AIM: Previous studies have suggested that big stick design (BSD) method can only be used in clinical trials of two treatments with equal proportion, which has good statistical performance and has become the recommended choice of randomized methods. This study expands BSD method, so that it can be applied to three groups, and provides more randomized methods for clinical trials. METHODS: On the basis of BSD method used in two treatments with equal proportion, the derivation conditional allocation probability of BSD method used in three treatments with equal proportion was carried out. BSD method was compared with simple randomization (SR) method, permuted block design (PBD) method and block urn design (BUD) method by Monte-Carlo simulation in balance and randomness. RESULTS: In terms of balance, PBD method was the best, followed by BUD method, BSD method, and SR method was the worst. In terms of randomness, SR method was the best, followed by BSD method, BUD method and PBD method. The comprehensive performance showed that BSD method was better than BUD method, PBD method and SR method. CONCLUSION: The expanded BSD method used in three treatments with equal proportion has good comprehensive performance, and it can be the recommended randomization method for clinical trials of three treatments with equal proportion.

OBJECTIVE To investigate the effects of nasal administration of non-mitogenic acid fibroblast growth factor(NMFGF1) loaded nanoparticles(NMFGF1-NPs) on the improvement of cognitive function in vascular dementia(VD) mice and its mechanism. METHODS Nanoparticles containing NMFGF1(NMFGF1-NPs) were prepared by water-in-water emulsion technique and characterized. The mice were divided into sham group, VD model group, blank-NPs group, NMFGF1 solution group and NMFGF1-NPs group after repeated cerebral ischemia-reperfusion to establish VD test model, and then given the corresponding form of drug intervention by nasal cavity. After drug intervention, Morris water maze was used to evaluate the learning and memory function of the animals in each group from the perspective of behavior. Meanwhile, the morphology, arrangement and apoptosis index(AI) of hippocampal neurons in each group were evaluated by pathological methods such as HE staining, FJB staining and Tunel apoptosis staining. In addition, ELISA and Western blotting were used to investigate the molecular mechanism of NMFGF1-NPs improving VD by nasal administration. RESULTS The morphology of NMFGF1-NPs was round. The encapsulation rate of NMFGF1-NPs respectively was (87.76±5.89)%. Morris water maze results showed that the behavioral indexes of mice in VD model group were significantly different from those in sham operation group(P<0.01). At the same time, the pathological results showed that the neurons in the CA1 region of the hippocampus in the VD model group were disordered, the cells morphology and structure were missing, and the AI was significantly increased compared with that in the sham operation group(P<0.01). Meanwhile, compared with the VD model group, the NMFGF1-NPs treatment group showed significant improvement in various behavioral indexes, and the hippocampal neuron cells were intact and orderly, and the AI index was significantly decreased(P<0.01). ELISA and Western blotting analysis showed that compared with that of VD model group and other intervention groups, the content of MDA in the brain of NMFGF1-NPs treatment group was significantly decreased. While the content of SOD, NO and the expressions of Nrf2, SOD-1 and GSTO1/2 was significantly increased (P<0.01). CONCLUSION Nasal administration of NMFGF1-NPs can play the role of antioxidant stress damage by activating Nrf2/ARE signal pathway, and ultimately improve the learning and cognitive function of VD mice.

Objective:To explore the teaching effect of individualized teaching based on problem-based learning (PBL) that applied in gynecology practice teaching under the background of conflicts between postgraduate examination preparation and clinical internship for medical undergraduates.Methods:A total of 157 medical students of the five-year program who started gynecology internship and meanwhile prepared for the postgraduate entrance examination in 2018 were enrolled in the study and divided into two groups randomly. One group received traditional teaching (control group), and the other group received individualized teaching mode based on PBL (observation group). After the internship, the two groups of students were assessed for their theoretical and clinical skills, and the students' evaluation of the teaching effect was acquired through a questionnaire survey. SPSS 22.0 was used to perform chi-square test.Results:The students in observation group had statistically significant higher scores in theory and skill tests than those in the control group ( P<0.001). The evaluation of boosting their enthusiasm for internship, advancing self-learning ability, conducing to improving learning methods in the future, and enhancing clinical skills and thinking ability in the observation group was significantly better than that in the control group ( P<0.05). Conclusion:The individualized teaching model based on PBL could efficiently alleviate the conflicts between internship and postgraduate entrance examination preparation and improve the effect of gynecology practice teaching.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Animals ; Antiviral Agents ; pharmacology ; therapeutic use ; Betacoronavirus ; drug effects ; physiology ; Binding Sites ; drug effects ; Cell Line ; Coronavirus Infections ; drug therapy ; virology ; Crotonates ; pharmacology ; Cytokine Release Syndrome ; drug therapy ; Drug Evaluation, Preclinical ; Gene Knockout Techniques ; Humans ; Influenza A virus ; drug effects ; Leflunomide ; pharmacology ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections ; drug therapy ; Oseltamivir ; therapeutic use ; Oxidoreductases ; antagonists & inhibitors ; metabolism ; Pandemics ; Pneumonia, Viral ; drug therapy ; virology ; Protein Binding ; drug effects ; Pyrimidines ; biosynthesis ; RNA Viruses ; drug effects ; physiology ; Structure-Activity Relationship ; Toluidines ; pharmacology ; Ubiquinone ; metabolism ; Virus Replication ; drug effects

OBJECTIVEThe research regarding the central mechanism of acupuncture (arrival of ) based on functional magnetic resonance imaging (fMRI) in recent 10 years was analyzed to summarize existing research achievements and experience.

METHODSThe literature regarding fMRI-based research published from January of 2007 through December of 2016 in CNKI and PubMed databases was collected. The research content and methods, including research design, inclusion criteria, acupoint selection and evaluation, were analyzed.

RESULTSTotally 18 articles regarding the central mechanism of acupuncture based on fMRI was included. According to research content, the literature was divided into two categories: research and sensation research. In research, the differences of and not on brain functional activity were compared to summarize the central response pattern of ; in sensation research, the differences of different sensations and intensities of on central response were compared to explore the effects of different sensations and intensities of on brain functional activity. In recent 10 years, the number of research gradually increased, and the type of design was various, mainly RCT and paired design. The majority of participants was healthy people, and single acupoint was the focus of researches, including Zusanli (ST 36), Waiguan (TE 5), Hegu (LI 4), etc. The evaluation of was based on visual analogue scale (VAS). The research contents were mainly the effects of and not and different sensations on brain function activities. The present studies confirmed that and not as well as different sensations had different impacts on brain functional effects, and different acupoints had specific activated brain areas. There was a positive correlation between the degree of and the intensity of the activation of brain regions. Furthermore, tingling sensation was not included to sensations.

CONCLUSIONThe number and quality of fMRI-based research need to be improved; the research content is simple, and research method is in exploratory stage. The results obtained in the literature are the phenomena of in the central level, and it is imperative to summarize the essential link between and the central effect through these phenomena to reveal the mechanism of . The specific impact of for brain function needs more clinical exploration.

Objective To discuss the effect of low-frequency pulsed electromagnetic field (ELF-PEMFs) combined with-whole-body vibration(WBV) on the bone mineral density,bone microstructure and the biological mechanics performance inhindlimb unloading osteoporosis rats.Methods Forty female 4 months aged SD rats were randomly divided into five groups:blank group,control group,ELF-PEMFs group,WBV group,low-frequency pulsed electromagnetic field combined with wholebody-vibration(ELF-PEMFs + WBV) group.The blank group was the normal control which comprise the healthy rats.The controlgroup was the disused osteoporosis model.Except for the blank group,thehind limb unloading rats were kept for six weeks.No intervention were provided to the blank group and the control group,other three groups were treated with physical therapy.The bodyweight of rats in each group was record.Bone mineral density was measured by Dual energy X-ray absorptiometry.The right femurs was analyzed by Micro-CT and the left femur was tested through a biomechanical machine.Results After 8 weeks of continuous treatment,the ELF-PEMFs group,WBV group,ELF-PEMFs+WBV group were significantly increased in weight and bonedensity (PELF-PEMFs=0.015,PWBV=0.016,PELF-PEMFs+WBV=0.007),(tELF-PEMFs=5.956,PELF-PEMFs=0.000;tWBV=6.127,PWBV=0.000;tELF-PEMFs+WBV=4.639,PELF-PVMFs+WBV=0.000).The difference was statistically significant (F=0.091,P=0.018).The ELF-PEMFs +WBV group was significantly higher in bone formation index.The items of BV/TV,Tb.N,Tb.Th and SMI in Micro-CT analysis increased,while Tb.Sp and Conn.D index decreased significantly.Trabecular bone structure of all the three groups was improved,however the ELF PEMFs +WBV group was better than the other two groups (vs.ELF-PEMF group,PBV/TV=0.041,PTb.N=0.026,PTb.Th=0.009,PConn.D=0.030,PTb.Sp=0.045,PSMI=0.032;VS.WBV group,PBv/Tv=0.018,PTb.N=0.004,PTb.Th=0.022,PConn.D=0.042,PTb.Sp=0.039,PSMI=0.049).The maximum load,energy absorption and bone stiffness index in biomechanicalperformance test were improved.The combination treatment group were significantly improved (F=0.167,P=0.038).Conclusion Low-frequencypulsed electromagnetic field combined with whole body vibration therapy can improve bone mineral density,bone microstructureand the biological mechanics performance.They have synergistic effect and the combination therapy is better than single treatment.

The paper is a systematic review on the efficacy of acupuncture manipulation on primary dysmenorrhea. Ten medical literatures database at home and abroad were retrieved, including CNKI, VIP, CBM, WANFANG, MEDLINE, Cochrane, CENTRAL, CINAHL PLUS, EMBASE, AMED and PsycINFO, as well as 6 clinical trial registration platforms. All of randomized controlled trials (RCTs) on primary dysmenorrhea treated with different acupuncture manipulations were collected. The data were extracted by two persons. Finally, RevMa 5.3 software was used for statistical analysis. Totally, 5 148 pieces of literature were retrieved and 8 pieces on RCTs were screened with 644 cases included. According to the results of statistical analysis on the total effective rate and other indicators of pain degree, it was showed that the effects of the manipulation with filiform needle, deep puncture with strong stimulation, and specific reinforcing and reducing needling technique were better than those without manipulation applied or with shallow puncture and weak stimulation and even needling technique in the treatment of primary dysmenorrhea. It is believed initially that acupuncture manipulation contributes to the improvement of the therapeutic effects of primary dysmenorrheal, but much higher quality studies are required for the further confirmation. Protocol registration number:PROSPERO:CRD42016038515.

Objective To explore the expression patterns of immune negative regulator FoxP3+Treg and PD-L1 protein in cervical carcinoma and its precancerous lesions. Methods The expression patterns of FoxP3+Treg and PD-L1 protein in 45 cases of cervical lesions tissues of the cervix and 20 cases of normal cervix tissues by using immunohistochemistry (IHC). Results Compared with the normal cervix,the expressions of FoxP3+Treg (H=43.211,P=0.000) and PD-L1 protein (t=213.00,P=0.001) were significantly increased in cervical lesions. Compared with the low-grade squamous cell carcinoma,the invasiveness of FoxP3+Treg was increased in high-grade squamous cell carcinoma (H=28.307,P=0.000),along with increased expression of PD-L1 protein (t=239.000,P=0.028). The FoxP3+Treg expression was positively correlated with PD-L1 protein expression in abnormally differentiated cells (r=0.364,P=0.003). Conclusion Along with the progression of cervical cancer,the FoxP3+Treg amount increases in the local microenvironment,along with enhanced PD-L1 protein expression in abnormally differentiated cells.
B7-H1 Antigen ; metabolism ; Carcinoma, Squamous Cell ; Female ; Forkhead Transcription Factors ; metabolism ; Humans ; Immunohistochemistry ; T-Lymphocytes, Regulatory ; immunology ; Tumor Microenvironment ; immunology ; Uterine Cervical Neoplasms ; immunology