Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells.

Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.

Joint Particle Swarm Optimization of Power and Phase Shift for IRS-Aided D2D Underlaying Cellular Systems.

Device-to-device (D2D) communication is a promising wireless communication technology which can effectively reduce the traffic load of the base station and improve the spectral efficiency. The application of intelligent reflective surfaces (IRS) in D2D communication systems can further improve the throughput, but the problem of interference suppression becomes more complex and challenging due to the introduction of new links. Therefore, how to perform effective and low-complexity optimal radio resource allocation is still a problem to be solved in IRS-assisted D2D communication systems. To this end, a low-complexity power and phase shift joint optimization algorithm based on particle swarm optimization is proposed in this paper. First, a multivariable joint optimization problem for the uplink cellular network with IRS-assisted D2D communication is established, where multiple DUEs are allowed to share a CUE's sub-channel. However, the proposed problem considering the joint optimization of power and phase shift, with the objective of maximizing the system sum rate and the constraints of the minimum user signal-to-interference-plus-noise ratio (SINR), is a non-convex non-linear model and is hard to solve. Different from the existing work, instead of decomposing this optimization problem into two sub-problems and optimizing the two variables separately, we jointly optimize them based on Particle Swarm Optimization (PSO). Then, a fitness function with a penalty term is established, and a penalty value priority update scheme is designed for discrete phase shift optimization variables and continuous power optimization variables. Finally, the performance analysis and simulation results show that the proposed algorithm is close to the iterative algorithm in terms of sum rate, but lower in power consumption. In particular, when the number of D2D users is four, the power consumption is reduced by 20%. In addition, compared with PSO and distributed PSO, the sum rate of the proposed algorithm increases by about 10.2% and 38.3%, respectively, when the number of D2D users is four.

Author Correction: Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex.

The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex structure to a resolution of 2.3 Å. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets.

Trough polymyxin B plasma concentration is an independent risk factor for its nephrotoxicity.

AIMS: Data regarding clinical pharmacokinetic/toxicodynamic (PK/TD) of polymyxin B is short of direct quantitative data. This study aims to investigate the risk factors of polymyxin B associated acute kidney injury (AKI) and to assess the relationship between polymyxin B plasma levels and its nephrotoxicity. METHODS: A retrospective study was performed in adult patients treated with polymyxin B. Risk factors associated with AKI and plasma trough concentrations of polymyxin B were identified via medical record review. A multivariate logistic regression model was established and the risk of polymyxin B-associated AKI were predicted by a receiver operating characteristic curve, with maximal Youden index used to identify safety thresholds among the study population. RESULTS: Fifty-four adult patients were included in the study. AKI was detected in 14 patients during polymyxin B treatment (25.9%, 14 out of 54). Cmin (odds ratio [OR] 2.071; 95% confidence interval [CI] 1.235-3.472) and baseline serum creatinine (OR 1.024; 95% CI 1.005-1.043) were significant independent risk factors for developing AKI. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was at maximum, the optimal cut-off point was 6.678 of the ROC curve. When Cmin ≥ 3.13 mg/L, the probability of AKI was more than 50%. CONCLUSION: In this study, when the calculated combined predictor value was >6.678, there was an increased risk of AKI. Maintaining a polymyxin B Cmin level below 3.13 mg/L may be helpful in reducing the incidence of polymyxin B associated nephrotoxicity.

Au-doped MOFs catalyzed electrochemiluminescence platform coupled with target-induced self-enrichment for detection of synthetic cannabinoid RCS-4.

A ternary composite material with Au, Co-based organic frameworks (ZIF-67) and perylene derivatives (PTCD-cys) has been synthesized for identification of synthetic cannabinoids. Through contact with Au-S, Au-ZIF-67 increased electrochemiluminescence (ECL) sensitivity and stability and efficiently catalyzed the ECL of PTCD-cys. Compared with the ECL response of PTCD-cys monomer, the ECL signal value of the composite material was significantly increased, and the onset potential of Au-ZIF-67/PTCD-cys favorably shifted more than that of PTCD-cys/GCE. When the target cannabinoid molecule RCS-4 appeared, Au-ZIF-67 captured and immobilized it on the sensor surface by adsorption to achieve target-induced self-enrichment of RCS-4. Under optimal conditions, the ECL sensor was found to be linearly related to the logarithm of the RCS-4 concentration ranging from 3.1 × 10-15 to 3.1 × 10-9 mol/L with a detection limit (LOD) of 6.0 × 10-16 mol/L (S/N = 3). The approach had the advantages of being simple to use, having a high sensitivity, a wide detection range, and good stability, making it a novel platform for RSC-4 detection in public health safety monitoring.

A lipoprotein lipase-GPI-anchored high-density lipoprotein-binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome.

Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex and its derivative, the LPL-GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3 (ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL-GPIHBP1 fusion protein exhibited high enzyme activity in in vitro assays. Importantly, both intravenous and subcutaneous administrations of the fusion protein lowered triglycerides in several mouse strains without causing adverse effects. These results indicate that the LPL-GPIHBP1 fusion protein has potential for use as a therapeutic for managing FCS.

A novel electrochemiluminescence aptasensor for sensitive detection of kanamycin based on the synergistic enhancement effects between black phosphorus quantum dots and silver-decorated high-luminescence polydopamine nanospheres.

Black phosphorus quantum dots (BPQDs), as a new type of nanomaterial, have excellent electrical and optical properties. In this work, an efficient monitoring method for kanamycin (KAN) was developed based on a sensitive and selective electrochemiluminescence (ECL) aptasensor. The construction of the ECL illuminant was based on BPQDs loaded on silver-nanoparticle modified high-luminescence polydopamine nanospheres (HLPNs@Ag). HLPNs possessed a large specific surface area and strong adhesion, which could support a great deal of BPQDs. Meanwhile, Ag NPs could accelerate the electron-transfer (ET) rate of the sensor and amplify the ECL signal of the BPQDs. Based on the synergistic enhancement effects between the above materials, the as-fabricated nanocomposites exhibited superior ECL performance. With the assistance of a KAN aptamer, the sensor can detect KAN sensitively and selectively. Under optimal conditions, the aptasensor could detect KAN in a wide linear range from 1 × 10-12 to 1.0 × 10-7 M with a detection limit of 1.7 × 10-13 M (S/N = 3). More importantly, this ultra-sensitive and rapid ECL aptasensor-based KAN detection system provided excellent applicability for the monitoring of environmental safety.

Au nanoparticle plasmon-enhanced electrochemiluminescence aptasensor based on the 1D/2D PTCA/CoP for diclofenac assay.

The combination of localized surface plasmon resonance (LSPR) and electrochemiluminescence (ECL) can be an effective way to amplify the signal intensity. In this work, an ECL aptasensor with 3,4,9,10-perylenetetracarboxylic acid-decorated cobalt phosphate (denoted as PTCA/CoP) as the ECL emitter and Au nanoparticles (NPs) as plasma was proposed for diclofenac assay. The prepared PTCA/CoP with special 1D/2D structure exhibited good ability and excellent ECL performance. The diclofenac aptamer acted as a bridge to link the PTCA/CoP and Au NPs; thus, the ECL performance of PTCA/CoP was greatly improved due to the plasma effect of Au NPs. Besides, it was found that the ECL signal of the aptasensor was obviously quenched by the introduction of diclofenac, which might be due to the transformation from the LSPR process to the resonance energy transform (RET) process. Under optimal conditions, the difference of ECL intensity was negatively correlated with the concentration of diclofenac in the range 0.1 pM to 10 µM with a low detection limit of 0.072 pM at the potential of -1.8 V vs. Ag/AgCl (S/N = 3). The aptasensor was proved to be suitable for the detection of diclofenac in real samples, suggesting its great practicability.

Distributed Learning Based Joint Communication and Computation Strategy of IoT Devices in Smart Cities.

With the development of global urbanization, the Internet of Things (IoT) and smart cities are becoming hot research topics. As an emerging model, edge computing can play an important role in smart cities because of its low latency and good performance. IoT devices can reduce time consumption with the help of a mobile edge computing (MEC) server. However, if too many IoT devices simultaneously choose to offload the computation tasks to the MEC server via the limited wireless channel, it may lead to the channel congestion, thus increasing time overhead. Facing a large number of IoT devices in smart cities, the centralized resource allocation algorithm needs a lot of signaling exchange, resulting in low efficiency. To solve the problem, this paper studies the joint policy of communication and computing of IoT devices in edge computing through game theory, and proposes distributed Q-learning algorithms with two learning policies. Simulation results show that the algorithm can converge quickly with a balanced solution.

Low-triggering-potential electrochemiluminescence based on mental-organic frameworks encapsulation of ruthenium for synthetic cathinone detection by coupling photonic crystal light-scattering signal amplification of covalent-organic frameworks.

Developing effective electrochemiluminescence (ECL) platforms is always an essential concern in highly sensitive bioanalysis. In this work, a low-triggering-potential ECL sensor was designed for detecting synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) based on a dual-signal amplification strategy. Initially, a probe was created by integrating Ruthenium into the hollow porphyrin-based MOF (PCN-222) structure to decrease the excitation potential and enhance ECL performance without external co-reaction accelerators. Additionally, for the first time, photonic crystals (PCs) assembled from covalent organic frameworks (COFs) were employed to amplify the ECL signal, thereby increasing the photon flux and the loading capacity of the ECL emitter to enhance sensitivity of the sensor. In the presence of the target MDPV, the aptamer labeled with Ferrocene (Fc) experienced conformational changes, causing Fc to approach the luminophore and resulting in ECL quenching. This effect was attributed to aptamer's conformational changes induced by the target, directly correlating with the target concentration. The constructed sensor showed good linearity with the target MDPV concentration, covering a dynamic range from 1.0 × 10-14 to 1.0 × 10-6 g/L and achieved an ultra-low detection limit of 4.79 × 10-15 g/L. This work employed dual amplification strategies to enhance ECL signals effectively, providing a novel method for developing highly responsive and bioactive sensors.

Dual-binding domain electrochemiluminescence biosensing platform with self-checking function for sensitive detection of synthetic cathinone in e-cigarettes.

Current single signal electrochemiluminescence (ECL) sensors are susceptible to false positive or false negative phenomena due to experimental conditions. Therefore, sensors with "self-checking" function are attracting democratic attention. In quick succession, a highly sensitive single-cathode dual ECL signal aptasensor with self-checking function to improve the shortcomings mentioned above was designed. This aptasensor used In-based metal-organic framework (MIL-68) as load and stabilizer to effectively attenuate the aggregation-induced quenching (ACQ) effect of porphyrin derivatives (Sn-TCPP) while improve ECL stability. The introduction of cooperative-binding split-aptamers" (CBSAs) aptamers increased the specificity of the aptasensor and its unique double-binding domains detection accelerated the detection efficiency. When analyzing 3,4-methylenedioxypyrovalerone (MDPV), we could calculate two concentrations based on the strength of ECL 1 and ECL 2. If the concentrations are the same, the result would be obtained; if not, it should be retested. Depending on the above operation, the results achieve self-check. It was found that the designed aptasensor could quantify the concentration of MDPV between 1.0 × 10-12 g/L and 1.0 × 10-6 g/L with the limit of detection (LOD) of 1.4 × 10-13 g/L and 2.0 × 10-13 g/L, respectively (3 σ/slope). This study not only improves the detection technology of MDPV, but also explores the dual-signal detection of porphyrin for the first time and enriches the definition of self-checking sensor.

Antenna effect of perylene-sensitized up-conversion luminescent material amplifies the signal of electrochemiluminescence biosensor platform for the ultra-sensitive detection of enrofloxacin.

Recently, up-conversion luminescent (UCL) materials have caught extensive sight on account of their excellent biocompatibility and weak automatic fluorescence background, but the low optical signal makes researchers shy away. Organic dye-sensitized UCL materials can improve the low optical signal drawback of UCL and rejuvenate it with adjustable optical properties and unique antenna effects. In this work, an efficient, simple and selective electrochemiluminescence (ECL) sensing platform was developed for determination of enrofloxacin (ENR). 3,4,9,10-perylene tetracarboxylic acid (PTCA) was successfully used as an "antenna" to improve the ECL performance of the UCL nanoparticles (PEI-NaYF4: Yb, Er) due to its appropriate excitation spectrum position and superior electron transfer rate. The specific recognition function of the aptamer enabled the sensor to eliminate the interference from conspecific impurity. In the presence of ENR, the specific combination of ENR with aptamer made the aptamer fall from surface of the electrode, thus we could see a considerable enhancement of signal. Under the most favourable conditions, the aptasensor based on antenna effect displayed a wide detection range (1.0 × 10-14∼1.0 × 10-6 M), low limit of detection (LOD = 3.0 × 10-15 M) and receivable recoveries (96.0%-102.4%) during water samples analysis. At this point, antenna effect provides a powerful strategy to expand the application of UCL in the field of ECL biosensing.

Ultrasensitive electrochemiluminescence sensor for the detection of synthetic cannabinoids based on perovskite as coreaction accelerator and light-scattering effects of photonic crystals.

As is common knowledge, a strong electrochemiluminescence (ECL) signal is required to ensure the high sensitivity of trace target detection. Here, a dual signal amplification strategy by integrating of perovskite and photonic crystal was fabricated for quantitative synthetic cannabinoids (AB-PINACA) detection based on Zr-connected PTCA and TCPP (PTCA-TCPP) with excellent ECL performance as luminophores. On the one hand, the co-reaction accelerator perovskite (LaCoO3) improved the effective electroactive area of the electrode and promoted the decomposition of K2S2O8, resulting in a stronger ECL signal value. On the other hand, polystyrene inverse opal (PIOPCs) formed after the swelling of PS microspheres not only taken advantage of the light scattering effect and excellent catalytic property of photonic crystals to amplify the ECL signal, but also could be used as a binder to fix LaCoO3 and PTCA-TCPP on the electrode surface to generate unprecedented ECL response and stable ECL signals. Subsequently, the detection substance AB-PINACA was loaded on the electrode surface via the amide bond with the luminophores PTCA-TCPP, thus quenching the ECL signal, so as to realize the sensitive detection of synthetic cannabinoids. Under the optimal conditions, the proposed sensor achieved highly sensitive AB-PINACA detection with a dynamic range from 1.0 × 10-12 to 1.0 × 10-3 g/L and the detection limit was 1.1 × 10-13 g/L, which had great application potential in the detection of synthetic cannabinoids.

Highly Efficient Dual-Color Luminophores for Sensitive and Selective Detection of Diclazepam Based on MOF/COF Bi-Mesoporous Composites.

Currently, studies on electrochemiluminescence (ECL) mainly focused on the single emission of luminophores while those on multi-color ECL were rarely reported. Here, a bi-mesoporous composite of the metal-organic framework (MOF)/covalent-organic framework (COF) with strong and stable dual-color ECL was prepared to construct a novel ECL sensor for sensitive detecting targets. A PTCA-COF with excellent ECL performance was loaded with a great amount of another ECL emitter Cu3(HHTP)2. Remarkably, the integrated composite had both ECL properties of PTCA-COF at 520 nm and Cu3(HHTP)2 at 600 nm wavelengths. Furthermore, Cu3(HHTP)2 with good electron transfer ability can greatly enhance the electrical conductivity and promote electrochemical activation. Thus, the simultaneous enhanced two-color ECL intensity and the catalytic properties of the conductive MOF exerted a dual enhancement effect on the ECL signal of the composite. Significantly, diclazepam can not only be adsorbed well on the multi-stage porous structure MOF/COF composite by π-π interactions but also selectively quench the ECL signal of the PTCA-COF, realizing the sensitive detection. The ECL sensor showed a wide detection range from 1.0 × 10-13 to 1.0 × 10-8 g/L, and the limit of detection (LOD) was as low as 2.6 × 10-14 g/L (S/N = 3). The proposed ECL sensor preparation method was simple and sensitive, providing a new perspective for the potential application of multi-color ECL in the sensing field.

Synergistic Multieffect Catalytic Amplified Cathodic Electrochemiluminescence Biosensor via Target Binding-Induced Aptamer Conformational Changes for the Ultrasensitive Detection of Synthetic Cathinone.

Signal amplification is a powerful approach to increasing the detection sensitivity of electrochemiluminescence (ECL). Here, we developed synergistic multieffect catalytic strategies based on CuCo2O4 nanorod combination of Ag NPs as coreaction accelerators to fabricate an efficient covalent organic framework (PTCA-COF)-based ternary ECL biosensor. Concretely, the high redox reversibility of Co3+/Co2+ and Cu2+/Cu+ would constantly promote the decomposition of S2O82- for ECL emission. Meanwhile, the introduction of Ag NPs with excellent electrocatalytic activity further realized multiple amplification of the ECL signal. Furthermore, the good hydrogen evolution reaction (HER) ability of Ag@CuCo2O4 nanorods could accelerate the proton transmission rate of the system to amplify ECL behavior. In the presence of the target synthetic cathinone 4-chloroethcathinone (4-CEC) as the quenching ECL signal-response probe, the Ferrocene (Fc)-labeled aptamer folded into the conformationally limited stem-loop structure, bringing Fc near the ECL luminophore and resulting in quenched ECL emission. The quenching effect was connected with target-induced aptamer conformational changes and consequently reflected the target concentration. Under optimum conditions, the proposed biosensor realized a highly sensitive assay for 4-CEC with a large dynamic range from 1.0 × 10-12 to 1.0 × 10-6 g/L and a detection limit as low as 2.5 × 10-13 g/L. This study integrated multiple amplification strategies for efficient ECL enhancement, which provided a novel approach to constructing highly bioactive and sensitive sensors.

Identification and characterization of novel synthetic cannabinoid ethyl-2-(1-(5-fluoropentyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate (5F-EDMB-PICA).

PURPOSE: The purpose of the current study was to evaluate an analytical characterization of a novel synthetic cannabinoid ethyl-2-(1-(5-fluoropentyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate (5F-EDMB-PICA), which has a similar chemical structure to the controlled synthetic cannabinoid 5F-MDMB-PICA. METHODS: The compound was analyzed by gas chromatography-mass spectrometry (GC-MS), supercritical fluid chromatography-quadrupole time-of-flight-mass spectrometry (SFC-QTOF-MS) and spectroscopic methods, such as attenuated total reflection (ATR)-Fourier transform infrared (FTIR), ultraviolet-visible (UV-VIS) and nuclear magnetic resonance (NMR) spectroscopies. RESULTS: In this study, we reported a comprehensive analytical data of 5F-EDMB-PICA. The data of analytical characterization for the 5F-EDMB-PICA were obtained by GC-MS, SFC-QTOF-MS, ATR-FTIR spectroscopy, UV-VIS spectroscopy, and 1H and 13C NMR spectroscopy. CONCLUSIONS: In this study, we presented a comprehensive analytical characterization of 5F-EDMB-PICA obtained by 1H NMR, 13C NMR, GC-MS, SFC-QTOF-MS, ATR-FTIR spectroscopy and UV-VIS spectroscopy. The analytical data of 5F-EDMB-PICA are very useful for forensic, toxicological, and clinical diagnosis.

Patterning High-Resolution Microstructures on Thermoplastics by Ceramic Nanoparticles Filled Epoxy Coated Molds for Duplicating Nature-Derived Functional Surfaces.

Patterning high-resolution microstructures on thermoplastic substrates is of fundamental importance for the commercialization of microfluidics, advanced functional surfaces, and optical elements. Though many methods are developed to fabricate micropatterned plastic devices with 100 µm resolution, they suffer substantially higher cost or lower productivity when the resolution of the micropatterns is to be further improved. Here, we develop low-cost molds consisting of thin ceramic-filled-epoxy composite coatings on steel substrates. By virtue of the loaded ZrO2 nanoparticle fillers, the enhanced mechanical and thermal properties of the composite molds enable the epoxy microstructures to survive harsh conditions in conventional thermoplastic processing methods including hot embossing, imprinting, and mold injection. With the ceramic-filled-epoxy coated molds, we are able to improve the fabrication resolution of microstructures on plastics to 10 µm with unprecedented low-cost and excellent durability.

Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients.

Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency. Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model. Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25-21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan-Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30-60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min. Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.