Therapeutic Drug Monitoring-Guided Vancomycin Therapy of a Pediatric Patient after Liver Transplantation: a Case Report.

BACKGROUND: Vancomycin administration is challenging in critically ill patients because of pharmacokinetic changes and requires careful therapeutic drug monitoring (TDM) to guide the appropriate dosing for an effective serum concentration and to avoid toxicity. METHODS: We reported a one-year-old female pediatric patient with a body mass index of 15.4 had successful TDM-guided vancomycin therapy after a living donor liver transplantation for biliary atresia. RESULTS: The patient was admitted to the Intensive Care Unit for sepsis after her second liver transplantation. Even with the administration of the maximum approved vancomycin dosage (40 mg/kg/day), the serum trough levels were less than the recommended therapeutic level. After several adjustments based on TDM, a continuous pump infusion of up to 800 mg/day was needed to reach the desired serum trough concentration of > 10 µg/mL. Sepsis was controlled, and the patient was transferred from the Intensive Care Unit to the general ward and finally discharged home on a regular follow-up plan. CONCLUSIONS: TDM-guided vancomycin continuous infusion may be an effective therapeutic option for pediatric patients after liver transplantation.

Comparative analysis of dosimetric and radiobiological models of IPSA and HIPO algorithms in combined intra-cavitary/interstitial brachytherapy for cervical cancer.

Purpose: To compare inverse planning simulated annealing (IPSA) and hybrid inverse planning optimization (HIPO) using dosimetric and radiobiological models, and provide a basis for selecting the optimization method for cervical cancer. Material and methods: This was a retrospective study including 32 patients with radical cervical cancer. Brachytherapy treatment plans were re-optimized using IPSA, HIPO1 (with a locked uterine tube), and HIPO2 (with an unlocked uterine tube). Dosimetric data, including isodose lines, HR-CTV (D100, V150%, V200%, HI, and CI), and (bladder, rectum, and intestines) D1cc, D2cc for organs at risk (OARs) were also collected. Additionally, TCP, NTCP, BED, and EUBED were calculated, and differences were analyzed using matched samples t-test and Friedman test. Results: Compared with IPSA and HIPO2, HIPO1 had better V150% and V200% (p < 0.05). Compared with IPSA and HIPO1, HIPO2 had better D100 and CI (p < 0.05). The doses to the bladder D1cc (4.72 ±0.33 Gy)/D2cc (4.47 ±0.29 Gy) and rectum D1cc (4.50 ±0.61 Gy)/D2cc (4.11 ±0.63 Gy) were lower in HIPO2 than in IPSA and HIPO1. EUBEDs for HR-CTV were higher in HIPO1 and HIPO2 than in IPSA by 1.39-1.63%. However, TCPs were not remarkably different among the three plans (p > 0.05). Also, the NTCP for the bladder was lower in HIPO2 than in IPSA and HIPO1 by 13.04% and 16.67%, respectively. Conclusions: Although the dosimetric parameters of IPSA, HIPO1, and HIPO2 are comparable, HIPO2 provides better dose conformability and lower NTCP. Therefore, HIPO2 is recommended as an optimization algorithm in IC/ISBT for cervical cancer.

Population pharmacokinetics and dosing optimisation of imipenem in critically ill patients.

OBJECTIVE: The objective of this study was to explore factors that affect the clearance of imipenem in critically ill patients and to provide a dosing regimen for such patients. METHODS: A prospective open-label study enrolled 51 critically ill patients with sepsis. Patients were between the ages of 18 and 96. Blood samples were collected in duplicate before (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after imipenem administration. The plasma imipenem concentration was determined by the high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method. A population pharmacokinetic (PPK) model was developed using nonlinear mixed-effects modelling methods to identify covariates. Monte Carlo simulations were performed using the final PPK model to explore the effect of different dosing regimens on the probability of target attainment (PTA). RESULTS: The imipenem concentration data were best described by a two-compartment model. Creatinine clearance (CrCl, mL/min) was a covariate that affected central clearance (CLc). Patients were divided into four subgroups based on different CrCl rates. Monte Carlo simulations were performed to assess the PTA differences between empirical dosing regimens (0.5 g every 6 hours (q6h), 0.5 g every 8 hours (q8h), 0.5 g every 12 hours (q12h), 1 g every 6 hours (q6h), 1 g every 8 hours (q8h), and 1 g every 12 hours (q12h)) and to determine the target achievement rate covariate. CONCLUSION: This study identified covariates for CLc, and the proposed final model can be used to guide clinicians administering imipenem in this particular patient population.

Radiobiological and dosimetric comparison of 60Co versus 192Ir high-dose-rate intracavitary-interstitial brachytherapy for cervical cancer.

BACKGROUND: High-dose-rate (HDR) intracavitary-interstitial brachytherapy (IC-ISBT) is an effective treatment for bulky, middle, and advanced cervical cancer. In this study, we compared the differences between 60Co and 192Ir HDR IC-ISBT plans in terms of radiobiological and dosimetric parameters, providing a reference for clinical workers in brachytherapy. METHODS: A total of 30 patients with cervical cancer receiving HDR IC-ISBT were included in this study, and IC-ISBT plans for each individual were designed with both 60Co and 192Ir at a prescribed dose of CTV D90 = 6 Gy while keeping the dose to OARs as low as possible. Physical dose and dose-volume parameters of CTV and OARs were extracted from TPS. The EQD2, EUBED, EUD, TCP, and NTCP were calculated using corresponding formulas. The differences between the 60Co and 192Ir IC-ISBT plans were compared using the paired t-test. RESULTS: In each patient's 60Co and 192Ir IC-ISBT plan, the average physical dose and EQD2 of 60Co were lower than those of 192Ir, and there were statistically significant differences in D2cc and D1cc for the OARs (p < 0.05); there were statistically significant differences in D0.1 cc for the bladder (p < 0.05) and no significant differences in D0.1 cc for the rectum or intestines (p > 0.05). The EUBED ratio (60Co/192Ir) at the CTV was mostly close to 1 when neither 60Co or 192Ir passed their half-lives or when both passed two half-lives, and the difference between them was not significant; at the OARs, the mean value of 60Co was lower than that of 192Ir. There was no statistical difference between 60Co and 192Ir in the EUD (93.93 versus 93.92 Gy, p > 0.05) and TCP (97.07% versus 97.08%, p > 0.05) of the tumors. The mean NTCP value of 60Co was lower than that of 192Ir. CONCLUSIONS: Considering the CTV and OARs, the dosimetric parameters of 60Co and 192Ir are comparable. Compared with 192Ir, the use of 60Co for HDR IC-ISBT can ensure a similar tumor control probability while providing better protection to the OARs. In addition, 60Co has obvious economic advantages and can be promoted as a good alternative to 192Ir.

Comparative Analysis of 60Co and 192Ir Sources in High Dose Rate Brachytherapy for Cervical Cancer.

High-dose-rate (HDR) brachytherapy (BT) is an essential treatment for cervical cancer, one of the most prevalent gynecological malignant tumors. In HDR BT, high radiation doses can be delivered to the tumor target with the minimum radiation doses to organs at risk. Despite the wide use of the small HDR 192Ir source, as the technique has improved, the HDR 60Co source, which has the same miniaturized geometry, has also been produced and put into clinical practice. Compared with 192Ir (74 days), 60Co has a longer half-life (5.3 years), which gives it a great economic advantage for developing nations. The aim of the study was to compare 60Co and 192Ir sources for HDR BT in terms of both dosimetry and clinical treatment. The results of reports published on the use of HDR BT for cervical cancer over the past few years as well as our own research show that this treatment is safe and it is feasible to use 60Co as an alternative source.

Real-world safety of ulinastatin: a post-marketing surveillance of 11,252 patients in China.

BACKGROUND: The safety assessment of ulinastatin can guide clinical practice. The present study aimed to investigate the real-world safety of ulinastatin in China. METHODS: This multicenter study retrospectively analyzed the post-marketing surveillance data of consecutive patients treated with ulinastatin between August 2014 and June 2017 in the general wards and the intensive care units (ICU) of nine hospitals in China. Adverse drug reactions/adverse drug events (ADRs/ADEs) were collected and evaluated in a post-marketing database. RESULTS: A total of 11,252 consecutive patients were included in the study: 7009 ICU patients and 4243 general ward patients. Eleven patients with ADRs/ADEs were observed, including nine ICU patients and two general ward patients. The clinical manifestations were liver dysfunction (n = 5 ICU cases, n = 1 general case), thrombocytopenia (n = 2 ICU cases, n = 1 general case), leukopenia (n = 1 ICU case), and rash (n = 1 ICU case). During the study period, the drug ADR/ADE rate of ulinastatin injection was 0.98‰ (11/11,252 × 1000‰). Among the 11,252 valid patients, only 327 received ulinastatin in accordance with the drug specifications. After excluding unreasonable drug use, the calculated ADR rate was 3.06‰ (1/327 × 1000‰) (95% confidence interval: 0.0‰-17.1‰). In ICU and general ward patients, the use of other drugs combined with ulinastatin was associated with the occurrence of ADRs/ADEs (100% with ADRs/ADEs vs. 0% in controls, P < 0.001). CONCLUSIONS: The incidence of ADRs/ADEs of ulinastatin is < 5‰. The ADRs/ADEs involved limited organs, mainly the skin, gastrointestinal tract, and blood. In most cases, the ADRs/ADEs gradually alleviated or recovered after drug withdrawal. The inappropriate/off-label use of ulinastatin should be the focus of surveillance.

Low-Dose NOACs Versus Standard-Dose NOACs or Warfarin on Efficacy and Safety in Asian Patients with NVAF: A Meta-Analysis.

BACKGROUND: The meta-analysis of randomized controlled trials has illustrated that the efficacy of low-dose non-vitamin K antagonist oral anticoagulants is inferior compared with standard-dose non-vitamin K antagonist oral anticoagulants, though they are still frequently prescribed for Asian patients with non-valvular atrial fibrillation. We aimed to further investigate the efficacy and safety of low-dose non-vitamin K antagonist oral anticoagulants by carrying out a meta-analysis of all relevant randomized controlled tri- als and cohort studies. METHODS: Cochrane Central Register of Controlled Trials, Embase, and MEDLINE were sys- tematically searched from the inception to September 9, 2021, for randomized controlled trials or cohorts that compared the efficacy and/or safety of low-dose non-vitamin K antagonist oral anticoagulants in Asian patients with non-valvular atrial fibrillation. The primary outcomes were stroke and major bleeding, and the secondary outcomes were mortality, intracranial hemorrhage, and gastrointestinal hemorrhage. Hazard ratios and 95% CIs were estimated using the random-effect model. RESULTS: Nineteen publications involving 371 574 Asian patients with non-valvular atrial fibrillation were included. Compared with standard-dose non-vitamin K antagonist oral anticoagulants, low-dose non-vitamin K antagonist oral anticoagulants showed compa- rable risks of stroke (hazard ratio, 1.18; 95% CI 0.98 to 1.42), major bleeding (hazard ratio, 1.00; 95% CI 0.83 to 1.21), intracranial hemorrhage (hazard ratio, 1.13; 95% CI 0.92 to 1.38), and gastrointestinal hemorrhage (hazard ratio, 1.07; 95% CI 0.87 to 1.31), though had a higher risk of mortality (hazard ratio, 1.34; 95% CI 1.05 to 1.71). Compared with warfarin, low-dose non-vitamin K antagonist oral anticoagulants were associated with lower risks of stroke (hazard ratio, 0.73; 95% CI 0.67 to 0.79), mortality (hazard ratio, 0.69; 95% CI 0.60 to 0.81), major bleeding (hazard ratio, 0.62; 95% CI 0.51 to 0.75), intracranial hemor- rhage (hazard ratio, 0.48; 95% CI 0.33 to 0.69), and gastrointestinal hemorrhage (hazard ratio, 0.78; 95% CI 0.65 to 0.93). CONCLUSION: Low-dose non-vitamin K antagonist oral anticoagulants were superior to warfarin, and comparable to standard-dose non-vitamin K antagonist oral anticoagu- lants considering risks of stroke, major bleeding, intracranial hemorrhage, and gastroin- testinal hemorrhage. Further, high qualified studies are warranted.

Real-World Comparisons of Low-Dose NOACs versus Standard-Dose NOACs or Warfarin on Efficacy and Safety in Patients with AF: A Meta-Analysis.

Objective: We aimed to further investigate the efficacy and safety of low-dose NOACs by performing a meta-analysis of cohort studies. Background: Meta-analyses of randomized controlled trials (RCTs) have demonstrated that low-dose non-vitamin K antagonist oral anticoagulants (NOACs) showed inferior efficacy compared with standard-dose NOACs, although they are still frequently prescribed for patients with atrial fibrillation (AF) in the clinical practice. Methods: Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and MEDLINE were systematically searched from the inception to September 9, 2021, for cohort studies that compared the efficacy and/or safety of low-dose NOACs in patients with AF. The primary outcomes were ischemic stroke and major bleeding, and the secondary outcomes were mortality, intracranial hemorrhage (ICH), and gastrointestinal hemorrhage (GH). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with the random-effect model. Results: Twenty-five publications involving 487856 patients with AF were included. Compared with standard-dose NOACs, low-dose NOACs had comparable risks of ischemic stroke (HR = 1.03, 95% CI 0.96 to 1.11), major bleeding (HR = 1.12, 95% CI 0.97 to 1.28), ICH (HR = 1.09, 95% CI 0.88 to 1.36), and GH (HR = 1.11, 95% CI 0.92 to 1.33), except for a higher risk of mortality (HR = 1.41, 95% CI 1.21 to 1.65). Compared with warfarin, low-dose NOACs were associated with lower risks of ischemic stroke (HR = 0.72, 95% CI .67 to 0.78), mortality (HR = 0.67, 95% CI 0.59 to 0.77), major bleeding (HR = 0.64, 95% CI 0.53 to 0.79), ICH (HR = 0.57, 95% CI 0.42 to 0.77), and GH (HR = 0.78, 95% CI 0.64 to 0.95). Conclusions: Low-dose NOACs were comparable to standard-dose NOACs considering risks of ischemic stroke, major bleeding, ICH, and GH, and they were superior to warfarin. Low-dose NOACs might be prescribed effectively and safely for patients with AF. Considering limitations, further well-designed prospective studies are foreseen.

Endorsement of the TRIPOD statement and the reporting of studies developing contrast-induced nephropathy prediction models for the coronary angiography/percutaneous coronary intervention population: a cross-sectional study.

OBJECTIVE: Clear and specific reporting of a research paper is essential for its validity and applicability. Some studies have revealed that the reporting of studies based on the clinical prediction models was generally insufficient based on the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) checklist. However, the reporting of studies on contrast-induced nephropathy (CIN) prediction models in the coronary angiography (CAG)/percutaneous coronary intervention (PCI) population has not been thoroughly assessed. Thus, the aim is to evaluate the reporting of the studies on CIN prediction models for the CAG/PCI population using the TRIPOD checklist. DESIGN: A cross-sectional study. METHODS: PubMed and Embase were systematically searched from inception to 30 September 2021. Only the studies on the development of CIN prediction models for the CAG/PCI population were included. The data were extracted into a standardised spreadsheet designed in accordance with the 'TRIPOD Adherence Assessment Form'. The overall completeness of reporting of each model and each TRIPOD item were evaluated, and the reporting before and after the publication of the TRIPOD statement was compared. The linear relationship between model performance and TRIPOD adherence was also assessed. RESULTS: We identified 36 studies that developed CIN prediction models for the CAG/PCI population. Median TRIPOD checklist adherence was 60% (34%-77%), and no significant improvement was found since the publication of the TRIPOD checklist (p=0.770). There was a significant difference in adherence to individual TRIPOD items, ranging from 0% to 100%. Moreover, most studies did not specify critical information within the Methods section. Only 5 studies (14%) explained how they arrived at the study size, and only 13 studies (36%) described how to handle missing data. In the Statistical analysis section, how the continuous predictors were modelled, the cut-points of categorical or categorised predictors, and the methods to choose the cut-points were only reported in 7 (19%), 6 (17%) and 1 (3%) of the studies, respectively. Nevertheless, no relationship was found between model performance and TRIPOD adherence in both the development and validation datasets (r=-0.260 and r=-0.069, respectively). CONCLUSIONS: The reporting of CIN prediction models for the CAG/PCI population still needs to be improved based on the TRIPOD checklist. In order to promote further external validation and clinical application of the prediction models, more information should be provided in future studies.

Antithrombotic therapy for secondary prevention of unprovoked venous thromboembolism: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Extended antithrombotic treatment is recommended for secondary prevention of unprovoked venous thromboembolism (VTE), however, there is no consensus on which antithrombotic strategy is preferable. AIM: To compare the efficacy and safety of different antithrombotic strategies for secondary prevention unprovoked VTE. METHODS: Cochrane Central Register of Controlled Trials, Embase, and MEDLINE were systematically searched from inception to 22 July 2020 for randomized controlled trials (RCTs) that compared the efficacy and/or safety of extended antithrombotic strategies including aspirin, warfarin and direct oral anticoagulants (DOACs) for secondary prevention of unprovoked VTE. The primary outcome was risk of major bleeding and the secondary outcomes were risks of recurrent VTE and all-cause death. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using pairwise and network meta-analysis with random effect. Possible ranking of extended antithrombotic strategies was plotted using the surface under the cumulative ranking curve and mean ranks. RESULTS: Seventeen RCTs met the inclusion criteria, and meta-analysis results showed that warfarin was associated with significantly higher risk of major bleeding than placebo/observation (OR 2.71, 95% CI 1.32-5.55) or apixaban (OR 10.65, 95% CI 1.06-107.13). Apixaban and low-apixaban were the top two strategies according to the ranking of major bleeding. Warfarin (OR 0.25, 95%CI 0.13-0.49), rivaroxaban (OR 0.18, 95%CI 0.03-0.90), apixaban (OR 0.18, 95%CI 0.04-0.85) and low-apixaban (OR 0.18, 95%CI 0.04-0.82) were related to significantly lower risk than placebo/observation; edoxaban was non-inferior to warfarin on the risk of recurrent VTE. Furthermore, apixaban was linked with significantly lower risk of all-cause death than placebo/observation (OR 0.29, 95% CI 0.09-0.88). CONCLUSION: Apixaban showed superiority to other antithrombotic strategies on major bleeding and all-cause death for secondary prevention of unprovoked VTE. Further studies are warranted owing to the limited number of studies and positive cases.Key messagesAll antithrombotic strategies including warfarin, DOACs and aspirin were superior to placebo/observation on recurrent VTE for secondary prevention of unprovoked VTE.Apixaban demonstrated lower risk of major bleeding than warfarin, and lower risk of all-cause death than placebo/observation.Further research about the efficacy and safety of antithrombotic treatments for secondary prevention of unprovoked VTE is warranted.

Long non-coding RNA miR155HG silencing restrains ovarian cancer progression by targeting the microRNA-155-5p/tyrosinase-related protein 1 axis.

Ovarian cancer (OC) is the third commonest gynecological malignancy worldwide. The long non-coding (lnc)RNA microRNA (miR)155HG functions as an oncogene in different human cancers. However, the function and molecular mechanism of miR155HG in OC remain elusive. The present study indicated that the expression levels of miR155HG and tyrosinase-related protein 1 (TYRP1) were significantly increased, whereas that of miR155-5p was decreased in OC tissues and cells, as detected by real-time quantitative polymerase chain reaction. It was demonstrated that knockdown of miR155HG markedly inhibited OC cell viability, migration and invasion while promoting apoptosis, as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, Transwell and western blot assays. Mechanistically, it was revealed that miR155HG and TYRP1 were both targeted by miR-155-5p with complementary binding sites in the 3' untranslated region. A dual-luciferase reporter assay was used to confirm the targeting relationship between miR155HG, miR-155-5p and TYRP1. In addition, the interaction between miR155HG and miR-155-5p was further demonstrated by radioimmunoprecipitation and pull-down assays. In addition, feedback approaches determined that miR-155-5p inhibition or TYRP1 overexpression markedly reversed the inhibitory effects of miR155HG knockdown on OC cell viability, migration and invasion as well as weakened the promotive effect of miR155HG knockdown on OC cell apoptosis. Thus, miR155HG silencing inhibited the malignant biological behavior of OC cells by targeting the miR-155-5p/TYRP1 axis. The present study provides novel insights into the underlying mechanism of OC progression.

Neoadjuvant chemotherapy combined with laparoscopic cytoreductive surgery in patients with advanced ovarian cancer.

PURPOSE: To explore the clinical efficacy and safety of neoadjuvant chemotherapy (NACT) combined with minimally invasive laparoscopic cytoreductive surgery in the treatment of patients with advanced ovarian cancer (AOC). METHODS: The clinical data of 116 patients with AOC were divided into NACT group (NACT combined with laparoscopic cytoreductive surgery, n=58) and control group (cytoreductive surgery alone, n=58). The short-term efficacy, surgery-related indexes, incidence of adverse reactions, and changes in levels of serum human epididymis protein 4 (HE4), vascular endothelial growth factor (VEGF) and carbohydrate antigen 125 (CA125) before and after treatment were compared between the two groups. The survival status of patients after treatment was recorded. RESULTS: The operation time, intraoperative blood loss, ascites volume, postoperative ventilation time, and average postoperative length of hospitalization in NACT group were all significantly shorter and less than those in the control group. The optimal cytoreduction rate in NACT group was far higher than that in the control group. The overall response rate in NACT group was obviously higher than that in the control group. After treatment, the levels of serum HE4, VEGF and CA125 greatly declined in the two groups compared with those before treatment, while they were obviously lower in the NACT group than those in the control group. The follow-up results revealed that the median overall survival (OS) was 31.1 months and 28.9 months, and the 3-year OS rate was 43.1% (25/58) and 31.0% (18/58), respectively, in the NACT group and control group. CONCLUSION: NACT can significantly shorten the duration of cytoreductive surgery of AOC, reduce intraoperative blood loss, accelerate postoperative recovery, raise the optimal cytoreduction rate, and enhance the clinical efficacy, without greatly improving the survival of patients.

Frequency and Patterns of Prescribing Antihypertensive Agents in Outpatient Kidney Transplant Recipients Among Six Cities in China from 2011 to 2018.

PURPOSE: Antihypertensive agents are frequently prescribed in kidney transplant recipients (KTRs). However, the frequency and patterns of prescribing antihypertensive agents remain uncharacterized in KTRs in China. Therefore, this investigation was carried out. METHODS: Retrospective prescription data dated 2011 to 2018 from KTRs in China were accessed using the Hospital Prescription Analysis Program database. Information about sex, birth date, and identification number of the patient; city, date, and department of the medical visit; major diagnoses; and the generic names, specifications, quantities, and usage of prescribed drugs were collected. Antihypertensive agents were grouped into 5 classes: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), ß-blockers (BBs), calcium channel blockers (CCBs), and diuretics. The frequency and patterns of prescribing these antihypertensive agents were analyzed. FINDINGS: Prescriptions from 174,749 KTRs (67.2% male; mean age, 42.5 [9.4] years) were obtained, and 58.2% of the patients were prescribed antihypertensive agents. The percentage of patients who received antihypertensive treatment increased from 52.9% in 2011 to 61.6% in 2018 and varied by city. Cyclosporine was associated with higher prescription frequency of antihypertensive agents than was tacrolimus (71.7% vs 63.4%; P < 0.0001). During the 8-year study period, CCBs were most frequently prescribed (39.0%), followed by ARBs (31.9%), BBs (14.3%), ACEIs (11.6%), and diuretics (3.2%). The mean (SD) number of antihypertensive drugs prescribed per KTR was 1.7 (0.8). Almost half of KTRs (51.2%) received just 1 antihypertensive drug. Co-administration of 2 or more antihypertensive drugs presented an obviously upward trend. The most commonly prescribed 2-drug combination was CCB + ARB (44.8%), followed by CCB + BB (20.1%) and CCB + ACEI (13.0%). In the patients who received 3 antihypertensive drugs, the 2 most frequently prescribed combinations were CCB + ARB + BB (37.5%) and CCB + ARB + ACEI (32.7%). Specific data varied by both year and city. IMPLICATIONS: The prescribing patterns of antihypertensive agents in KTRs varied by city even within same country. Hence, more high-quality research studies on the use of antihypertensive agents in KTRs are needed.

Pharmacokinetic and Pharmacodynamic Analysis of Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Imipenem.

PURPOSE: This study explores factors that affect behavior in critically ill patients receiving continuous renal replacement therapy (CRRT) with imipenem and provides dosing regimens for these patients. METHODS: A prospective, open-label study was conducted in a clinical setting. Both blood and effluent samples were collected pairwise at the scheduled time points. Plasma and effluent imipenem concentrations were determined by HPLC-UV. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method. The final model was evaluated by a bootstrap and visual predictive check. A population pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulations was performed to explore the effects of empirically used dosing regimens (0.5 g q6h, 0.5 g q8h, 0.5 g q12h, 1 g q6h, 1 g q8h, and 1 g q12h) on the probability of target attainment. FINDINGS: Thirty patients were included in the population model analysis. Imipenem concentration data were best described by a 3-compartment model (central, peripheral, and dialysis compartments). The clearance of the dialysis compartment (CLd) was used to characterize drug elimination from the dialyzer. Creatinine clearance (CrCl) was the covariate that influenced the central clearance (CLc), and the effects of dialysate flow (Qd) was significant for CLd. Model validation revealed that the final model had qualified stability and acceptable predictive properties. A pharmacokinetic and pharmacodynamic analysis was conducted by Monte Carlo simulation, and patients were categorized into 12 subgroups based on different CrCl values (<30, 31-60, 61-90, and >90 mL/min) and Qd values (300, 500, and 1000 mL/h). Under the same MIC value and administration regimen, probability of target attainment values decreased with an increase of CrCl and Qd. IMPLICATIONS: CrCl and Qd had significant effects on CLc and CLd, respectively. The proposed final model may be used to guide practitioners in imipenem dosing in this specific patient population.

Electrosprayed nanoparticles of poly(p-dioxanone-co-melphalan) macromolecular prodrugs for treatment of xenograft ovarian carcinoma.

Ovarian cancer is considered to be the most fatal reproductive cancers. Melphalan is used to treat ovarian cancer as an intraperitoneal chemotherapy agent. However, elucidating its pharmacokinetic behavior and preparing it for administration are challenging since it undergoes spontaneous hydrolysis. In this study, melphalan is transformed into a macromolecular prodrug by copolymerizing with p-dioxanone. The hydrophobicity of copolymer chains protects melphalan from hydrolysis. Poly(p-dioxanone-co-melphalan; PDCM) is electrosprayed and converted into nanoparticles (PDCM NPs) with diameters of ~300-350 nm to facilitate its intracellular delivery. UPLC-MS and HPLC are applied to verify and monitor the release of melphalan from PDCM NPs. PDCM NPs could suppress the proliferation of SKOV-3 cells. The IC50 of 4.3% melphalan-containing PDCM-3 NP was 70 mg/L, 72 h post administration. These suppression characteristics not only affected by the degradation and then the extracellular release of melphalan from PDCM NPs, but also the uptake via phagocytosis phenomenon in SKOV-3 cells. As revealed by flow cytometry, phagocytosis is a first-order process. Once phagocytosed, PDCM NPs are digested by lysosomes, causing a rapid release of melphalan into the cytoplasm, which ultimately causes suppression of SKOV-3 cell proliferation. Finally, the in vivo antitumor effects of PDCM NPs are verified in xenograft ovarian carcinoma. After a 20-day treatment, the tumor growth rate of the PDCM-3 NP group was (266 ± 178%) which was lower than those in the free melphalan group (367 ± 150%) and control group (648 ± 149%). Besides, significant tissue necrosis and growth suppression were observed in animals administered injections of PDCM NPs. Furthermore, the in vivo tracing results of Nile red-labeled PDCM NPs demonstrated that PDCM-3 NPs might be phagocytosed by macrophages and then taken to adjacent lymph nodes, which is a way of prevention or early treatment of lymphatic metastasis of tumors.

High Expression of RING Finger Protein 126 Predicts Unfavorable Prognosis of Epithelial Ovarian Cancer.

BACKGROUND Ovarian cancer (OC) is one of the leading causes of cancer-related mortality worldwide. The clinical outcome of EOC remains unsatisfactory with current therapeutic approaches such as surgery and platinum/taxane-based chemotherapy. Therefore, novel prognostic markers and personalized therapies targeting specific molecules are urgently needed. Here, we explored whether RNF126, an E3 ubiquitin ligase, is a potential biomarker for epithelial ovarian cancer (EOC). MATERIAL AND METHODS This was a retrospective cohort study of 122 EOC patients. The chi-square test was used to assess correlations between RNF126 level and clinical characteristics of enrolled patients. Univariate and multivariate analyses were performed to monitor the prognosis of enrolled patients. In addition, proliferation and invasion assays were conducted to assess the cellular effects of RNF126 on SKOV3 cell progression. RESULTS Immunohistochemistry analysis (IHC) revealed that RNF126 was upregulated in EOC tissues compared to adjacent ovarian tissues. In addition, RNF126 expression was remarkably associated with LN metastasis, pathological differentiation, and FIGO stage. RNF126 protein level was found to be an independent biomarker for predication of prognosis in ovarian cancer patients. Cellular results showed that RNF126 enhanced the proliferation and invasion abilities of SKOV3 cells. CONCLUSIONS Upregulated protein level of RNF126 in EOC tissues is a biomarker predicting poor outcomes of EOC patients.

Pharmacologic Prophylaxis of Stress Ulcer in Non-ICU Patients: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

PURPOSE: Acid-suppressive medications are widely used in non-intensive care unit (non-ICU) patients for stress ulcer (SU) prophylaxis. However, SU prophylaxis in this population is still controversial. The purpose of this study was to systematically evaluate the efficacy and tolerability of these agents for SU prophylaxis in non-ICU patients. METHODS: Electronic databases including Cochrane, ClinicalTrials.gov, Ovid-Medline, Embase, Chinese CNKI, and Wanfang Data were systematically searched on July 10, 2019, for randomized controlled trials (RCTs) that evaluated acid-suppressive medications in non-ICU patients. Network meta-analysis and pairwise meta-analysis were performed to calculate odds ratios (ORs) and 95% CIs. A random-effects model was used for generating pooled estimates. The primary outcome was occurrence of SU bleeding, and the adverse drug events (ADEs) were described as the secondary outcome. FINDINGS: A total of 17 RCTs involving 1985 patients were eligible. Meta-analysis results indicated that the occurrence of SU bleeding was significantly decreased with all acid-suppressive medications compared with placebos (gastric mucosa protectants, OR = 0.29 [95% CI, 0.14-0.61]; H2-receptor antagonists, OR = 0.3 [95% CI, 0.18-0.50]; proton pump inhibitors [PPIs]: OR = 0.08 [95% CI, 0.04-0.16]). The occurrence of SU bleeding was significantly decreased with PPIs compared with gastric mucosa protectants (OR = 0.29; 95% CI, 0.12-0.72) and H2-receptor antagonists (OR = 0.28; 95% CI, 0.16-0.48). There was no significant difference between any 2 classes of PPIs on SU bleeding or any 2 acid-suppressive medications on ADEs. IMPLICATIONS: PPIs could significantly decrease SU bleeding risk without increasing ADEs than other acid-suppressive medications for SU prophylaxis in non-ICU patients. However, RCTs of high quality were required to confirm the findings of this investigation.

Development and Validation of a Risk Prediction Model of Vancomycin-Associated Nephrotoxicity in Elderly Patients: A Pilot Study.

This exploratory study aimed to develop a risk prediction model of vancomycin-associated nephrotoxicity (VANT) in elderly patients. Clinical information of elderly patients who received vancomycin therapy from January 2016 to June 2018 was retrieved. A total of 255 patients were included in this study. Univariate analysis and multivariable logistic regression analysis revealed that vancomycin trough concentration ≥ 20 mg/L (odds ratio (OR) = 3.009; 95% confidence interval (CI) 1.345-6.732), surgery (OR = 3.357; 95% CI 1.309-8.605), the Charlson Comorbidities Index ≥ 4 points (OR = 2.604; 95% CI 1.172-5.787), concomitant use of cardiotonic drug (OR = 3.283; 95% CI 1.340-8.042), plasma volume expander (OR = 3.459; 95% CI 1.428-8.382), and piperacillin/tazobactam (OR = 2.547; 95% CI 1.680-6.007) were risk factors for VANT in elderly patients. Furthermore, a VANT risk prediction model was developed, which had good discriminative power and was well-calibrated.

Analysis of the relationship between COMT polymorphisms and endometriosis susceptibility.

This study was aimed to explore the correlation between catechol-O-methyltransferase (COMT) gene polymorphisms and endometriosis susceptibility in Chinese Han population.This case-control study recruited 134 endometriosis patients and 139 healthy individuals. COMT gene rs4680, rs2020917, and rs4646312 polymorphisms in the subjects were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Association between COMT polymorphisms and endometriosis susceptibility was evaluated by χ test and adjusted by Logistic regression. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to present the relative risk of endometriosis.A allele of rs4680 was distinctly correlated with increased susceptibility of endometriosis (OR = 1.450, 95% CI = 1.012-2.076). However, when adjusted by the confounding factors, these associations become not significant. We failed to find any significant association between rs2020917 and endometriosis risk in the crude results. The adjusted results suggested that rs2020917 TT genotype and T allele were distinctly correlated with enhanced endometriosis risk (TT vs CC: P = .038, OR = 2.894, 95% CI = 1.060-7.903; T vs C: P = .039, OR = 1.481, 95% CI = 1.021-2.149). Besides, rs4646312 C allele was significantly correlated with endometriosis risk both in the crude (P = .027, OR = 1.502, 95% CI = 1.047-2.154) and adjusted (P = .019, OR = 1.564, 95% CI = 1.078-2.269) results.COMT polymorphisms might predict the occurrence of endometriosis.