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Can-Can Zhou,1,* Fang Huang,1,* Jing-Ming Zhang,1 Yu-Gang Zhuang2 1Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China; 2Department of Emergency Medicine, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Gang Zhuang, Email zhuangyg07@sina.comAbstract: Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide tigecycline dosing in different patient subpopulations through comparing the published population pharmacokinetic models of tigecycline, as well as summarizing and determining the potential covariates that markedly influence tigecycline pharmacokinetics. In this review, literature was systematically searched from the PubMed database from inception to March 2022. The articles focusing on population pharmacokinetics for tigecycline in healthy volunteers or patients were included; finally, a total of eight studies were included in this review. NONMEM methods were used in five studies to generate the population pharmacokinetic models. Tigecycline pharmacokinetics were mostly described by a two-compartment model in these included studies. Estimated clearance and volumes of distribution of tigecycline at steady state (Vss) varied widely in different target patient populations, with a range of 7.5– 23.1 L/h and 212.7– 1087.7 L, respectively. Body-weight and creatinine clearance were the most important predictors of clearance in these studies, while other predictors include age, gender, bilirubin and aspartate aminotransferase. In conclusion, this review showed the large variability of tigecycline population pharmacokinetics, which can provide guide dosing in different target populations. For clinicians, the individual dosing adjustment should be based not only on the indication and pathogen susceptibility but also on the potential important predictors. However, more studies were needed to confirm the necessity of modified dosage regimens in different patient subpopulations.Keywords: tigecycline, population pharmacokinetics, modelling, NONMEM

Sheng Wang,1,* Xiu M Mo,2,* Bo J Jiang,1 Cheng J Gao,1 Hong S Wang,2 Yu G Zhuang,1 Li J Qiu21Department of Emergency and Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, People's Republic of China; 2State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University, Shanghai, People’s Republic of China *These authors contributed equally to this workAbstract: The poor patency rate following small-diameter vascular grafting remains a major hurdle for the widespread clinical application of artificial blood vessels to date. Our previous studies found that electrospun poly(L-lactide-co-epsilon-caprolactone) (P[LLA-CL]) nanofibers facilitated the attachment and growth of endothelial cells (EC), and heparin incorporated into P(LLA-CL) nanofibers was able to release in a controlled manner. Hence, we hypothesized that heparin-bonded P(LLA-CL) vascular scaffolds with autologous EC pre-endothelialization could significantly promote the graft patency rate. To construct a small-diameter vascular scaffold, the inner layer was fabricated by heparin-bonded P(LLA-CL) nanofibers through coaxial electrospinning, while the outer layer was woven by pure P(LLA-CL) nanofibers. Except dynamic compliance (5.4 ± 1.7 versus 12.8 ± 2.4 × 10-4/mmHg, P < 0.05), maximal tensile strength, burst pressure, and suture retention of the composite, scaffolds were comparable to those of canine femoral arteries. In vitro studies indicated that the scaffolds can continuously release heparin for at least 12 weeks and obtain desirable endothelialization through dynamic incubation, which was confirmed by EC viability and proliferation assay and scanning electronic microscopy. Furthermore, in vivo studies demonstrated that pre-endothelialization by autologous ECs provided a better effect on graft patency rate in comparison with heparin loading, and the united application of pre-endothelialization and heparin loading markedly promoted the 24 weeks patency rate of P(LLA-CL) scaffolds (88.9% versus 12.5% in the control group, P < 0.05) in the canine femoral artery replacement model. These results suggest that heparin-bonded P(LLA-CL) scaffolds have similar biomechanical properties to those of native arteries and possess a multiporous and biocompatible surface to achieve satisfactory endothelialization in vitro. Heparin-bonded P(LLA-CL) scaffolds with autologous EC pre-endothelialization have the potential to be substitutes for natural small-diameter vessels in planned vascular bypass surgery.Keywords: electrospinning, heparin, vascular graft, endothelialization, patency rate

Background: The alarming mortality rate of sepsis in ICUs has garnered significant attention. The precise etiology remains elusive. Mitochondria, often referred to as the cellular powerhouses, have been postulated to have a dysfunctional role, correlating with the onset and progression of sepsis. However, the exact causal relationship remains to be defined., Method: Employing the Mendelian randomization approach, this study systematically analyzed data from the IEUOpenGWAS and UKbiobank databases concerning mitochondrial function-related proteins and their association with sepsis, aiming to delineate the causal relationship between the two., Results: The findings underscored a statistically significant association of GrpE1 with sepsis, registering a P value of 0.005 and an OR of 0.499 (95% CI: 0.307-0.810). Likewise, HTRA2, ISCU, and CUP3 each manifested significant associations with sepsis, yielding OR values of 0.585, 0.637, and 0.634, respectively. These results suggest potential implications of the aforementioned proteins in the pathogenesis of sepsis., Conclusion: The present study furnishes novel evidence elucidating the roles of GrpE1, HTRA2, ISCU, and CUP3 in the pathophysiology of sepsis. Such insights pave the way for a deeper understanding of the pathological mechanisms underpinning sepsis and hint at promising therapeutic strategies for the future., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Aim: To determine the prognostic value of lymphocyte subpopulations in predicting intensive care unit (ICU)-acquired infections among patients admitted to the ICU with sepsis., Methods: Data on peripheral blood lymphocyte subpopulations [CD3+ T cells, CD4+ T cells, CD8+ T cells, CD16+CD56+ natural killer (NK) cells and CD19+ B cells] were collected continuously from 188 patients admitted to the study ICUs with sepsis between January 2021 and October 2022. Clinical data collected from these patients, including medical history, number of organ failures, severity of illness scores, and characteristics of ICU-acquired infections, were reviewed., Results: Lymphocyte subpopulation counts were significantly lower in patients who acquired an infection in the ICU compared with those who did not. Univariate analyses showed that the number of organ failures [odds ratio (OR) 3.37, 95% confidence interval (CI) 2.25-5.05], severity of illness scores [Sequential Organ Failure Assessment score - OR 1.69, 95% CI 1.41-2.02; Acute Physiology and Chronic Health Evaluation II score - OR 1.26, 95% CI 0.17-1.36], history of immunosuppressant use (OR 2.41, 95% CI 1.01-5.73) and lymphocyte subpopulations (CD3+ T cells - OR 0.60, 95% CI 0.51-0.71; CD4+ T cells - OR 0.51, 95% CI 0.41-0.63; CD8+ T cells - OR 0.32, 95% CI 0.22-0.47; CD16/CD56+ NK cells - OR 0.41, 95% CI 0.28-0.59; CD19+B cells - OR 0.52, 95% CI 0.37-0.75) were associated with ICU-acquired infections. Multi-factor logistic regression analysis demonstrated that APACHE II score (OR 1.25, 95% CI 1.13-1.38), CD3+ T cells (OR 0.66, 95% CI 0.54-0.81) and CD4+ T cells (OR 0.64, 95% CI 0.50-0.82) were independent significant risk factors for ICU-acquired infections., Conclusion: Assessing CD3+ T cells and CD4+ T cells within 24 h of ICU admission may help in identification of patients at risk for developing ICU-acquired infections., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The influence of continuous renal replacement therapy (CRRT) on the steady-state plasma concentration of high-dose tigecycline was investigated in septic shock patients to provide references for drug dosing. Methods: In this prospective observational study, 17 septic shock patients presenting with severe infections needing a broad-spectrum antibiotic therapy with high-dose tigecycline (100 mg per 12 h) in the intensive care unit were included and divided into CRRT group ( n = 6) or non-CRRT group ( n = 11). The blood samples were collected and plasma drug concentration was determined by SHIMADZU LC-20A and SHIMADZU LCMS 8040. The steady-state plasma concentration was compared between groups using unpaired t -test. Furthermore, between-groups comparisons adjusted for baseline value was also done using multivariate linear regression model. Results: Peak concentration (C max ) of tigecycline was increased in CRRT group compared to non-CRRT group, but there were no statistical differences (505.11 ± 143.84 vs . 406.29 ± 108.00 ng/mL, p -value: 0.129). Trough concentration (C min ) of tigecycline was significantly higher in CRRT group than in non-CRRT group, with statistical differences (287.92 ± 41.91 vs . 174.79 ± 33.15 ng/mL, p -value: 0.000, adjusted p -value: 0.000). In safety, C min was reported to be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL. In our studies, C min of all patients in CRRT group was lower than 474.8 ng/mL. Conclusion: The plasma concentration of tigecycline was increased in septic shock patients with CRRT treatment and only C min shown statistical differences. No dose adjustment seems needed in the view of hepatotoxicity. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2000037475., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Cao, Yan, Mao, Wang, Huang, Qiu, Lu, Li and Zhuang.)

Background: Systemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines (interleukin-17 [IL-8], IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post-cardiac arrest period., Methods: This was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated "survivors". The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays., Results: Plasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC., Conclusion: These results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients., Trial Registration: Clinicaltrial.govNCT02297776, 2014-11-21.

Background: Adipokines are a group of cytokines or peptides secreted by adipose tissue to exert numerous biological functions. In the present study, we measured the plasma levels of four adipokines (adiponectin, leptin, fatty acid-binding protein 4 (FABP4), and visfatin) in cardiac arrest patients following return of spontaneous circulation (ROSC)., Methods: Totally, 21 patients who experienced cardiac arrest and successful ROSC with expected survival of at least 48 hours (from January 2016 to December 2017) were consecutively enrolled into this prospective observational clinical study. Of the 21 enrolled patients, ten survived, and other eleven died between 2 days and 6 months post ROSC. Venous blood was drawn at three time points: baseline (<1 hour post ROSC), 2 days post ROSC, and 7 days post ROSC. Plasma concentrations of adiponectin, leptin, FABP4, and visfatin were determined using commercial enzyme-linked immunosorbent assays., Results: The plasma visfatin levels at 2 or 7 days post ROSC increased significantly compared with the baseline ( P < 0.01), while plasma levels of adiponectin, leptin, and FABP4 did not change. Moreover, plasma visfatin levels in survivors at 2 or 7 days post ROSC were higher than those in nonsurvivors ( P < 0.01). Plasma visfatin levels at 2 or 7 days post ROSC were negatively correlated with Acute Physiology and Chronic Health Evaluation (APACHE) II score and time to ROSC. Moreover, receiver operating characteristic curve analysis showed that the plasma visfatin levels at 2 or 7 days post ROSC were good predictors for survival of the patients., Conclusion: Elevated plasma visfatin levels may be a marker for better outcome of cardiac arrest patients post ROSC., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Yuan-Zhuo Chen et al.)

Background: Noninvasive monitoring of intra-abdominal pressure (IAP) by measuring abdominal wall tension (AWT) was effective and feasible in previous postmortem and animal studies. This study aimed to investigate the feasibility of the AWT method for noninvasively monitoring IAP in the intensive care unit (ICU)., Methods: In this prospective study, we observed patients with detained urethral catheters in the ICU of Shanghai Tenth People's Hospital between April 2011 and March 2013. The correlation between AWT and urinary bladder pressure (UBP) was analyzed by linear regression analysis. The effects of respiratory and body position on AWT were evaluated using the paired samples t test, whereas the effects of gender and body mass index (BMI) on baseline AWT (IAP<12 mmHg) were assessed using one-way analysis of variance., Results: A total of 51 patients were studied. A significant linear correlation was observed between AWT and UBP (R=0.986, P<0.01); the regression equation was Y=-1.369+9.57X (P<0.01). There were significant differences among the different respiratory phases and body positions (P<0.01). However, gender and BMI had no significant effects on baseline AWT (P=0.457 and 0.313, respectively)., Conclusions: There was a significant linear correlation between AWT and UBP and respiratory phase, whereas body position had significant effects on AWT but gender and BMI did not. Therefore, AWT could serve as a simple, rapid, accurate, and important method to monitor IAP in critically ill patients.

Background: Insulin have been recommended to decrease glycosylated hemoglobin (HbA1c) level in type 2 diabetes mellitus (T2DM) patients whose blood glucose control are unsatisfactory by using oral hypoglycemic drugs., Aim: To systematically estimate the therapeutic effect and security of insulin glargine and insulin detemir for treatment of type 2 diabetes mellitus., Materials and Methods: We searched the Cochrane library, PubMed, EMBASE, etc databases. Quality evaluation of all randomized control tests (RCT) enrolled was conducted according to Cochrane manual, and meta-analysis was performed by using RevMan5.0 software., Results: Both insulin glargine and insulin detemir can effectively control T2DM patient's blood glucose., Conclusions: Insulin detemir has evident superiority on reducing body weight than insulin glargine. As the doses are concerned, daily insulin dose of insulin detemir is higher than insulin glargine.

To develop some promising anticancer drug loaded solid lipid nanoparticles (SLN) for further clinical application, SLN carrying mitoxantrone (MTO), paclitaxel (PCT), methotrexate (MTX) were prepared and their cytotoxic effects on the human breast cancer cell line, MCF-7 were investigated. The 50 % inhibitory concentration (IC50) values were interpolated from growth curves obtained by MTT assay. Moreover, the inhibition effects of the drugs incorporated in SLN on a murine breast cancer model induced by MCF-7 cells were further examined. In vitro cytotoxicity of MTO loaded SLN (IC50/72h=1.25 +/- 0.19 microM vs 2.13 +/- 0.37 microM) and MTX loaded SLN (IC50/72h = 93.80 +/- 6.54 nM vs 153.16 +/- 11.54 nM) was higher than that of free drug formulations. In vitro cytotoxicity of PCT-loaded SLN and free drug formulation IC50/72 h were similar. Then, the MCF-7 breast cancer model in mice was established. In mice treated with SLN injections for a month, tumor was significantly inhibited. Mean tumor size of mice treated with SLN was significantly smaller than that with free drug (P<0.05). Additionally, the percent inhibition of mice treated with SLN was obviously lower than that with free drug (P<0.05). Therefore, the conclusion can be drawn that anticancer drugs carried by SLN, including mitoxantrone, methotrexate and paclitaxel, may be more effective than free anticancer drugs for breast cancer treatment.

In the title compound, C(17)H(13)Cl(2)N(3), the dihedral angle between the pyrazole ring system and 4-chloro-phenyl ring is 26.1 (2)°. The C=N bond linking the two aromatic rings has an E conformation.

In the title compound, C(12)H(10)N(2)O, the dihedral angle between the pyridine ring system and the phenyl ring is 1.8 (1)°. There is an intra-molecular N-H⋯N hydrogen bond between the pyridine N atom and the amide NH function.

In the title compound, C(17)H(12)O(4), the chromene unit is approximately planar, the maximum deviation from the mean plane being 0.0166 Å. The attached phenyl ring makes a dihedral angle of 53.2 (1)° with the fused ring system. The packing of the mol-ecules in the crystal structure is governed by C-H⋯O and O-H⋯O hydrogen-bonding inter-actions.

Objective: To determine the effect of dobutamine, a beta-adrenergic agonist, on the alveolar fluid clearance (AFC) in acute lung injury (ALI)., Methods: Thirty two male Sprague-Dawley rats were randomly divided into four equal groups: normal control group; ALI group, infused with endotoxin to induce ALI; dobutamine control group, receiving sustained intravenous injection of dobutamine at the dose of 5 microg/kg/min, and dobutamine treatment group, receiving sustained intravenous injection of dobutamine at the dose of 5 microg/kg/min after the administration of endotoxin. Experiment began 45-60 minutes after the circulation was stable. Blood pressure was measured and blood gas analysis was conducted at the beginning of the experiment and one hour later. Perfusion fluid with (125)I-albumin with the radioactivity of 1.5 microCi/ml was perfused into the lung. One hour after the mechanical ventilation the mice were killed and their lungs were taken out. Alveolar fluid was taken out to calculate the AFC by single nuclide tracer technique. RT-PCR was used to detect the expression of alpha, beta, and gamma-rat epithelial sodium channel (rENaC) mRNA., Results: (1) The AFC of ALI group was 14.0 +/- 1.2%, significantly lower than that of the normal control group (21.0 +/- 3.9%, P < 0.05). (2) The AFC of the dobutamine control group was 26.6 +/- 1.6%, significantly higher than that of the normal control group (P < 0.05). and the AFC of the dobutamine treatment group was 20.0 +/- 3.9%, significantly higher than that of the ALI group (P < 0.05). (3) The expression of a-rENaC mRNA was 1.40 +/- 0.40 in the ALI group and was 1.38 +/- 0.13 in the dobutamine treatment group, both significantly higher than those in the dobutamine control group (1.01 +/- 0.14) and in the normal control group (0.44 +/- 0.11, all P < 0.05). The expression of beta-rENaC mRNA was 0.70 +/- 0.8 in the ALI group was 0.71 +/- 0.17 in the dobutamine treatment group, both significantly higher than those in the dobutamine control group (0.58 +/- 0.12) and in the normal control group (0.44 +/- 0.11, all P < 0.05). There were not significant differences in expression of alpha and beta-rENaC mRNA between the normal control group and dobutamine control group, and between the ALI group and dobutamine treatment group (both P > 0.05). (4) The gamma-rENaC mRNA expression was 0.90 +/- 0.19 in the dobutamine control group and was 0.97 +/- 0.15 in the dobutamine treatment group, both significantly higher than that in the normal control group (0.69 +/- 0.10) and in the ALI group (0.70 +/- 0.32) (all P < 0.05)., Conclusion: Able to upregulate the gamma-rENaC expression and improve the AFC in acute lung injury, beta-adrenergic agonist may be beneficial to reduce lung edema in ALI patients.