Objective To compare the effects of esketamine and magnesium sulfate on hemodynamics,stress reaction and postoperative analgesia in elderly patients undergoing laparoscopic cholecystectomy(LC).Methods The subjects of this study,156 elderly patients who underwent LC from June 2021 to October 2023,were randomly divided into 3 groups,each with 52 cases.15 min prior to anesthesia induction,the esketamine group was administered with esketamine hydrochloride injection 0.20 mg/kg intravenously,magnesium sulfate group received intravenous infusion of magnesium sulfate injection 50.00 mg/kg,and physiological saline group received intravenous infusion of equivalent stroke-physiological saline solution.The heart rate(HR)and blood pressure(BP)of three groups were monitored using a monitor immediately after entering the room(T0),immediately after anesthesia induction(T1),immediately after tracheal intubation(T2),immediately after pneumoperitoneum(T3),immediately after cholecystectomy(T4),and immediately before tracheal extubation(T5).The levels of serum stress reaction indicators[cortisol(Cor)and norepinephrine(NE)]in three groups were tested at T0,T4,and T5 respectively.Intraoperative anesthetic dosage and use of atropine and phenylephrine,sufentanil dosage 24 h after surgery,awakening time,extubation time,and directional force recovery time were compared among the three groups.Patients'pain level was assessed respectively 2,6,12 and 24 h after the operation.Adverse reactions were compared among the three groups.Results The magnesium sulfate group and physiological saline group saw much lower HR,systolic blood pressure(SBP),and diastolic blood pressure(DBP)at T1 than they did at T0,the differences were statistically significant(P<0.05),while the physiological saline group had significant higher HR,SBP,DBP at T2,T3,T4,T5 than it did at T0,the differences were statistically significant(P<0.05).Compared with the esketamine group over the same period,the magnesium sulfate group showed a significant decrease in HR at T1 and T2,and a remarkable decrease in SBP and DBP at T1,the differences were statistically significant(P<0.05).At T1,HR,SBP,and DBP in the physiological saline group were much lower,while the HR,SBP,and DBP in this group at T2,T3,T4,and T5 were obviously higher than those in esketamine group,the differences were statistically significant(P<0.05).The physiological saline group witnessed much higher HR,SBP and DBP at T1,T2,T3,T4,T5 as compared with the magnesium sulfate group over the same period,the differences were statistically significant(P<0.05).All the three groups had significantly higher Cor and NE levels at T4 and T5 than they did at T0(P<0.05).The serum Cor and NE levels at T4 and T5 in the esketamine group and magnesium sulfate group were significantly lower than those in the physiological saline group during the same period,the differences were statistically significant(P<0.05).There was no significant difference in serum Cor and NE levels between the esketamine group and magnesium sulfate group at T4 and T5 over the same period,the differences were not statistically significant(P>0.05).The intraoperative consumption of propofol and remifentanil in the esmketamine group and the magnesium sulfate group were significantly less than those in the physiological saline group,and the esmketamine group was significantly more than the magnesium sulfate group(P<0.05).There were no significant difference in the utilization rate of intraoperative atropine and phenylephrine among the three groups(P>0.05).Sufentanil dosage 24 h after surgery in magnesium sulfate group and esketamine group were less than that of physiological saline group,the differences were statistically significant(P<0.05).However,there was no significant difference in the consumption of sufentanil dosage 24 h after surgery between the magnesium sulfate group and the esmketamine group(P>0.05).Extubation time and directional force recovery time in magnesium sulfate group and esketamine group were shorter than those of physiological saline group,the differences were statistically significant(P<0.05),but the differences were not statistically significant between the magnesium sulfate group and esketamine group(P>0.05).The pain visual analogue scale(VAS)score at 2,6,12,and 24 h after the operation in the esketamine group and magnesium sulfate group were significantly lower than those in the physiological saline group,the differences were statistically significant(P<0.05),but the differences were not statistically significant between the magnesium sulfate group and esketamine group(P>0.05).There was no significant difference in postoperative adverse reactions among the three groups(P>0.05).Conclusion In treating elderly people undergoing LC,esketamine and magnesium sulfate are alike in effects on stabilizing hemodynamics,inhibiting stress reaction,and mitigating postoperative pain.

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

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.

Based on ultra-performance liquid chromatography-quadrupole-electrostatic field Orbitrap high-resolution mass spectrometry(UPLC-Q-Orbitrap HRMS) technology and molecular docking, the bitter-tasting substances(hereafter referred to as "bitter substances") in Cistanche deserticola extract were investigated, and the bitter taste and efficacy relationship was explored to lay the foundation for future research on de-bittering and taste correction. Firstly, UPLC-Q-Orbitrap HRMS was used for the qualitative analysis of the constituents of C. deserticola, and 69 chemical components were identified. These chemical components were then subjected to molecular docking with the bitter taste receptor, leading to the screening of 20 bitter substances, including 6 phenylethanol glycosides, 5 flavonoids, 3 phenolic acids, 2 cycloalkenyl ether terpenes, 2 alkaloids, and 2 other components. Nine batches of fresh C. deserticola samples were collected from the same origin but harvested at different months. These samples were divided into groups based on harvest month and plant part. The bitterness was quantified using an electronic tongue, and the content of six potential bitter-active compounds(pineconotyloside, trichothecene glycoside, tubulin A, iso-trichothecene glycoside, jinshihuaoside, and jingnipinoside) was determined by high-performance liquid chromatography(HPLC). The total content of phenylethanol glycosides, polysaccharides, alkaloids, flavonoids, and phenolic acids was determined using UV-visible spectrophotometry. Chemometric analyses were then conducted, including Pearson's correlation analysis, gray correlation analysis, and orthogonal partial least squares discriminant analysis(OPLS-DA), to identify the bitter components in C. deserticola. The results were consistent with the molecular docking findings, and the two methods mutually supported each other. Finally, network pharmacological predictions and analyses were performed to explore the relationship between the targets of bitter substances and their efficacy. The results indicated that key targets of the bitter substances included EGFR, PIK3CB, and PTK2. These substances may exert their bitter effects by acting on relevant disease targets, confirming that the bitter substances in C. deserticola are the material basis of its bitter taste efficacy. In conclusion, this study suggests that the phenylethanol glycosides, primarily pineconotyloside, mauritiana glycoside, and gibberellin, are the material basis for the "bitter taste" of C. deserticola. The molecular docking technique plays a guiding role in the screening of bitter substances in traditional Chinese medicine(TCM). The bitter substances in C. deserticola not only contribute to its bitter taste but also support the concept of the "taste-efficacy" relationship in TCM, providing valuable insights and references for future research in this area.
Molecular Docking Simulation ; Taste ; Chromatography, High Pressure Liquid ; Cistanche/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Humans ; Mass Spectrometry

Objective To compare the effects of esketamine and magnesium sulfate on hemodynamics,stress reaction and postoperative analgesia in elderly patients undergoing laparoscopic cholecystectomy(LC).Methods The subjects of this study,156 elderly patients who underwent LC from June 2021 to October 2023,were randomly divided into 3 groups,each with 52 cases.15 min prior to anesthesia induction,the esketamine group was administered with esketamine hydrochloride injection 0.20 mg/kg intravenously,magnesium sulfate group received intravenous infusion of magnesium sulfate injection 50.00 mg/kg,and physiological saline group received intravenous infusion of equivalent stroke-physiological saline solution.The heart rate(HR)and blood pressure(BP)of three groups were monitored using a monitor immediately after entering the room(T0),immediately after anesthesia induction(T1),immediately after tracheal intubation(T2),immediately after pneumoperitoneum(T3),immediately after cholecystectomy(T4),and immediately before tracheal extubation(T5).The levels of serum stress reaction indicators[cortisol(Cor)and norepinephrine(NE)]in three groups were tested at T0,T4,and T5 respectively.Intraoperative anesthetic dosage and use of atropine and phenylephrine,sufentanil dosage 24 h after surgery,awakening time,extubation time,and directional force recovery time were compared among the three groups.Patients'pain level was assessed respectively 2,6,12 and 24 h after the operation.Adverse reactions were compared among the three groups.Results The magnesium sulfate group and physiological saline group saw much lower HR,systolic blood pressure(SBP),and diastolic blood pressure(DBP)at T1 than they did at T0,the differences were statistically significant(P<0.05),while the physiological saline group had significant higher HR,SBP,DBP at T2,T3,T4,T5 than it did at T0,the differences were statistically significant(P<0.05).Compared with the esketamine group over the same period,the magnesium sulfate group showed a significant decrease in HR at T1 and T2,and a remarkable decrease in SBP and DBP at T1,the differences were statistically significant(P<0.05).At T1,HR,SBP,and DBP in the physiological saline group were much lower,while the HR,SBP,and DBP in this group at T2,T3,T4,and T5 were obviously higher than those in esketamine group,the differences were statistically significant(P<0.05).The physiological saline group witnessed much higher HR,SBP and DBP at T1,T2,T3,T4,T5 as compared with the magnesium sulfate group over the same period,the differences were statistically significant(P<0.05).All the three groups had significantly higher Cor and NE levels at T4 and T5 than they did at T0(P<0.05).The serum Cor and NE levels at T4 and T5 in the esketamine group and magnesium sulfate group were significantly lower than those in the physiological saline group during the same period,the differences were statistically significant(P<0.05).There was no significant difference in serum Cor and NE levels between the esketamine group and magnesium sulfate group at T4 and T5 over the same period,the differences were not statistically significant(P>0.05).The intraoperative consumption of propofol and remifentanil in the esmketamine group and the magnesium sulfate group were significantly less than those in the physiological saline group,and the esmketamine group was significantly more than the magnesium sulfate group(P<0.05).There were no significant difference in the utilization rate of intraoperative atropine and phenylephrine among the three groups(P>0.05).Sufentanil dosage 24 h after surgery in magnesium sulfate group and esketamine group were less than that of physiological saline group,the differences were statistically significant(P<0.05).However,there was no significant difference in the consumption of sufentanil dosage 24 h after surgery between the magnesium sulfate group and the esmketamine group(P>0.05).Extubation time and directional force recovery time in magnesium sulfate group and esketamine group were shorter than those of physiological saline group,the differences were statistically significant(P<0.05),but the differences were not statistically significant between the magnesium sulfate group and esketamine group(P>0.05).The pain visual analogue scale(VAS)score at 2,6,12,and 24 h after the operation in the esketamine group and magnesium sulfate group were significantly lower than those in the physiological saline group,the differences were statistically significant(P<0.05),but the differences were not statistically significant between the magnesium sulfate group and esketamine group(P>0.05).There was no significant difference in postoperative adverse reactions among the three groups(P>0.05).Conclusion In treating elderly people undergoing LC,esketamine and magnesium sulfate are alike in effects on stabilizing hemodynamics,inhibiting stress reaction,and mitigating postoperative pain.

Objective:To analyze the clinical characteristics of immune-related psoriasis caused by immune checkpoint inhibitors (ICIs).Methods:The patients with newly developed or worsening psoriasis after ICIs treatment in Department of Oncology, the Affiliated Hospital of Qingdao University from November 2019 to October 2023 were enrolled in this study. The patients′ gender, age, tumor type and stage, usage and dosage of ICIs, drugs applied in combination, history of psoriasis, the time of new onset or deterioration, clinical manifestations, intervention measures and outcomes were collected, and descriptive statistical analysis was performed.Results:A total of 13 patients were enrolled in the study, including 10 males and 3 females, with a median age of 66 years. The primary diseases included lung cancer (in 7 patients), gastric cancer (in 5 patients), and cholangiocarcinoma (in 1 patient). The tumor stage was Ⅳ in 12 patients and Ⅲ in 1 patient. Ten patients were treated with programmed cell death 1 receptor (PD-1) inhibitors, 2 with programmed cell death ligand 1 (PD-L1) inhibitors, and one with a PD-1/cytotoxic T-lymphocyte-associated antigen 4 combination antibody. All 13 patients were treated with other anti-tumor drugs at the same time. There were 10 patients with a history of psoriasis and 3 patients with newly developed psoriasis. The median time from the use of ICIs to the onset or deterioration of psoriasis was 54 days. Ten patients were plaque psoriasis and 3 were drip psoriasis. Among the 13 patients, 5, 5, and 3 patients were classified as mild, moderate, and severe, respectively. ICIs treatment was suspended in 11 patients and not stopped in 2 patients. After treatment with glucocorticoids, the skin lesions of 13 patients were improved and ICIs were restarted in 3 patients.Conclusions:ICIs-related psoriasis usually occurs within 2 months after the use of ICIs. The clinical types are plaque-like and drop-like, mostly mild or moderate. The prognosis is good after discontinuing ICIs or giving glucocorticoids and other drugs. Some patients can restart ICIs treatment.

A high-throughput three-dimensional (3D) hepatocyte culture model is constructed in this study. It is capable of replicating the 3D in vivo environment and offers the advantages of high throughput, enhanced reproducibility, low cost, and simplified operation, rendering a valuable tool for hepatotoxicity screening of traditional Chinese medicine (TCM). First, we constructed the 3D high throughput liver chip model using collagen hydrogel. The precision and its difference with traditional cell culture plates were assessed using acetaminophen, Tripterygium hypoglaucum, and Qili San as the references. The feasibility of this model was also investigated by comparing the hepatotoxicity among four batches of T. hypoglaucum and Qili San. The methodology verification shows that the 3D hepatocyte model is better than traditional two-dimensional (2D) cell culture model in precision and feasibility. Subsequently, we compared the hepatotoxicity of different samples over a period of three or seven days and found that the hepatotoxicity of TCM extracts increased over time. Finally, we compared the hepatotoxicity of T. hypoglaucum and its compound formula Kunxian capsule under equivalent concentration. The results showed that the compound Kunxian capsule could significantly reduce hepatotoxicity of T. hypoglaucum. Generally, we constructed a high-throughput, robust 3D liver-on-a-chip model with the potential of rapid assessing TCM-induced liver toxicity.

Objective To explore the correlation between healthcare-associated infection(HAI)and partial inde-xes in the diagnosis-related groups(DRGs)of patients in thoracic surgery intensive care unit(ICU).Methods DRGs,case mix index(CMI),relative weight(RW),and HAI of patients in thoracic surgery ICU and four subspe-cialty departments(pulmonary surgery group,esophageal surgery group,mediastinum group[mainly thymic sur-gery],and trachea group)in a tertiary chest hospital in Shanghai from January to December 2022 were retrospec-tively analyzed and compared through DRGs index grouping.Results A total of 1 429 patients in the department of thoracic surgery ICU were analyzed,including 59 HAI cases,with a HAI rate of 4.13％.The incidences of HAI in pulmonary surgery group,esophageal surgery group,mediastinum group and trachea group were 3.74％(30/803),5.84％(25/428),1.27％(2/157)and 4.88％(2/41),respectively.There was no statistically significant differ-ence in the incidences of HAI among different subspecialty groups(P＞0.05).A total of 35 DRGs were involved,with CMI of 2.75,3.41,2.35 and 1.25 in pulmonary surgery group,esophageal surgery group,mediastinum group and trachea group,respectively,and RW ranged from 0.53 to 12.62.In the pulmonary surgery group,inci-dence of HAI in male patients was higher than that in female patients.Higher RW score level was associated with higher incidence of HAI.Differences were all statistically significant(all P 0.05).Among patients in the esophageal surgery group,the age of HAI group was higher than that of the non-HAI group(P＜0.05).Higher RW score level was associated with higher incidence of HAI(P＜0.05).Among patients in the mediastinum sur-gery group,the age of patients in the infected group was higher than that in the non-infected group(P＜0.05).Among the 59 HAI cases,31 were infected with MDROs.Conclusion Focusing on CMI and RW in the DRGs in-dex system,analyzing HAI from the perspectives of disease complexity and overall technical difficulties of medical services can provide reference for the precise management of HAI in the new era.

Objective To observe the value of apparent diffusion coefficient(ADC)for evaluating short-term efficacy of TACE for treating colorectal cancer liver metastases(CRLM).Methods Data of 60 liver metastases in 28 CRLM patients who underwent TACE were retrospectively analyzed.Based on MRI after the first TACE,according to the response evaluation criteria of solid tumors,the liver metastases were divided into response group(n=38)and non-response group(n=22).ADC parameters obtained with diffusion weighted imaging(DWI)before and after TACE,including ADC before TACE(ADCpre),after the first TACE(ADCpost1)and after the second TACE(ADCpost2)were compared between groups,while ADC change value(ΔADC)and the percentage of ΔADC were calculated.The maximum diameter of the target foci were measured,and the correlation between ΔADCpost1 and the change of the maximum diameter of target foci were analyzed.Receiver operating characteristic curve was drawn,the area under the curve(AUC)was calculated to observe the efficacy of ΔADCpost1 for evaluating short-term efficacy of TACE for CRLM.Results No significant difference of ADCpre was found between groups(P=0.484).After the first TACE,ADCpost1,ΔADCpost1 and percentage of ΔADCpost1 in response group were all higher than those in non-response group(all P＜0.05).After the second TACE,no significant difference of ADCpost2,ΔADCpost2 nor percentage of ΔADCpost2 was found between groups(all P＞0.05).The maximum diameter change of the target foci after the first TACE was(-0.48±0.93)cm,which was negatively correlated with ΔADCpost1(rs=-0.347,P=0.007).AUC of ΔADCpost1 for evaluating short-term efficacy of TACE for CRLM was 0.717.Conclusion ADC had good efficacy for evaluating short-term efficacy of TACE for treating CRLM.

Objective To observe the regulating effect and mechanism of Yichang Sanjie Granules on intestinal flora and immune function in mice with colon cancer.Methods Sixty mice were randomly divided into six groups,i.e.,the normal group,the model group,the low-,medium-and high-dose groups of Yichang Sanjie Granules,and the overexpression of melanoma absent gene 2(AIM2)plasmid(pcDNA-AIM2)intervention group,with 10 mice in each group.Colorectal cancer model was prepared by oxidized azomethine(AOM)/dextran sulfate sodium(DSS)induction method in all groups except normal group.After drug administration,the survival curves of mice in each group were plotted and the tumor volume was calculated;serum levels of immunoglobulin(Ig)G,IgM,interleukin(IL)-1β and IL-18 were detected by enzyme-linked immunosorbent assay(ELISA);peripheral blood levels of CD3+,CD4+,CD8+ T cells were detected by flow cytometry;the splenic index was determined;Hematoxylin-eosin(HE)staining was used to observe the pathological changes in colon tissues;16S-rDNA intestinal flora sequencing was used to detect the α-diversity of intestinal flora and the structure of intestinal flora communities;and protein immunoblotting(Wetsern Blot)was used to detect the protein expressions of AIM2,apoptosis-associated speckled-like protein containing a CARD(ASC),and cystatinase-1(caspase-1)in colon tissues.Results Compared with the normal group,the survival rate,serum levels of IgG and IgM,peripheral blood levels of CD3+ and CD4+ and CD4+/CD8+ ratio,protein expression levels of colon tissue AIM2,ASC and caspase-1 in the model group were significantly decreased,and the tumor volume,serum levels of IL-1β and IL-18,peripheral blood level of CD8+,and splenic index were significantly increased(all P＜0.05),and the HE staining results showed the characteristic manifestations of colon cancer;compared with the model group,the survival rate,serum levels of IgG and IgM,peripheral blood levels of CD3+ and CD4+ and CD4+/CD8+ ratio,protein expression levels of colon tissue AIM2,ASC and caspase-1 in the low-,medium-and high-dose groups of Yichang Sanjie Granules and the pcDNA-AIM2 group were significantly increased,and the tumor volume,serum levels of IL-1β and IL-18,level of peripheral blood CD8+,and splenic index were significantly decreased(all P＜0.05),and the HE staining results showed the manifestations of colon cancer were improved.Compared with the normal group,the Observed index,Chao1 index,Shannon index,the relative abundance of Bacteroidetes,Proteobacteria,Muribaculaceae,Lachnospiraceae-NK4A136group,and Ruminiclostridium in the model group were significantly decreased,while the relative abundance of Firmicutes,Actinobacteria,Patescibateria,Lactobacillus,Odoribacter,Alistipes,Ruminococcaceae-uncultured and Bacteroides was increased in the model group(P＜0.05);compared with the model group,the Observed index,Chao1 index,Shannon index,the relative abundance of Bacteroidetes,Proteobacteria,Muribaculaceae,Lachnospiraceae-NK4A136group and Ruminiclostridium were significantly increased,and the relative abundance of Firmicutes,Actinobacteria,Patescibateria,Lactobacillus,Odoribacter,Alistipes,Ruminococcaceae-uncultured and Bacteroides was decreased in the low-,medium-and high-dose groups of Yichang Sanjie Granules and the pcDNA-AIM2 group(all P＜0.05).Conclusion Yichang Sanjie Granules can increase autoimmunity and improve intestinal flora structure in mice with colon cancer,and its mechanism is related to the activation of AIM2 inflammatory vesicles.