Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

Positive Thyroid Peroxidase Antibody and Thyroglobulin Antibody are Associated With Better Clinicopathologic Features of Papillary Thyroid Cancer.

OBJECTIVE: To compare the thyroid autoantibody status of patients with papillary thyroid cancer (PTC) and benign nodular goiter as well as possible associations between thyroid autoantibodies and clinicopathologic features of PTC. METHODS: A total of 3934 participants who underwent thyroidectomy were enrolled in this retrospective study. Patients were divided into PTC and benign nodule groups according to pathological diagnosis. Based on the preoperative serum antibody results, PTC patients were divided into thyroid peroxidase antibody (TPOAb)-positive, thyroglobulin antibody (TgAb)-positive, dual TPOAb- and TgAb-positive, or antibody-negative groups. RESULTS: Of the 3934 enrolled patients, 2926 (74.4%) were diagnosed with PTC. Multivariate regression analyses suggested that high thyroid-stimulating hormone levels (adjusted odds ratio [OR] = 1.732, 95% CI [1.485-2.021], P < .001), positive TgAb (adjusted OR = 1.768, 95% CI [1.436-2.178], P < .001), and positive TPOAb (adjusted OR = 1.452, 95% CI [1.148-1.836], P = .002) were independent risk factors for predicting malignancy of thyroid nodules. Multinomial multiple logistic regression analyses indicated that positive TPOAb alone was an independent predictor of less central lymph node metastasis in PTC patients (adjusted OR = 0.643, 95% CI [0.448-0.923], P = .017), whereas positive TgAb alone was significantly associated with less extrathyroidal extension (adjusted OR = 0.778, 95% CI [0.622-0.974], P = .028). PTC patients with dual-positive TPOAb and TgAb displayed a decreased incidence of extrathyroidal extension (adjusted OR = 0.767, 95% CI [0.623-0.944], P = .012) and central lymph node metastasis (adjusted OR = 0.784, 95% CI [0.624-0.986], P = .037). CONCLUSION: Although preoperative positive TPOAb and TgAb are independent predictive markers for PTC, they are also associated with better clinicopathologic features of PTC.

Up-regulation of paired-related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a.

Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). The aim of this study is to investigate whether the transcriptional factor paired-related homeobox 2 (Prrx2) regulates Wnt5a gene expression and the role in myocardial fibrosis following MI. The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodelling was assessed by measuring interstitial fibrosis performed with Masson staining. Cell differentiation was examined by analysis the expression of alpha-smooth muscle actin (α-SMA). Both Prrx2 and Wnt5a gene expressions were up-regulated in mice following MI, accompanied with increased mRNA and protein levels of α-SMA, collagen I and collagen III, compared to mice with sham surgery. Adenovirus-mediated gene knock down of Prrx2 increased survival rate, alleviated cardiac fibrosis, decreased infarction sizes and improved cardiac functions in mice with MI. Importantly, inhibition of Prrx2 suppressed ischaemia-induced Wnt5a gene expression and Wnt5a signalling. In cultured cardiac fibroblasts, TGF-ß increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. Further, overexpression of Prrx2 or Wnt5a mirrored the effects of TGF-ß on cell differentiations of cardiac fibroblasts. Gene silence of Wnt5a also ablated cell differentiations induced by Prrx2 overexpression in cardiac fibroblasts. Mechanically, Prrx2 was able to bind with Wnt5a gene promoter to up-regulate Wnt5a gene expression. In conclusions, targeting Prrx2-Wnt5a signalling should be considered to improve cardiac remodelling in patients with ischaemic heart diseases.

Berberine suppresses the ectopic expression of miR-133a in endothelial cells to improve vascular dementia in diabetic rats.

Objective: Vascular dementia is the second leading cause of dementia, which is strongly associated with diabetes. Ectopic expression of miR-133a in endothelial cells is involved in endothelial dysfunction in diabetes. Whether berberine, as a natural product in Coptis chinensis, improves vascular dementia induced by diabetes remains unknown.Methods: Diabetes and subsequent vascular dementia were induced in rats by injecting streptozotocin (50 mg/kg/day) for five consecutive days. The expression of miR-133a was determined by fluorescence in situ hybridization. The learning and memory were evaluated by step-down, step-through, and morris water maze (MWM) tests.Results: In streptozotocin-injected rats, hyperglycemia dramatically induced miR-133a ectopic expressions in vascular endothelium, reduced GTPCH1 gene expressions and BH4 levels, which were reversed by berberine administration (1.0 g/kg/day, 8 weeks). Hyperglycemia also inhibited acetylcholine-induced vasorelaxation in middle cerebral artery and reduced blood supply to the brain, which were bypassed by berberine. Ex vivo studies indicated that miR-133a agomirs abolished these beneficial effects of berberine on acetylcholine-induced vasorelaxation, while supplement of L-sepiapterin prevented endothelial dysfunction in middle cerebral artery isolated from rats. By performing step-down, step-through, and MWM tests, we observed that hyperglycemia significantly caused the impairments of learning and memory in streptozotocin-injected rats. Importantly, these aberrant phenotypes in diabetic rats were normalized by berberine therapy. Finally, berberine reduced miR-133a expression, and increased both BH4 levels and NO production in cultured endothelial cells treated with high glucose.Conclusion: Berberine improves vascular dementia in diabetes, which is possibly related to the suppression of miR-133a ectopic expression in endothelial cells.

The Differences in the Epidemiology and Predictors of Death between Candidemia Acquired in Intensive Care Units and Other Hospital Settings.

OBJECTIVE: The burden of candidemia is shifting from intensive care units (ICU) to non-ICU settings. This study aimed to define the differences in epidemiology and predictors of death between ICU-acquired candidemia (ICUAC) and non-ICUAC. METHODS: We conducted a retrospective study of 80 patients with ICUAC and 147 patients with non-IUCAC at five hospitals. RESULTS: The distribution of Candida species and resistance to antifungal agents did not differ between the ICUAC and non-ICUAC groups. ICUAC patients received more echinocandins and less triazoles, as well as more adequate antifungal therapy than non-ICUAC patients (all p<0.05). ICUAC patients had a significantly higher average acute physiology and chronic health evaluation (APACHE) II score (21.0±7.9 vs. 17.8±8.6; p<0.01), Sequential Organ Failure Assessment score (9.2±5.5 vs. 7.4±3.9; p<0.05) and day-90 mortality rate (52.5% vs. 36.7%; p<0.05) when compared to non-ICUAC patients. Using a multivariate logistic analysis, adequate antifungal therapy was found to be the only protective factor for death in both groups. Respiratory failure supported with invasive mechanical ventilation, renal failure supported with replacement therapy and an APACHE II score ≥20 were independent predictors of death in ICUAC patients, while age ≥60 years, concurrent bacteremia and APACHE II score ≥20 were independent predictors of death in non-ICUAC patients. CONCLUSION: The Candida species and antifungal resistance profiles in patients with ICUAC were similar to non-ICUAC patients, but led to worse outcomes. The protective and risk factors for death may therefore be relevant for the clinical management of patients with candidemia in ICU and non-ICU settings.

Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload.

Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and ß-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis.

The epidemiology, antifungal use and risk factors of death in elderly patients with candidemia: a multicentre retrospective study.

BACKGROUND: The elderly patients affected by candidemia are growing in proportion to inpatients, but available data are limited. We aimed to determine the epidemiology, antifungal management and clinical risk factors of death in the elderly population with candidemia in China. METHODS: This retrospective study included 63 elderly (≥65 years) and 84 younger patients (16-60 years) at 4 tertiary hospitals. Multivariable logistic regression model was used to identify independent risk factors of death in elderly patients. RESULTS: The distribution of Candida species did not differ between elderly and younger patients (p >0.05). Resistance to fluconazole and voriconazole for non-Candida albicans species in elderly patients was approximately double that in younger patients. Host-related risk factors (e.g., underlying solid tumour, diabetes mellitus and chronic renal failure) and hospital-related factors (e.g., prior stay in an intensive care unit, mechanical ventilation, central vascular and urethral catheters placement) were identified more common in elderly patients. Elderly patients less often received triazoles and were less likely to receive antifungal therapies mostly because elderly or their guardians quit antifungal therapies. APACHE II scores and 30-day mortality were higher for elderly than younger patients (31.7% vs. 16.7%, p =0.032). For elderly patients, antifungal therapy administered before microbiological documentation was the only protective factor for death, whereas absence of antifungal therapies, receipt of mechanical ventilation and APACHE II score ≥20 were independent predictors of death. CONCLUSIONS: Elderly patients with candidemia had poor prognoses characterized by certain host and hospital-related risk factors and special pathogen resistance features. More awareness of the burden of this disease is required, and the absence of antifungal therapies should be avoided to improve the prognoses of elderly patients with this severe infection.

[Comparison of 3-hour and 30-minute infusion regimens for meropenem in patients with hospital acquired pneumonia in intensive care unit: a randomized controlled clinical trial].

OBJECTIVE: To Compare the clinical efficacy and safety of meropenem with a 3-hour extended infusion or conventional 30-minute infusion regimen in treatment of hospital acquired pneumonia (HAP) in intensive care unit (ICU) patients. METHODS: An open-label randomized controlled clinical trial was conducted. 100 HAP patients, admitted to ICU of Qilu Hospital of Shandong University, who needed meropenem therapy were enrolled from September 1st, 2012 to September 30th, 2013. The patients were randomly divided into two groups. Patients who did not conform to the study protocol were excluded. A total of 78 patients were included for the study of clinical efficacy evaluation, with 38 cases in study group, and 40 in control group. The patients in study group received intravenous 1 g of meropenem (dissolved in 40 mL saline) within 10 minutes, and followed by the remaining 750 mg by continuous intravenous infusion for 3 hours, and the treatment was repeated every 8 hours. The patients in control group received meropenem by injection of 1 g (dissolved in 40 mL saline), i.e. by intravenous infusion within 30 minutes every 8 hours. This regime was carried out for at least 7 days. Clinical efficacy, bacterial clearance rate, improvement of critical illness scoring, and safety were observed and compared after meropenem withdrawal between two groups. RESULTS: Compared with control group, the clinical cure rate and 28-day survival rate in study group were significantly increased [clinical cure rate: 71.1% (27/38) vs. 42.5% (17/40), χ² = 6.461, P=0.011; survival rate: 81.6% (31/38) vs. 60.0% (24/40), χ² = 4.364, P=0.037]. The improvement of clinical pulmonary infection score (CPIS) and sequential organ failure assessment (SOFA) score in study group were more marked than those in control group (difference of CPIS score: -3.47 ± 2.48 vs. -1.50 ± 2.48, t=-3.513, P=0.001; difference of SOFA score: -2.10 ± 2.38 vs. -1.00 ± 2.21, t=-0.800, P=0.037). There were no significant differences in duration of meropenem treatment, acute physiology and chronic health evaluation II (APACHEII) score, procalcitonin (PCT), duration of mechanical ventilation, ICU stay days, secondary infection, and bacterial clearance rate between two groups. The main adverse reactions observed were transient elevation of liver enzymes and diarrhea in both groups, but no significant difference in their incidence was found between study and control groups [elevated liver enzymes: 28.9% (11/38) vs. 30.0% (12/40), χ² = 0.010, P=0.919; diarrhea: 7.9% (3/38) vs. 10.0% (4/40), χ² = 0.000, P=1.000]. CONCLUSIONS: Compared with conventional regime of 30-minute infusion of meropenem in the treatment of HAP in ICU patients, the clinical efficacy can be improved, the severity of the disease can be reduced, the recovery of organ failure and long-term prognosis can be improved with 3 hour extended infusion of meropenem.

Antibiotics exposure, risk factors, and outcomes with Candida albicans and non-Candida albicans candidemia. Results from a multi-center study.

OBJECTIVE: To define the differences in antibiotics exposure, risk factors, and outcome in hospitalized patients with Candida albicans (C. albicans) and non-C. albicans candidemia. METHODS: This is a multi-center retrospective study of 132 patients with candidemia from 5 tertiary-care educational hospitals in Shandong, China conducted between January 2009 and June 2010. Fifty-six of 132 (42.4%) patients had candidemia due to C. albicans and 76/132 (57.6%) had non-C. albanians candidemia. RESULTS: Patients with non-C. albicans candidemia received anti-anaerobic agents more often (23.7% versus 8.9%; p=0.027) and beta-lactam/beta-lactamase inhibitors less often (34.2% versus 51.8%; p=0.043) than those with C. albicans candidemia. Independent risk factors of non-C. albicans candidemia were prior anti-anaerobic and antifungal therapies and central venous catheter placement. Overall, 30-day mortality was higher for patients with C. albicans than non-C. albicans candidemia (50% versus 31.6%; p=0.032). Multivariate logistic regression analysis revealed that C. albicans candidemia, advanced age, and concomitant bacteremia were associated with death due to candidemia. CONCLUSION: Patients who received anti-anaerobic or antifungal agents were likely to develop non-C. albicans candidemia. Candida albicans infection was associated with poorer prognosis. An awareness of these factors is needed to guide therapy and decrease the high mortality of candidemia.