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.

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.

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.

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 investigate the clinical efficacy of precise hepatectomy for the treatment of recurrent unilateral hepatolithiasis and prognostic factors.Methods:The retrospec-tive case-control study was conducted. The clinicopathological data of 166 patients with recurrent unilateral hepatolithiasis who were treated by precise hepatectomy in the First Affiliated Hospital of Anhui Medical University from January 2015 to January 2021 were collected. There were 51 males and 115 females, aged (58±12)years. Observation indicators: (1)diagnosis and classification; (2) surgical and intraoperative situations; (3) postoperative situations; (4) follow-up; (5) analysis of prognostic factors. Follow-up was conducted using the outpatient examination and telephone inter-view to detect final stone clearance or recurrence and survival of patients up to August 2021. Patients with T-tube were performed T-tube cholangiography or choledochoscopy to evaluate the final stone clearance rate at postoperative week 8. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers or percentages. Univariate and multi-variate analyses were conducted using the Logistic regression model. Results:(1) Diagnosis and classifica-tion: 166 patients were diagnosed as hepatolithiasis by preoperative imaging examination and intraoperative evaluation, including 134 cases with common bile duct stones. Of the 166 patients, 115 cases had stones located in the left lobe of liver and 51 cases had stones located in the right lobe of liver. There were 111 cases with bile pigment stones, 31 cases with cholesterol stones, 24 cases with mixed type of stones. There were 9 cases classified as Tsunoda type Ⅰ, 89 cases as Tsunoda type Ⅱ, 65 cases as Tsunoda type Ⅲ, 3 cases as Tsunoda type Ⅳ. There were 12 cases classified as type Ⅰ, 99 cases as type Ⅱ, 47 cases as type Ⅲ, 8 cases as type Ⅳ according to Japanese classification in 2001. All the 166 patients were classified as type Ⅰ based on Chinese classification. According to the classification of author team, 166 patients were classified as type Ⅱ. (2) Surgical and intra-operative situations: 119 of 166 patients had liver lobe or segment atrophy. All the 166 patients underwent precise hepatectomy combined with different methods of drainage, of which 28 cases underwent left hemihepatectomy, 11 cases underwent right hemihepatectomy, 1 case underwent liver resection of segment Ⅰ, 5 cases underwent liver resection of segment Ⅱ, 5 cases underwent liver resection of segment Ⅲ, 8 cases underwent liver resection of segment Ⅳ (left medial lobe), 3 cases underwent liver resection of segment Ⅴ, 2 cases underwent liver resection of segment Ⅵ, 2 cases underwent liver resection of segment Ⅷ, 68 cases underwent liver resection of segment Ⅱ and Ⅲ (left lateral lobe), 3 cases underwent liver resection of segment Ⅴ and Ⅵ, 6 cases underwent liver resection of segment Ⅴ and Ⅷ (right anterior lobe), 21 cases underwent liver resection of segment Ⅵ and Ⅶ (right posterior lobe), 1 case underwent liver resection of segment Ⅱ, Ⅲ and Ⅳa, 1 case underwent liver resection of segment Ⅴ, Ⅵ and Ⅶ, 1 case underwent liver resection of segment Ⅰ, Ⅱ, Ⅲ and Ⅳ. For biliary drainage methods of 166 patients, 120 patients received T-tube external drainage, 23 cases received choledochojejunostomy, 23 cases received choledochojejunostomy combined with T-tube external drainage. The original cholangiojejunal anastomotic stenosis was found and reconstructed in 10 patients. The operation time was (258±87)minutes and intraopera-tive blood transfusion rate was 16.87%(28/166) of 166 patients. All the 166 patients underwent fiber choledochoscopy, showing 77 cases with normal function of Oddi sphincter, 38 cases with disorder, 40 cases with dysfunction. There were 11 patients undergoing choledochojejunostomy who were not evaluate the function of Oddi sphincter. There were 21.69%(36/166)of patients with intra-hepatic biliary stricture. One hundred and forty-nine of 166 patients were conducted bile culture, showing the positive rate as 75.17%(112/149). There were 22 cases cultured multiple kinds of bacteria. The most common bacterium was Escherichia coli (43 cases), followed by Pseudomonas aeruginosa (12 cases), Klebsiella pneumoniae (9 cases), Klebsiella oxytoca (7 cases), Enterococcus faecium (7 cases). (3) Postoperative situations. The postoperative complication rate of 166 patients was 16.87%(28/166). In the 8 patients with serious complications of Clavien-Dindo grade Ⅲ, 6 cases were performed thoracocentesis or abdominocentesis for effusion, 1 case was stopped bleeding under gastroscopy for stress ulcerbleeding, 1 case was performed surgery for adhesive intestinal obstruction. Two patients with septic shock of Clavien-Dindo grade Ⅳ were converted to intensive care unit for treatment and discharged after recovery. There were 13 patients with biliary leakage, 10 patients with pulmonary infection, 6 cases with incision infection, which were improved after conservative treatments. There was no perioperative death. The instant stone clearance rate of 166 patients was 81.93%(136/166). The duration of postoperative hospital stay of 166 patients was (11±6)days. (4) Follow-up: 166 patients were followed up for (37±17)months. The final stone clearance rate and stone recurrence rate of 166 patients were 94.58%(157/166) and 16.87%(28/166), respectively. According to Terblanche classification of prognosis, there were 91, 36, 25, 14 cases of grade Ⅰ, Ⅱ, Ⅲ, Ⅳ in 166 patients, respectively. Five of the 166 patients underwent intrahepatic secondary malignancy in which 4 cases died. (5) Analysis of prognostic factors: results of univariate analysis showed that biliary culture, the number of previous surgeries, immediate stone clearance, final stone clearance were related factors affecting the prognosis of precise hepatectomy in patients with recurrent unilateral hepatolithiasis ( odds ratio=2.29, 7.48, 2.69, 4.52, 95% confidence interval as 1.09?4.85, 2.80?19.93, 1.16?6.25, 1.15?17.77, P<0.05). Results of multivariate analysis showed that the number of previous surgeries ≥3 was an independent risk factor affecting the prognosis of precise hepatectomy in patients with recurrent unilateral hepato-lithiasis ( odds ratio=6.05, 95% confidence interval as 2.20?16.62, P<0.05). Conclusions:Precise hepatectomy is safe and effective for the treatment of patients with recurrent unilateral hepato-lithiasis. The number of previous surgeries ≥3 is an independent risk factor affecting the prognosis of precise hepatectomy in patients with recurren t unilateral hepatolithiasis.

Objective:To evaluate the effect of preoperative oral carbohydrate on gastric emptying in the patients undergoing laparoscopic cholecystectomy.Methods:One hundred patients of both sexes, aged 18-64 yr, with body mass index of 18-30 kg/m 2, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, were divided into 2 groups ( n=50 each) using the random number table method: control group (group C) and preoperative oral carbohydrate group (group P). Patients underwent solid food fasting after 20: 00 on the night before surgery in both groups and drinking fasting after 21: 30 on the night before surgery in group C. Group P received 800 ml of 12.5% oral carbohydrate at 21: 30 on the night before surgery and 400 ml of oral similar carbohydrate from 5: 00 to 5: 30 in the morning before surgery.All the patients underwent ultrasound examination of the gastric sinus at 7: 30 on the operation day (2 h after oral carbohydrate, T 1) to determine the nature of gastric contents according to the qualitative analysis of images, and Perlas grade was performed, and the cross-sectional area (CSA) of the gastric sinus in a semi-sitting position and right lateral decubitus position was calculated, and gastric volume (GV) and gastric volume to weight ratio (GV/W) were calculated.For solids in the stomach or GV > 1.5 ml/kg was defined as a full stomach.Patients assessed as a full stomach at T 1 underwent antrum ultrasonography again before induction of anesthesia (at 3 h after oral carbohydrate, T 2). The occurrence of satiety at T 1 and T 2 in each group was recorded.The patient′s hunger score, thirst score, and satisfaction score during fasting were recorded at T 2.The reflux aspiration, occurrence of nausea and vomiting at 24 h after operation, postoperative time to first flatus and postoperative total length of hospital stay were recorded. Results:Compared with group C, the CSA in a semi-sitting position, CSA, GV and GV/W ratio in a right lateral decubitus position, incidence of satiety, and Perlas grade were significantly increased at T 1 ( P<0.05), no significant change was found in the incidence of satiety at T 2 ( P>0.05), preoperative hunger and thirst scores were significantly decreased, satisfaction scores were increased, the incidence of nausea and vomiting was decreased at 24 h after surgery, and the postoperative time to first flatus was shortened ( P<0.05), and no significant change in the postoperative total length of hospital stay was found in group P ( P>0.05). Conclusions:Oral carbohydrates before laparoscopic cholecystectomy may result in delayed gastric emptying in the patients with cholelithiasis, and the time window for oral carbohydrates can be appropriately shifted forward (3 h before surgery).