Abstract: Large-scale clinical trial is an important measure of clinical evaluation on drugs. This paper introduces the concept and features of large-scale clinical trial, the possibility and necessity of large-scale clinical trial of traditional Chinese medicine, as well as its administration and quality control, with Myocardial Infarction Secondary Prevention Study in Traditional Chinese Medicine (MISPS-TCM), a National Program Subject, as an example.

Case recruitment of large-scale clinical trials should be strictly checked in quality and quantity for it is the key to clinical trial. This study discusses the main difficulties and countermeasures in the case recruitment of large sample, multi-center clinical trials according to the national research project "Myocardial Infarction Secondary Prevention Study in Traditional Chinese Medicine".

Background Traditional Chinese medicine (TCM), especially herbal medicine, has been widely used in China and now is also being increasingly used in other countries for the treatment of cardiovascular diseases. Although many studies have demonstrated that certain Chinese herbal products are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its safety, effectiveness are necessary.QiShen YiQi Dripping Pills (QSYQDP) is a herbal preparation clinically used in the treatment and prevention of coronary artery disease. Preliminary observations have shown its safety and effectiveness. Methods/Design This randomized, controlled trial will recruit 3600 patients with a history of myocardial infarction. Patients will be randomized into two groups by a Centr-Randomized System. One group receives QSYQDP, the other group receive aspirin. This trial protocol will describe eligibility criteria, detailed information on the treatment definition, blinding, endpoints, statistical methods, sample size determination, data management, legal aspects, and the current status of the trial. Discussion This trial is one of the first randomized, controlled clinical trial to evaluate the efficacy and safety of traditional Chinese herbal medicine in the treatment and secondary prevention of coronary artery disease. The results of this study should help to define the role of TCM in modern medical care, as well as to provide the management strategy for CAD patients in China and other countries.

Neural crest-derived mesenchymal stem cells (MSCs) are known to play an essential function during tooth and skeletal development. PRX1⁺ cells constitute an important MSC subtype that is implicated in osteogenesis. However, their potential function in tooth development and regeneration remains elusive. In the present study, we first assessed the cell fate of PRX1⁺ cells during molar development and periodontal ligament (PDL) formation in mice. Furthermore, single-cell RNA sequencing analysis was performed to study the distribution of PRX1⁺ cells in PDL cells. The behavior of PRX1⁺ cells during PDL reconstruction was investigated using an allogeneic transplanted tooth model. Although PRX1⁺ cells are spatial specific and can differentiate into almost all types of mesenchymal cells in first molars, their distribution in third molars is highly limited. The PDL formation is associated with a high number of PRX1⁺ cells; during transplanted teeth PDL reconstruction, PRX1⁺ cells from the recipient alveolar bone participate in angiogenesis as pericytes. Overall, PRX1⁺ cells are a key subtype of dental MSCs involved in the formation of mouse molar and PDL and participate in angiogenesis as pericytes during PDL reconstruction after tooth transplantation.
Animals ; Cell Differentiation ; Mesenchymal Stem Cells ; Mice ; Molar ; Osteogenesis/physiology* ; Periodontal Ligament

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na⁺/H⁺ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA's cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.
Animals ; Diabetes Mellitus ; Diabetes Mellitus, Type 2/drug therapy* ; Glucose ; Humans ; Mice ; Myocardial Infarction/metabolism* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Ventricular Remodeling

Objective: To investigate the utilization of inpatient health care among the elderlies in Shandong province, and to analyze the factors affecting the inpatient services utilization, so as to provide reference for the elderlies to utilize the inpatient services reasonably. Methods: The survey was conducted in Shandong province in August 2017. Multi-stage stratified cluster random sampling method was used to select 7 070 residents aged 60 and above in 6 counties and districts of Shandong province as the objects of the survey. The survey included the basic family and personal information of the elderlies as well as the utilization of hospitalization services. Chi-square test and rank sum test were used for univariate analysis, and logistic regression was applied for influencing factors. Results: The annual hospitalization rate of the elderlies in Shandong province was 18.1%, and 9.6% of those in need of hospitalization failed to enjoy the service. The annual hospitalization rate of the elderlies aged 80 years and over was 19.9%, and 5.5% of the patients in need had not been hospitalized. Among the inpatient institutions, the proportion of township health centers/community health service centers, county-level(district) medical institutions, prefecture-level medical institutions and provincial-level medical institutions was 29.2%, 29.1%, 37.7% and 1.4%, respectively.Factors influencing the utilization of hospitalization services for the elderlies included age, self-assessment of health, physical examination, chronic diseases, type of medical insurance and income level. Conclusions More attention should be paid to the hospitalization services for the elderlies aged 80 years and over. Effective measures should be taken to guide the elderlies to fully use primary medical resources. The prevention and control of chronic diseases should be strengthened to promote the rational use of inpatient health services among the elderlies. In addition, more attention should be paid to low-income elderlies to meet their hospitalization needs.

Objective: To understand the referral status and the willingness for downward referral among rural elderlies with hospital stay experiences in the past year in Shandong province, and to explore its influencing factors on the willingness for downward referral. Methods: Three prefecture-level cities in Shandong province were sampled by multi-stage stratified random sampling in August 2017. Questionnaire survey was conducted among 910 rural elderlies(over 60 years old)who had been hospitalized in the past year. The study included the basic information, the hospitalization experience, and perception of essential medicines system, ego-resiliency, the referral status and willingness for downward referral. Rank sum test, Chi-square test and t test were used for univariate analysis, and logistic regression was applied for influencing factors. Results: Among 910 rural elderlies who had been hospitalized in the past year, 53(5.8%) were referred to other medical institutions in their recent hospitalization, and 597(65.6%)were willing to be referred downward. The main reason for their reluctance for downward referral was that the medical competency of primary medical institutions was low; and the main reason for willingness for downward referral was being close to home. The results showed that marital status, impression for the national essential medicines system and ego-resiliency were the influencing factors of their willingness to downward referral among rural elderlies who had been hospitalized in the past year(P<0.05). Conclusions The referral rate and willingness for downward referral among the rural elderlies in Shandong province are relatively low. We should further enhance the service capacity of primary medical institutions, strengthen the publicity and implementation of the national essential medicines system, pay attention to help with the elderlies′ negative emotions caused by diseases, and improve their ego-resiliency.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC₅₀ > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.