Search

Purpose: The purpose of this retrospective observational study conducted in patients with hepatic impairment was to assess the variability of linezolid trough concentrations, to determine the risk factors for linezolid overexposure, and to investigate the effect of linezolid overexposure on linezolid-induced thrombocytopenia. Methods: All enrolled patients received a standard dose (600 mg every 12 h) of linezolid and underwent therapeutic drug monitoring. The Child–Pugh-Turcotte score was used to divide patients into three groups: mild, moderate, and severe hepatic impairment. The risk factors for linezolid overexposure (Cmin > 8 mg/L) and linezolid-induced thrombocytopenia were examined using logistic regression. And the Kaplan–Meier curve was used to describe the association between linezolid overexposure and linezolid-induced thrombocytopenia. Results: Seventy-seven patients were included, 37 (48.1%) of whom experienced linezolid overexposure. Patients with severe hepatic impairment had a substantially higher median Cmin of linezolid than those with mild (20.7 mg/L vs 5.51 mg/L, P < 0.001) or moderate (20.7 mg/L vs 6.70 mg/L, P = 0.001) hepatic impairment. Severe hepatic impairment was significantly associated with linezolid overexposure (OR 7.037, 95%CI 1.426–34.727, P = 0.017). After linezolid treatment, linezolid-induced thrombocytopenia occurred in 32 (41.6%) patients, and Cmin > 8 mg/L was a significant predictor of linezolid-induced thrombocytopenia (OR 3.024, 95%CI 1.083–8.541, P = 0.035). Conclusion: Patients with hepatic impairment who received standard doses of linezolid are at greater risk of linezolid overexposure, which may lead to a higher incidence of linezolid-induced thrombocytopenia. [ABSTRACT FROM AUTHOR]

Laser shock peening (LSP), as a powerful surface engineering technique to improve the fatigue performance of metallic components, requires elaborately designed process pattern to maximize its benefits. In this study, a numerical method, combining finite element method (FEM) and residual stress intensity factor (SIF) analysis, was used to predict the effect of LSP pattern on the crack propagation behavior of the compact tension (CT) samples. The 3D FEM model was fully benchmarked using the mesh sensitivity study and time step calibration. The model was further validated using residual stresses data measured using the X-ray diffraction method. After that, the simulation of LSP of CT sample was conducted using five representative cases, and the corresponding residual stress fields were obtained. A mixed-mode SIF model was then applied to evaluate the effect of the residual stress field in resisting crack propagation. Based on the calculated residual SIFs from different LSP patterns, the best LSP patterns in terms slowing crack propagation speed were identified. To validate the simulation results, LSP experiments were conducted on CT samples using two identified LSP patterns and the crack growth rates were tested. The experiment results were consistent with the numerical prediction. This work demonstrates that FEM model combining residual SIF analysis can be applied to design appropriate LSP patterns on components with complex geometries. [ABSTRACT FROM AUTHOR]

Context: As a glucocorticoid drug, dexamethasone has good therapeutic effects for ulcerative colitis. pH-sensitive hydrogels could make conventional changes of volume in response with different pH values. Meanwhile, they could load drugs depending on its internal three-dimensional network structure. Objective: Appropriate methods were used to improve the drug-loading capacity of hydrogel and exploring the colon-targeting character of dexamethasone hydrogel. Materials and methods: Different solvents (ethanol and 1,2-propanediol) were employed to dissolve dexamethasone as well as hydrogel monomer materials (poly(ethylene glycol) methyl ether (MPEG)–poly(lactide acid)–acryloyl chloride macromonomer, itaconic acid (IA) and MPEG–methacrylate), then mixing them together to prepare hydrogel through the heat-initiated free radical polymerization method. Differential scanning calorimetry and X-ray diffraction methods were used to verify whether dexamethasone was loaded into hydrogels.In vitrodrug release behavior andin vivopharmacokinetic study were also investigated in detail. Results: Dexamethasone was successfully loaded into hydrogel, and its loading capacity was improved (5 mg/g). Both thein vitrorelease study and thein vivopharmacokinetic study showed the good colon-targeting character of the pH-sensitive P(LE–IA–MEG) hydrogel (Tmax = 1.0 h, Cmax = 2.16 µg/ml of dexamethasone; Tmax = 3.9 h, Cmax = 0.43 µg/ml of dexamethasone hydrogel). Discussion: Dexamethasone could be targeted to the colon site by P(LE–IA–MEG) hydrogel, thereby improving its therapeutic effect and reduce its side effects. Conclusion: P(LE–IA–MEG) hydrogel might have great potential application in colon-targeted drug delivery systems. [ABSTRACT FROM AUTHOR]

In our previous study, we synthesized a pH-sensitive hydrogel based on poly (ɛ-caprolactone) (PCL), Pluronic (Poloxamer) and methacrylic acid (MAA) using UV-initiated free-radical polymerization. In the present study, we evaluated the safety of the obtained GMA–PCFC–GMA copolymer and a P(CFC–MAA–MEG) hydrogel both in vitro and in vivo . The pharmacokinetics study and distribution characteristics of dexamethasone in rat blood and mouse colon were investigated in detail. The in vitro toxicity of the GMA–PCFC–GMA copolymer was evaluated using a cell viability assay with HEK293 cells. An acute oral toxicity test was conducted by orally administering mice with a total of 10,000 mg/kg body weight of the P(CFC–MAA–MEG) hydrogel. The mice were then observed continuously for 14 days. After which, they were sacrificed and their blood collected for routine blood and serum chemistry tests. Pharmacokinetic and colonic tissue distribution studies were conducted using high-performance liquid chromatography to detect the concentration of dexamethasone in rat blood and mouse colon tissue. All of the results indicated that both the GMA–PCFC–GMA copolymer and P(CFC–MAA–MEG) hydrogel were nontoxic. Moreover, the hydrogel significantly enhanced the colon-targeting behavior of dexamethasone. These results suggested that the novel hydrogel has great potential in colon-targeted drug delivery. [ABSTRACT FROM AUTHOR]

We have applied both the master equation method and harmonic transition state theory to interpret the velocity-dependent friction behavior observed in atomic friction experiments. To understand the discrepancy between attempt frequencies measured in atomic force microscopy experiments and those estimated by theoretical models, both thermal noise and instrumental noise are introduced into the model. It is found that the experimentally observed low attempt frequency and the transition point at low velocity regimes can be interpreted in terms of the instrumental noise inherent in atomic force microscopy. In contrast to previous models, this model also predicts (1) the existence of a two-slope curve of velocity dependence and (2) the decrease of critical velocity with temperature, which provides clues for further experimental verification of the influence of instrumental noise in friction measurements. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulation and the two-temperature method are carried out to model the effects of substrate roughness as well as electron–phonon coupling on thickness-dependent friction on graphene. It is found that substrate roughness can significantly enhance friction of graphene, which is orders of magnitude larger than that on smooth substrate due to puckering effect. Additionally, the adhesive force between graphene and substrate plays opposite roles for smooth and rough substrates. While on a smooth substrate, a larger adhesion hinders the wrinkle formation in graphene, therefore suppressing friction, on a rough substrate, adhesion helps induce atomic roughness in graphene and leads to friction enhancement. We also incorporate electron–phonon coupling into the atomistic modelling through a two-temperature method, and discover that its effect on friction is very small compared to that of roughness. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulation and atomic force microscopy are used to study the nature of friction between nanoscale tips and graphite step edges. Both techniques show that the width of the lateral force peak as the probe moves up a step is directly correlated with the size and shape of the tip. The origin of that relationship is explored and the similarities and differences between the measurements and simulations are discussed. The observations suggest that the relationship between lateral force peak width and tip geometry can be used as a real-time monitor for tip wear during atomic scale friction measurements. [ABSTRACT FROM AUTHOR]

Slip behavior of three liquids with distinct molecular shapes-linear (hexadecane), branched (pentaerythritol tetra), and a chain of rings (polypheny lether)-is studied using molecular dynamics simulation and reduced-order modeling. Slip at a liquid-solid interface is shown to be affected by the molecular structure of the liquid. A two-dimensional Frenkel-Kontorova model captures the fundamental structural features of the liquid molecules and gives insight into how molecules flex and slip along the surface. We formulate an approximation to the Peierls-Nabarro energy which incorporates both the position of liquid atoms relative to substrate atoms and molecular flexibility. We find that increased molecular flexibility can lead to reduced slip by allowing the liquid to conform epitaxially to the substrate with only a small energetic penalty. Liquid molecules which are less flexible can conform to the substrate only with greater expense of conformational energy, and so exhibit larger slip. [ABSTRACT FROM AUTHOR]

In this methods article, we describe application of Prandtl-Tomlinson models and their extensions to interpret dry atomic-scale friction. The goal is to provide a practical overview of how to use these models to study frictional phenomena. We begin with the fundamental equations and build on them step-by-step-from the simple quasistatic one-spring, one-mass model for predicting transitions between friction regimes to the two-dimensional and multi-atom models for describing the effect of contact area. The intention is to bridge the gap between theoretical analysis, numerical implementation, and predicted physical phenomena. In the process, we provide an introductory manual with example computer programs for newcomers to the field, and an illustration of the significant potential for this approach to yield new fundamental understanding of atomic-scale friction. [ABSTRACT FROM AUTHOR]

Friction between a nanoscale tip and a reconstructed Au(111) surface is investigated both by atomic force microscopy (AFM) and molecular statics calculations. Lateral force AFM images exhibit atomic lattice stick-slip behavior with a superstructure corresponding to the herringbone reconstruction pattern. However, the superstructure contrast is not primarily due to variations in the local frictional dissipation (which corresponds to the local width of the friction loop). Rather, the contrast occurs primarily because the local centerline position of the friction loop is periodically shifted from its usual value of zero. Qualitatively, similar behavior is reproduced in atomistic simulations of an AFM tip sliding on the reconstructed Au(111) substrate. In both simulations and experiments, this centerline modulation effect is not observed on unreconstructed surfaces. Similarly, using a topographically flat surface as a hypothetical control system, the simulations show that the centerline modulation is not caused by variations in the reconstructed surface's topography. Rather, we attribute it to the long-range variation of the local average value of the tip-sample interaction potential that arises from the surface reconstruction. In other words, surface atoms located at unfavorable sites, i.e., in the transition between face-centered-cubic (FCC) and hexagonal-close-packed (HCP) regions, have a higher surface free energy. This leads to a varying conservative force which locally shifts the centerline position of the friction force. This demonstrates that stick-slip behavior in AFM can serve as a rather sensitive probe of the local energetics of surface atoms, with an attainable lateral spatial resolution of a few nanometers. [ABSTRACT FROM AUTHOR]

We introduce a model AFM tip/substrate system that includes full atomistic detail as well as system compliance to study the transitions between three regimes of atomic friction: smooth sliding, stick-single slip, and stick-multiple slip. We characterize these atomic friction regimes in terms of static and dynamic effects, and investigate how the slip modes affect the mean friction. Molecular statics calculations show that reduced-order model predictions of possible transitions between slip regimes are generally adequate for a fully atomistic system, even for complex reaction coordinates. However, molecular dynamics simulations demonstrate that, while static features of the system govern possible slip regimes, dynamic effects ultimately determine actual transitions between slip regimes. [ABSTRACT FROM AUTHOR]

• An analytical model based on the Hertzian contact theory and the Neuber's plasticity law was used to predict residual stresses generated by UNSM. • Simulation was conducted with 18876 sets of UNSM cases to study the impacts of the UNSM parameters. • The effects of UNSM parameters on the residual stress magnitude and depth and surface finish were systematically studied. • A big-data based approach was used to identify the optimal UNSM parameters for different engineering needs. In this work, we have developed a fast and robust analytical model based on the Hertzian contact theory and the Neuber's plasticity law to predict the residual stress generated by ultrasonic nanocrystal surface modification (UNSM). The measured residual stresses data for a number of different metals was used to validate the analytical model. Sensitivity studies as well as the linear regression analysis were conducted to study the effects of UNSM parameters (striking amplitude, static load, spacing, scanning speed and temperature) on the distribution of residual stresses and the surface finish. The analysis shows that a balance between residual stress and surface finish needs to be considered when choosing the UNSM parameters: the increase of ultrasonic striking amplitude and static load improve the magnitude and depth of the residual stress at the risk of deteriorating the surface finish; a higher temperature leads to a lower magnitude but deeper residual stress as well as a better surface finish; smaller tip size can significantly increase the magnitude of residual stresses but it also deteriorates the surface finish. Finally, an experimental design based on a large database (with a total of 18876 sets of UNSM parameters) was introduced to find the optimal UNSM parameters for different engineering needs. [Display omitted] [ABSTRACT FROM AUTHOR]

• The crystal plasticity model describes the plasticity induced in metals by high frequency short duration pulsed currents. • Higher peak current density results in more significant flow stress reduction. • The effects of magnetoplasticity, electron-wind, and Joule heating on the flow stress are studied using the model. A crystal plasticity model incorporating the effects of magnetoplasticity, electron-wind, imbalance of charges near grain boundaries and Joule heating in high frequency short duration electric current pulsed metals has been developed for metals with a face center cubic (FCC) structure. The model decouples the athermal and thermal effects on dislocation activity and quantifies their effects on flow stress. The Joule heating affects the thermal activation in plastic deformation. The magnetoplasticity and electron-wind reduce the slip barrier or contribute additional force to assist dislocation motion. Imbalance of charges near grain boundaries may amplify or minimize the contribution of thermal or other athermal effects. The developed crystal plasticity model has been implemented in DAMASK and verified by simulating electroplasticity in aluminum. The results reveal that the magnetoplasticity reduces flow stress and the reduction increases with the peak current density. Joule heating is generally less important during the processing due to the short pulse duration but becomes more significant when the frequency goes up. The impact of imbalance of charges near grain boundaries on Joule heating depends on the thickness of grain boundaries, the distribution of current density and conductivity, while it always reduces the effect on magnetoplasticity. The electron-wind effect on flow stress is negligible compared to the other three factors. This work provides some new insights in the understanding of electroplasticity in metals. [ABSTRACT FROM AUTHOR]

• Posaconazole pharmacokinetics differ considerably in patients vs. healthy volunteers. • DR-tablet is superior to SUS, with higher and robust F, but it is not equivalent to IV. • There is no evidence to indicate that Chinese patients need different doses to Caucasians. • Consider IV or increase DR-tablet dose with therapeutic drug monitoring for insufficiently exposed patients. To investigate the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics in patients using an integrated population pharmacokinetic model for posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous (IV) infusion that was developed in healthy volunteers (HV). 1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three posaconazole formulations were pooled with 3898 concentrations from 182 HV. Clinical characteristics were tested for significance. The impact of Chinese race was assessed using 292 opportunistic samples from 80 Chinese patients receiving SUS. Bioavailability of SUS (F sus) in patients decreased from 38.2% to 24.6% when the dose was increased from 100 mg to 600 mg. Bioavailability of DR-tablet (F tab) was 59% regardless of dose. Mucositis, diarrhoea, administration through a nasogastric tube, and concomitant use of proton pump inhibitors or metoclopramide reduced F sus by 61%, 36%, 44%, 48%, and 29%, respectively, putting patients with these characteristics at increased risk of inadequate exposure. Clearance decreased from 7.0 to 5.1 L/h once albumin levels were <30 g/L. Patients showed an 84.4% larger peripheral volume of distribution (V p) and 67.5% lower intercompartmental clearance (Q) compared with HV. No racial difference could be identified. Pharmacokinetics of posaconazole in patients differ considerably to those in HV, with altered F sus that is also impacted by clinical covariates, an F tab similar to fasted conditions in HV, and altered parameters for clearance, V p , and Q. There was no evidence to indicate that Chinese patients require a different dose to Caucasian patients. [ABSTRACT FROM AUTHOR]

Over the past few years, therapeutic drug monitoring (TDM) has gained practical significance in antimicrobial precision therapy. Yet two categories of mainstream TDM techniques (chromatographic analysis and immunoassays) that are widely adopted nowadays retain certain inherent limitations. The use of biosensors, an innovative strategy for rapid evaluation of antimicrobial concentrations in biological samples, enables the implementation of point-of-care testing (POCT) and continuous monitoring, which may circumvent the constraints of conventional TDM and provide strong technological support for individualized antimicrobial treatment. This comprehensive review summarizes the investigations that have harnessed biosensors to detect antimicrobial drugs in biological matrices, provides insights into the performance and characteristics of each sensing form, and explores the feasibility of translating them into clinical practice. Furthermore, the future trends and obstacles to achieving POCT and continuous monitoring are discussed. More efforts are necessary to address the four key 'appropriateness' challenges to deploy biosensors in clinical practice, paving the way for personalized antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

• An AUC 24 /MIC of 100 was required to achieve a bacterial51 eradication rate of 80% for sepsis patients treated with linezolid. • An 800 mg/12 h (safety probability 66.8%) dosing regimen was appropriate for sepsis patients with normal renal function or mild kidney damage. • There is a high thrombocytopenia probability with 600 mg/12 h for sepsis patients on CRRT, so dosing should be adjusted based on TDM. Significant alterations in the pharmacokinetic characteristics of linezolid are often seen in sepsis patients. The study aimed to identify a target pharmacokinetics/pharmacodynamics (PK/PD) index of the efficacy of linezolid treatment, and to estimate the optimum dosage regimen of linezolid in sepsis patients. The PK data were modeled using the one-compartment model, which determined the target PK/PD index for successful treatment by logistic regression. The probability of thrombocytopenia was identified by establishing a logistic model. Different dosing regimens were evaluated using Monte Carlo simulation. Reaching 80% bacterial eradication required an AUC 24 /MIC of 100, which defined the therapeutic target. The proposed regimen to attain a cumulative fraction of response ≥80% was 800 mg/12 h (safety probability 66.8%) for sepsis patients with normal renal function or mild kidney damage. By contrast, the target cumulative fraction of response was attained with a standard dosing regimen in sepsis patients on continuous renal replacement therapy [600 mg/12 h (safety probability 49.7%)]. This study identified different dosing strategies to achieve target linezolid PK/PD values according to whether sepsis patients were treated with continuous renal replacement therapy. Due to the high incidence of thrombocytopenia in sepsis patients on continuous renal replacement therapy, therapeutic drug monitoring should be encouraged for optimizing linezolid exposure in sepsis patients. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) remains the most common malignant cancer. We identified 43140 advanced NSCLC patients from the SEER database to develop and validate a new prognostic model. The prognostic performance was evaluated by P value, concordance index, net reclassification index, integrated discrimination improvement, and decision curve analysis. The following variables were contained in the final prognostic model: age, sex, race, TNM stage, and grade and treatment options. Compared to the AJCC staging system, this prognostic model is conducive to the implementation of individualized clinical treatment schemes and can be an important part of the precise medical care of NSCLC tumors. [ABSTRACT FROM AUTHOR]

A recent note by Lu et al. presented a theoretical study of atomic friction using a two-spring Tomlinson model. In this comment, we argue that the conclusion of the note can be understood in a simple manner, and that the discussion of the criterion for the onset of stick-slip is unnecessarily complicated and potentially misleading. [ABSTRACT FROM AUTHOR]

Abstract Being a typical layer structured two-dimensional material, graphene has a high potential as an efficient and atomically-thin solid lubricant. However, the outstanding lubricating property of graphene is found to be seriously impacted by environmental humidity, exhibiting a complicated and sometimes contradicting trend. In this work, the anti-wear performance of graphene was explored by nanoscale scratch tests under different humidities. The experimental results show that wear of graphene primarily occurs at the step edge where dangling bonds are most abundant. In general, humid environment would improve wear resistance of graphene due to dangling bond passivation by condensed water, as confirmed by molecular dynamics simulations. However, for substrate surfaces that can strongly interact with the carbon atoms at the graphene edge, a noticeably improved anti-wear performance, less dependent on humidity, can be observed due to substrate pinning effect. The revealed mechanisms successfully clarify humidity dependence of wear characteristics of graphene on various substrates. The findings also provide a general strategy for improving the performance of graphene in a broad range of mechanical applications. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

An LC-MS/MS method was developed for simultaneous determination of voriconazole and its main metabolite voriconazoleN-oxide in human plasma. Plasma pretreatment was simple one-step protein precipitation with acetonitrile, and separation was achieved on a Hypersil GOLD aQ column. A triple-quadrupole tandem mass spectrometer with electrospray ionization source was operated by multiple reaction monitoring (MRM) in positive ion mode, and the precursor–product ion pairs used for MRM werem/z350.1→281.0, 365.8→224.1, and 531.3→489.2 for voriconazole, voriconazoleN-oxide, and internal standard, respectively. The total analytical run time was 6 min. The proposed method was linear over the range 0.001–1 µg/mL for voriconazole and voriconazoleN-oxide. The lower limit of quantification was 1 ng/mL for both of them. The specificity, accuracy, precision, recovery, matrix effect, stability as well as dilution integrity of this method were within acceptable limits during validation period. This method was successfully applied to therapeutic drug monitoring of voriconazole and to evaluate its metabolite profile. [ABSTRACT FROM PUBLISHER]

Study Objective: Few studies have been conducted to quantify the exposure target of vancomycin in intensive care unit (ICU) patients undergoing continuous renal replacement therapy (CRRT) and provide optimized dosage regimens. We aimed to determine vancomycin exposure target and dosing recommendations using data from an open database in critically ill patients undergoing CRRT. Design: A retrospective observational cohort study. Data Source: A large public database. Patients: The adult patients who received intravenous vancomycin and CRRT treatment in the database between 2017 and 2019 were reviewed to determine eligibility. A total of 180 patients with 1186 observations were included in the population pharmacokinetic (PPK) model development. The clinical efficacy of vancomycin was analyzed in 159 eligible patients. Methods: A PPK model was developed to estimate individual pharmacokinetic (PK) parameters. The area under the concentration‐time curve (AUC) was estimated by a Bayesian approach based on individual vancomycin concentrations. Multivariate logistic regression analyses were performed to identify the factors of clinical outcomes. Threshold of vancomycin exposure in predicting efficacy was identified via receiver operating characteristic (ROC) curve. Dosing recommendations were designed using Monte Carlo Simulations (MCS) based on the optimized exposure target. Measurements and Main Results: On covariate analysis, CRRT intensity significantly affected vancomycin PK. The AUC above 427 mg*h/L was the only significant predictor of clinical efficacy (adjusted odds ratio (aOR): 1.008, 95% confidence interval (CI): 1.004–1.011, p = 0.000). MCS indicated that vancomycin dosage regimens of 5 mg/kg q12h or 7.5 mg/kg q12h were recommended for patients with CRRT intensities of 20–25 mL/kg/h or 25.1–45 mL/kg/h, respectively. Conclusions: An AUC threshold of 427 mg*h/L (assuming the minimal inhibitory concentration (MIC) = 1 mg/L) was a recommended efficacy exposure target of vancomycin for critically ill patients undergoing CRRT. Vancomycin 5–7.5 mg/kg q12h is recommended as the initial dosage regimens for ICU patients undergoing CRRT. [ABSTRACT FROM AUTHOR]

The effect of ultrasonic nanocrystalline surface modification (UNSM) on the water droplet erosion (WDE) performance of Ti 6Al 4V was studied. It was observed that UNSM induces deep levels of compressive residual stresses in both the scanning and transverse directions. The treated surface revealed microdimples in a micro-tracked fashion. Mechanical deformation marks were observed within the grains due to excessive plastic deformation and variation in grain size was observed across the ultrasonically modified layer. Microhardness of the UNSM condition was enhanced significantly as compared with the untreated (As-M) condition. The WDE performance tests for the UNSM and As-M conditions were conducted in a rotating disc rig in accordance with ASTM G73 standard. Influence of impact speed on WDE was explored on two different sample geometries (T-shaped flat and airfoil). WDE results showed that the flat UNSM samples had enhanced WDE performance at speeds 250, 275 and 300 m/s as compared with the As-M condition. At 350 m/s, both UNSM and As-M conditions showed similar performance. UNSM airfoil samples showed mild enhancement in the WDE performance at 300 m/s during the advanced stage as compared with the As-M condition. At 350 m/s, the UNSM airfoils do not show enhancement in WDE performance. [ABSTRACT FROM AUTHOR]

In this study, the plasticity behavior of an AZ31B magnesium alloy subjected to short-duration (100 μs), high-frequency (120–800 Hz) pulsed current was investigated using tensile tests. The key finding is that the effect of pulsed current on plastic deformation goes beyond the Joule heating effect. In our experiments, the frequency was adjusted to maintain a constant effective current density and, thus, the same Joule heating effect. A comparison with continuous current having the same Joule heating effect was made as well. It was observed that when the peak current density is higher than a critical value, a higher peak current density will yield a more significant reduction in flow stress even though the thermal heating effect is the same. This critical current density decreases with the increase in the effective current density. Pulsed current with a higher peak current density can more effectively reduce the dislocation density through electric-induced annealing, induce more severe grain rotation, and, thus, lower the resistance for dislocations to pass through barriers like grain boundaries, resulting in a more significant flow stress reduction. X-ray diffraction characterizations were also conducted for the deformed specimen to show that a higher peak current density induces more severe grain rotation and, thus, more effectively decreases dislocation density. [ABSTRACT FROM AUTHOR]

What Is Known and Objective: There are few reports on the distribution of the plasma trough concentration (Cmin) of teicoplanin in patients with augmented renal clearance (ARC) and on the safety of a high‐dose regimen (HD; 800 mg loading dose for q12h three times followed by an 800 mg qd maintenance dose). The objective of this study was to determine the Cmin values of teicoplanin in ARC patients using HD teicoplanin to provide a reference for individualized medication. Methods: Data on patients treated with teicoplanin from January 2019 to January 2021 were collected retrospectively and divided into ARC (creatinine clearance rate [CCr] >130 ml/min, n = 22) and non‐ARC (60 ml/min ≤ CCr ≤130 ml/min, n = 24) groups. The Cmin values in the two patient groups were analysed during the HD and the low‐dose regimen (LD; all other regimens) on the third day of medication and during the dose maintenance period. Liver and kidney function indexes were also analysed before and after medication. Results and Discussions: On the third day of the HD, Cmin did not differ significantly between the ARC and non‐ARC groups (17.3 ± 9.2 mg/L [mean ± SD] vs. 15.5 ± 7.9 mg/L, p = 0.663), while Cmin in the ARC group was significantly lower for the LD (6.8 ± 3.9 mg/L, p = 0.039). During the dose maintenance period, Cmin in the ARC group when receiving the HD (18.3 ± 5.1 mg/L) was significantly lower than that in the non‐ARC group (25.5 ± 11.9 mg/L, p = 0.016) and significantly higher than that for the LD (12.2 ± 6.3 mg/L, p = 0.022). Nephrotoxicity and hepatotoxicity incidence rates did not differ significantly between these groups. What Is New and Conclusion: These results suggest that it is necessary to apply a loading dose of 800 mg (but not higher) q12h three times for patients with ARC, with 800 mg needed as a maintenance dose during severe infection, and 600 mg or 400 mg for mild infection. [ABSTRACT FROM AUTHOR]

• Etest method is useful for in vitro testing of combination antifungal therapy. • A combination of caspofungin and triazoles was effective for Candida infections. • Caspofungin and triazole combination was effective for Candida. glabrata with FKS mutation. Increased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. In this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). For Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata , direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. A combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure.Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included.A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid.In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.Methods: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure.Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included.A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid.In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.Results: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure.Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included.A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid.In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.Conclusion: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure.Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included.A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid.In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid. [ABSTRACT FROM AUTHOR]

• The quality of CPGs for CRGNB treatment was heterogeneous among different domains. • The highest domain score of methodological quality was for 'clarity of presentation'. • The quality of 'stakeholder involvement' and 'applicability' domains were suboptimal. • The overall reporting quality was imperfect, with proportions between 45.7 and 85.7%. • Both monotherapy with novel drugs and combination therapy are important strategies. This study aimed to appraise clinical practice guidelines (CPGs) for the treatment of carbapenem-resistant Gram-negative Bacilli (CRGNB) infections and to summarise the recommendations. A systematic search of the literature published from January 2012 to March 2023 was undertaken to identify CPGs related to CRGNB infections treatment. The methodological and reporting quality of eligible CPGs were assessed using six domains of the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool and seven domains of the Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist. Basic information and recommendations of included CPGs were extracted and compared. A total of 21 CPGs from 7953 relevant articles were included. The mean overall AGREE II score was 62.7%, and was highest for "clarity of presentation" (90.2%) and lowest for "stakeholder involvement" (44.8%). The overall reporting quality of all of the CPGs was suboptimal, with the proportion of eligible items ranging from 45.7 to 85.7%. The treatment of CRGNB infections is related to the type of pathogen, the sensitivity of antimicrobial agents, and the site of infection. In general, the recommended options mainly included novel β-lactam/ β-lactamase inhibitors, cefiderocol, ampicillin-sulbactam (mainly for carbapenem-resistant Acinetobacter baumannii [CRAB]), and combination therapy, involving polymyxin B/colistin, tigecycline (except for carbapenem-resistant Pseudomonas aeruginosa), aminoglycosides, carbapenems, fosfomycin, and sulbactam (mainly for CRAB). The methodological and reporting quality of CPGs for the treatment of CRGNB infections are generally suboptimal and need further improvement. Both monotherapy with novel drugs and combination therapy play important roles in the treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30–35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6–8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8–10 mg/kg every 24 h was optimal under 30–35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin. [ABSTRACT FROM AUTHOR]

Background: Bacterial infections are common complications in patients with cirrhosis or liver failure and are correlated with high mortality. Clinical practice guideline (CPG) is a reference used to help clinicians make decisions. This systematic appraisal aimed to evaluate the methodological quality and summarize the recommendations of reported CPGs in these patients.Methods: We systematically searched CPGs published from 2008 to 2019. The methodological quality of the included CPGs was assessed using the AGREE II instrument. We extracted and compared recommendations for prophylactic and empirical treatment strategies.Results: Fourteen CPGs with a median overall score of 56.3% were included. The highest domain score was Clarity of Presentation (domain 4, 85.4%), and the lowest was for Stakeholder Involvement (domain 2, 31.3%). Three CPGs had an overall score above 80%, and 6 CPGs had a score above 90% in domain 4. Prophylaxis should be strictly limited to patients with varicose bleeding, low ascites protein levels and a history of spontaneous bacterial peritonitis. Fluoroquinolones (norfloxacin and ciprofloxacin), third-generation cephalosporins (G3) (ceftriaxone and cefotaxime) and trimethoprim-sulfamethoxazole (SXT) are recommended for preventing infections in patients with cirrhosis or liver failure. G3, β-lactam/β-lactamase inhibitor combinations (BLBLIs) and carbapenems are recommended as the first choice in empirical treatment according to local epidemiology of bacterial resistance.Conclusions: The methodological quality of CPGs focused on patients with cirrhosis or liver failure evaluated by the AGREE II instrument is generally poor. Three CPGs that were considered applicable without modification and 6 CPGs that scored above 90% in domain 4 should also be paid more attention to by healthcare practitioners. Regarding recommendations, norfloxacin, ciprofloxacin, ceftriaxone, cefotaxime, and SXT are recommended for prophylactic treatment appropriately. G3, BLBLIs, and carbapenems are recommended for use in empirical treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: Severely ill Intensive Care Unit (ICU) patients have an increased risk of developing multiresistant Gram-positive infections, largely due to the inappropriate use of antimicrobials. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid, an antibiotic against Gram-positive infections, was characterised in eight critically ill patients admitted to the ICU. Remarkable variation amongst patients in the PK parameters of linezolid was observed, including a 5–7-fold difference in peak serum concentration (C max) (mean±standard deviation 15.70±6.58mg/L) and 12-h area under the serum concentration–time curve (AUC0–12) (96.73±56.45mgh/L), although the minimum inhibitory concentration (MIC) was similar amongst patients. In particular, variation amongst patients was found in the ratio of AUC0–24/MIC (range 31.66–216.82, mean 96.73) and the percentage of time that the serum concentration exceeded the MIC (T >MIC) (range 53.4–100%), two parameters used to predict linezolid efficacy. These variations highlight the importance of individual monitoring of linezolid PK/PD properties in critically ill patients. Furthermore, it was observed that regardless of AUC0–24/MIC and T >MIC values, the clinical and microbiological responses of patients were primarily affected by the individual''s pathophysiological condition. In summary, these findings point to highly variable PK/PD properties of linezolid in severely ill patients, providing the rationale for targeting linezolid dosage to each individual patient''s specific properties. An optimal dosage regimen based on individual PK/PD properties and pathophysiological conditions will help reduce the occurrence of resistance in Gram-positive bacteria. [Copyright &y& Elsevier]

Rationale: In order to characterize the intracellular pharmacokinetic properties of tigecycline, we developed and fully validated a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantification of tigecycline in human lung epithelial (BEAS‐2B) cells and polymorphonuclear neutrophils (PMNs). Methods: Tetracycline was used as an internal standard and chromatographic separation was achieved on a C18 Hypersil Gold aQ column using two mobile phases, a solution of water (containing 0.1% formic acid) and acetonitrile. The flow rate was 0.4 mL/min for 5.0 min. Tigecycline drug uptake was evaluated by incubating the BEAS‐2B cells and the PMNs for up to 3 h at tigecycline concentrations of 1 mg/L. Results: The assay was linear over the tested concentration range of 0.01–2 mg/L for tigecycline in BEAS‐2B cells and PMNs (r2 >0.99). The inter‐ and inter‐day precisions (RSD, %) were <10.02% and the accuracies (%) were within the range of 85–115%. The uptake study showed that after incubation with tigecycline (1 mg/L) for 3 h at 37°C, the intracellular peak concentration of BEAS‐2B cells was 14.44 ± 7.12 mg/L at 1 h, and 41.43 ± 25.66 mg/L in PMNs at 20 min. The mean intracellular concentrations fluctuated in the range of 0.8–14.44 mg/L in BEAS‐2B cells and 10.14–41.43 mg/L in PMNs for 1 mg/L tigecycline exposure. Conclusions: Validated LC/MS/MS is a simple, rapid, and sensitive method for determining the intracellular concentration of tigecycline, and tigecycline has good penetrations both in human BEAS‐2B cells and PMNs. The method can be efficiently used for future studies of the intracellular pharmacokinetics of tigecycline. [ABSTRACT FROM AUTHOR]

Background: Cirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics, and optimal regimens of voriconazole are currently not well defined in cirrhotic patients. Design: Retrospective pharmacokinetics study. Setting: Two large, academic, tertiary‐care medical center. Patients: Two hundred nineteen plasma trough concentrations (Cmin) from 120 cirrhotic patients and 83 plasma concentrations from 11 non‐cirrhotic patients were included. Methods: Data pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model‐based simulation was used to optimize voriconazole dosage regimens. Results: Voriconazole‐related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold Cmin for AE was 5.12 mg/L. A two‐compartment model with first‐order elimination adequately described the data. The Child‐Pugh class and body weight were the significant covariates in the final model. Voriconazole clearance in non‐cirrhotic, Child‐Pugh class A and B cirrhotic (CP‐A/B) and Child‐Pugh class C cirrhotic (CP‐C) patients was 7.59, 1.86, and 0.93 L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model‐based simulations showed that a loading dose regimen of 200 mg/12 hours intravenously or orally led to 65.0–75.7% of voriconazole Cmin in therapeutic range on day 1, and the appropriate maintenance dosage regimens were 75 mg/12 hours and 150 mg/24 hours intravenously or orally for CP‐A/B patients, and 50 mg/12 hours and 100 mg/24 hours intravenously or orally for CP‐C patients. The predicted probability of achieving the therapeutic target concentration for optimized regimens at steady‐state was 66.8–72.3% for CP‐A/B patients and 70.3–74.0% for CP‐C patients. Conclusions: These results recommended that the halved loading dose regimens should be used, and voriconazole maintenance doses in cirrhotic patients should be reduced to one‐fourth for CP‐C patients and to one‐third for CP‐A/B patients compared to that for patients with normal liver function. [ABSTRACT FROM AUTHOR]

This study explored the corrosion resistance of 7075-T6 aluminum alloy by immersing it in a 3.5% NaCl solution to induce corrosion damage, and subsequently repairing the sample surface using ultrasonic nanocrystal surface modification (UNSM). UNSM was found to effectively repair the defects on the surface of the pre-corroded sample and improve its stress corrosion crack (SCC) resistance. The improvement in corrosion resistance and SCC resistance of sample was mainly due to the compressive residual stress and grain refinement caused by UNSM, which not only improved the pitting resistance but also effectively inhibited the initiation and extension of stress corrosion cracks. • UNSM refined the grains and increased the hardness of the surface layer. • UNSM introduced compressive residual stresses in the surface layer. • UNSM improved the corrosion resistance and SCC resistance of aluminum alloy. • UNSM can effectively repair corrosion damage of aluminum alloy. [ABSTRACT FROM AUTHOR]

A surface ceramic protective film was prepared on Ti-6Al-4V alloy using laser-assisted ultrasonic nanocrystal surface modification technology (LA-UNSM). The uniform ceramic protective film, which was comprised of Al 2 O 3 and small amounts of TiO 2 and TiN, showed very strong adhesion to the substrate. LA-UNSM treatment dramatically increased the dislocation density and atomic diffusion rate by introducing thermomechanical activation energy, which further greatly reduced the energetic barriers of the oxide to nitride nucleation and growth. Due to the formation of a ceramic protective film and a nanocrystalline gradient reinforcement layer on the sample surface, the surface hardness was dramatically enhanced after LA-UNSM treatment. The electrochemical corrosion behavior in simulated seawater and the fretting wear behavior of samples were also investigated. The results revealed the ceramic protective film and gradient nanocrystalline layer introduced by LA-UNSM could substantially reduce the corrosion current density by 83 % and the wear volume by 90 % as compared to control samples. These results show that LA-UNSM effectively promotes the corrosion and wear property of titanium alloy through forming a ceramic protective film. [Display omitted] • A surface ceramic protective layer was rapidly formed through LA-UNSM. • Significant surface hardening was achieved through grain refinement, work-hardening and the formation of the ceramic phase. • The corrosion resistance and fretting wear resistance of Ti-6Al-4V alloy were dramatically improved through LA-UNSM. [ABSTRACT FROM AUTHOR]

• Probability characteristics of the partition curve were analyzed. • The differential partition curve is asymmetric and fat-tailed. • A skew normal-Laplace model with three parameters was developed. • Accuracy and ability of this model were validated by comparison with other models. • The parameters transformation law when the separation density changed was provided. The mathematical model of partition curve is fundamental to evaluate and predict the gravity separation performance in coal cleaning industry. Existing models have achieved good fitting accuracy but lack explicit physical meanings. From the perspective of probability and error distribution, the common characteristics of actual partition curve and its differential curve were analyzed according to the generalized central limit theorem. A skew normal-Laplace (SNL) model with three parameters was established based on asymmetry and fat tail characteristics. Parameters in the SNL model represent location, scale and skewness of partition curve, which reflect separation density and error distribution, therefore it is convenient to evaluate the efficiency of the whole process. Compared with the existing models, the SNL model achieved smaller deviation with fewer parameters and conformed better to physical reality. For practical application, the parameters transformation law when separation density changed was provided according to their properties. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations are performed to study the frictional behavior of graphene. It is found that the friction between a diamond tip and graphene decreases with increasing number of graphene layers. This behavior is also affected by the graphene sheet size; specifically, the effect of the number of layers on friction becomes significant only when the modeled graphene sheets exceed a critical length. We further show that the frictional behavior can be directly correlated to the height of near-contact wrinkles that resist sliding. These observations are rationalized in terms of the ability of multiple sheets to act as a single material as they resist wrinkle formation. [ABSTRACT FROM AUTHOR]

In this study, boron carbide (B 4 C) was reactively sputtered with acetylene to form a boron containing diamond-like carbon (DLC) coating. The flow rate of acetylene significantly affects the composition and thus the mechanical behavior of the coating. When optimal acetylene flow rate was used (10 sccm in this study), the coating has a B/C ratio of ~1% and possesses the high hardness of B 4 C and the low friction of DLC in addition to good adhesion with the 52100 steel substrate. It was found that the new coating consisted of nanocrystalline boron carbide precipitates homogeneously distributed in an amorphous hydrocarbon matrix forming a boron-doped a-C:H film. The new coating exhibited wear resistance superior to a commercial W-doped DLC coating currently used on rolling element bearings and gears. The best wear resistance and lowest friction coefficients were obtained in coatings with a B/C ratio of ~1%. • Boron carbide was reactively sputtered with acetylene to form a boron containing diamond-like carbon (DLC) coating. • Boron carbide precipitates homogeneously distribute in an amorphous hydrocarbon matrix forming a boron-doped a-C:H film. • The new coating combines the high hardness of boron carbide and the low friction of DLC. • Its wear resistance is superior to a commercial W-doped DLC coating currently used on rolling element bearings and gears. [ABSTRACT FROM AUTHOR]

What is known and objective: Caspofungin is commonly used in kidney transplant patients for prophylaxis or treatment of invasive fungal infections (IFIs) caused by Candida spp. and Aspergillus spp. Factors such as concomitant medications, co‐morbidity and rejection often cause caspofungin pharmacokinetic parameters alterations in kidney transplant patients. Here, we aimed to investigate factors influencing caspofungin plasma concentrations and evaluate its prophylaxis and treatment efficiency for IFIs in kidney transplant patients. Methods: The prophylaxis and treatment efficiency of caspofungin for IFIs were assessed in 164 kidney transplant patients in the study. Six hundred and fifty‐two caspofungin trough concentrations (Cmin) from the 164 patients were monitored by the liquid chromatography‐tandem mass spectrometry method. Basic demographic variables, baseline disease, surgery, rejection, indwelling catheter, coinfection, concomitant medication and other caspofungin‐related factors were collected. Univariate and multivariate analyses were used to assess factors influencing caspofungin plasma concentrations. Results and discussion: The success rates were 94.96% (132/139) for caspofungin prevention and 80% (20/25) for caspofungin for IFIs. Caspofungin Cmin in the kidney recipients varied largely compared with healthy volunteers (0.10‐12.25 mg/L vs. 1.12‐1.78 mg/L). Caspofungin Cmin significantly increased in patients with continuous renal replacement therapy before transplantation (P =.001), concomitant medication of cyclosporine A (CsA, P =.009), ALB concentration of > 30 g/L (P =.019). What is new and conclusion: This is an uncontrolled observational study of caspofungin as prophylaxis or treatment for IFIs in kidney transplant patients. Caspofungin could be an effective and well‐tolerated option for antifungal prophylaxis and treatment in kidney transplant patients, and a number of factors could influence caspofungin Cmin in these patients. [ABSTRACT FROM AUTHOR]

A vancomycin steady‐state trough concentration (Cmin) of 15‐20 mg/L is recommended for achieving a ratio of the 24‐hour area under the curve to the minimum inhibitory concentration (AUC0‐24/MIC) of ≥400 in adults. Since few paediatric data are available, our objectives were to (a) measure the pharmacokinetic indices of vancomycin and (b) determine the correlation between Cmin and AUC0‐24/MIC in paediatric patients. Population‐based pharmacokinetic modelling was performed for paediatric patients to estimate the individual parameters. The relationship between Cmin and the calculated AUC0‐24/MIC was explored using linear regression and a probabilistic framework. A sensitivity analysis was also conducted using Monte Carlo simulations. Body‐weight significantly influenced the pharmacokinetics of vancomycin. Based on real data and simulations, Cmin ranges of 5.0‐5.9 and 9.0‐12.9 mg/L were associated with AUC0‐24/MIC ≥400 for MIC values of ≤0.5 and ≤1 mg/L, respectively. Vancomycin regimens of 10 and 15 mg/kg every 6 hours achieved a Cmin of 5.0‐5.9 mg/L and AUC0‐24/MIC ≥400 in >90% of the children when MIC was ≤0.5 mg/L. At a MIC of ≤1 mg/L, vancomycin at 15 mg/kg every 6 hours achieved Cmin of 9.0‐12.9 mg/L and AUC0‐24/MIC ≥400 in 2.0‐ and 1.6‐fold as many children compared to a dose of 10 mg/kg every 6 hours, respectively. Vancomycin Cmin values of 5.0‐12.9 mg/L were strongly predictive of achieving AUC0‐24/MIC ≥400, and rational dosing regimens of 10‐15 mg/kg q6h were required in paediatric patients, depending on the pathogen. [ABSTRACT FROM AUTHOR]

• The methodological quality of guidelines for treatment on candidiasis is suboptimal. • Only the ESCMID guideline had a quality score >70% in all domains except applicability. • The CPGs noted an important role for fluconazole as an initial drug in prophylaxis. • Echinocandins are considered preferred in both empirical and targeted therapy. • The timing of initiating prophylaxis and empirical/pre-emptive therapy are unclear. Recommendations in clinical practice guidelines (CPG) may differ and cause confusion. Our objective was to appraise CPGs for antifungal treatment of invasive candidiasis (IC) in non-neutropenic critically ill adult patients. We systematically searched the literature for CPGs published between 2008 and 2018. We assessed the quality of each guideline using six domains of the AGREE II instrument. We extracted and compared recommendations for different treatment strategies and assessed content quality. Of 19 guidelines, the mean overall AGREE II score was 58%. The domain 'clarity of presentation' received the highest scores (88%) and 'applicability' the lowest (18%). CPGs provided detailed recommendations on antifungal prophylaxis (n = 10), with fluconazole recommended as initial prophylaxis in all seven CPGs citing a specific drug. Echinocandin was recommended as the initial drug in all 16 CPGs supporting empirical/pre-emptive treatment; and in 18 of 19 for targeted invasive candidiasis treatment. However, it remains unclear when to initiate prophylaxis, empirical or pre-emptive therapy or when to step down. The methodological quality of CPGs for antifungal treatment of IC in non-neutropenic critically ill patients is suboptimal. Some treatment recommendations were inconsistent across indications and require local guidance to help clinicians make better informed decisions. [ABSTRACT FROM AUTHOR]

In this research, a surface plastic deformation layer was induced on 300M ultra-high strength steel using ultrasonic nanocrystal surface modification (UNSM). The UNSM-treated and control specimens were then nitrided at 450 °C for 6 h. After gas nitriding, the microstructure, corrosion and wear resistance of 300M steel with and without UNSM pre-treatment were investigated. After nitriding, the UNSM-treated specimens generated a dense surface nitride layer that was thicker than that of the control specimens. The high defect density and refined lath martensite induced by UNSM were found to accelerate the nitrogen diffusion and efficiency. X-ray diffraction patterns revealed that α-Fe phase occupied the largest proportion in the nitriding layer of specimens without UNSM pre-treatment. However due to the higher nitriding efficiency, the main phase of UNSM-treated specimens after nitriding was found to be ε-Fe 2-3 N. Compared with the specimens without pre-treatment, UNSM-treated specimens exhibited higher surface hardness as well as higher corrosion and wear resistance after nitriding. Unlabelled Image • Refined and distorted lath martensite generated in UNSM-treated 300M steels resulted in much higher nitriding efficiency. • UNSM + nitriding generated a denser and deeper surface nitride layer that contributed to higher corrosion resistance. • UNSM + nitriding induced high surface hardness that contributed to higher wear resistance of 300M steel. [ABSTRACT FROM AUTHOR]

In this study, an innovative surface treatment method, electropulsing assisted laser shock peening (EP-LSP), was used to process Ti64 samples. In EP-LSP, metallic samples are subjected to simultaneous high strain rate plastic deformation and high-frequency (100–500 Hz) short-duration (100 μs) pulsed electric current. The effects of EP-LSP on surface finish, microstructure, and micro-hardness of Ti64 alloy were investigated and compared with continuous current assisted LSP (CC-LSP) having the same bulk heating effect. It was observed that EP-LSP produced higher surface hardness and deeper hardened layer, both of which indicate greater plastic deformation. Tensile tests were carried out to evaluate the plasticity of Ti64 subjected to pulsed current and continuous current with the same bulk heating effect. It was observed that pulsed current can more effectively decrease the flow stress and thus resulted in greater plasticity in Ti64 compared with continuous current, even though the bulk heating effect was the same. In addition, the higher the peak current density, the more effective the flow stress reduction. As a result, pulsed current can more effectively improve the effectiveness of LSP treatment, as manifested by higher surface hardness and deeper plastic deformation layer. It is believed that an athermal effect in addition to the thermal effect related to pulsed current exists in EP-LSP. • EP-LSP results in higher surface hardness and deeper hardened layer compared with LSP. • Higher peak current density leads to more effective EP-LSP treatment. • Pulsed current is more effective in improving the plasticity of Ti64 compared with continuous current. • An athermal effect that cannot be explained by resistive heating exists in EP-LSP. [ABSTRACT FROM AUTHOR]

Previously, we reported that 3, 4-oxo-isopropylidene-shikimic acid (ISA) has therapeutic potential in experimental colitis in rats. This study aimed to elucidate the potential mechanisms of ISA on the inflammatory response in rats with 2, 4, 6-trinitrobenzenesulfonic acid-induced colitis. After the induction of colitis, rats were orally administered ISA for 12 days. Then, the expression levels of inflammatory cytokines, cell adhesion molecules, and matrix metalloproteinase (MMP) in the blood and colon tissues, and the protein level of nuclear factor kappa B (NF-κB) p65 in cytoplasm and nucleus of colon tissues were evaluated. As a result, an enhanced inflammatory response was observed in rats with experimental colitis. However, the treatment with ISA significantly ameliorated the inflammatory response, which was manifested as a significant decrease in the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, IL-8, TNF-α mRNA, P-selectin, E-selectin, intercellular cell adhesion molecule-1, MMP9 and MMP9 mRNA in rat blood and colon tissues, respectively, and a significant decrease in the levels of IFN-γ/IL-4, and the NF-κBp65 activity coefficient. Therefore, the therapeutic effect of ISA on experimental colitis may be related to its inhibitory effect on the expression of cytokines, adhesion molecules, and MMP9, which may be involved in the inhibition of the activation and nuclear translocation of NF-κBp65. [ABSTRACT FROM AUTHOR]

Voriconazole (VOR) – induced liver injury is a common adverse reaction, and can lead to serious clinical outcomes. It is of great significance to describe the metabolic characteristics of VOR – induced liver injury and to elucidate the potential mechanisms. This study investigated the changes of plasma metabolic profiles in a rat model of VOR – induced liver injury by non – targeted metabolomics. Correlation analysis was performed between differentially expressed metabolites and plasma liver function indexes. The metabolites with strong correlation were determined for their predictive performance for liver injury using receiver operating characteristic (ROC) curve analysis. Potential biomarkers were then screened combined with liver pathological scores. Finally, the expression level of genes that involved in lipid metabolism were determined in rat liver to verify the mechanism of VOR – induced liver injury we proposed. VOR – induced liver injury in rats was characterized by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, the lipid droplets accumulation in liver, as well as inflammation and fibrosis. Significant changes of plasma metabolites were observed, with a decrease in lipid metabolites accounting for over 50% of all changed metabolites, and alterations of cholesterol and bile acids metabolites. The decrease of 3 phosphatidylcholine (PC) in plasma could indicate the occurrence of VOR – induced liver injury. Decreased fatty acids (FA) oxidation and bile acid excretion might be the potential mechanisms of VOR – induced liver injury. This study provided new insights into the molecular characterization of VOR – induced liver injury. [Display omitted] • Voriconazole induced lipid accumulation, inflammation and fibrosis in rat liver. • Non – targeted metabolomics analysis of rat plasma revealed abnormal metabolism. • 3 phosphatidylcholine might be potential biomarkers. • Decreased fatty acids oxidation and bile acid excretion might the mechanisms. [ABSTRACT FROM AUTHOR]

Herein, hyaluronic acid (HA) and β-cyclodextrin (β-CD) is used to form targeted drug delivery platform HCPC/DEX NPs with previously prepared carbon dots (CDs) as cross-linker, dexamethasone (DEX) is loaded for rheumatoid arthritis (RA) treatment. The drug loading capacity of β-CD and M1 macrophage targeting of HA were utilized for efficient delivery of DEX to the inflammatory joints. Because of the environmental responsive degradation of HA, DEX can be released in 24 h and inhibit the inflammatory response in M1 macrophages. The drug loading of NPs is 4.79 %. Cellular uptake evaluation confirmed that NPs can specifically target to M1 macrophages via HA ligands, the uptake of M1 macrophages is 3.7 times that of normal macrophages. In vivo experiments revealed that NPs can accumulate in RA joints to alleviate inflammation and accelerate cartilage healing, the accumulation can be observed in 24 h. The cartilage thickness increased to 0.45 mm after HCPC/DEX NPs treatment, indicating its good RA therapeutic effect. Importantly, this study was the first to utilize the potential acid and reactive oxygen species responsiveness of HA to release drug and prepare M1 macrophage targeting nanodrug for RA treatment, which provides a safe and effective RA therapeutic strategy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Severe plastic deformation behavior of AM repaired Ti-6Al-4V alloy samples subjected to LA-UNSM treatment was thoroughly investigated. • Sufficient grain refinement, with a mix of elongated and ultra-fine grains, was produced on the surface of the LA-UNSM sample, eliminating larger columnar grains. • Improved roughness, hardness, compressive stress, and fatigue life were achieved after LA-UNSM treatment. • Fatigue life was enhanced by LA-UNSM's work hardening and dynamic precipitation effects. Ultrasonic nanocrystal surface modification (UNSM) combined with localized laser heating (LA) were implemented to enhance the surface fatigue life of additively repaired Ti-6Al-4V alloy parts in this study. The effect of induced surface severe plastic deformation on microstructure development and grain refinement is analyzed. The results showed that surface metallurgical defects, hardness, residual stress, and roughness were significantly improved after LA-UNSM treatment. As a result of the improved surface textures and higher grain refinement, the fatigue life of the LA-UNSM treated samples was an order of magnitude longer. Surface free of pores and displaying a healthy topography provides evidence. [ABSTRACT FROM AUTHOR]

Based on the biocompatibility and macrophage targeting of natural polysaccharides, combined with the physiological and pathological characteristics of the gastrointestinal tract and colonic mucosa of ulcerative colitis (UC), we prepare dexamethasone (Dex)-loaded oral colon-targeted nano-in-micro drug delivery systems coated with multilayers of chitosan (CS), hyaluronic acid (HA), and finally Eudragit S100 (ECHCD MPs) using a layer-by-layer coating technique for UC treatment through regulating the M1/M2 polarization of intestinal macrophages. HA/CS/Dex nanoparticles (HCD NPs) are ingested by macrophages via CD44 receptor-mediated endocytosis to regulate M1-to-M2 macrophage polarization and exert anti-inflammatory effects. Moreover, ECHCD MPs show better colon-targeting properties than Dex-loaded chitosan nanoparticles (CD NPs) and HCD NPs which is demonstrated by stronger mucoadhesion to inflamed colon tissues. After oral administration, ECHCD MPs exert significant anti-UC effects. Therefore, ECHCD MPs are proven to be as promising oral colon-targeting drug delivery systems for Dex and have potential application in UC treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract It was recently reported that the presence of vacancy could dramatically increase nanoscale friction of graphene, while its underlying mechanism remains unknown [1]. In this study, molecular dynamics simulation is carried out to examine the possible mechanisms that could contribute to friction enhancement on chemically modified and/or vacancy-contained graphene. It is found that the change in out-of-plane flexibility due to vacancies has only a limited influence on friction. In contrast, the Schwoebel barrier, the chemical reactivity of dangling bonds at the atomic step edges, as well as the roughening induced by functional groups can contribute more to nanoscale friction of graphene. This study provides a friction-mechanism map that correlates frictional behavior to various atomic scale mechanisms, which is useful for understanding the nanoscale friction of defected graphene. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract Surface severe plastic deformation (SSPD) can significantly improve the mechanical properties of metallic components by inducing surface nanocrystallization and beneficial compressive residual stresses. The effectiveness of the SSPD processes is significantly dependent on the plasticity of the target metals. Here, we report an innovative surface thermomechanical process called laser-assisted ultrasonic nanocrystal surface modification (LA-UNSM) that integrates localized laser heating with high strain rate plastic deformation. The laser beam locally heats the target metal and increases the local plasticity, making the SSPD treatment more effective. After LA-UNSM, a microstructure featuring a nanocrystalline layer embedded with nanoscale precipitates was achieved in Ti64, resulting in an unprecedented 75.2% increase in hardness. After LA-UNSM processing, a 25-μm severe plastic deformation layer was produced that was 2.5 times thicker than that of the room-temperature UNSM-processed material. The grains at the top surface were refined down to 37 nm, indicating a similar degree of nanocrystallization to that produced by UNSM at room temperature. Nanoscale precipitate particles with diameters in the range of 5–21 nm were non-uniformly distributed in the nanocrystalline surface layer. These precipitates were produced through laser-assisted dynamic precipitation. The extremely high surface strength obtained for the Ti64 was attributed to the composite microstructure featured by nanoscale grains embedded with nanoscale precipitates and the work-hardening. Highlights • Laser assisted ultrasonic nanocrystal surface modification (LA-UNSM) integrates laser heating with UNSM. • In additional to nanocrystallization, LA-UNSM produce nanoscale precipitates through dynamic precipitation. • By fabricating a unique nanocomposite microstructure, LA-UNSM significantly increase the surface strength of Ti64. • LA-UNSM can significantly increase the plastic affected depth due to material softening by laser heating. • Local heating from laser effectively suppress grain coarsening as compared with traditional furnace heating. [ABSTRACT FROM AUTHOR]