Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers.

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.

High-factor interpolation method based on space-time modulation and a Kalman filter for optical encoders.

A high-factor interpolation method based on space-time modulation and a Kalman filter for optical encoders is proposed. Space-time modulation employs a reference time signal to modulate the output displacement signal of the optical encoder into a displacement space-time signal. Subsequently, high-frequency pulse signals are used for interpolation, which detect the phase of the reference time signal and the displacement space-time signal to obtain displacement information from the optical encoder output. The interpolation factor of this method depends on the frequencies of the high-frequency pulse signal and the reference time signal, and is independent of the moving speed. A Kalman filter is employed to estimate the velocity, compensating for time lag errors in the displacement information output by space-time modulation to improve the real-time performance of displacement output. The proposed method is simple and effective, which can be implemented on an FPGA. The effectiveness of the proposed method is verified through simulation and experimentation.

Pharmacokinetics, pharmacodynamics and safety of 15 mg-tolvaptan administered orally for 7 consecutive days to Chinese patients with child-Pugh B cirrhosis.

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15 mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites. Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15 mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded. Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%). Conclusion: Tolvaptan at a daily dose of 15 mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis. Clinical Trial Registration: https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.

First-in-Human Safety, Tolerability, and Pharmacokinetics of Single-Dose Kukoamine B Mesylate in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase I Study.

INTRODUCTION: Kukoamine B mesylate (KB) is a mesylate chrysamine B targeting lipopolysaccharides and CpG DNA, two potential treatment targets in sepsis. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase I study was conducted from July 2014 to May 2015 to explore the safety, tolerability, and pharmacokinetics of KB in healthy subjects. This study consisted of a pre-phase (four participants; KB at 0.005 mg/kg) and a dose escalation phase (eight participants/dose group, randomized 6:2 to KB or placebo; KB at 0.02, 0.04, 0.08, 0.12, 0.24, and 0.48 mg/kg). The primary endpoint was safety. RESULTS: Fifty-two participants were enrolled, including four in the pre-phase and 48 in the dose escalation phase. Among the 40 participants who received KB, 12 (30.0%) experienced adverse events (AEs), while two (16.7%) experienced AEs among 12 participants who received the placebo. The most common AEs in the KB group were headache (5.0%), influenza (5.0%) and positive white blood cell in urine (5.0%). After the administration of KB, the mean plasma elimination half was around 1.61-4.24 h. The relationship between the KB plasma exposure of KB and the administered dose was not linear. The percentage of cumulative urinary excretion of KB was similar among the different dose groups (21.7-35.2%) and the urinary excretion of KB decreased significantly about 8 h after administration. CONCLUSIONS: Single-dose KB demonstrated favorable safety and tolerability in healthy subjects at the dose level of 0.005-0.48 mg/kg. KB exhibited a non-linear pharmacokinetic profile with a half-life of about 1.61-4.24 h, which mainly distributed in plasma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02219971.

Thermoelectric Generator Through Dual-Direction Thermal Regulation by Thermal Diodes for Waste Heat Harvesting.

Thermal energy harvesting provides an opportunity for multi-node systems to achieve self-power autonomy. Thermoelectric generators (TEGs), either by thermocouple arrangement with higher-aspect-ratios or thermoelectric films overlay, are limited by the small temperature difference and its short-duration (less than dozens of minutes), hindering the harvesting efficiency. Here, by introducing thermal diodes with dual-direction thermal regulation ability to optimize the heat flux path, the proposed TEGs exhibit enhanced power-supply capability with unprecedented long-duration (more than hours). In contrast with conventional TEGs with fixed-leg dimensions enabled single output, these compact-TEGs can supply up to fourteen output-channels for selection, the produced power ranges from 1.11 to 921.99 µW, open circuit voltage ranges from 8.07 to 51.32 mV, when the natural temperature difference is 53.84 °C. Compared to the most recent TEGs, the proposed TEGs in this study indicate higher power (more than hundreds times) and much longer output duration (2.4-120 times) in a compact manner.

Flexible Platform Composed of T-Shaped Micropyramid Patterns toward a Waterproof Sensing Interface.

Antifouling is essential to guaranteeing the sensitivity and precision of flexible sensing interfaces. Materials and structures are the two primary strategies. However, optimizing the inherent microstructures to integrate waterproofing and sensing is rarely reported. To improve the liquid repellency of micropyramid structures, this work presents a study of the design and fabrication of T-shaped micropyramid structures. These structures are patterned uniformly and largely on polydimethylsiloxane (PDMS) skin by the new process of two-step magnetic induction. The waterproofing is related to the breakthrough pressure and the liquid repellency, both of which are a function of structural characteristics, D, and material properties, θY. At the breakthrough transition, two failure models distinguished by θY appear: the depinning transition and the sagging transition. Meanwhile, when considering D in practice, some models will shift and occur early. The D value regulates the transition of the material's wettability to the liquid repellency. The influence of the material's inherent nonwettability on liquid repellency diminishes as D decreases, and the transition from completely wetting liquids to super-repellents can be achieved. Experiments demonstrate that for D = 0.3 under water the resistance is approximately 142 times larger than the depth of the structure, considerably facilitating the waterproofing of conventional micropyramid arrays. This work provides a novel method for fabricating flexible T-shaped micropyramid array structures and opens a new window on flexible sensing interfaces with excellent waterproofing.

Actuation-enhanced multifunctional sensing and information recognition by magnetic artificial cilia arrays.

Artificial cilia integrating both actuation and sensing functions allow simultaneously sensing environmental properties and manipulating fluids in situ, which are promising for environment monitoring and fluidic applications. However, existing artificial cilia have limited ability to sense environmental cues in fluid flows that have versatile information encoded. This limits their potential to work in complex and dynamic fluid-filled environments. Here, we propose a generic actuation-enhanced sensing mechanism to sense complex environmental cues through the active interaction between artificial cilia and the surrounding fluidic environments. The proposed mechanism is based on fluid-cilia interaction by integrating soft robotic artificial cilia with flexible sensors. With a machine learning-based approach, complex environmental cues such as liquid viscosity, environment boundaries, and distributed fluid flows of a wide range of velocities can be sensed, which is beyond the capability of existing artificial cilia. As a proof of concept, we implement this mechanism on magnetically actuated cilia with integrated laser-induced graphene-based sensors and demonstrate sensing fluid apparent viscosity, environment boundaries, and fluid flow speed with a reconfigurable sensitivity and range. The same principle could be potentially applied to other soft robotic systems integrating other actuation and sensing modalities for diverse environmental and fluidic applications.

Study on the influence of surface roughness on the diffraction efficiency of two-dimensional gratings.

This study investigates the effect of surface roughness on the diffraction efficiency of two-dimensional gratings. Firstly, a roughness model was constructed using FDTD, followed by a significant analysis of the ridge roughness, groove roughness, and sidewall roughness on diffraction efficiency. Then, the impact of each roughness type on diffraction efficiency was studied separately. Results indicate that ridge roughness has a negative impact on diffraction efficiency, whereas groove roughness and sidewall roughness have a positive impact on the diffraction efficiency of two-dimensional gratings. When ridge, groove, and sidewall roughness coexist, diffraction efficiency decreases with an increase in roughness, consistent with previous research. However, under conditions of minimal roughness, diffraction efficiency actually increases. Finally, an experiment was conducted to verify the conclusions. The results of this study have significant reference value for the application and development of precision measurement techniques for gratings.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of aficamten in healthy Chinese participants: a randomized, double-blind, placebo-controlled, phase 1 study.

Objectives: Aficamten is a selective, small-molecule allosteric inhibitor of cardiac sarcomere being developed as a chronic oral treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy. This was the first-in-Chinese study aiming to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of aficamten in healthy adults. Methods: This double-blind, randomized, placebo-controlled, phase 1 study was conducted in 28 healthy male and female Chinese participants after single ascending dose (SAD) and multi-dose (MD) administrations of aficamten. In the SAD cohort, 16 participants were randomized to receive a single oral dose of aficamten: 10 mg, 20 mg, or placebo. In the MD cohort, 12 participants were randomized to receive multiple doses of aficamten: 5 mg or placebo once daily for 14 days. Safety was monitored throughout the study with electrocardiograms, echocardiograms, clinical laboratory tests, and reporting of adverse events (AEs). Pharmacokinetic profiles of aficamten and metabolites, as well as CYP2D6 genetic impact, were evaluated. Results: A total of 35 treatment-emergent AEs were reported by 14 (50%) participants with mild severity. There were no serious AEs or adverse decreases in left ventricular ejection fraction below 50% during the study. Aficamten was dose-proportional over the dose range of 5-20 mg and accumulated in the MD cohort. Conclusion: Aficamten was safe and well-tolerated in the healthy Chinese adult participants. The pharmacokinetics of aficamten in the Chinese population was comparable to those previously found in Western participants. These phase 1 data support the progression of aficamten into future clinical studies in Chinese patients. Clinical Trial registration: https://clinicaltrials.gov, identifier: NCT04783766.

Electrodeposited Superhydrophilic-Superhydrophobic Composites for Untethered Multi-Stimuli-Responsive Soft Millirobots.

To navigate in complex and unstructured real-world environments, soft miniature robots need to possess multiple functions, including autonomous environmental sensing, self-adaptation, and multimodal locomotion. However, to achieve multifunctionality, artificial soft robots should respond to multiple stimuli, which can be achieved by multimaterial integration using facile and flexible fabrication methods. Here, a multimaterial integration strategy for fabricating soft millirobots that uses electrodeposition to integrate two inherently non-adherable materials, superhydrophilic hydrogels and superhydrophobic elastomers, together via gel roots is proposed. This approach enables the authors to electrodeposit sodium alginate hydrogel onto a laser-induced graphene-coated elastomer, which can then be laser cut into various shapes to function as multi-stimuli-responsive soft robots (MSRs). Each MSR can respond to six different stimuli to autonomously transform their shapes, and mimic flowers, vines, mimosas, and flytraps. It is demonstrated that MSRs can climb slopes, switch locomotion modes, self-adapt between air-liquid environments, and transport cargo between different environments. This multimaterial integration strategy enables creating untethered soft millirobots that have multifunctionality, such as environmental sensing, self-propulsion, and self-adaptation, paving the way for their future operation in complex real-world environments.

Safety, Tolerability, and Pharmacokinetics of Kukoamine B in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Phase I Study.

INTRODUCTION: Kukoamine B (KB) is a novel sepsis therapeutic drug targeting lipopolysaccharide and CpG DNA. This study aims to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple doses of KB in healthy volunteers. METHODS: Healthy volunteers were randomized at a 1:1:1:1 ratio to receive multiple intravenous infusion doses of KB 0.06 mg/kg, 0.12 mg/kg, 0.24 mg/kg or placebo (administered every 8 h per day) for 7 days and subsequently followed up for another 7 days at Peking Union Medical College Hospital. Primary endpoints were adverse events (AEs), and the secondary endpoints were PK parameters of the first administration and the last administration. RESULTS: Data of the 18 health volunteers in KB groups and 6 in the placebo group were pooled and analyzed. AEs occurred in 12 (66.67%) volunteers in the KB groups and 4 (66.67%) volunteers in the placebo group. Treatment-related adverse events (TRAEs) occurred in 8 (44.44%) volunteers in the KB groups and 2 (33.33%) volunteers in the placebo group. Hypertriglyceridemia (4 [22.22%] vs. 2 [33.33%]) and sinus bradycardia (3 [16.67%] vs. 0) were the most common AEs. The mean elimination half-life, clearance, and distribution volume of KB were 3.40-4.88 h, 9.35-13.49 L/h, and 45.74-101.90 L, respectively. The average accumulation ratios of area under the plasma concentration-time curve and maximum plasma concentration were 1.06 and 1.02, respectively. CONCLUSION: Single and multiple intravenous infusions of KB at a dose range of 0.06-0.24 mg/kg are safe and tolerable in healthy volunteers. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02690961.

Safety, tolerability, pharmacokinetics, and efficacy of kukoamine B in patients with sepsis: A randomized phase IIa trial.

PURPOSE: To evaluate the safety, tolerability, pharmacokinetics, and efficacy of kukoamine B (KB), an alkaloid compound with high affinity for both lipopolysaccharide (LPS) and oligodeoxynucle-otides containing CpG motifs (CpG DNA), in patients with sepsis-induced organ failure. MATERIALS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled phase IIa trial. Patients with sepsis-induced organ failure were randomized to receive either KB (0.06, 0.12, or 0.24 mg/kg) or placebo, every 8 h for 7 days. Primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) parameters, changes in inflammatory mediators' level, and prognostic parameters. RESULTS: Of 44 patients enrolled, adverse events occurred in 28 patients [n = 20, 66.7% (KB pooled); n = 8, 57.1% (placebo)], while treatment emergent adverse events were reported in 14 patients [n = 10, 33.3% (KB pooled); n = 4, 28.6% (placebo)]. Seven patients died at 28-day follow-up [n = 4, 13.3% (KB pooled); n = 3, 21.4% (placebo)], none was related to study drug. PK parameters suggested dose-dependent drug exposure and no drug accumulation. KB did not affect clinical outcomes such as ΔSOFA score, vasopressor-free days or ventilator-free days. CONCLUSIONS: In patients with sepsis-induced organ failure, KB was safe and well tolerated. Further investigation is warranted. TRIAL REGISTRATION: http://ClinicalTrials.gov, NCT03237728.

Development and validation of an HPLC coupled with tandem mass spectrometry method for the determination of HSK7653, a novel super long-acting dipeptidyl peptidase-4 inhibitor, in human plasma and urine and its application to a pharmacokinetic study.

HSK7653 is a novel super long-acting dipeptidyl peptidase-4 inhibitor, which is promising for the treatment of type 2 diabetes mellitus with the twice-monthly dosing regimen. In this article, a robust and sensitive HPLC coupled with tandem mass spectrometry method for determining the concentration of HSK7653 in human plasma and urine was developed and validated for the first time. Plasma and urine samples were prepared by protein precipitation. After that, the extracts were analyzed using an LC-20A HPLC system coupled with API 4000 tandem MS equipped with an electrospray ionization source in positive mode. Separation was obtained using an XBridge Phenyl column (2.1 × 50 mm, 3.5 µm) with a gradient elution of acetonitrile and water containing 0.1% formic acid and 5% acetonitrile at room temperature. This bioanalysis method has been fully validated and the results showed good sensitivity and specificity. In brief, the standard curves were linear over the concentration range of 2.00-2000 ng/ml for plasma and 20.0-20,000 ng/ml for urine, respectively. In addition, the precisions of inter- and intra-run of HSK7653 were less than 12.7% and the accuracies were -3.3% to 6.3% for both plasma and urine. Finally, this method was successfully applied to explore the pharmacokinetic characteristics of HSK7653 in Chinese healthy volunteers in a first-in-human study.

Development and validation of two bioanalysis methods for the determination of etimicin in human serum and urine by liquid chromatography-tandem mass spectrometry: Applications to a human pharmacokinetic and breakpoint study.

Etimicin is a fourth-generation aminoglycoside antibiotic. It has potent activity and low toxicity when employed for the treatment of Gram-negative and Gram-positive bacterial infections. The pharmacokinetics of etimicin in humans have not been elucidated completely. Two liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical methods, without the use of any ion-pairing reagents, were developed and validated for the quantification of etimicin in human samples of serum and urine. Using a deuterated reagent as the internal standard, analytes in serum and urine samples were extracted by protein precipitation and dilution before LC-MS/MS analysis, respectively. For the two methods, chromatographic separations were undertaken under isocratic elution of water-ammonia solution-acetic acid (96:3.6:0.2, v/v/v) and methanol at 50%:50% and a flow rate of 0.35 ml/min within 5 min. A Waters XTerra MS C18 column (2.1 × 150 mm, 3.5 µm) and a column temperature of 40°C were chosen. A Sciex Qtrap 5500 mass spectrometer equipped with an electrospray ion source was used in both methods under multiple-reaction monitoring in positive-ion mode. The two methods showed good linearity, accuracy, and precision with high recovery and a minimal matrix effect in the range of 50.0-20000 ng/ml for serum samples and 50.0-10000 ng/ml for urine samples, respectively. Carry-over effects were not observed. Etimicin remained stable in human samples of serum or urine under the storage, preparation, and analytical conditions of the two methods. These two simple and reliable methods were applied successfully to a dose-escalation, phase I clinical trial of etimicin in Chinese healthy volunteers after intravenous administration of single and multiple doses. Based on these two methods we ascertained, for the first time, the comprehensive pharmacokinetics of etimicin in humans, which will be used for the exploration of the breakpoint research further.

Dynamics of Droplets Impacting on Aerogel, Liquid Infused, and Liquid-Like Solid Surfaces.

Droplets impacting superhydrophobic surfaces have been extensively studied due to their compelling scientific insights and important industrial applications. In these cases, the commonly reported impact regime was that of complete rebound. This impact regime strongly depends on the nature of the superhydrophobic surface. Here, we report the dynamics of droplets impacting three hydrophobic slippery surfaces, which have fundamental differences in normal liquid adhesion and lateral static and kinetic liquid friction. For an air cushion-like (super)hydrophobic solid surface (Aerogel) with low adhesion and low static and low kinetic friction, complete rebound can start at a very low Weber (We) number (∼1). For slippery liquid-infused porous (SLIP) surfaces with high adhesion and low static and low kinetic friction, complete rebound only occurs at a much higher We number (>5). For a slippery omniphobic covalently attached liquid-like (SOCAL) solid surface, with high adhesion and low static friction similar to SLIPS but higher kinetic friction, complete rebound was not observed, even for a We as high as 200. Furthermore, the droplet ejection volume after impacting the Aerogel surface is 100% across the whole range of We numbers tested compared to other surfaces. In contrast, droplet ejection for SLIPs was only observed consistently when the We was above 5-10. For SOCAL, 100% (or near 100%) ejection volume was not observed even at the highest We number tested here (∼200). This suggests that droplets impacting our (super)hydrophobic Aerogel and SLIPS lose less kinetic energy. These insights into the differences between normal adhesion and lateral friction properties can be used to inform the selection of surface properties to achieve the most desirable droplet impact characteristics to fulfill a wide range of applications, such as deicing, inkjet printing, and microelectronics.

Mechanobiology Platform Realized Using Photomechanical Mxene Nanocomposites: Bilayer Photoactuator Design and In Vitro Mechanical Forces Stimulation.

Mechanotransduction is the process by which cells convert external forces and physical constraints into biochemical signals that control several aspects of cellular behavior. A number of approaches have been proposed to investigate the mechanisms of mechanotransduction; however, it remains a great challenge to develop a platform for dynamic multivariate mechanical stimulation of single cells and small colonies of cells. In this study, we combined polydimethylsiloxane (PDMS) and PDMS/Mxene nanoplatelets (MNPs) to construct a soft bilayer nanocomposite for extracellular mechanical stimulation. Fast backlash actuation of the bilayer as a result of near-infrared irradiation caused mechanical force stimulation of cells in a controllable manner. The excellent controllability of the light intensity and frequency allowed backlash bending acceleration and frequency to be manipulated. As gastric gland carcinoma cell line MKN-45 was the research subject, mechanical force loading conditions could trigger apoptosis of the cells in a stimulation duration time-dependent manner. Cell apoptotic rates were positively related to the duration time. In the case of 6 min mechanical force loading, apoptotic cell percentage rose to 34.46% from 5.5% of the control. This approach helps apply extracellular mechanical forces, even with predesigned loading cycles, and provides a solution to study cell mechanotransduction in complex force conditions. It is also a promising therapeutic technique for combining physical therapy and biomechanics.

Distance and depth modulation of Talbot imaging via specified design of the grating structure.

For positioning Talbot encoder and Talbot lithography, etc., properties manipulation of Talbot imaging is highly expected. In this work, an investigation on the distance and depth modulation of Talbot imaging, which employs a specially designed grating structure, is presented. Compared with the current grating structure, the proposed grating structure is characterized by having the phase layers with uneven thicknesses. Such a specific structural design can cause the offset of Talbot image from its nominal position, which in turn generates the spatial distance modulation of self-imaging and imaging depth expansion. Theoretical analysis is performed to explain its operating principle, and simulations and experiments are carried out to demonstrate its effectiveness.

Slippery Liquid-Like Solid Surfaces with Promising Antibiofilm Performance under Both Static and Flow Conditions.

Biofilms are central to some of the most urgent global challenges across diverse fields of application, from medicine to industries to the environment, and exert considerable economic and social impact. A fundamental assumption in anti-biofilms has been that the coating on a substrate surface is solid. The invention of slippery liquid-infused porous surfaces─a continuously wet lubricating coating retained on a solid surface by capillary forces─has led to this being challenged. However, in situations where flow occurs, shear stress may deplete the lubricant and affect the anti-biofilm performance. Here, we report on the use of slippery omniphobic covalently attached liquid (SOCAL) surfaces, which provide a surface coating with short (ca. 4 nm) non-cross-linked polydimethylsiloxane (PDMS) chains retaining liquid-surface properties, as an antibiofilm strategy stable under shear stress from flow. This surface reduced biofilm formation of the key biofilm-forming pathogens Staphylococcus epidermidis and Pseudomonas aeruginosa by three-four orders of magnitude compared to the widely used medical implant material PDMS after 7 days under static and dynamic culture conditions. Throughout the entire dynamic culture period of P. aeruginosa, SOCAL significantly outperformed a typical antibiofilm slippery surface [i.e., swollen PDMS in silicone oil (S-PDMS)]. We have revealed that significant oil loss occurred after 2-7 day flow for S-PDMS, which correlated to increased contact angle hysteresis (CAH), indicating a degradation of the slippery surface properties, and biofilm formation, while SOCAL has stable CAH and sustainable antibiofilm performance after 7 day flow. The significance of this correlation is to provide a useful easy-to-measure physical parameter as an indicator for long-term antibiofilm performance. This biofilm-resistant liquid-like solid surface offers a new antibiofilm strategy for applications in medical devices and other areas where biofilm development is problematic.

Preserved pharmacokinetics and pharmacodynamics of insulin degludec and liraglutide when administered as insulin degludec/liraglutide in a Chinese population.

We report the findings of a single-dose, randomized, three-period cross-over, clinical trial in healthy Chinese individuals (n = 24) comparing the pharmacokinetics of insulin degludec/liraglutide (IDegLira) with its individual components. Furthermore, we report a population pharmacokinetic analysis of a 26-week, phase III, treat-to-target, randomized trial of 720 Chinese individuals with type 2 diabetes. Participants were randomized to IDegLira, degludec or liraglutide, all once daily with metformin. The pharmacokinetic profiles of IDegLira were similar to its individual components. Dose proportionality was indicated for both IDegLira components. Although there were no relevant covariate effects on degludec exposure, liraglutide exposure was inversely correlated with bodyweight. In conclusion, for the Chinese population, the pharmacokinetics of the fixed-ratio combination IDegLira is similar to that of its individual components.