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BackgroundCOVID-19 is a continued leading cause of hospitalization and death. Safe and efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, SARS-CoV-2 Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. MethodsWe report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase 1 study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a 3-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (BID) dosing was evaluated over 10 days in 5 parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase 2/3 clinical trials were supported by integrating modelling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). ResultsIn SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase 2/3 trials (300/100 mg BID), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients and prevent development of severe disease, hospitalization, and death. ConclusionsAn innovative and seamless trial design expedited establishment of phase 1 safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase 2/3 dose selection and accelerated pivotal trials initiation. NCT04756531
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Objective To investigate the prevalence and associated risk factors for pterygium among people aged 50 years and above in Funing County,Jiangsu Province.Methods A cluster random sampling method was performed,the subjects aged 50 years or above were randomly selected from 30 survey sites in Funing County,Jiangsu Province.Questionnaires,visual acuity tests,the examinations of eye surface,anterior segment,fundus examinations were conducted.Pterygium was diagnosed and graded clinically by slit lamp examination.The risk factors were acquired from questionnaires and analyzed by the multivariate logistic regression analysis.This study protocol was approved by Ethic Committee of Affiliated Hospital of Nantong University (NO.2010-05).Written informed consent was obtained from each subject prior to entering study cohort.Results A total of 6 145 persons aged 50 years and above were enumerated,and actually 5 947 (96.8%) participants were examined.Among them,1 950 cases were diagnosed as pterygium in either eye and 1 228 cases were diagnosed as pterygium in binoculus,which was equivalent to the 32.79% [95% confidence interval(CI):31.60%-33.98%] of pterygium in either eye and 20.65% (95% CI:19.62%-21.68%) in bilateral pterygium.Among 2467 male subjects,838 were diagnosed as pterygium (33.97%,95% CI:32.10%-35.84%).Among 3480 female subjects,1 112 were diagnosed as pterygium (31.95%,95% CI:30.40%-33.51%).There was no significant difference in the prevalence of pterygium between genders (P =0.135).Multivariate Logistic analysis showed that,older age (50 ~ <60 years:odds ratio [OR] =1.00;60 ~ <70 years:OR=1.54,P<0.001;70 ~ <80 years,OR=1.83,P<0.001;≥80 years:OR=1.99,P<0.001),low educational level (no education:OR =1.00;<primary:OR =0.87,P =0.031;primary education:OR =0.72,P =0.002;≥ secondary education:OR =0.63,P =0.002),farmer occupations (OR =1.34,P =0.020),and long outdoor work time (OR =1.13,P =0.026) were independent risk factors for pterygium.Gender,marriage,income,hypertension,diabetes,smoking and alcohol use history were not associated with pterygium (all at P>0.05).Conclusions The prevalence of pterygium in Funing County is 32.79% in people aged 50 years and above.The high prevalence of pterygium may be associated with older age,low education level and long outdoor work time.
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Objective To evaluate the implementation feasibility of the nurse performance appraisal and allocation plan based on the holistic nursing mode, and the clinical effect in mobilizing nursing staff's work enthusiasm and ensuring the quality of nursing service. Methods The nurse performance appraisal and allocation plan were further improved based on the previous research of this index system construction. The model were implemented in 32 clinical departments of Yidu Center Hospital of Weifang City. Four aspects data were collected for analysis six months later to evaluate the effect. They were nurses on merit pay distribution satisfaction, patients′satisfaction, doctors′satisfaction with nursing job, different clinical departments′nursing quality scores. Results Six months later, four factor scores of nurses to the satisfaction of merit pay distribution were significantly improved. The scores of fairness and impartiality evaluation of the merit pay distribution, incentive effect evaluation, pay and return on equity evaluation and performance pay gap rationality evaluation were higher than before [(3.39 ±0.64) points vs. (1.88 ±0.33) points, (3.28 ±0.74) points vs. (1.84 ±0.49) points , (3.28 ±0.71) points vs. (1.88 ±0.42) points and (3.38 ±0.67) points vs. (2.01±0.53) points, t=19.28, 16.22, 18.08, 16.79, all P<0.05]. Patients′satisfaction, doctors′satisfaction with nursing job and different clinical department' nursing quality scores were significantly increased as well [(99.14±0.82) points vs. (96.78±0.84) points, (96.59±0.91) points vs. (93.59±1.27) points and(97.67±0.41) points vs. (95.70±1.13) points]. Difference had statistical significance (t=11.79, 11.63, 9.60, P<0.05). Conclusions The performance salary allocation plan can effectively improve the hospital nurses on performance salary allocation satisfaction, patients′satisfaction, doctor′s satisfaction with nursing work and the quality of nursing department, and has good incentive in arousing the work enthusiasm of nursing staff and in ensuring the quality of nursing service.
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Objective To explore the expression of transient receptor potential channel 6(TRPC6)in human breast cancer cells, and to clarify the correlation of TRPC6 with the invasion potential of breast cancer cells. Methods The human breast cancer cell strains MCF-7 (hypo-invasion group)and MDA-MB-231 (hyper-invasion group)were cultured.The expressions of TRPC6 mRNA and protein in in two groups were detected by RT-PCR and Western blotting methods.Then the MDA-MB-231 cells were divided into control group and SKF96365 group, the effects of SKF96365 on the invasion ability of MDA-MB-231 cells invitro were explored by wound healing assay and Transwell experiment.Results The results of Western blotting and RT-PCR showed that the expression levels of TRPC6 mRNA and protein in MDA-MB-231 cells were higher than that in MCF-7 cells(P<0.05).The wound healing assay showed the numbers of migrating cells in 5,25 and 40μmol·L-1 SKF96365 groups (76.24±7.54, 45.33±4.50,25.12±1.57)were lower than those in control group (130.48±9.55)(P<0.05).The Transwell experiment results indicated that the invasiveness of MDA-MB-231 cells were inhibited significantly by SKF96365 compared with control group (P<0.05).Conclusion The invasion ability of human breast cancer MDA-MB-231 cells is promoted by upregulating the TRPC6 expression, which indicates that the TRPC6 may play role in the metastasis of human breast cancer.
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Objective To analyse the effects of anastomat to the resection surgery in 1800 esophageal and gastric cardiac carcinoma patients. Methods The Esophagus-gaster and Esophagus-intestine were stapled by anastomat in the cervical region in 182 cases、 intrathoracically in 1296 cases and intraperitoneal in 322cases. The occurrence of complications caused by anastomat, including anastomotic fistula,anastomotic stricture,anastomotic bleeding and mechanical failure,were observed. Results Anastomotic fistula occurred in 15 cases ( 15/1800,0.83% ,ten cases took Shanghai-made GF-I anastomat ,five cases took YH-W single disposable single anastomat ), among which 6 cases had the cervical anastomosis; Anastomotic stricture occurred in 41 cases ( 41 /1800,3.11%, fifteen cases took Shanghai-made GF-I anastomat, twenty-six took YH-W single disposable single anastomat) ,but all of them recovered after dilatation; Anastomotic bleeding occurred in 21 cases (21/18001.16%, thirteen cases took Shanghai-made GF-I anastomat, eight took YH-W single disposable single anastomat) ;Anastomat mechanical failure in operation occurred in 14 cases( 14/1800,0. 78% ,ten cases took Shanghai-made GF-I anastomat, four took YH-W single disposable single anastomat). Conclusion Anastomat is an effective method in reducing the postoperational complications of esophageal and gastric cardiac carcinoma resection. Disposable single anastomat has higher clinical value.