The pathological changes of myocardial infarction （MI） are mainly characterized by progressive myocardial ischemic necrosis， decline in cardiac diastolic function， thinning of the ventricular wall， and enlargement of the ventricles. The clinical manifestations include myocardial ischemia， heart failure， arrhythmia， shock， and even sudden cardiac death， rendering MI one of the most perilous cardiovascular diseases. Currently， the clinical treatment for MI primarily involves interventional procedures and drug therapy. However， due to their significant side effects and high complication rates associated with these treatments， they fail to ensure a satisfactory quality of life and long-term prognosis for patients. On the other hand， traditional Chinese medicine has demonstrated remarkable potential in improving patient prognosis while reducing side effects. Research has elucidated that various signaling pathways such as nuclear transcription factor-κB （NF-κB）， adenosine 5̒-monophosphate-activated protein kinase （AMPK）， transforming growth factor-β （TGF-β）/Smads， mitogen-activated protein kinase （MAPK）， Wnt/β-catenin （β-catenin）， and phosphatidylinositol 3-kinase （PI3K）/protein kinase B（Akt） play crucial roles in regulating the occurrence and development of MI. Effectively modulating these signaling pathways through its therapeutic interventions， traditional Chinese medicine can enhance MI management by inhibiting apoptosis， providing anti-inflammatory properties， alleviating oxidative stress levels， and resisting myocardial ischemia. Due to its notable efficacy and favorable safety， it has become an area of focus in clinical practice.

OBJECTIVE: To investigate the effect of relaxing needling at the contracted sites of meridian-muscle regions in the patients with post-stroke shoulder-hand syndrome (SHS) at acute stage. METHODS: Eighty patients with post-stroke SHS at acute stage were randomized into an observation group (40 cases, 1 case dropped out) and a control group (40 cases, 1 case was eliminated). In the control group, the routine medication, basic rehabilitation training, and hyperbaric oxygen therapy were administered. In the observation group, besides the treatment as the control group, relaxing needling was delivered at the contracted sites of meridian-muscle regions. These contracted sites were distributed along three yin meridians of hand and three yang meridians of hand on the affected upper limbs. The intervention was given once daily, 5 times a week and for 4 weeks. Before and after treatment, the scores of visual analogue scale (VAS) for pain, edema degree, modified Barthel index (MBI), and Fugl-Meyer assessment (FMA) for motor function, and the integrated electromyography (iEMG) of surface electromyogram (sEMG) were observed in the two groups. The curative effect was evaluated after treatment and in follow-up of 2 months after treatment in the two groups. RESULTS: After treatment, VAS scores and the scores of edema degree were reduced when compared with those before treatment in the two groups (P<0.05), and the scores in the observation group were lower than those in the control group (P<0.05). MBI and FMA scores increased after treatment compared with those before treatment in the two groups (P<0.05), and the scores in the observation group were higher than those in the control group (P<0.05) after treatment. The iEMG values of the biceps brachii, triceps brachii, and wrist extensors were elevated after treatment in comparison with those before treatment (P<0.05) in the two groups, and the values in the observation group were larger than those in the control group after treatment (P<0.05). The total clinical effective rate in the observation group was 92.3% (36/39), which was better than that of the control group (74.4%, 29/39, P<0.05) after treatment; and that of the observation group was 97.4% (38/39), which was better than 82.1% (32/39) in the control group (P<0.05) in follow-up. CONCLUSION Relaxing needling at the contracted sites of meridian-muscle regions in treatment of post-stroke SHS at acute stage can attenuate the symptoms such as upper limb pain, swelling and spasm, improve motor function and the activity of daily living of patients.
Humans ; Male ; Female ; Middle Aged ; Acupuncture Therapy ; Aged ; Meridians ; Stroke/complications* ; Reflex Sympathetic Dystrophy/etiology* ; Adult ; Acupuncture Points

OBJECTIVE To investigate the ameliorative effects and potential mechanism of total secondary ginsenosides （TSG） on hypertrophic changes of primary cardiomyocytes stimulated by angiotensin Ⅱ （Ang Ⅱ）. METHODS Primary cardiomyocytes were isolated from the hearts of neonatal SD rats and divided into the following groups： control group， AngⅡ group （2 µmol/L）， TSG group （7.5 µg/mL）， PFK-015 group [6-phosphofructo-2-kinase/fructose-2， 6-bisphosphatase 3 （PFKFB3） inhibitor， 10 nmol/L]， and TSG+PFK-015 group （TSG 7.5 µg/mL+PFK-015 10 nmol/L）. The surface area， protein synthesis， energy metabolism-related indicators [free fatty acid （FFA）， coenzyme A （CoA）， acetyl coenzyme A （acetyl-CoA）]， and the expressions of glycolysis-related factors [hypoxia-inducible factor 1α （HIF-1α）， glucose transporter protein 4 （GLUT-4）， lactate dehydrogenase A （LDHA）， pyruvate dehydrogenase kinase 1 （PDK1） and PFKFB3] in primary cardiomyocytes of each group were measured. RESULTS Compared with the control group， the surface area of primary cardiomyocytes and protein synthesis were significantly increased， the content of FFA， protein and mRNA expressions of HIF-1α， LDHA， PDK1 and PFKFB3 were significantly increased or up-regulated in the AngⅡ group， while the contents of CoA and acetyl-CoA， the protein and mRNA expressions of GLUT-4 were significantly decreased or down-regulated （P＜0.05）. Compared with the AngⅡ group， both TSG group and PFK-015 group showed significant improvements in these indexes， with the TSG+PFK-015 group generally demonstrating superior effects compared to either treatment alone （P＜0.05）. CONCLUSIONS TSG can reduce the surface area of AngⅡ-induced primary cardiomyocytes， decrease protein synthesis， and inhibit their hypertrophic changes. These effects may be related to improving energy metabolism and the inhibition of glycolysis activity.

OBJECTIVES: To evaluate the short-term clinical efficacy of transcatheter edge-to-edge repair (TEER) in patients with moderate to severe mitral regurgitation. METHODS: Clinical data of patients with moderate to severe mitral regurgitation who underwent TEER in the Department of Cardiology, the First Affiliated Hospital of Xi'an Jiaotong University from April 2021 to May 2024, were retrospectively analyzed, including preoperative baseline clinical and echocardiography data, intraoperative data and 6-month postoperative follow-up data. RESULTS: A total of 67 patients' (47 males and 20 females) data were included, of whom 62 completed 6-month follow-up. The immediately postoperative success rate was 88.1% (59/67), and 83.9% (52/62) patients exhibited mitral regurgitation ≤2+ at 6 months postoperatively, showing significant improvement compared with preoperative (P<0.05). The proportion of patients with mitral regurgitation ≤2+ at 6 months was significantly higher in the degenerative mitral regurgitation (DMR) group than that in the functional mitral regurgitation (FMR) group (P<0.05). The mean mitral valve gradient (MVG) in DMR group was increased from (3.1±1.2) mmHg (1 mmHg=0.133 kPa) to (3.7±1.2) mmHg 6 months after operation (P<0.05), while there was no significant change in FMR group (P>0.05). Compared with those before operation, the N-terminal pro-B-type natriuretic peptide levels in both FMR and DMR groups were significantly lower at 6 months postoperatively (all P<0.05), and the left atrial volume index and left atrial anteroposterior diameter were also significantly lower (all P<0.05). The left ventricular end-diastolic diameter and left ventricular end-systolic diameter were significantly reduced 6 months after operation in the FMR group (all P<0.05), but no significant changes were observed in the DMR group (all P>0.05). The ejection fraction was not significantly changed before and after operation in both groups (all P>0.05). The mitral regurgitation, tricuspid regurgitant, and pulmonary artery pressure were significantly reduced in both groups at 6 months postoperatively (all P<0.05). CONCLUSIONS TEER is effective for moderate to severe mitral regurgitation. The improve-ments in left ventricular remodeling are more pronounced in patients with FMR while the degree of mitral regurgitation is more significant in DMR patients. However, MVG elevation is more common during the follow-up.
Humans ; Mitral Valve Insufficiency/surgery* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Aged ; Treatment Outcome ; Mitral Valve/surgery* ; Cardiac Catheterization/methods* ; Heart Valve Prosthesis Implantation/methods* ; Adult ; Follow-Up Studies

ObjectiveTo evaluate the clinical effectiveness and safety of Modified Zhigancao Granules （炙甘草汤加味颗粒） for preventing the early recurrence following radiofrequency ablation in patients with atrial fibrillation （AF） of qi-yin deficiency syndrome. MethodsA multi-center， randomized， double-blind， placebo-controlled trial was designed. A total of 116 patients with atrial fibrillation of qi-yin deficiency syndrome who underwent radiofrequency ablation for the first time were enrolled from 3 centers， and they were randomly divided into a treatment group （59 cases） and a control group （57 cases）. Both groups received basic western medicine treatment after surgery. In addition， the treatment group was given oral Modified Zhigancao Granules， while the control group was given oral placebo granules. The dosage for both groups was 20 g each time， twice a day， with continuous treatment for 12 weeks. The recurrence of atrial fibrillation in both groups was recorded at 24 hours， 4 weeks， 8 weeks， and 12 weeks after surgery. The serum levels of B-type natriuretic peptide （BNP）， interleukin-6 （IL-6）， high-sensitivity C-reactive protein （hs-CRP）， and tumor necrosis factor-α （TNF-α） were detected before treatment and 12 weeks after treatment in both groups. The scores of Atrial Fibrillation Effect on QualiTy-of-life （AFEQT） Questionnaire （including scores of the daily life dimension， symptom dimension， treatment worry dimension， treatment satisfaction dimension， and total score） and traditional Chinese medicine （TCM） syndrome scores were compared before treatment and at 4 weeks， 8 weeks， and 12 weeks between groups. Safety indicators such as blood routine， urine routine， liver function， and renal function were monitored before and after treatment. ResultsNine of the treatment group and seven of the control group dropped out. Finally， 50 patients in each group were included in the statistical analysis. At 24 hours， 4 weeks， 8 weeks， and 12 weeks after surgery， the recurrence rates of AF in the treatment group were 2.0% （1/50）， 2.0% （1/50）， 4.0% （2/50）， and 10.0% （5/50）， respectively； while those in the control group were 2.0% （1/50）， 26.0% （13/50）， 28.0% （14/50）， and 34.0% （17/50）， respectively. Compared with the control group at the same time points， the early recurrence rates of AF in the treatment group were significantly lower at 4 weeks， 8 weeks， and 12 weeks after surgery （P＜0.01）. Compared with the baseline within group， BNP， hs-CRP， IL-6， and TNF-α in the treatment group all decreased after 12 weeks of treatment （P＜0.05）； the difference in hs-CRP levels （before vs. after treatment） in the treatment group was higher than that in the control group （P＜0.01）. Compared with the baseline within group， both groups showed decreases in the total score of AFEQT Questionnaire， scores of the daily life dimension， treatment worry dimension， symptom dimension， and TCM syndrome scores at 4 weeks， 8 weeks， and 12 weeks after treatment. Meanwhile， the score of the treatment satisfaction dimension of AFEQT increased in both groups （P＜0.01）， and the improvements in all the above scores in the treatment group were superior to those in the control group at all time points （P＜0.05 or P＜0.01）. All safety indicators of patients in both groups were within the normal range before treatment and at 12 weeks after treatment， and no adverse reactions or adverse events occurred in either group. ConclusionModified Zhigancao Granules can reduce the early recurrence rate following radiofrequency ablation in AF patients with qi-yin deficiency syndrome， improve clinical symptoms and quality of life， suppress inflammatory response， and show good safety.

Objective : To analyze the current status of anti-PD-1 combined with chemotherapy in advanced gastric cancer. Methods: The clinical data of 120 patients with advanced gastric cancer treated with chemotherapy or anti-PD-1 plus chemotherapy were retrospectively analyzed. The efficacy [measures include objective response rate(ORR), disease control rate(DCR), and progression-free survival(PFS)]and the occurrence of adverse reactions in patients was monitored. Univariate and multivariate Cox were used to analyze the relationship between clinicopathologic data [including age, gender, body mass index(BMI), differentiation degree, and related hematological indexes], specific treatment conditions and PFS, and to analyze the influence of treatment plan and line number on the curative effect. Results : The PFS of chemotherapy plus immunotherapy was significantly better than that of chemotherapy alone(P<0.05), and the median PFS of the two was 7.17 months(95%CI5.85-8.49) and 5.33 months(95%CI3.96-5.70), respectively. In the combination group, the overall ORR was 27.5% and DCR was 94.8%. In the chemotherapy group alone, the overall ORR was 9.7% and DCR was 69.4%.In the chemotherapy plus anti-PD-1 group, a high prognostic nutritional index(PNI) level also provided superior PFS in patients with a 47% reduction in the risk of progression versus a low PNI level [HR0.53(95%CI0.30-0.96);P<0.05]. The median PFS was 7.47 months(95%CI5.83-9.11) with a high PNI level versus 6.00 months(95%CI4.45-7.55) with a low PNI level. The overall incidence of adverse reactions of chemotherapy combined with anti-PD-1 was slightly higher than that of chemotherapy alone, and the incidence of adverse reactions of grade 3-4 was similar, within a controllable range, and could be improved after clinical treatment. Conclusion The efficacy of anti-PD-1 combined with chemotherapy in patients with advanced gastric cancer is better than that of chemotherapy, and the adverse reactions are controllable. In the chemotherapy plus anti-PD-1 group, patients with high PNI levels achieved a higher PFS.

Objective:To analyze the risk factors affecting regional lymph node metastasis in salivary gland mucoepidermoid carcinoma (MEC) and to establish a nomogram model for individually predicting lymph node metastasis in salivary gland MEC.Methods:The clinical data of 2 152 patients with salivary gland MEC from 1975 to 2020 were collected from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. The collected data were divided into training cohort (1 506 cases) and validation cohort (646 cases) according to the ratio of 7∶3. Single-factor regression and multi-factor logistic regression were used to screen factors related to local lymph node metastasis in salivary gland MEC, with constructing of a nomogram. Calibration curve, receiver operating characteristic (ROC) curve, area under the ROC curve (AUC) and decision curve analysis were used to evaluate model performance in the validation cohort and the total cohort. Statistical tests were performed using SPSS (26.0) and R (4.3.0) software.Results:Multivariate logistic regression results showed that M stage [ OR(95% CI):12.360(3.295-46.365), P=0.014], pathological grade Ⅱ、Ⅲ、Ⅳ[ OR(95% CI): 1.956(1.329-2.879), 9.654(6.309-14.772), 9.298(6.072-14.238), P<0.001], T staging T2, T3, T4[ OR(95% CI): 1.706(0.932-3.124), 3.021(1.790-5.096), 3.311(1.925-5.695), P<0.001], and gender [ OR(95% CI):0.759(0.593-0.972), P=0.029] were independent factors affecting local lymph node metastasis in salivary gland MEC. Through verification in the validation cohort and the total cohort, the AUC values were greater than 0.8, and the calibration curve was close to the perfect reference line, proving that the constructed nomogram model had good specificity and sensitivity for predicting local lymph node metastasis in salivary gland MEC. Conclusion:M stage, pathological grade, T stage, and gender are risk factors for predicting regional lymph node metastasis and the established-nomogram has good predictive performance for local lymph node metastasis in salivary gland MEC.

ObjectiveTo evaluate the effect and safety of Jiuxin Pill （救心丸） on exercise tolerance and quality of life in patients with stable angina pectoris （SAP）. MethodsA randomised， double-blind， placebo-controlled， multicentre study design was used to enroll 170 patients of SAP from nine centres， which were divided into 85 patients each in the trial group and control group with 1∶1 ratio. Both groups maintained the original western medicine treatment plan， and added Jiuxin Pill or placebo respectively， 2 pills （0.05 g） each time twicely for 28 days. The main outcomes were total exercise time （TED） in the exercise treadmill test and Seattle Angina Questionnaire （SAQ） scores including physical limitation （PL）， angina stability （AS）， angina frequency （AF）， treatment satisfaction （TS）， and disease perception （DP）. The secondary outcomes were exercise treadmill test indicators including heart rate recovery in 1 min （HRR1）， metabolic equivalents （METs）， maximum magnitude of ST-segment depression， and the Borg rating of perceived exertion scale， the average number of angina attacks per week， withdrawal and reduction rate of nitroglycerin， traditional Chinese medicine syndrome scores， incidence of major adverse cardiovascular events. Safety indicators were evaluated and the occurrence of adverse events during the trial was recorded. Data was collected before treatment， day 28±2 in treatment period， and follow-up at day 56 which is 28±2 days after treatment period finished. ResultsEighty-four and eighty-five patients respectively from trial group and control group were included to the full analysis set （FAS） and safety analysis set （SS）. Compared with the group before treatment and with the control group after treatment， the trial group had higher TED， HRR1， and METs， and lower maximum magnitude of ST-segment depression and Borg rating of perceived exertion scores after treatment （P＜0.01）. Compared with the group before treatment and with the control group after treatment and at follow-up， the total SAQ score and scores of AS， AF， TS and DP of the trial group after treatment and at follow-up elevated， while the average number of angina attacks per week and traditional Chinese medicine syndrome scores reduced （P＜0.01）. There was no statistically significant difference in the withdrawal and reduction rate of nitroglycerin between groups （P＞0.05）. Major adverse cardiovascular events occurred in 1 case （1/84， 1.19%） in the trial group and 1 case （1/85， 1.18%） in the control group， and the difference between groups was not statistically significant （P＞0.05）. A total of 3 cases of adverse events occurred in the trial group （3/84， 3.57%）， and a total of 6 cases of adverse events occurred in the control group （6/85， 7.06%）， and there was no statistically significant difference in the incidence of adverse events between groups （P＞0.05）. ConclusionIn the treatment of SAP， Jiuxin Pill combined with conventional western medicine can further enhance exercise tolerance， improve quality of life， and demonstrate great safety.

Objective This study aims to examine the potential mechanism of Shenfu Yixin Granules on heart failure(HF)based on network pharmacology,molecular docking,and experimental verification.Methods(1)The active components of herbs in Shenfu Yixin Granules were screened and retrieved through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).PubChem database and Swiss Target Prediction platform were used to predict targets.GeneCards and OMIM databases were used to screen HF-related targets.The intersection of active ingredient targets of Shenfu Yixin Granules and HF-related targets was performed by using Venny 2.1.0 platform to obtain common targets,which were the potential targets for anti-HF effect of Shenfu Yixin Granules.The potential targets were imported into the STRING database to construct a protein-protein interaction(PPI)network and screen the core targets of Shenfu Yixin Granules for the treatment of HF.GO functional and KEGG pathway enrichment analysis of potential targets were carried out by using DAVID database.AutoDock Vina software was used for molecular docking validation of key active ingredients and core targets.(2)SD rats were randomly allocated into sham operation group,model group,Shenfu Yixin Granules(5.28 g·kg-1)group,and positive control group(sacubitril-valsartan,20.8 mg·kg-1),with eight rats in each group.A rat model of HF after myocardial infarction was established by ligating the left anterior descending coronary artery.The rats were subsequently administered orally with the corresponding drugs once daily for a period of four weeks.Cardiac function including left ventricular ejection fraction(LVEF)and left ventricular fraction shortening(LVFS)in rats was assessed by echocardiography.Additionally,the histopathological alterations in rat heart tissue were examined using hematoxylin-eosin(HE)staining and Masson staining.The serum levels of brain natriuretic peptide(BNP),artial natriuretic peptide(ANP),and aldosterone(ALD)were determined by enzyme-linked immunosorbent assay(ELISA).Furthermore,real-time quantitative PCR and Western Blot were employed to detect mRNA and protein expressions of CAV1、F2 and MAPK1 in heart tissue.Results(1)A total of 210 active ingredients and 1 196 targets of Shenfu Yixin Granules,as well as 801 HF-related targets were obtained.Venny 2.1.0 platform was used to acquire 97 potential targets(common targets)of Shenfu Yixin Granules for the treatment of HF.Key active ingredients,such as quercetin,luteolin,arachidonic acid,kaempferol,and tanshinaldehyde were screened by"drugs-active ingredients-disease-targets"network analysis.The core targets including MAPK1、F2、CAV1、EDN1 and GJA1 were identified through PPI network analysis.The potential targets are mainly concentrated in multiple biological processes,namely,the positive regulation of gene expression,cardiac development,and the positive regulation of MAPK cascade,and involve multi key pathways including MAPK signaling pathway,HIF-1 signaling pathway and PI3K/Akt signaling pathway etc.Good binding activities were observed between MAPK1,CAV1,EDN1,F2 and quercetin,luteolin,kaempferol,tanshinaldehyde,as well as MAPK1,F2 and arachidonic acid.(2)Compared with sham operation group,LVEF and LVFS of rats significantly reduced(P＜0.01),heart mass index obviously increased(P＜0.05)in the model group.Myocardial tissue appears obvious pathological damage,and the degree of interstitial fibrosis was serious.The collagen volume fraction of the heart significantly increased(P＜0.01).The levels of serum BNP,ANP and ALD significantly increased(P＜0.01).The mRNA and protein expressions of CAV1、F2 and MAPK1 in heart tissue significantly increased(P＜0.05,P＜0.01).Compared with the model group,LVEF and LVFS of rats obviously increased(P＜0.01),but the decrease in heart mass index was not significant(P＞0.05)in Shenfu Yixin Granules group and positive control group.The pathological damage in myocardial tissues was significantly improved,the degree of interstitial fibrosis was significantly reduced.The collagen volume fraction of the heart significantly decreased(P＜0.01).The levels of serum BNP,ANP and ALD significantly decreased(P＜0.01).The mRNA and protein expressions of CAV1、F2 and MAPK1 in heart tissue significantly decreased(P＜0.05,P＜0.01).Conclusion Shenfu Yixin Granules may improve heart function and myocardial fibrosis in heart failure rats through the interaction between the active ingredients(quercetin,luteolin,arachidonic acid,kaempferol,and tanshinaldehyde)and targets(MAPK1,F2,CAV-1,and EDN1),so as to regulate MAPK signaling pathway and PI3K/Akt signaling pathway.

Objective To comprehensively review the clinical research on the treatment of hyperlipidemia with traditional Chinese Medicine(TCM)through the evidence mapping,and to understand the distribution of evidence in this field. Methods Databases including CNKI,Wangfang,VIP,SinoMed,PubMed,Cochrane Library,and Embase were searched from January 2004 to December 2023 to collect clinical studies,systematic reviews/meta-analyses,guidelines and clinical pathways related to the treatment of hyperlipidemia with TCM. The results were analyzed and displayed in charts and graphs according to the screening criteria,and the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool and the Preferred Reporting Item for Systematic Review and Meta-analysis of Chinese herbal medicine (PRISMA-CHM) were used to evaluate the quality of the systematic review/meta-analysis. Results A total of 1223 studies were included in the analysis according to Population,Intervention,Comparison,Outcome and Study design(PICOS) principles,involving 920 RCTs,249 non-RCTs,49 systematic reviews/meta-analyses,and 5 guidelines/expert consensus. In recent years,the overall number of clinical research publications has shown a downward trend. Hyperlipidemia frequently occurs in middle-aged and elderly people,and age of onset tends to be younger. The sample size of randomized controlled studies is mostly concentrated in 60-300 cases. There are many types of clinical treatment regimens for the treatment of hyperlipidemia with TCM,among which TCM decoction (50.13％) and Chinese patent medicine (38.41％) account for a relatively high proportion,and TCM exercise therapy (0.51％) is the lowest treatment. Jiangzhi Decoction has attracted more attention in trial group of TCM decoction,while Xuezhikang Capsule has attracted more attention in trial group of Chinese patent medicine. In terms of methodological design,199 papers(21.63％) explicitly mentioned the method of generating random sequence,17 papers(1.85％) mentioned allocation concealment,37 papers (4.02％) mentioned blinding. The control group was dominated by the statins,including simvastatin and atorvastatin. The outcome indicators mainly include the total effective rate,TCM syndrome score,blood lipid level,coagulation index,and adverse reactions,while the attention of TCM characteristic efficacy,inflammation,oxidative stress,and vascular endothelial index were low. The methodological and reporting quality of the systematic review/Meta-analysis were generally not high. AMSTAR-2 evaluation was extremely low,and the average PRISMA-CHM score was 15. Conclusion TCM has certain advantages in the treatment of hyperlipidemia,but there is a lack of high-quality evidence-based proof,and more high-quality clinical studies are still needed to further provide evidence supports in the future. It has been suggested that more large-sample and multi-center clinical studies should be carried out in the future. We should formulate systematic reviews/Meta analysis and guidelines/expert consensus according to the guidelines of clinical practice issues,also consult international standards and regulations,enhance normativity and reliability to improve the quality of their evidence.