Dupilumab significantly improves sleep in adults with atopic dermatitis: results from the 12-week placebo-controlled period of the 24-week phase IV randomized double-blinded placebo-controlled DUPISTAD study.

BACKGROUND: Sleep disturbance is a prominent symptom of atopic dermatitis (AD) and can result in insomnia, daytime fatigue, drowsiness, reduced productivity and impaired quality of life (QoL). OBJECTIVES: The Dupilumab Effect on Sleep in AD Patients (DUPISTAD) phase IV randomized double-blinded placebo-controlled study evaluated the impact of dupilumab treatment on sleep and other patient- and physician-reported outcomes. METHODS: Adults with moderate-to-severe AD were randomized 2 : 1 to dupilumab 300 mg once every 2 weeks (q2w) or placebo for 12 weeks; concomitant topical corticosteroids were permitted. Patients subsequently entered an open-label phase and received dupilumab 300 mg q2w for a further 12 weeks. The primary endpoint was the percentage change in sleep quality from baseline to week 12, assessed using a novel numeric rating scale (NRS). Secondary and exploratory endpoints included percentage change in peak pruritus NRS (PP NRS), change in SCORing Atopic Dermatitis (SCORAD), SCORAD sleep visual analogue scale (VAS), Eczema Area and Severity Index, Patient-Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment T-score and the Epworth Sleepiness Scale. Sleep diary and wrist actigraphy measurements were recorded throughout the study. RESULTS: In total, 127 patients received dupilumab and 61 patients received placebo. Demographic and baseline disease characteristics were balanced between groups. Sleep quality NRS significantly improved in patients treated with dupilumab by week 12 vs. placebo [least squares mean of the difference (LSMD) -15.5%, P < 0.001]. PP NRS (LSMD -27.9%, P < 0.001), SCORAD (LSMD -15.1, P < 0.001), SCORAD sleep VAS (LSMD -2.1, P < 0.001) and PROMIS T-score (LSMD -3.6, P < 0.001) were also significantly improved at week 12 with dupilumab vs. placebo. The overall percentage of patients reporting treatment-emergent adverse events was lower in the dupilumab group (56.7%) than in the placebo group (67.2%). CONCLUSIONS: Dupilumab significantly improved sleep quality and perception of sleep continuity, itch, metrics of AD severity and QoL in adults with moderate-to-severe AD, with an acceptable safety profile compared with placebo.

Multifunctional Branched Nanostraw-Electroporation Platform for Intracellular Regulation and Monitoring of Circulating Tumor Cells.

Downstream analysis of circulating tumor cells (CTCs) has provided new insights into cancer research. In particular, the detection of CTCs, followed by the regulation and monitoring of their intracellular activities, can provide valuable information for comprehensively understanding cancer pathogenesis and progression. However, current CTC detection techniques are rarely capable of in situ regulation and monitoring of the intracellular microenvironments of cancer cells over time. Here, we developed a multifunctional branched nanostraw (BNS)-electroporation platform that could effectively capture CTCs and allow for downstream regulation and monitoring of their intracellular activities in a real-time and in situ manner. The BNSs possessed numerous nanobranches on the outer sidewall of hollow nanotubes, which could be conjugated with specific antibodies to facilitate the effective capture of CTCs. Nanoelectroporation could be applied through the BNSs to nondestructively porate the membranes of the captured cells at a low voltage, allowing the delivery of exogenous biomolecules into the cytosol and the extraction of cytosolic contents through the BNSs without affecting cell viability. The efficient delivery of biomolecules (e.g., small molecule dyes and DNA plasmids) into cancer cells with spatial and temporal control and, conversely, the repeated extraction of intracellular enzymes (e.g., caspase-3) for real-time monitoring were both demonstrated. This technology can provide new opportunities for the comprehensive understanding of cancer cell functions that will facilitate cancer diagnosis and treatment.

Nanospikes functionalization as a universal strategy to disperse hydrophilic particles in non-polar media.

Dispersion of hydrophilic particles in non-polar media has many important applications yet remains difficult. Surfactant or amphiphilic functionalization was conventionally applied to disperse particles but is highly dependent on the particle/solvent system and may induce unfavorable effects and impact particle hydrophilic nature. Recently 2 µm size polystyrene microbeads coated with ZnO nanospikes have been reported to display anomalous dispersity in phobic media without using surfactant or amphiphilic functionalization. However, due to the lack of understanding whether this phenomenon was applicable to a wider range of conditions, little application has been derived from it. Here the anomalous dispersity phenomenons of hydrophilic microparticles covered with nanospikes were systematically assessed at various conditions including different particle sizes, material compositions, particle morphologies, solvent hydrophobicities, and surface polar groups. Microparticles were functionalized with nanospikes through hydrothermal route, followed by dispersity test in hydrophobic media. The results suggest nanospikes consistently prevent particle aggregation in various particle or solvent conditions, indicating the universal applicability of the anomalous dispersion phenomenons. This work provides insight on the anomalous dispersity of hydrophilic particles in various systems and offers potential application to use this method for surfactant-free dispersions.

Study on nonlinear dynamics characteristics of dual speed dual clutch transmission system based on bond graph.

The variable speed transmission system employs compound planetary gear trains and clutches. Compared to traditional aviation transmission systems, the added control parts in the variable transmission system result in a stronger coupling between components and more complex dynamic response characteristics. Modeling using the central mass method is complex and abstract. This study proposes a bond graph-based method for modeling and analyzing the dynamic behavior of the variable transmission system. The transmission system is divided into multiple component-level real-time dynamic models, and obtain a nonlinear multi-energy domain shift dynamic models based on energy flow paths coupling. The mathematical model is numerically solved using the Runge-Kutta method. Simulation results show that there is a delay in the speed response during the shifting process. Further analysis reveals that this "give and take" phenomenon is related to the mechanical structure and passive working principle of the one-way clutch. Subsequently, the time-domain response of the output speed under the hydraulic loading characteristic curves of linear, exponential, S-shaped, and composite functions, as well as the clutch torque, were studied. The impact of different hydraulic loading durations based on the exponential curve on component speed and torque was also analyzed. The simulation results provide a theoretical basis for designing low-shift impact, high-reliability, and high-performance variable transmission systems.

Research on nonlinear dynamic characteristics of high-speed gear in two-speed transmission system.

The working performance and service life of the two-speed transmission system directly affects the performance and service life of helicopters and other equipment. One of the main tasks of the two-speed transmission system research is to improve its dynamic characteristics. For the two-speed transmission system in high-speed gear, a purely torsional nonlinear dynamic differential equation set considering the number of planetary gears, backlash, and clutch dynamic load is established by using the lumped parameter method, and the equations are dimensionless. Then the dimensionless differential equation set is solved by using the variable step-size fourth-order Runge-Kutta method, and the phase diagram and Poincare diagram of high-speed gear are obtained. By changing the dynamic friction coefficient of the friction clutch and the backlash of the gear pair, the influence of parameter change on the nonlinear dynamic characteristics of the system is analyzed. The results show that, with the increase of excitation frequency, the system has experienced single cycle, quasi-cycle, chaos, and double cycle, then changed from double cycle to chaotic motion, and then changed from chaotic motion to double cycle and single cycle motion in turn, and found the path to chaos. In the low-frequency band, reducing the friction coefficient of the friction clutch can reduce vibration amplitude; In the middle-frequency band, reducing the friction coefficient will make the system tend to unstable vibration. In the high-frequency band, it is a single-cycle movement, which is not affected by friction coefficient.

Baseline Demographics, Comorbidities, Treatment Patterns and Burden of Atopic Dermatitis in Adults and Adolescents from the GLOBOSTAD Long-Term Observational Study.

INTRODUCTION: Insights into real-world treatment of atopic dermatitis (AD) are relevant to clinical decision making. The aim of this analysis was to characterize patients who receive dupilumab for AD in a real-world setting. METHODS: The GLOBOSTAD registry is an ongoing, longitudinal, prospective, observational study of patients with AD who receive dupilumab according to country-specific prescribing information. We report baseline characteristics, comorbidities and treatment patterns for patients enrolled from July 11, 2019 to March 31, 2022. Analyses are descriptive; no formal statistical comparisons were performed. RESULTS: Nine hundred fifty-two adults and adolescents were enrolled in GLOBOSTAD. Patients had a high disease burden before starting dupilumab: (mean [standard deviation]) percent body surface area affected (44.8 [24.42]), Eczema Area and Severity Index total score (24.8 [12.95]), SCORing Atopic Dermatitis total score (60.5 [16.34]), Patient-Oriented Eczema Measure total score (19.7 [6.37]) and Dermatology Life Quality Index total score (13.7 [7.02]). Overall, 741 (77.8%) patients reported ≥ 1 type 2 inflammatory comorbidities, most frequently allergic rhinitis (492 [51.7%]), asthma (323 [33.9%]), food allergy (294 [30.9%]) or another allergy (274 [28.8%]). In the previous 12 months, 310 (32.6%) patients had received systemic non-steroidal immunosuppressants and 169 (17.8%) systemic corticosteroids; 449 (47.2%) had received topical corticosteroids, most commonly potent topical corticosteroids; 141 (14.8%) had received topical calcineurin inhibitors and 32 (3.4%) ultraviolet therapy. Most (713 [74.9%]) patients started dupilumab because of prior treatment failure. CONCLUSION: Patients enrolled in GLOBOSTAD demonstrated considerable multidimensional burden of disease across AD signs, symptoms and quality of life despite previous use of systemic and non-systemic AD treatments. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03992417. Video Abstract.

Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults.

BACKGROUND: Immunotherapy for allergic rhinoconjunctivitis (ARC) in North America is generally administered subcutaneously, but alternative formulations might be safer and more convenient. Trials of sublingual formulations in North America are needed to confirm European efficacy and safety data. OBJECTIVE: We sought to investigate the efficacy and safety of timothy grass allergy immunotherapy tablet (AIT) treatment in North American subjects with ARC. METHODS: Four hundred thirty-nine adults with grass pollen-induced ARC with or without asthma were randomized to once-daily 2,800 bioequivalent allergen units of standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 standardized quality tablet, containing approximately 15 µg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). The primary end point was the average total combined score of the daily symptom score and the daily medication score during the GPS. Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) scores, Phl p 5-specific IgG4 levels, and IgE-blocking factor levels were additional end points. Adverse events (AEs) were monitored for safety. RESULTS: Relative to placebo, grass AIT treatment improved total combined scores by 20% (P = .005), daily symptom scores by 18% (P = .02), and RQLQ(S) scores by 17% (P = .02). Daily medication scores were improved by 26% and trended toward significance (P = .08). Phl p 5-specific IgG4 and IgE-blocking factor levels were higher after grass AIT treatment compared with those after placebo at the end of the GPS (P < .001). Grass AIT treatment was safe and well tolerated. The majority of AEs were transient mild local reactions with no investigator-diagnosed grass AIT-related serious AEs or reports of anaphylactic shock/respiratory compromise. In the grass AIT group, 1 subject received epinephrine after experiencing a possible grade 1 systemic reaction (local site reactions, chest discomfort, and rash). CONCLUSIONS: Timothy grass AIT treatment (cross-reactive with related Pooideae grasses) was demonstrated to be effective, generally safe, and well tolerated in North American adults with grass pollen-induced ARC.

Anti-biofouling NH3 gas sensor based on reentrant thorny ZnO/graphene hybrid nanowalls.

Since toxic gas leakage may cause ecological environmental problems and even life-threatening damage, effective monitoring of toxic gas is of great importance and subject to increasing demand. However, complicated environmental factors, as well as various coexisting interferences can easily affect the sensitivity and selectivity of gas sensors, hindering their performance. Recent reports have successfully demonstrated the development of hierarchical nanostructures with desirable self-cleaning properties, yet gas sensors that can resist contamination have rarely been realized. Here, we developed a reentrant thorny ZnO/graphene hybrid nanowall structure that simultaneously repels liquid contamination and possesses NH3 gas sensing properties. The unique reentrant and hierarchical structure, featuring an interconnected vertical graphene nanowall framework with numerous ZnO nanospikes branched on the top nanowall, is highly repellent to liquids, even biofluids with low surface tension. The hierarchical structure consisting of gas sensing graphene and ZnO can be successfully applied as an NH3 gas sensor at room temperature, exhibiting not only excellent sensitivity, selectivity, and repeatability, but also outstanding stability even after bacterial contamination. This study provides a versatile method for fabricating reentrant and hierarchical structures with excellent liquid repellency, and offers a promising method for designing reliable gas sensors with anti-biofouling properties.

Stretchable Strain Vector Sensor Based on Parallelly Aligned Vertical Graphene.

The development of wearable strain sensors for the human-machine interface has attracted considerable research interest. Most existing wearable strain sensors were incapable of simultaneously detecting strain amplitudes and directions, and they failed to fully record stretching vectors that occurred on the body. Graphene and graphene-derived materials have been utilized to construct wearable strain sensors with excellent electrical sensitivities. Although the growth techniques of planar graphene and vertical graphene (VG) have been established, the fabrication of VG aligned in parallel within a larger area has not been previously achieved. Here, parallelly aligned VG (PAVG) in a large area was successfully fabricated and constructed as a wearable strain vector sensor. The PAVG was fabricated via inductively coupled plasma chemical vapor deposition assisted by metal inducers. The as-fabricated sensor was electrically anisotropic because of the profiles of the VG nanosheets aligned in parallel. Therefore, the sensor could simultaneously and sensitively detect the direction and the amplitude of the strain vectors with excellent accuracy. Application of this strain vector sensor for the human-sensor interface to identify the stretching directions and amplitudes of finger joints was also demonstrated. This work established the fabrication methodology of graphene with unique vertical and parallel alignment morphology. This study introduced a new opportunity of developing wearable sensors that could fully detect multidirectional human actions.

Nanospikes-mediated Anomalous Dispersities of Hydropobic Micro-objects and their Application for Oil Emulsion Cleaning.

Many fields of applications require dispersion of hydrophobic particles in water, which is traditionally achieved by using surfactants or amphiphilic molecules to modify particle surfaces. However, surfactants or amphiphilic molecules may disturb the native solution or particles' surface hydrophobicity, limiting extended applications such as oil emulsion cleaning. Recently one example of 2 µm-size polystyrene microparticles covered with ZnO nanospikes has been shown to exhibit excellent dispersity in water in spite of surface hydrophobicity. Whether this anomalous dispersion phenomenon was applicable to other hydrophobic microparticle systems was still unclear and its application scope was limited. Here the anomalous dispersities of different hydrophobic spiky micro-objects were systematically explored. The results show that the anomalous dispersion phenomenon was universally observed on different hydrophobic spiky micro-objects including different hydrophobic coating, particle sizes, material compositions and core particle morphologies. In addition, the spiky micro-objects displayed anomalous dispersity in water without compromising surface hydrophobicity, and their applications for oil spills absorption and oil emulsion cleaning were demonstrated. This work offers unique insight on the nanospikes-mediated anomalous dispersion phenomenon of hydrophobic micro-object and potentially extends its applicability and application scopes.

Hollow Nanoneedle-Electroporation System To Extract Intracellular Protein Repetitively and Nondestructively.

Techniques used to understand the dynamic expression of intracellular proteins are critical in both fundamental biological research and biomedical engineering. Various methods for analyzing proteins have been developed, but these methods require the extraction of intracellular proteins from the cells resulting in cell lysis and subsequent protein purifications from the lysate, which limits the potential of repetitive extraction from the same set of viable cells to track dynamic intracellular protein expression. Therefore, it is crucial to develop novel methods that enable nondestructive and repeated extraction of intracellular proteins. This work reports a hollow nanoneedle-electroporation system for the repeated extraction of intracellular proteins from living cells. Hollow nanoneedles with ∼450 nm diameter were fabricated by a material deposition and etching process, followed by integration with a microfluidic device. Long-lasting electrical pulses were coupled with the nanoneedles to permeate the cell membrane, allowing intracellular contents to diffuse into the microfluidic channels located below the cells via hollow nanoneedles. Using lactate dehydrogenase B (LDHB) as the model intracellular protein, the nanoneedle-electroporation system effectively and repeatedly extracted LDHB from the same set of cells at different time points, followed by quantitative analysis of LDHB via standard enzyme-linked immunosorbent assay. Our work demonstrated an efficient method to nondestructively probe intracellular protein levels and monitor the dynamic protein expression, with great potential to help understanding cell behaviors and functions.

Anomalous dispersion of magnetic spiky particles for enhanced oil emulsions/water separation.

In situ effective separation of oil pollutants including oil spills and oil emulsions from water is an emerging technology yet remains challenging. Hydrophobic micro- or nano-materials with ferromagnetism have been explored for oil removal, yet the separation efficiency of an oil emulsion was compromised due to the limited dispersion of hydrophobic materials in water. A surfactant coating on microparticles prevented particle aggregation, but reduced oil absorption and emulsion cleaning ability. Recently, polystyrene microbeads covered with nanospikes have been reported to display anomalous dispersion in phobic media without surfactants. Inspired by this phenomenon, here magnetic microparticles attached with nanospikes were fabricated for enhanced separation of oil emulsions from water. In this design, the particle surfaces were functionalized to be superhydrophobic/superoleophilic for oil absorption, while the surface of the nanospikes prevented particle aggregation in water without compromising surface hydrophobicity. The magnetic spiky particles effectively absorbed oil spills on the water surface, and readily dispersed in water and offered facile cleaning of the oil emulsion. In contrast, hydrophobic microparticles without nanospikes aggregated in water limiting the particle-oil contact, while surfactant coating severely reduced particle hydrophobicity and oil absorption ability. Our work provides a unique application scope for the anomalous dispersity of microparticles and their potential opportunities in effective oil-water separation.