ObjectiveTo investigate the influence of empagliflozin combined with donafenib or lenvatinib on the pharmacokinetic parameters of each drug， and to provide a reference for combined medication in clinical practice. MethodsA total of 48 healthy male Sprague-Dawley rats were divided into 8 groups： empagliflozin group 1 and 2， donafenib group， lenvatinib group， donafenib pretreatment+empagliflozin group， lenvatinib pretreatment + empagliflozin group， empagliflozin pretreatment+donafenib group， and empagliflozin pretreatment+lenvatinib group， with 6 rats in each group. The doses of empagliflozin， donafenib， and lenvatinib were 2.5 mg/kg， 40 mg/kg， and 1.2 mg/kg， respectively. The rats in the empagliflozin group， donafenib group， and lenvatinib group were given a blank solvent by gavage for 7 consecutive days， followed by a single dose of empagliflozin， donafenib， or lenvatinib on day 7 after the administration of the blank solvent； the rats in the pretreatment groups were given the pretreatment drug by gavage for 7 consecutive days， followed by a single dose of drug combination on day 7 after administration of the pretreatment drug. Blood samples were collected at different time points， and plasma was separated to measure the concentration of each drug. A validated ultra-performance liquid chromatography-tandem mass spectrometry method was used to measure the plasma concentrations of donafenib， lenvatinib， and empagliflozin， and a non-compartmental model was used to calculate the main pharmacokinetic parameters of each drug （area under the plasma concentration-time curve ［AUC］， time to peak ［T_max］， peak concentration ［C_max］， and half-life time ［t_1/2］）. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. ResultsCompared with the empagliflozin group， the donafenib pretreatment+empagliflozin group had significant increases in the AUC_0-t and AUC_0-∞ of empagliflozin （P=0.011 and 0.008）， while the lenvatinib pretreatment+empagliflozin group had no significant change in the AUC of empagliflozin， with a slightly shorter T_max （P=0.019）. Compared with the donafenib group， the empagliflozin pretreatment+donafenib group had significant increases in the AUC_0-t and AUC_0-∞ of donafenib （P=0.027 and 0.025）， as well as a significant increase in C_max （P=0.015） and significant reductions in CLz/F and Vz/F （P=0.005 and 0.004）； compared with the lenvatinib group， the empagliflozin pretreatment+lenvatinib group had a reduction in the t_1/2 of lenvatinib by approximately 5 hours （P=0.002）， with a trend of reduction in AUC_0-t （P0.05）. ConclusionEmpagliflozin combined with donafenib may alter the pharmacokinetic parameters of both drugs， leading to a significant increase in the exposure levels of both drugs， and efficacy and adverse reactions should be monitored during co-administration. There are no significant changes in the exposure levels of empagliflozin and lenvatinib during co-administration.

Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

ObjectiveTo explore the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) in M1 region combined with dorsolateral prefrontal cortex (DLPFC) on electroencephalogram (EEG) θ frequency band amplitude of patients with neuropathic pain (NP) after spinal cord injury. MethodsFrom June, 2022 to June, 2023, 50 NP patients after SCI in Qingdao University Affiliated Hospital were included and divided into M1 region stimulation group (n = 25) and M1 region combined with DLPFC stimulation group (the combined stimulation group, n = 25). M1 region stimulation group received 10 Hz rTMS in the left M1 region, while the combined stimulation group received same stimulation in left M1 region combined with DLPFC, for three weeks. Before and after intervention, the pain was assessed with Short Form of McGill Pain Questionnaire (SF-MPQ), the depression and anxiety status were evaluated using Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), and the EEG θ frequency band amplitude was recorded to detect the changes of brain electrophysiological activity. ResultsFour cases in M1 region stimulation group, and two cases in the combined stimulation group were dropped. After intervention, the total score of SF-MPQ and the scores of the subscales, the scores of HMMD and HAMA decreased in both groups (|t| > 2.523, P < 0.05). The EEG θ frequency band amplitude significantly reduced in the prefrontal and frontal regions in M1 region stimulation group (|t| > 5.243, P < 0.001), and it also significantly reduced in the prefrontal, frontal regions, central and parietal regions in the combined stimulation group (|t| > 4.630, P < 0.001). All the scores were lower (|t| > 2.270, Z = -1.973, P < 0.05), and the EEG θ frequency band amplitude in the prefrontal, frontal regions, central and parietal regions were lower (P < 0.05) in the combined stimulation group than in M1 region stimulation group. ConclusionHigh frequency rTMS is an effective analgesic method on NP after SCI, which can improve their depression and anxiety symptoms and reduce the EEG θ frequency band amplitude. Compared with M1 region rTMS stimulation, the combination of M1 region and DLPFC rTMS is more effective.

Objective To investigate the effects of basic fibro-blast growth factor(FGF-2)and Panax notoginseng saponins(PNS)alone or combined together on the differentiation of bone marrow mesenchymal stem cells(BMSCs)into cardiomyocytes(CMs)and the mechanism of action of PNS and FGF-2 in the differentiation.Methods BMSCs were isolated from 3-week-old SD rats(20～30 g)by whole bone marrow adherence,and then the purity of BMSCs was identified by flow cytometry.After the purity was qualified,PNS and FGF-2 alone or in combination,or combined with LY294002(phosphatidylinositol 3 kinase inhibitor),were used to induce BMSCs to differentiate.According to the corresponding culture time,the cells were divided into control group,PNS group,FGF-2 group,and PNS+FGF-2 group.The expression levels of Desmin and Cx43 after induction were detected by immunohistochemical assay.Western blotting was used to measure the expression levels of myocardium-specific proteins,related pathway proteins,and apoptosis-related proteins.RT-qPCR was conducted to detect the expression of myocardial transcription factors.Results The expression levels of myocardium-specific proteins and genes were increased in each single induction group(PNS group and FGF-2 group)and combined induction group(PNS+FGF-2 group,P＜0.05),and the highest expression levels were observed in the combined group.PNS and FGF-2 combined with LY294002 decreased the expression levels of myocardium-specific proteins and genes,decreased the phosphorylation of pathway-related protein Akt,decreased the level of Bcl-2,increased the level of Bax,and decreased the ratio of Bcl-2/Bax when compared with the 2 single induction groups(P＜0.05).Conclusion Both PNS and FGF-2 can induce BMSCs to differentiate into CMs after induction,and the combined induction is more effective in the differentiation.The PI3K/Akt signaling pathway is involved in the differentiation process by PNS and FGF-2,and PNS and FGF-2 play a role in reducing apoptosis.

BACKGROUND:Repetitive magnetic stimulation of either S3 nerve root or M1 area can improve the urination function of patients with urinary retention after spinal cord injury,but there are few reports on the repetitive magnetic stimulation of both sites in patients with urinary retention after spinal cord injury. OBJECTIVE:To observe the effect of repetitive magnetic stimulation of both S3 nerve root and M1 area on urinary retention after spinal cord injury. METHODS:Forty patients with urinary retention after spinal cord injury were enrolled and were randomly divided into two groups(n=20 per group):group A(repetitive magnetic stimulation in both S3 nerve root and M1 area)and group B(repetitive magnetic stimulation in the S3 nerve root and sham stimulation in the M1 area).Patients in both groups were given 4-week repetitive magnetic stimulation based on conventional bladder function intervention.The stimulation time and duration of treatment were same in both groups,with a treatment time of 21 minutes daily,5 days per week,for 4 weeks in total.The urination diary and urodynamics were compared between two groups. RESULTS AND CONCLUSION:Before treatment,there were no statistically significant differences in the average daily catheterization times,average daily catheterization volume,average single urinary volume,urinary storage period(maximum bladder volume,bladder pressure),and urinary voiding period(detrusor pressure,residual urine volume)between the two groups(P>0.05).After 4 weeks of treatment,the average daily catheterization times in group A were lower than before treatment(P<0.05),while the average single urination volume in group A was higher than that before treatment(P<0.05);and the average daily catheterization times in group B were lower than before treatment(P<0.05).After 4 weeks of treatment,the average daily catheterization times in group A were lower than those in group B,and the average single urination volume was higher than that in group B(P<0.05).After 4 weeks of treatment,the maximum bladder volume and detrusor pressure during urination were increased in both groups compared with before treatment(P<0.05),while the bladder pressure and residual urine volume at the maximum volume of the two groups were decreased compared with those before treatment(P<0.05).Compared with group B,the maximum bladder volume and detrusor pressure during urination were higher in group A,while the bladder pressure and residual urine volume at maximum volume were lower in group A(P<0.05).To conclude,two treatments can both improve the urination function of patients with urinary retention after spinal cord injury,and repetitive magnetic stimulation of both S3 nerve root and M1 area is superior to repetitive magnetic stimulation of S3 nerve root alone.Repetitive magnetic stimulation of both S3 nerve root and M1 area can effectively improve the urination function of patients with urinary retention after spinal cord injury.

A number of drugs for the treatment of type 2 diabetes mellitus(T2DM)are currently under clinical investigation,including the sodium-dependent glucose transporters 2(SGLT2)inhibitor rongliflozin,the SGLT1/2 inhibitor LIK066,the di-peptidyl peptidase-4(DPP-4)inhibitor DBPR108,the glucagon-likepeptide-1 receptor(GLP-1R)ago-nist CJC-1134-PC,the G-protein-coupled receptor 40(GRP40)agonist SCO-267 and the Glucokinase(GK)agonist PB201.This article briefly reviews the clinical research progress of drugs targeting the above targets in the field of T2DM treatment,in or-der to provide reference for the treatment of T2DM patients.

Objective:To analyze the research hot points and trend of general practice in China.Methods:It was a bibliometric analysis. Research papers presentated on Chinese Society of General Practice from 2014 to 2022 were collected. The distribution and its trend were analysed in terms of titles, submission time, research topics, methods and contents as well as authors′ affilation.Results:A total of 944 research papers were included in the analysis. The results showed a general increasing trend in number of research papers presented on annual conferences from 2014 to 2022 with some fluctuation. The papers covered 28 research dimensions; the highest number of papers was on the development of general practice system, the training and education system for general practitioners, and the construction of information technology (576 papers, 61.0%). The most common topic was on primary health services (230 papers, 24.4%), followed by education and training (225, 23.8%) and chronic disease management (212, 22.5%); while fewer papers were dealing with community-based care (39, 4.1%) and rational medication (7, 0.7%). In terms of the affiliation of the first author, 437 papers (46.3%) were from affiliated hospitals of medical universities/colleges, 223 (23.6%) from community health service institutions, 132 (14.0%) from higher education institutions, 118 (12.5%) from non-affiliated hospitals, and 35 (3.7%) were from administration institutions. In terms of regions, it covered all provinces (municipalities/autonomous regions) (including Hong Kong and Taiwan) with few overseas. Shanghai and Beijing contributed more papers than other regions. In terms of research methodology, most papers used quantitative studies (882, 93.7%), less used qualitative studies (39, 4.1%) or mixed studies (23, 2.4%).Conclusion:The analysis indicates that a wide range of contents are involved in general practice research in China, and more high-quality studies are from medical colleges/universities and their affiliated general hospitals, and most papers use quantitative studies.

BACKGROUND: Early fluid resuscitation is one of the fundamental treatments for acute pancreatitis (AP), but there is no consensus on the optimal fluid rate. This systematic review and meta-analysis aimed to compare the efficacy and safety of aggressive vs. controlled fluid resuscitation (CFR) in AP. METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science databases were searched up to September 30, 2022, for randomized controlled trials (RCTs) comparing aggressive with controlled rates of early fluid resuscitation in AP patients without organ failure on admission. The following keywords were used in the search strategy: "pancreatitis," "fluid therapy,""fluid resuscitation,"and "randomized controlled trial." There was no language restriction. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to assess the certainty of evidence. Trial sequential analysis (TSA) was used to control the risk of random errors and assess the conclusions. RESULTS: A total of five RCTs, involving 481 participants, were included in this study. For primary outcomes, there was no significant difference in the development of severe AP (relative risk [RR]: 1.87, 95% confidence interval [CI] 0.95-3.68; P = 0.07; n = 437; moderate quality of evidence) or hypovolemia (RR: 0.98, 95% CI: 0.32-2.97; P = 0.97; n = 437; moderate quality of evidence) between the aggressive and CFR groups. A significantly higher risk of fluid overload (RR: 3.25, 95% CI: 1.53-6.93; P <0.01; n = 249; low quality of evidence) was observed in the aggressive fluid resuscitation (AFR) group than the controlled group. Additionally, the risk of intensive care unit admission ( P = 0.02) and the length of hospital stay ( P <0.01) as partial secondary outcomes were higher in the AFR group. TSA suggested that more studies were required to draw precise conclusions. CONCLUSION: For AP patients without organ failure on admission, CFR may be superior to AFR with respect to both efficacy and safety outcomes. REGISTRATION PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; CRD 42022363945.
Humans ; Randomized Controlled Trials as Topic ; Fluid Therapy ; Hypovolemia ; Pancreatitis/therapy*

Objective To analyze the target volume margins and positioning errors in the radiotherapy for nasopharyngeal carcinoma(NPC)using the cone-beam computed tomography(CBCT)of Halcyon linear accelerator for providing a reference for the margin from clinical target volume to planning target volume(CTV-to-PTV margin)in the radiotherapy for NPC using Halcyon linear accelerator,hence improving treatment precision and effectiveness.Methods A total of 117 NPC patients who received volumetric modulated arc therapy using Halcyon linear accelerator from May 2020 to June 2022 in Jinshazhou Hospital of Guangzhou University of Chinese Medicine were enrolled.The 3861 CBCT images collected from the patients were matched with the CT images to obtain the correction values of the treatment couch in lateral(Lat),longitudinal(Lng)and vertical(Vrt)directions for positioning error analysis.The CTV-to-PTV margin was obtained by the equation(margin =2.5∑+0.7δ).Results The positioning errors in the radiotherapy for NPC using Halcyon linear accelerator were 0.10(0.00,0.10)cm,0.10(0.00,0.20)cm and 0.20(0.10,0.30)cm in Lat,Lng and Vrt directions,respectively.The CTV-to-PTV margins in Lat,Lng and Vrt directions were 0.12,0.12 and 0.09 cm,respectively.Conclusion Low positioning errors can be achieved for NPC patients undergoing image-guided treatment using Halcyon linear accelerator.

Objective:To evaluate the effects of controlled low central venous pressure (CLCVP) on the cerebral blood flow in the patients undergoing open hepatectomy.Methods:Thirty American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ patients of either sex, aged 18-60 yr, with body mass index of 18-30 kg/m 2, with Child-Pugh classification A and expected operation time of 2-4 h, undergoing elective open hepatectomy, were enrolled.After anesthesia induction, patients were placed at head-up tilt position, nitroglycerin 0.5-1.5 μg·kg -1·min -1 was infused, and furosamide 5-10 mg was intravenously injected when necessary to maintain CVP less than 5 cmH 2O during hepatectomy.After the end of hepatectomy, CLCVP was stopped, the infusion rate was increased to 10 ml·kg -1·h -1 with a crystalline gel ratio of 1∶2 to restore CVP to more than 5 cmH 2O.At 5 min after anesthesia induction (T 0), 5 min after head-up tilt (T 1), 5 and 15 min after CVP reaching the target (T 2, 3) and 5 min after the end of CLCVP (T 4), the blood flow of internal carotid artery was detected by ultrasound, and peak systolic velocity(IBVs), end diastolic velocity (IBVd)and vessel diameter of the internal carotid artery (ID)were measured by doppler ultrasound.Mean velocity [IBVm=(IBVs+ IBVd×2)÷3] and internal carotid artery blood flow [IBF=IBVm×π×(ID/2) 2×HR] were calculated.Heart rate (HR), mean arterial blood pressure (MAP), cardiac output (CO), stroke volume (SV), end-tidal pressure of carbon dioxide (P ETCO 2) and maximum airway pressure (P max) were recorded at each time point. Results:Compared with the baseline at T 0, MAP, CO, SV, IBVm and IBF were significantly decreased at T 2, 3 ( P<0.001), and no significant change was found in HR, P ETCO 2 and P max at T 1-4 ( P>0.05). The results of linear mixed-effects model analysis showed that the regression coefficients for CO, MAP, HR, and SV were 0.600 3, 0.022 88, 0.363 7, and 0.614 8, respectively ( P<0.05 or 0.01). Conclusions:CLCVP can decrease the cerebral blood flow in the patients, which is closely associated with decreased CO, MAP, HR and SV when used for open hepatectomy.