The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective:To explore the effects of the Otago Exercise Program (OEP) in aged patients diagnosed with sarcopenia.Methods:Totally 80 sarcopenic patients admitted to the Department of Geriatric Diseases at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine between January 2022 and January 2023 were selected by convenience sampling. Using a random number table, patients were allocated into control and intervention groups, each containing 40 individuals. The control group underwent routine follow-ups, while the intervention group received a 12-week OEP in addition to the regular follow-up. Measures were taken before and after the intervention for muscle strength (grip strength, 5-times sit-to-stand test time) , muscle mass (skeletal muscle mass index) , physical function (6 m walking speed, Short Physical Performance Battery, SPBB) , and quality of life (Sarcopenia Quality of Life, SarQoL) .Results:Post-intervention, the 5-times sit-to-stand test time was lower in the intervention group compared to the control group ( P<0.05) . Moreover, the 6 m walking speed, SPBB scores, and SarQoL scores were higher in the intervention group ( P<0.05) . However, no significant statistical differences were found between the two groups regarding grip strength and skeletal muscle mass index ( P>0.05) . Conclusions:The OEP can enhance lower limb muscle strength, improve physical function, and elevate the quality of life in aged sarcopenic patients. This provides medical professionals with a reference for designing exercise plans for these individuals.

Objective To investigate the change features of the 3-dimensional speckle tracking imaging (3D-STI) for quantitative evaluation of whole strain of left ventricular before and after left atrial appendage closure in the patients with non valvular atrial fibrillation and to evaluate its clinical application value.Methods Thirty patients who received left atrial appendage (LAA) closure from June, 2016 to A-pril, 2017 in Changhai Hospital were enrolled as research subjects .The patients received routine ultrasonic cardiography and 3D-STI, and left ventricular fractional shortening (LVFS), left ventricular ejection fractions (LVEF), global peak longitudinal strain (GPLS), global peak circumferential strain (GPCS), global peak radial strain (GPRS)as well as global peak area strain (GPAS) were respectively detected before surgery, 2 days, 1 and 3 months after surgery.Results In the 30 patients who received LAA closure, LVFS and LVEF were evaluated by u-sing routine ultrasonic cardiography and the data detected before surgery , 2 days, 1 and 3 months after surgery were compared between the two, and results showed that there was no statistical significance, when comparisons were made between them (P>0.05).In the 30 patients who were implemented with LAA closure, GPLS, GPCS, GPRS and GPAS values were detected using 3D-STI.The detected data 2 days after surgery were significantly higher as compared with those before surgery and 1 and 3 months after surgery(e.g.GPAS:39.90 ±10.22/27.80 ± 5.00, 26.20 ±6.05, 27.60 ±7.58), and there was statistical significance, when comparisons were made between them (P<0.05).However, there was no statistical significance in the data of GPLS, GPRS, GPCS and GPAS detected before surgery and 1 and 3 months after surgery, when comparisons were made between the two (P>0.05).Conclusion 3D-STI could be used for quantitative evaluation of the changes in left ventricular systolic function before and after LAA closure.The whole strain of the left ventricle of the patient was considerably increased 2 days after surgery, and the whole strain of the left ventricle recovered to pre-surgical level one month after surgery.

Objective: To explore the application of real-time three-dimensional ultrasound in locating the course, the brand and the blind end of internal opening of congenital preauricular fistula. Methods: Congenital preauricular fistula patients from Changhai Hospital were studied. All the cases were evaluated using two-dimensional and three-dimensional ultrasound before surgeries. The surgery findings were utilized as the gold standard. The imaging features of 3D ultrasound were described to determine the accuracy of the blind end location, the course of the main fistula tract and the branch tracts. The diagnosis was compared with the surgery findings. Results: In 89 cases, among which there were 21 branch fistulae. There were 68 bend fistulae without branch. The diagnostic accuracy of both two-dimensional ultrasound and three-dimensional ultrasound was 100%. The accuracy in locating the blind end of internal opening, the course of the branch tracts with 3D ultrasound was 92.1%(82/89), 85.7%(18/21) , compared to 80.9%(72/89), 57.1%(12/21) with 2D ultrasound. It was obvious that 3D ultrasound had more advantages. These differences were statistically significant (χ²=4.8, P<0.05; χ²=4.2, P<0.05). Conclusions Compared with 2D ultrasound, 3D ultrasound can accurately locate the blind end of internal opening, the course, and the branch of preauricular fistula, clearly display the morphology and the spatial structure of preauricular fistulaand its surroundings. It has high clinical application value in preoperative imaging examination.

Objective To investigate the effect of nursing intervention on the prevention of postoperative recurrence of bladder cancer by bladder irrigation of hydroxycamptothecine.Methods A total of 45 bladder cancer patients by bladder irrigation of hydroxycamptothecine after operation were as observation group,given intensive nursing intervention,and 43 cases in the same period were as control group,given routine nursing.The psychological state of patients was investigated by mood state scale (POMS),and the treatment compliance,complications and recurrence of the two groups were compared.Results The POMS scores such as depression,fatigue,panic and anger in the observation group were lower than that in the control group,the difference was statistically significant (P ＜ 0.05).The treatment compliance in the observation group was higher,the complication was less than that in the control group,the differences were statistically significant (P ＜ 0.05).The recurrence rate in the observation group was lower than that in the control group,but there was no statistical significant difference (P ＞ 0.05).Conclusion Nursing intervention can improve the patients 'state of mind and treatment compliance,and reduce the complications and recurrence rate.

Objective To investigate the effect of nursing intervention on the prevention of postoperative recurrence of bladder cancer by bladder irrigation of hydroxycamptothecine.Methods A total of 45 bladder cancer patients by bladder irrigation of hydroxycamptothecine after operation were as observation group,given intensive nursing intervention,and 43 cases in the same period were as control group,given routine nursing.The psychological state of patients was investigated by mood state scale (POMS),and the treatment compliance,complications and recurrence of the two groups were compared.Results The POMS scores such as depression,fatigue,panic and anger in the observation group were lower than that in the control group,the difference was statistically significant (P ＜ 0.05).The treatment compliance in the observation group was higher,the complication was less than that in the control group,the differences were statistically significant (P ＜ 0.05).The recurrence rate in the observation group was lower than that in the control group,but there was no statistical significant difference (P ＞ 0.05).Conclusion Nursing intervention can improve the patients 'state of mind and treatment compliance,and reduce the complications and recurrence rate.

Objective To optimize the prescription of flaxseed lignans sustained release tables by central composite design-response surface methodology.MethodsWith HPMC, EC and starch dosage as factors, and flaxseed lignans in 2, 6 and 12 h of cumulative release as evaluation indexes, central composite design-response surface optimization method was used to conduct prescription optimization experiments, and optimized prescription analysis was carried out.Results The optimal prescription of flaxseed lignans sustained release tables was as following: HPMC dosage was 43%; EC was 26%; starch content was 17%. Optimized index forecast values were very close to the observed values. In vitro release test of three selected optimal formulations indicated that there existed high approximation between the observed and estimated values.Conclusion It shows that the established model is suitable for flaxseed lignans sustained release tables, which can be used in the optimization of the prescription of flaxseed lignans sustained release tables.