Effective supervision of the clinical research management department can guarantee and improve the quality of the investigator initiated trials(IIT). The authors analyzed relevant clinical research regulations and literature and summarized the current situation of risk-based IIT project process quality management. On such basis, they determined the risk-based IIT project process quality management method in combination with the previous research of the research group.From 2021 to 2022, this method was used to implement process quality management for 353 IIT projects in Shanghai′s tertiary hospitals. More than 3 000 risk points were identified through centralized supervision, and then on-site supervision was carried out to correct the problems found. As proven by the results, the method could find existing problems in time and define the risk level of the project, and also formulate an individualized risk supervision plan accordingly, so as to effectively ensure the data reliability and scientific results. It is suggested that the clinical research management department implement risk based management for the whole process of IIT projects, increase funding and staffing, and implement hierarchical management for the projects by research types, so as to promote the sustainable development of IITs.

Objective:To assess possible risk factors and their respective levels in the whole process of investigator initiated trial(IIT)projects proposed in the proposal stage, for reference in formulation of risk management plans.Methods:Through literature analysis and research group discussions, the risk factors of IIT projects and risk level assessment criteria were preliminarily identified, and a consultation questionnaire was developed as a result. Delphi method was used to further optimize the risk factors and determine their risk levels. Data obtained from the consulfation were analysied by descriptive.Results:The recovery rates of two rounds of expert consultation were both 100%, and the degree of expert authority was 0.942. The survey finalized 38 risk factors, including extremely high risk, high risk, medium risk, low risk and very low risk factors of 17(44.7%), 15(39.5%), 3(7.9%), 2(5.3%) and 1(2.6%) respectively.Conclusions:This study determined a risk evaluation system of IIT projects in the proposal stage. This system can identify risks of IIT projects at an early stage, facilitating early intervention of problems existing in such projects, and minimize risks to the rights and safety of patients.

Objective: To evaluate the efficacy and safety of different positions external physical vibration lithecbole (EPVL) therapy for ureteral calculi related renal colic. Methods: This study was a prospective multicenter randomized controlled trial. The inclusion criteria was that patients volunteered to participate in the trial and signed informed consent, patients’age ranged from 18-65 years old, ureteral calculi related with renal colic, stone diameter was less than 7 mm, patients were not treated with analgesia, antispasmodic drugs. The exclusion criteria was that combination of severe urinary tract infection, severe hydronephrosis, urinary malformation, severe hypertension, history of cerebrovascular disease, vital organ dysfunction, obesity (BMI>35 kg/m²), history of ureteral calculi exceeded 2 months, abnormal blood coagulation. Patients were randomized into observation group and control group using random number table method. The observation group and the control group were placed on the physical vibration stone arranging machine with head low foot high position and head high foot low position respectively. The inclination angle was 24°. The secondary vibrator vibrated for 6 minutes, then the patient took the prone position and opened the main, the secondary vibrator. The treatment is completed after 6 minutes of vibration. The analgesic effect, stone removal, follow-up effects and adverse reactions in the two groups was compared. We defined the pain relief rate as(VAS score before treatment-VAS score after treatment)/VAS score before treatment×100%. Results: A total of 100 patients were included in the study, 50 in the observation group and 50 in the control group. There were no statistical difference in the age of the two groups [(41.8±11.7)years and (46.6±13.9 years)], gender distribution [37(male)/13(female) and 42(male)/ 8(female)], location of stones (in the observation group, 19 cases in upper ureter, 7 cases in the middle ureter and 24 cases in the lower ureter; in the control group, 12 cases in the upper ureter, 3 cases in the middle ureter, and 35 in the lower ureter), left and right distribution of stones [21(right)/ 29 (left) and 22 (right)/ 28(left)], long diameter of stones [(5.2±0.9)mm and(5.1±1.1)mm], VAS scores before treatment (7.5±1.4 and 7.6±1.5), and readmission rate [22%(11/50)With 18%(9/50)], 1 week stone removal rate [70%(35/50) and 64%(32/50)]. The incidence of adverse reactions was 8%(4/50) in the observation group including 3 cases of nausea, 1 case of vomiting. The incidence of adverse reactions was 4% in the control group (2/50), which 2 cases showed nausea. The number of patients who chose EPVL, ESWL or surgery for the subsequent treatment in observation group was 35 cases, 9 cases, and 6 cases respectively. The number of patients who chose EPVL, ESWL or surgery for the subsequent treatment in the control group was 35 cases, 10 cases and 5 cases respectively. There was no significant difference between the two groups (P>0.05). The VAS score after treatment of the observation group was lower than that of the control group (2.4±1.3 and 3.7±1.5, P<0.01). The total effective rate of the observation group was higher than that of the control group [94%(47/50) and 76%(38/50), P<0.01]. 46 patients underwent urinary ultrasonography to check the degree of hydronephrosis. The reduction rate of hydronephrosis was higher in the observation group than in the control group [54.5%(18/33) and 30.8%(4/13)], but there was no significant difference between the two groups (P=0.146). In the upper ureteral calculi, the VAS score of the observation group was lower than that of the control group (2.4±0.3 and 3.9±0.4, P<0.01). There was no significant difference in the total effective rate between the two groups. In the lower ureteral calculi, the observation group had low VAS score after treatment. In the control group (2.4±0.2 and 3.5±0.2, P<0.01), there was no significant difference in the total effective rate between the two groups; the middle segment stones were less included (10 in total) and were not discussed. Conclusions The external physical vibration lithecbole adopts " head high and low position" has better effect than "head low foot high position" in treatment of ureteral calculi with renal colic, and security is acceptable.

The recent discovery of activator compounds binding to an allosteric site on the NAD

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.