Objective:To evaluate the predictive performance of the individualized drug delivery decision-making system including Smart Dose, PharmVan and JPKD on predicting the Vancomycin plasma concentration and to analyze the related factors affecting the predictive performance.Methods:The clinical data of patients who were treated with Vancomycin and received therapeutic drug monitoring (TDM) admitted to the First Affiliated Hospital of Wenzhou Medical University from January 2018 to July 2020 were retrospectively collected. Smart Dose and PharmVan were used to predict the plasma concentration of Vancomycin of the initial regimen. Smart Dose, PharmVan and JPKD were used to predict the plasma concentration of Vancomycin of the adjustment regimen for patients whose initial steady-state trough concentration were not qualified. The relative predictive error (PE) between the measured plasma concentration and predicted plasma concentration was calculated and box plotted. Mann-Whitney U test was used to evaluate the difference of the absolute value of PE (APE) predicted by each software for Vancomycin plasma concentration. The TDM results were divided into accurate prediction group (APE < 30%) and the inaccurate prediction group (APE≥30%) according to the APE value. Patients and disease characteristics including gender, age, body weight complication, Vancomycin medication and TDM results were collected from electronic medical records. Univariate analysis and multivariate Logistic regression analysis were used to screen the related factors that influence the predictive performance of Smart Dose, PharmVan and JPKD; and receiver operating characteristic curve (ROC curve) was drawn to evaluate its predictive value. Results:A total of 185 patients were enrolled, and 258 plasma concentration of Vancomycin were collected, including 185 concentrations of initial regimen and 73 concentration of adjustment regimen. There was no significant difference in the APE of the initial regimen of plasma concentration between Smart Dose and PharmVan. No significant difference in the APE of the adjustment regimen of plasma concentration was found among Smart Dose, PharmVan and JPKD. The accuracy of Smart Dose in predicting the plasma concentration of the adjustment regimen was better than that of the initial regimen [22.94% (10.50%, 36.24%) vs. 29.33% (13.07%, 47.99%), P < 0.05]. The univariate analysis of factors affecting the performance of Smart Dose in predicting the concentration of initial regimen showed that the proportion of patients with hypertension in the accurate prediction group was significantly higher than that in the inaccurate prediction group [43.3% (42/97) vs. 27.3% (24/88), P < 0.05]. The univariate analysis of factors affecting the performance of Smart Dose in predicting the concentration of adjustment regimen showed that the proportion of patients with valvular heart disease in the accurate prediction group was significantly lower than that in the inaccurate prediction group [23.4% (11/47) vs. 46.2% (12/26), P < 0.05]. The univariate analysis of factors affecting the performance of JPKD in predicting the concentration of adjustment regimen showed that the body weight of patients in the accurate prediction group was significantly higher than that in the inaccurate prediction group (kg: 62.8±14.9 vs. 54.8±12.8, P < 0.05). Multivariate Logistic regression analysis indicated that hypertension was a beneficial factor for Smart Dose to predict the initial plasma concentration of Vancomycin [odds ratio ( OR) = 0.526, 95% confidence interval (95% CI) was 0.281-0.983, P = 0.044], and low body weight was an independent risk factor for the inaccurate prediction of JPKD for adjustment regimen ( OR = 1.042, 95% CI was 1.001-1.085 , P = 0.043). ROC curve analysis indicated that the area underROC curve (AUC) of the body weight for evaluating the accuracy of JPKD in predicting Vancomycin plasma concentration was 0.663, and 95% CI was 0.529-0.796 ( P = 0.023). When the body weight was less than 55.95 kg, the risk of inaccurate prediction of JPKD in predicting Vancomycin plasma concentration was increased, and the predictive sensitivityand specificity were 75% and 60% respectively. Conclusions:There is no significant difference in the predictive performance of Smart Dose, PharmVan or JPKD on Vancomycin plasma concentration. Smart Dose had a better predictive performance for the Vancomycin plasma concentration of adjustment regimen than initial regimen. Smart Dose had a better predictive performance when the patient was concomitant with hypertension. JPKD had a poor predictive performance for low-body weight patients. The predictive performance of JPKD was decreased when the body weight was lower than 55.95 kg.

In this study ECG signal of unstrained rat was recorded by telemetry device, and heart rate variability (HRV) was analyzed in order to evaluate 24h autonomic nervous activity. The results demonstrated an obvious circadian rhythm in the autonomic nervous activity: sympathetic activity being dominant during wake phase, and parasympathetic activity, dominant during sleep phase. The ratio of the low frequency to high frequency components in HRV power spectrum (LF/HF) fluctuates with the change in the sleep stages. It is concluded that 24h HRV analyses may reveal plentiful information about the behavior of autonomic nervous system and thus facilitate the investigation of its regulating role in physiological and pathological processes.
Animals ; Autonomic Nervous System ; physiology ; Circadian Rhythm ; Electrocardiography ; Heart Rate ; physiology ; Male ; Rats ; Rats, Sprague-Dawley ; Telemetry

Objective:To investigate the expression and significance of Toll-like receptor 4 (TLR4) in renal tissue and peripheral blood of children with idiopathic nephrotic syndrome(INS).Methods:The renal biopsy tissues of 78 children with INS diagnosed in the First Affiliated Hospital of Xinxiang Medical University from October 2015 to June 2018 and normal renal tissues of 21 children (control group 1) were collected, and the expressions of TLR4 in the renal tissue was detected by using immunohistochemical method.The expression of TLR4 in different renal pathological types and clinical types of INS was compared, and the correlation of TLR4 with 24-hour urinary protein and serum albumin was analyzed.The expression levels of TLR4 in peripheral blood of children with INS before and after treatment (active stage and remission stage) and 23 healthy children (control group 2) were detected by enzyme linked immunosorbent assay(ELISA). The serum expression levels of TLR4 in different renal pathological types and clinical types of INS were compared, and the correlation of TLR4 with 24-hour urinary protein and serum albumin was analyzed; The correlation between TLR4 expression in renal tubules and in the serum of children with INS was also analyzed.Results:(1)Compared with the expression of TLR4 in normal renal tissues[(0.93±0.26)%], the expression of TLR4 in glomeruli and interstitium of all pathological types of INS [mesangial proliferative glomerulonephritis (MsPGN): (0.93 ± 0.21)%, focal segmental glomerulosclerosis (FSGS): (1.02±0.25)%, membranous glomerulonephritis(MN): (1.03±0.09)%, minimal change disease(MCD): (1.02±0.27)%]was not significantly different ( F=0.741, P=0.562), but the expression of TLR4 in renal tubules[MCD: (82.94±4.62)%, MN: (63.54±1.98)%, MsPGN(42.32±2.97)%, FSGS: (22.60±2.07)%] was significantly increased ( F=1 929.842, P<0.01), Especially, the expression of TLR4 in renal tubules of MCD type INS was significantly higher than that of MN, MsPG N and FSGS [MCD: (82.94±4.62)%, MN: (63.54±1.98)%, MsPGN: (42.32±2.97)%, FSGS: (22.60±2.07)%], and the differences were statistically significant(all P<0.01). TLR4 expression in renal tubules was the highest in steroid-sensitive nephrotic syndrome (SSNS) type and the lowest in INS patients with steroid-resistant nephrotic syndrome (SRNS) type, and the differences were statistically significant( F=220.951, P<0.01). (2)The expression of serum TLR4 in INS children at the active stage [MsPNG: (143.36±12.99) ng/L, FSGS(75.94±7.29) ng/L, MN(210.22±14.66) ng/L, MCD(283.93±21.58) ng/L]was significantly higher than that in INS children at remission stage [MsPNG: (29.51±4.93) ng/L, FSGS(15.66±3.78) ng/L, MN(45.40±5.73) ng/L, MCD(62.29±7.90) ng/L]and control group 2[(0.69 ± 0.33) ng/L], and the differences were statistically significant(all P<0.01); the expression of serum TLR4 in INS children at remission stage was significantly higher than that in the control group 2 ( F=286.287, P<0.01). TLR4 had the highest expression level in serum of MCD type INS children at active and remission stages, followed by MN and FSGS successively.The expression of serum TLR4 was highest in SSNS and lowest in SRNS, and the differences were statistically significant ( F=147.438, P<0.01). (3)The expression of TLR4 in renal tubules of children with INS[(62.82 ±20.94)%]was positively correlated with the expression of TLR4 in serum[(213.26±73.33) ng/L] ( r=0.852, P< 0.05). The expression levels of TLR4 in renal tubules and serum of INS patients at active stage were positively correlated with 24-hour urinary protein level[(123.05±33.55) mg/kg] ( r=0.401, 0.427, all P<0.05), and negatively correlated with serum albumin level[(19.54±3.55)g/L] ( r=-0.602, -0.617, all P<0.05). Conclusions:The expression of TLR4 in renal tubules and serum of children with INS increases, and may be related to different renal pathological types and clinical types of children with INS, as well as disease activity.

Objective:To explore the feasibility and effectiveness of the construction of urban unmanned aerial vehicle (UAV) blood distribution system, and to provide a novel way for the distribution of emergency blood.Methods:The study was completed in Hangzhou from April 2019 to January 2021, and the main participants were from the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Province Blood Center and Hangzhou Fast Ant Network Technology Co., Ltd. Firstly, an unmanned aircraft delivery system was built for urban emergency blood and a special blood storage box for drones were developed. The drone was used to deliver blood products from Zhejiang Province Blood Center to Binjiang Campus, the Second Affiliated Hospital of Zhejiang University School of Medicine, and the following indicators were obtained: (1) flight time of the drone blood delivery; (2) real-time temperature of blood products during transportation; (3) Baidu map software was used to measure the blood delivery time of road traffic, which was compared with the flight time of the drone.Results:The urban drone blood delivery system consists of intelligent logistics drones, cryogenic blood storage tanks, unmanned logistics hub stations, and cloud-based operation control platforms. The drone route distance from Zhejiang Provincial Blood Center to Binjiang Campus, the Second Affiliated Hospital of Zhejiang University School of Medicine was 2.36±0.06 km, and the ground distance was 5.8 km, with 27 flights from April 12, 2019 to January 29, 2021, and the drone flight time was, shorter than the road travel time for a round trip [(6.37±0.35) min vs. (17.00±1.94) min]. At different time points of the day, UAV blood delivery could save 15.98-4.28 min, with an average saving of 10.62±1.87 min. Conclusions:Urban UAV blood delivery systems have the advantages of being fast, unaffected by ground traffic conditions, and can ensure the safety of blood products during transportation, and are worthy of further exploration.

Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.