the phenotype characteristics for seven years at this hospital.Methods Using Whonet 5.6 software,the drug sensitivity data of PA isolated and reported from clinical specimens at Kunming First People's Hospital from 2016 to 2022 were analyzed annually.Imipenem,meropenem,ceftazidime,and cefepime were the main observation objects,statisticaly analyze the resistance of other antibiotics under different drug resistance combinations of the above-mentioned drugs Results A total of 1 920 strains of PA were detected in 7 years,with polymyxins exhibiting the lowest resistance rate at 1%.The average resistance rates for Amikacin,Gentamicin and Tobramycin were 6.4%,8.6%and 5.1%,respectively.The resistance rates of Quinolones,Piperacillin/Tazobactam,Ceftazidime,and Cefepime were similar,ranging from 10%～20%.Imipenem and Meropenem did not show better sensitivity,with resistance rates of 21.3%and 18.4%,respectively.The resistance rates of major antibiotics have fluctuated over the past 7 years,mostly increasing from 2017 to reaching a peak in 2018 and then falling back.And then stabilized with the domestic average level.1 393 strains were sensitive to Imipenem,and the sensitivity rate of Meropenem in this part was 96.2%.1 451 strains were sensitive to Imipenem,and 89%of them were sensitive to Meropenem at the same time.369 strains were both resistant to Imipenem and Meropenem,and 33.1%of them were sensitive to Ceftazidime.The more resistant to β-lactam,the lower the sensitivity rate to Amikacin and Ciprofloxacin.Conclusion The overall drug sensitivity of PA in this hospital is relatively good.Should adhere to strict management of antibiotic use.Aminoglycosides can be the preferred drugs for empirical treatment,followed by Quinolones,and Carbapenems and Ceftazidime are also candidates.PA has diverse resistance mechanisms to β-lactam antimicrobials,and carbapenem-resistant strains can be mediated by different mechanisms or jointly.

Objective To investigate the predictive value of lactic acid to albumin ratio in the in-hospital mortality of the patients with intra-abdominal infection sepsis in ICU.Methods The clinical data in 175 pa-tients with sepsis caused by intra-abdominal infection admitted and treated in the intensive care medicine de-partment of this hospital from January 2018 to December 2021 were retrospectively analyzed.The patients were divided into the survival group (n=94) and death group (n=81) according to whether or not having in-hospital death.The general data,blood lactic acid and albumin levels of the patients at admission were collect-ed,and the LAR value was calculated.The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of LAR for the in-hospital mortality of sepsis patients in ICU.The Cox regression analysis and Kaplan-Meier curves were used to analyze the independent correlation between LAR and ICU mortality. Results There were statistically significant differences in the acute physiology and chronic health scoring sys-tem Ⅱ (APACHⅡ) score,sequential organ failure assessment (SOFA) score,mean arterial pressure,oxygen-ation index,PCT,lactic acid,albumin,LAR and the proportion of surgical patients between the two groups (P<0.05).The area under the curve (AUC) of LAR for predicting the prognosis in the patients with ICU sepsis was 0.765 (95％CI:0.695-0.835),which was higher than that of the APACHEⅡscore,SOFA score,lactic acid and PCT.With LAR=1.295 as the cutoff value,the sensitivity and specificity for its prediction were 0.679 and 0.707,respectively.The Kaplan-Meier curve showed that the ICU motality rate in high LAR (LAR≥1.29) was higher than that in low LAR,and the difference was statistically significant(63.2％ vs. 41.5％,P<0.05).The Cox regression analysis results showed that the mortality in sepsis showed the increas-ing trend with the LAR level increase (P<0.05).Conclusion LAR is an influencing factor of the death in the intra-abdominal infection sepsis in ICU,which could effectively predict the risk of in-hospital death of the patients.