Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.

This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of "Sedation" was greater than that of "Not-sedation" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44-2.08 mg/kg for children aged 2-3 years, 0.35-1.65 mg/kg for children aged 4-7 years, 0.24-1.27 mg/kg for children aged 8-12 years, and 0.20-1.10 mg/kg for adolescents aged 13-18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.

Rapid identification of potential nonsteroidal anti-inflammatory drug overdose-induced liver toxicity and prediction of follow-up exposure: Integrating bioanalytical and population pharmacokinetic assay.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs that can cause liver toxicity. The aim of this study was to integrate bioanalytical and population pharmacokinetic (PopPK) assay to rapidly screen and quantify the concentrations of NSAIDs in plasma and monitor clinical safety. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetaminophen (APAP), flurbiprofen (FLB), aspirin (ASP), and ibuprofen (IBP), four commonly used NSAIDs. The PopPK model of the signature toxicant was analyzed based on the published literature. The LC-MS/MS method was successfully validated and applied to determine NSAID concentrations in patient plasma samples. APAP, ASP, and IBP data were best fitted using a one-compartment model, and FLB data were best fitted using a two-compartment model. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. A fast, simple, and sensitive LC-MS/MS method was developed and validated for determining APAP, FLB, ASP, and IBP in human plasma. Combined with the PopPK model, this method was applied to rapidly analyze the concentrations of NSAIDs in clinical samples from patients presenting to the emergency department with acute liver dysfunction and monitored NSAIDs clinical safety.

Real Depth-Correction in Ground Penetrating RADAR Data Analysis for Bridge Deck Evaluation.

When ground penetrating radar (GPR) is used for the non-destructive evaluation of concrete bridge decks, the rebar reflection amplitudes should be corrected for rebar depths to account for the geometric spreading and material attenuation of the electromagnetic wave in concrete. Most current depth-correction methods assume a constant EM wave velocity in the entire bridge deck and correct GPR amplitudes based on the two-way travel time (TWTT) instead of the actual rebar depth. In this paper, we proposed a depth-correction algorithm based on the real rebar depths. To compare different depth-correction methods, we used gprMax software to simulate GPR signals in four models with various dielectric constants and conductivity. The comparison shows that the TWTT-based depth-correction method tends to over-correct GPR amplitudes so that underestimates the deterioration level of concrete decks at certain locations. Two depth-based correction methods are proposed that use migrated amplitudes and further normalize the corrected amplitude by rebar depth (attenuation rate). These methods are then applied to GPR data collected on two bridges, and the results were validated by other NDE methods and chloride concentration test.

Ubiquitin-Modified Proteome of SARS-CoV-2-Infected Host Cells Reveals Insights into Virus-Host Interaction and Pathogenesis.

The outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a serious threat to global public health. The mechanism of pathogenesis and the host immune response to SARS-CoV-2 infection are largely unknown. In the present study, we applied a quantitative proteomic technology to identify and quantify the ubiquitination changes that occur in both the virus and the Vero E6 cells during SARS-CoV-2 infection. By applying label-free, quantitative liquid chromatography with tandem mass spectrometry proteomics, 8943 lysine ubiquitination sites on 3086 proteins were identified, of which 138 sites on 104 proteins were quantified as significantly upregulated, while 828 sites on 447 proteins were downregulated at 72 h post-infection. Bioinformatics analysis suggested that SARS-CoV-2 infection might modulate host immune responses through the ubiquitination of important proteins, including USP5, IQGAP1, TRIM28, and Hsp90. Ubiquitination modification was also observed on 11 SAR-CoV-2 proteins, including proteins involved in virus replication and inhibition of the host innate immune response. Our study provides new insights into the interaction between SARS-CoV-2 and the host as well as potential targets for the prevention and treatment of COVID-19.

A Study on the Classification Effect of sEMG Signals in Different Vibration Environments Based on the LDA Algorithm.

Myoelectric prosthesis has become an important aid to disabled people. Although it can help people to recover to a nearly normal life, whether they can adapt to severe working conditions is a subject that is yet to be studied. Generally speaking, the working environment is dominated by vibration. This paper takes the gripping action as its research object, and focuses on the identification of grasping intentions under different vibration frequencies in different working conditions. In this way, the possibility of the disabled people who wear myoelectric prosthesis to work in various vibration environment is studied. In this paper, an experimental test platform capable of simulating 0-50 Hz vibration was established, and the Surface Electromyography (sEMG) signals of the human arm in the open and grasping states were obtained through the MP160 physiological record analysis system. Considering the reliability of human intention recognition and the rapidity of algorithm processing, six different time-domain features and the Linear Discriminant Analysis (LDA) classifier were selected as the sEMG signal feature extraction and recognition algorithms in this paper. When two kinds of features, Zero Crossing (ZC) and Root Mean Square (RMS), were used as input, the accuracy of LDA algorithm can reach 96.9%. When three features, RMS, Minimum Value (MIN), and Variance (VAR), were used as inputs, the accuracy of the LDA algorithm can reach 98.0%. When the six features were used as inputs, the accuracy of the LDA algorithm reached 98.4%. In the analysis of different vibration frequencies, it was found that when the vibration frequency reached 20 Hz, the average accuracy of the LDA algorithm in recognizing actions was low, while at 0 Hz, 40 Hz and 50 Hz, the average accuracy was relatively high. This is of great significance in guiding disabled people to work in a vibration environment in the future.

Thermal modulation of nonlinear ultrasonic wave for concrete damage evaluation.

A nonlinear ultrasonic test is proposed for material damage evaluation using thermal modulation. Temperature change excites and modulates nonlinear behavior of ultrasonic waves in concrete. Coda wave interferometry was used to analyze the relative velocity change of ultrasonic wave with temperature variations. On concrete samples with different levels of thermal damage, experimental results indicate that the samples with a higher damage level demonstrated higher sensitivity to temperature variations. In addition, a slow dynamics nonlinear behavior was observed. When the temperature changed and then remained constant, the wave velocity gradually approached to its equilibrium value.

SEMG Feature Extraction Based on StockwellTransform Improves Hand MovementRecognition Accuracy.

Feature extraction, as an important method for extracting useful information from surfaceelectromyography (SEMG), can significantly improve pattern recognition accuracy. Time andfrequency analysis methods have been widely used for feature extraction, but these methods analyzeSEMG signals only from the time or frequency domain. Recent studies have shown that featureextraction based on time-frequency analysis methods can extract more useful information fromSEMG signals. This paper proposes a novel time-frequency analysis method based on the Stockwelltransform (S-transform) to improve hand movement recognition accuracy from forearm SEMGsignals. First, the time-frequency analysis method, S-transform, is used for extracting a feature vectorfrom forearm SEMG signals. Second, to reduce the amount of calculations and improve the runningspeed of the classifier, principal component analysis (PCA) is used for dimensionality reduction of thefeature vector. Finally, an artificial neural network (ANN)-based multilayer perceptron (MLP) is usedfor recognizing hand movements. Experimental results show that the proposed feature extractionbased on the S-transform analysis method can improve the class separability and hand movementrecognition accuracy compared with wavelet transform and power spectral density methods.

Nondestructive Evaluation of Concrete Bridge Decks with Automated Acoustic Scanning System and Ground Penetrating Radar.

Delamanintions and reinforcement corrosion are two common problems in concrete bridge decks. No single nondestructive testing method (NDT) is able to provide comprehensive characterization of these defects. In this work, two NDT methods, acoustic scanning and Ground Penetrating Radar (GPR), were used to image a straight concrete bridge deck and a curved intersection ramp bridge. An acoustic scanning system has been developed for rapid delamination mapping. The system consists of metal-ball excitation sources, air-coupled sensors, and a GPS positioning system. The acoustic scanning results are presented as a two-dimensional image that is based on the energy map in the frequency range of 0.5⁻5 kHz. The GPR scanning results are expressed as the GPR signal attenuation map to characterize concrete deterioration and reinforcement corrosion. Signal processing algorithms for both methods are discussed. Delamination maps from the acoustic scanning are compared with deterioration maps from the GPR scanning on both bridges. The results demonstrate that combining the acoustic and GPR scanning results will provide a complementary and comprehensive evaluation of concrete bridge decks.

Acoustic evaluation of concrete delaminations using ball-chain impact excitation.

This letter presents an automated acoustic sensing device for rapid detection of delamination in concrete. The device consists of ball-chains for continual impact excitation and multi-channel microphones for acoustic sensing. A ball-chain is formed by multiple metal balls connected by flexible ropes and is dragged on concrete surface to excite vibration of delaminations. Compared to the conventional chain drag test, the ball-chain generates acoustic signals with higher signal-to-noise ratio (S/N) because the balls give isolated but continual impacts on concrete surface during dragging. The proposed method was validated on a concrete specimen with artificial delaminations.

CXCR7 suppression modulates microglial chemotaxis to ameliorate experimentally-induced autoimmune encephalomyelitis.

Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE), widely used as an animal model of MS, classically manifests as an ascending paralysis that is characterized by extensive infiltration of the CNS by inflammatory cells. Although several studies uncover the significant role of microglia in the development of EAE, the cellular mechanisms of microglia that govern EAE pathogenesis remain unknown. In the current study, we report that CXCR7 expression is dynamic regulated in activated microglia during CNS autoimmunity and positively correlates with the clinical severity of EAE. In addition, microglial chemotaxis is mediated by CXCR7 during CNS autoimmunity, signaling through extracellular signal-regulated kinase (ERK)1/2 activation, whereas p38 mitogen-activated protein kinase (MAPK) and (c-Jun N-terminal kinase) JNK are not involved. Most importantly, CXCR7 neutralizing treatment ameliorates the clinical severity of EAE along with ERK1/2 phosphorylation reduction. Collectively, our data demonstrate that CXCR7 suppression modulates microglial chemotaxis to ameliorate EAE.

A Hand Gesture Recognition Strategy Based on Virtual-Dimension Increase of EMG.

The electromyography(EMG) signal is the biocurrent associated with muscle contraction and can be used as the input signal to a myoelectric intelligent bionic hand to control different gestures of the hand. Increasing the number of myoelectric-signal channels can yield richer information of motion intention and improve the accuracy of gesture recognition. However, as the number of acquisition channels increases, its effect on the improvement of the accuracy of gesture recognition gradually diminishes, resulting in the improvement of the control effect reaching a plateau. To address these problems, this paper presents a proposed method to improve gesture recognition accuracy by virtually increasing the number of EMG signal channels. This method is able to improve the recognition accuracy of various gestures by virtually increasing the number of EMG signal channels and enriching the motion intention information extracted from data collected from a certain number of physical channels, ultimately providing a solution to the issue of the recognition accuracy plateau caused by saturation of information from physical recordings. Meanwhile, based on the idea of the filtered feature selection method, a quantitative measure of sample sets (separability of feature vectors [SFV]) derived from the divergence and correlation of the extracted features is introduced. The SFV value can predict the classification effect before performing the classification, and the effectiveness of the virtual-dimension increase strategy is verified from the perspective of feature set differentiability change. Compared to the statistical motion intention recognition success rate, SFV is a more representative and faster measure of classification effectiveness and is also suitable for small sample sets.

Postharvest ripening of newly harvested corn: Weakened interactions between starch and protein.

The effects of postharvest ripening of corn on the mechanisms of starch and protein interactions were investigated using molecular dynamics and several chemical substances. Sodium dodecyl sulfate (SDS) treatment all significantly affected the starch content, molecular weight of proteins, relative crystallinity, pasting characteristics and dynamic viscoelasticity in samples before and after postharvest ripening. In the corn that had not undergone postharvest ripening, there were also significant electrostatic interactions and hydrogen bonds between starch and protein. In addition, molecular dynamics had demonstrated that the forces between starch and protein in corn were mainly hydrophobic interactions, electrostatic interaction, and hydrogen bonds. Compared with zein, corn glutelin was more tightly bound to starch. The binding energy of starch to both proteins was reduced in after postharvest-ripened corn. This study laid a rationale for investigating the change mechanism of corn postharvest ripening quality and improving processing property and edible quality of corn.

Microbial fungicides can positively affect aubergine photosynthetic properties, soil enzyme activity and microbial community structure.

Background: This study examined the effects of microbial agents on the enzyme activity, microbial community construction and potential functions of inter-root soil of aubergine (Fragaria × ananassa Duch.). This study also sought to clarify the adaptability of inter-root microorganisms to environmental factors to provide a theoretical basis for the stability of the microbiology of inter-root soil of aubergine and for the ecological preservation of farmland soil. Methods: Eggplant inter-root soils treated with Bacillus subtilis (QZ_T1), Bacillus subtilis (QZ_T2), Bacillus amyloliquefaciens (QZ_T3), Verticillium thuringiensis (QZ_T4) and Verticillium purpureum (QZ_T5) were used to analyse the effects of different microbial agents on the inter-root soils of aubergine compared to the untreated control group (QZ_CK). The effects of different microbial agents on the characteristics and functions of inter-root soil microbial communities were analysed using 16S rRNA and ITS (internal transcribed spacer region) high-throughput sequencing techniques. Results: The bacterial diversity index and fungal diversity index of the aubergine inter-root soil increased significantly with the application of microbial fungicides; gas exchange parameters and soil enzyme activities also increased. The structural and functional composition of the bacterial and fungal communities in the aubergine inter-root soil changed after fungicide treatment compared to the control, with a decrease in the abundance of phytopathogenic fungi and an increase in the abundance of beneficial fungi in the soil. Enhancement of key community functions, reduction of pathogenic fungi, modulation of environmental factors and improved functional stability of microbial communities were important factors contributing to the microbial stability of fungicide-treated aubergine inter-root soils.

Transient axial solution for plane and axisymmetric waves focused by a paraboloidal reflector.

A time domain analytical solution is presented to calculate the pressure response along the axis of a paraboloidal reflector for a normally incident plane wave. This work is inspired by Hamilton's axial solution for an ellipsoidal mirror and the same methodology is employed in this paper. Behavior of the reflected waves along reflector axis is studied, and special interest is placed on focusing gain obtained at the focal point. This analytical solution indicates that the focusing gain is affected by reflector geometry and the time derivative of the input signal. In addition, focused pressure response in the focal zone given by various reflector geometries and input frequencies are also investigated. This information is useful for selecting appropriate reflector geometry in a specific working environment to achieve the best signal enhancement. Numerical simulation employing the finite element method is used to validate the analytical solution, and visualize the wave field to provide a better understanding of the propagation of reflected waves. This analytical solution can be modified to apply to non-planar incident waves with axisymmetric wavefront and non-uniform pressure distribution. An example of incident waves with conical-shaped wavefront is presented.

A focused electric spark source for non-contact stress wave excitation in solids.

A focused electric spark is used as a non-contact acoustic source to excite stress waves in solids. The source consists of an electric spark source located at the near focus of an ellipsoidal reflector that focuses the acoustic disturbance generated by the spark source to the far focal point. Experimental studies using both contact and non-contact sensors indicate that the source has the capability to excite the Rayleigh surface wave and impact-echo mode (S1-zero-group-velocity Lamb mode) in a 250 mm thick concrete slab and to enable fully air-coupled testing of concrete specimens.

Thermo-acoustoelastic effect of Rayleigh wave: Theory and experimental verification.

Previous studies showed that the thermally-induced ultrasonic bulk wave velocity change could be used to measure acoustoelastic coefficients and third-order elastic constants of elastic materials. This method is naturally immune from the ambient temperature effect and has improved sensitivity and a simpler test setup than the conventional acoustoelastic test. However, Rayleigh wave is preferred for thick components or structures with only one accessible surface. In this work, the thermo-hyperelastic constitutive equation, along with acoustoelastic theory, is used to derive the expression of the thermo-acoustoelastic coefficient (TAEC) of Rayleigh wave. The numerical relationship between the TAEC of Rayleigh wave and Murnaghan constants (l, m and n) are given for common metals. The TAEC expressions for Rayleigh wave and shear wave are similar, and both are dominated by the constant m. The TAEC of Rayleigh wave was measured on an aluminum 6061 specimen using the thermal modulation experiment in a temperature range of 22 ∼35 °C. The measured TAEC shows good agreement with the theoretical calculation. Then the third-order elastic constants were calculated based on TAECs of bulk waves and Rayleigh wave.

Postharvest ripening of two varieties of corns: Structure, antioxidant activities and physicochemical properties of zein.

The newly harvested Jidan 66 (JD66) and Liangyu 99 (LY99) varieties of corns were stored for 56 days at constant temperature of 15 and 25 °C with relative humidity of 55%. The postharvest ripening resulted in more disordered secondary structure and less compact tertiary conformation of zein. The emulsifying activity and foaming stability reached maximum after storage of corns at 15 and 25 °C for 14 days, while the emulsifying stability and foaming capacity were the highest at two temperatures of storage for 7 days and 28 days, respectively. Furthermore, zein had the highest viscoelasticity as well as the strongest antioxidant activities after the storage of JD66 at two temperatures for 28 days and the storage of LY99 at 15 °C for 42 days and at 25 °C for 28 days. Therefore, appropriate postharvest ripening of corns changed the structure of zein, improving its antioxidant activities and physicochemical properties.

Pharmacokinetic Interaction of Anaprazole, Amoxicillin and Clarithromycin after Single-Dose Simultaneous Administration and the Effect of Adding Bismuth on Their Pharmacokinetics in Healthy Male Chinese Subjects.

BACKGROUND AND OBJECTIVE: Helicobacter pylori-positive ulcers are treated with a proton pump inhibitor (PPI) + two antibiotics with/without bismuth. The objective of this study was to investigate the pharmacokinetic interaction of the novel PPI anaprazole, amoxicillin and clarithromycin with/without bismuth. METHODS: This single-centre, randomised, open-label phase 1 pharmacokinetic study included healthy Chinese male participants, comprising two cohorts (cohort 1, 4 × 4 crossover design; cohort 2, 2 × 2 crossover design). In cohort 1, 24 participants received four treatment cycles with a different treatment in each cycle; the washout period between cycles was 9 days. Participants were randomly assigned to one of the following four treatment sequences (1:1:1:1): anaprazole sodium enteric-coated tablet 20 mg monotherapy, amoxicillin 1000 mg monotherapy, clarithromycin 500 mg monotherapy, and a three-drug combination (anaprazole 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg). During each treatment cycle, study drugs were administered twice daily for four consecutive days and once in the morning on the fifth day. Cohort 2 participants were administered a single dose of the three-drug combination and a single dose of a four-drug combination (three-drug combination + bismuth 0.6 g) with a washout period of 11 ± 2 days between treatments. Blood samples were collected for pharmacokinetic analysis. RESULTS: Twenty-nine of 32 enrolled participants (cohort 1, n = 24; cohort 2, n = 8) completed the study. There were no significant differences in exposure or time to reach maximum concentration (Tmax) between each single drug or the three-drug combination (cohort 1) or between the three- and four-drug combinations (cohort 1) for any of the drugs/metabolites. CONCLUSIONS: Dose adjustments for individual drugs are not necessary with combined dosing of anaprazole, amoxicillin, clarithromycin and bismuth.

Safety, Pharmacokinetics, and Pharmacodynamics of Midazolam Gel After Rectal Administration in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: Midazolam rectal gel is a novel rectal formulation that may be a promising and potential alternative to oral administration for pediatric sedation. The objective of this study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and absolute bioavailability of midazolam rectal gel in healthy Chinese subjects. METHODS: An open-label, single-dose, randomized, two-period, two-treatment, crossover clinical study was conducted in 22 healthy subjects (16 males and six females), each receiving 2.5 mg intravenous midazolam in one period and 5 mg midazolam rectal gel in another period (the dosages here were calculated as active midazolam). Safety, pharmacokinetic, and pharmacodynamic assessments were conducted throughout the study. RESULTS: All of the subjects completed both treatment periods. The formulation of rectal gel was well tolerated, with no serious adverse events occurring. After a single rectal dose of 5 mg midazolam rectal gel, it was absorbed rapidly with a median value of time to peak concentration (Tmax) of 1.00 h, and mean values of the peak concentration (Cmax) and area under the concentration-time curve (AUC0-t) of 37.2 ng/mL and 137 h·ng/mL, respectively. The absolute bioavailability of rectal gel was 59.7%. The rectal gel exhibited a relatively delayed onset but a more stable sedative effect and a longer duration when compared with intravenous midazolam. CONCLUSION: Midazolam rectal gel may be a feasible alternative with a high level of acceptance in pediatric sedation and enhanced bioavailability compared to an oral formulation. The modeling results may help to disclose out the exposure-response relationship of midazolam rectal gel and support the design of an escalating-doses study and pediatric extrapolation study. CLINICAL TRIAL REGISTRATION: The study was registered at http://www.chinadrugtrials.org.cn (No. CTR20192350).

The Brucella Effector Protein BspF Regulates Apoptosis through the Crotonylation of p53.

The Brucella type IV secretion system (T4SS) can promote the intracellular survival and reproduction of Brucella. T4SS secretes effector proteins to act on cellular signaling pathways to inhibit the host's innate immune response and cause a chronic, persistent Brucella infection. Brucella can survive in host cells for a long time by inhibiting macrophage apoptosis and avoiding immune recognition. The effector protein, BspF, secreted by T4SS, can regulate host secretory transport and accelerate the intracellular replication of Brucella. BspF has an acetyltransferase domain of the GNAT (GCN5-related N-acetyltransferases) family, and in our previous crotonylation proteomics data, we have found that BspF has crotonyl transferase activity and crotonylation regulation of host cell protein in the proteomics data. Here, we found that BspF attenuates the crotonylation modification of the interacting protein p53, which reduces the p53 expression through the GNAT domain. BspF can inhibit the transcription and protein expression of downstream apoptotic genes, thereby inhibiting host cell apoptosis. Additionally, the Brucella ΔbspF mutant stain promotes apoptosis and reduces the survival rate of Brucella in the cells. In conclusion, we identified that the T4SS effector protein BspF can regulate host cell apoptosis to assist Brucella in its long-term survival by attenuating crotonylation modification of p53 and decreasing p53 expression. Our findings reveal a unique mechanism of elucidating how Brucella regulates host cell apoptosis and promotes its proliferation through the secretion of effector proteins.