Objective To evaluate the pharmacokinetics(PK)of tenofovir alafenamide Fumarate tablets(25 mg)in healthy Chinese subjects after single oral administration to provide a basis for bioequivalence evaluation.Methods Using a single-dose,randomized,open-lable,two-period,two-way crossover design under fasting condition,while three-way crossover design under fed condition,42 healthy subjects respectively for fasting and fed study were enrolled,and randomized into two groups to receive a single dose of test product(T)or reference product(R)25 mg.Plasma concentration of tenofovir alafenamide and tenofovir were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS)method.The pharmacokinetic parameters were calculated by WinNonlin software(8.1 version)using non-compartmental model,and bioequivalence evaluation was performed for the two preparations.Relevant safety evaluations were performed during the trial.Results The test product and the reference product under fasting study,the main PK parameters of tenofovir alafenamide were as follows:Cmax were(215.17±94.24)and(199.30±71.11)ng·mL-1;AUC0-t were(135.44±71.60)and(123.91±53.82)h·ng·mL-1;the main PK parameters of tenofovir were as follows:Cmax were(7.30±2.27)and(7.12±1.74)ng·mL-1,AUC0-t of tenofovir were(237.16±47.09)and(230.06±43.41)h·ng·mL-1,respectively.The test product and the reference product under fed study,the main PK parameters of tenofovir were as follows:Cmax were(197.69±82.19)and(197.10±110.54)ng·mL-1;AUC0-t were(197.69±82.19)and(197.10±110.54)h·ng·mL-1;the main PK parameters of tenofovir were as follows:CMax were(2.57±1.37)and(2.58±1.31)ng·mL-1;AUC0-t were(227.08±74.33)and(238.51±128.30)h·ng·mL-1,respectively.The 90％confidence interval for geometric mean ratio of Cmax,AUC0-tof T and R under fed condition were between 80.00％-125.00％,respectively.The incidence of adverse events in fasting and fed tests was 21.43％and 30.95％,respectively,and no serious adverse event was reported.Conclusion The test formulation and reference formulation of tenofovir alafenamide fumarate tablets were equivalent and was safe.

Based on the standards of modern Chinese medicinal materials, literature and records of ancient books, this article reviewed the preliminary processing of Aucklandiae Radix and processing of its decoction pieces. There are some problems in the records of the initial processing of Aucklandiae Radix, such as lack of specific parameters, inconsistent processing sequence, unclear removal methods of fibrous roots and soil, inconsistent cutting specifications, drying methods and temperature. Different processing methods of Aucklandiae Radix decoction pieces can lead to differences in the content of their index components. From the initial processing of the producing area to softening, slicing, and then secondary drying, it may increase production costs and time, and lead to the loss of active components. There are more than 20 kinds of processing methods in ancient books, such as stirfrying, baking, simmering, grinding juice and so on. However, only paper simmering, bran stirfrying and Coptidis Rhizoma processing are commonly used at present, and other processing methods have great exploration space. Referring to the research results of freshcut processing of other Chinese materia medica containing volatile components, it is considered that the key to ensure the quality of Chinese materia medica and decoction pieces is to formulate a standardized process flow of freshcut processing of Aucklandiae Radix.

Anterior subcutaneous internal fixation(INFIX)is one of the current representatives of minimally invasive fix-ation of injuries to the anterior pelvic ring.The nail insertion point of this technique is located at the anterior inferior iliac spinous screw,with an angle of 30° outward and 20° backward.Screw in at an angle,and note that the screw head should be above the deep fascia and maintain a safe distance of 20 to 25 mm from the bone surface.Its improved versions include 3 or 4 nails INFIX with added pubic tubercle screws,unilateral INFIX,short-rod INFIX,and double INFIX.These improvements fur-ther enhance stability.The lateral femoral cutaneous nerve(LFCN)is relatively easy to be damaged during anatomy,so special attention should be paid during the operation.Biomechanical stability has advantages over external fixation,and its application is flexible.It is not limited to pubic ramus fracture,symphyseal separation,etc.It also plays an important role in combined an-terior and posterior ring fixation.It can be combined with posterior sacroiliac screws,iliac lumbar screws,etc.Fixed etc.Good clinical results have also been reported in children,pregnant women,and people with contraindications for subcutaneous con-necting rods.In addition,the current application of robots,reduction frames and other technologies has greatly reduced the dif-ficulty of reduction and improved the quality of closed reduction,making it possible to fix complex pelvic fracture.This tech-nique has high reduction quality and is as effective as traditional steel plates.A common complication is LFCN injury.Careful exposure and adjustment of the position and depth of internal fixation during surgery can effectively avoid this complication.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

Humans ; Consensus ; Hypersensitivity ; Desensitization, Immunologic/adverse effects* ; Immunotherapy/adverse effects* ; Injections, Subcutaneous ; Allergens

With the development of small-molecule immunotherapy drugs, its combination with the programmed cell death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) antibodies would provide a new opportunity for cancer treatment. Therefore, targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity and considered as the next generation of tumor immunotherapy. In the present study, we investigated the anti-tumor role of salvianolic acid B (SAB) by regulating the PD-L1 level in tumors. Changes of total PD-L1 and membrane PD-L1 levels were determined by Western blot, flow cytometry and PD-1/PD-L1 interaction assays. The expression of mRNA level of PD-L1 was detected by real-time PCR. The cytotoxicity of activated peripheral blood mononuclear cell (PBMC) cells toward co-cultured tumor cells was measured by cell impedance assay and crystal violet experiment. Surface plasma resonance technique was used to analyze the direct interaction between SAB and ubiquitin carboxyl-terminal hydrolase 2 (USP2). The antitumor effect of SAB in vivo was examined by C57BL/6 mice bearing MC38 xenograft tumor (all animal experiments were conducted in accordance with the Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences). Western blot and flow cytometry assay showed that SAB can significantly downregulate the abundance of PD-L1 in RKO and PC3 cells in dose- and time-dependent manner. PD-1/PD-L1 binding assay revealed that SAB reduces the binding of tumor cells to recombinant PD-1 protein. Mechanism studies revealed that SAB can bind directly to USP2 protein and inhibit its activity, thus promote the ubiquitin-proteasome pathway degradation of PD-L1 proteins. In addition, Cell impedance and crystal violet staining indicated that SAB enhances the killing activity of co-cultured PBMC cells toward tumor cells. MC38 tumor transplanted mouse experiments revealed that SAB treatment displayed significant suppression in the growth of MC38 tumor xenografts in C57BL/6 mice with an inhibition rate of 63.2% at 20 mg·kg^-1. Our results demonstrate that SAB exerts its anti-tumor activity by direct binding and inhibiting the activity of USP2 and reducing the PD-L1 level. Our study provides an important material basis and scientific basis for the potential application of SAB in tumor immunotherapy drug targeting USP2-PD-L1 axis.

Objective: To evaluate the effectiveness of mucosal flap combined with silicone keel for preventing and treating anterior commissure adhesion in canines and clinical cases. Methods: A prospective experiment was performed from November 2019 to June 2021. Twenty five canines were randomly divided into 5 groups(A, B, C, D, E). Group A, B, C, D received anterior commissure injury by CO₂ laser, then separately treated with free mucosal flap-keel complex,intralaryngeal mucosal flap-keel complex, silicone keels and without treatment, group E didn't injure the vocal cord after intubation. The keel was removed after 2 weeks, the larynx was harvested after 4 weeks. The effectiveness of anterior commissure adhesion prevention was evaluated by manifestation under laryngoscope, standard vocal cord length and standard glottic area. A retrospective analysis was performed on sixteen patients with anterior commissure lesion, who underwent mucosal flap-keel technique in Huashan Hospital of Fudan University from January 2019 to January 2021 (10 cases with free mucosal flap-keel complex and 6 cases with intralaryngeal mucosal flap-keel complex). All the patients underwent evaluation of laryngeal function included manifestation under laryngoscope each month and voice analysis before and 3 month after surgery. SPSS 20.0 software was used for statistical analysis. Results: No surgery accident or complication happened in canines and patients. The standard vocal cord length and standard glottic area after 4 weeks in group B were significantly higher than those in group A, C, D (H_{standard vocal cord length}=31.688, H_{standard glottic area}=16.444, P<0.05). The standard vocal cord length and standard glottic area after 4 weeks in group A were also significantly higher than those in group C, D(H_{standard vocal cord length}=20.936, H_{standard glottic area}=11.786, P<0.05). The standard vocal cord length and standard glottic area after 4 weeks in group A, B, E were not significantly different to that before surgery(t_{A left standard vocal cord length}=2.636, t_{A right standard vocal cord length}=2.582, t_{B left standard vocal cord length}=2.707, t_{B right standard vocal cord length}=2.673, t_{E left standard vocal cord length}=0.370, t_{E right standard vocal cord length}=0.821, t_{A standard glottic area}=2.731, t_{B standard glottic area}=2.753, t_{E standard glottic area}=-0.529, P>0.05). The standard vocal cord length and standard glottic area after 4 weeks in group C, D were significantly lower than those before surgery(t_{C left standard vocal cord length}=16.137, t_{C right standard vocal cord length}=13.984, t_{D left standard vocal cord length}=11.903, t_{D right standard vocal cord length}=14.587, t_{C standard glottic area}=10.280, t_{D standard glottic area}=22.974, P<0.05). During 6-18 months of follow-up in clinical patients, no one developed a glottic web. Three months after surgery, Jitter, Shimmer, noise to harmonic ratio(NHR), the maximum phonation time(MPT)in all patients were significantly different from preoperative(t_{intralaryngeal mucosal flap jitter}=24.885, t_{intralaryngeal mucosal flap shimmer}=22.643, t_{intralaryngeal mucosal flap NHR}=6.202, t_{intralaryngeal mucosal flap MPT}=-9.661, t_{free mucosal flap jitter}=25.459, t_{free mucosal flap shimmer}=18.683, t_{free mucosal flap NHR}=5.705, t_{free mucosal flap MPT}=-20.840, P<0.05). Conclusion: Mucosal flap combined with silicone keel is an effective technique for preventing and treating anterior commissure adhesion. The effect of pedicled intralaryngea lmucosal flap is better.
Animals ; Dogs ; Free Tissue Flaps ; Glottis ; Humans ; Laryngeal Neoplasms/surgery* ; Prospective Studies ; Retrospective Studies ; Vocal Cords/surgery*

More and more studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome has become the regulatory factor of inflammatory response and protective immunity, and the assembly and activation of NLRP3 inflammasomes are closely related to the anti-tumor immunity effect. Depending on the cell type and stimuli, activation of the NLRP3 inflammasome can induce immune cells to become polarized, hyperactive, or pyroptotic, releasing interleukin (IL)-1β and IL-18, which leads to cascade immune or inflammatory responses, and its role in tumor immunity has received extensive attention. Here, we review the mechanisms of the NLRP3 inflammasome enhancing CD8⁺ T cells-mediated anti-tumor immunity by inducing the pyroptosis of tumor cell, the pyroptosis or hyperactive state of dendritic cells (DCs), and the pyroptosis or polarization of the macrophages. Different anti-tumor immune roles of NLRP3 inflammasome activation in tumor cells and immune cells provide new directions for future research and may influence the development of next-generation immunotherapy.

OBJECTIVE To study the effects of Shenfu yixin granule on mitochondrial autophagy of cardiomyocytes in rats with heart failure after acute myocardial infarction. METHODS The model of heart failure after acute myocardial infarction was established by ligaturing the anterior descending branch of the left coronary artery in rats. The model rats were divided into model group，Shenfu yixin granule low-dose and high-dose groups （1.76，8.8 g/kg），Fosinopril sodium tablets group （positive control ，4 mg/kg），sham operation group was set up （only threading without ligation at the same position ），with 8 rats in each group. After 4 weeks of drug intervention ，the hemodynamic indexes of rats in each group were measured by physiological recorder. The pathological changes of myocardial tissue were observed in each group. The level of oxidative stress in cardiomyocytes ， mitochondrial membrane potential ，protein expression of PTEN-induced putative kinase 1（PINK1），E3 ubiquitin ligase Parkin and ubiquitin binding protein P 62 in myocardial tissue of rats in each group were detected. RESULTS Compared with sham operation group ，the pathological injuries such as myocardial fiber morphology disorder and inflammatory cell infiltration were serious. The left ventricular end systolic pressure （LVESP），maximum rate of rise of left ventricular internal pressure （+dp/dtmax）， maximun rate of decrease of left ventricular internal pressure （－dp/dtmax），total antioxidant capacity ，mitochondrial membrane potential，PINK1，Parkin and P 62 protein expression were significantly decreased in model group （P＜0.01）. The left ventricular end diastolic pressure （LVEDP），the level of reactive oxygen species and the activity of reduced nicotinamide adenine dinucleotide phosphate in left ventricular ischemic cardiomyocytes were significantly increased （P＜0.01）. Compared with model group ，the pathological injuries of myocardial tissue in intervention groups were alleviated ，and above indexes were improved in varying degrees（P＜0.01 or P＜0.05）. CONCLUSIONS Shenfu y ixin granule can reduce the level of oxidative stress and alleviate heart failure after acute myocardial infarction ，which may be related to the activation of Parkin-dependent pathway to strengthen mitochondrial autophagy and reduce mitochondrial dysfunction.