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Aim: Comparing pharmacokinetics and safety of CT-P17 and EU-approved reference adalimumab (EU–adalimumab) in Japan. Materials & methods: Double-blind, parallel-group phase I trial at three hospitals. Healthy Japanese adults were randomized (1:1) to CT-P17 or EU–adalimumab (single 40-mg subcutaneous dose). The primary end point was pharmacokinetic equivalence for area under the concentration–time curve from time zero to infinity and maximum serum concentration. Results: Of the 205 randomized subjects (102 CT-P17, 103 EU–adalimumab), 204 received study drug. CT-P17 and EU–adalimumab were pharmacokinetically equivalent: 90% CIs for geometric least-squares mean ratios were within predefined 80–125% equivalence margins. Secondary pharmacokinetic end points, safety and immunogenicity were similar between the groups. Conclusion: CT-P17 had pharmacokinetics, safety and immunogenicity comparable to EU–adalimumab in healthy Japanese adults.

Since chemical, biological, radiological, nuclear, and high yield explosive (CBRNE) attacks can cause catastrophic damage, it is important to detect and eliminate the means of attack at the origin. In surveillance operations, efficient allocation of friendly intelligence assets and enemy targets is critical for continuous and reliablemonitoring. In this research, we investigate a mathematical model for exchanging target–asset pairs when there are sudden changes in various operational environments. For this task, we refer to the kidney exchange model as a benchmark. In particular, the methods for constructing and solving the target–asset exchange problem in near realtime are presented. Additionally, we introduce the methodology and results for obtaining a feasible solution of the weapon target assignment problem using the exchange model. Our method can facilitate decisions in reconnaissance operations, especially when countless targets and assets are intricately intertwined in future battlefield scenarios.

Smart materials can respond to stimuli and adapt their responses based on external cues from their environments. Such behavior requires a way to transport energy efficiently and then convert it for use in applications such as actuation, sensing, or signaling. Ultrasound can carry energy safely and with low losses through complex and opaque media. It can be localized to small regions of space and couple to systems over a wide range of time scales. However, the same characteristics that allow ultrasound to propagate efficiently through materials make it difficult to convert acoustic energy into other useful forms. Recent work across diverse fields has begun to address this challenge, demonstrating ultrasonic effects that provide control over physical and chemical systems with surprisingly high specificity. Here, we review recent progress in ultrasound–matter interactions, focusing on effects that can be incorporated as components in smart materials. These techniques build on fundamental phenomena such as cavitation, microstreaming, scattering, and acoustic radiation forces to enable capabilities such as actuation, sensing, payload delivery, and the initiation of chemical or biological processes. The diversity of emerging techniques holds great promise for a wide range of smart capabilities supported by ultrasound and poses interesting questions for further investigations.

Novel solution-processable dithieno[3,2-d:2′,3′-d]thiophene (DTT) derivatives with alkylated thiophene or alkyl chain substituents, 2,6-bis(5-octylthiophen-2-yl)dithieno[3,2-b:2′,3′-d]thiophene (compound 1), 2,6-bis(5-(2-ethylhexyl)thiophen-2-yl)dithieno[3,2-b:2′,3′-d]thiophene (compound 2), and 2,6-dioctyldithieno[3,2-b:2′,3′-d]thiophene (compound 3), have been synthesized and employed as small molecular organic semiconductors for organic field-effect transistors (OFETs). All compounds exhibited good thermal stability over 290 °C, while different side groups of DTT compounds afforded different melting temperatures. The molecular orbital energy levels were experimentally and theoretically calculated, and their trend was almost the same. The developed compounds were employed as active layers for top-contact/bottom-gate OFETs with average charge carrier mobility as high as 0.10 cm2/Vs and current on/off ratio &gt, 107 in ambient atmosphere. Notably, DTT derivative with linear alkyl chain (-octyl) substituents showed the best device performance. High device performance could be attributed to the large grains and continuous surface coverages as well as high film texture of the corresponding semiconductor films.

We report a visual detection of Cr(VI) ions using silver-coated gold nanorods (AuNR@Ag) as sensing probes. Au NRs were prepared by a seed-mediated growth process and AuNR@Ag nanostructures were synthesized by growing Ag nanoshells on Au NRs. Successful coating of Ag nanoshells on the surface of Au NRs was demonstrated with TEM, EDS, and UV–vis spectrometer. By increasing the overall amount of the deposited Ag on Au NRs, the localized surface plasmon resonance (LSPR) band was significantly blue-shifted, which allowed tuning across the visible spectrum. The sensing mechanism relies on the redox reaction between Cr(VI) ions and Ag nanoshells on Au NRs. As the concentration of Cr(VI) ions increased, more significant red-shift of the longitudinal peak and intensity decrease of the transverse peak could be observed using UV–vis spectrometer. Several parameters such as concentration of CTAB, thickness of the Ag nanoshells and pH of the sample were carefully optimized to determine Cr(VI) ions. Under optimized condition, this method showed a low detection limit of 0.4 μM and high selectivity towards Cr(VI) over other metal ions, and the detection range of Cr(VI) was tuned by controlling thickness of the Ag nanoshells. From multiple evaluations in real sample, it is clear that this method is a promising Cr(VI) ion colorimetric sensor with rapid, sensitive, and selective sensing ability.

Transurethral resection of the prostate (TURP) is a minimally invasive endoscopic procedure that requires experience and skill of the surgeon. To permit surgical training under realistic conditions we report a novel phantom of the human prostate that can be resected with TURP. The phantom mirrors the anatomy and haptic properties of the gland and permits quantitative evaluation of important surgical performance indicators. Mixtures of soft materials are engineered to mimic the physical properties of the human tissue, including the mechanical strength, the electrical and thermal conductivity, and the appearance under an endoscope. Electrocautery resection of the phantom closely resembles the procedure on human tissue. Ultrasound contrast agent was applied to the central zone, which was not detectable by the surgeon during the surgery but showed high contrast when imaged after the surgery, to serve as a label for the quantitative evaluation of the surgery. Quantitative criteria for performance assessment are established and evaluated by automated image analysis. We present the workflow of a surgical simulation on a prostate phantom followed by quantitative evaluation of the surgical performance. Surgery on the phantom is useful for medical training, and enables the development and testing of endoscopic and minimally invasive surgical instruments.

Gold nanoparticles (Au NPs) are arguably the most versatile nanomaterials reported to date. Recent advances in nanofabrication and chemical synthesis have expanded the scope of Au NPs from classical homogeneous nanospheres to a wide range of hybrid nanostructures with programmable size, shape and composition. Novel physiochemical properties can be achieved via design and engineering of the hybrid nanostructures. In this review we discuss the recent progress in the development of complex hybrid Au NPs and propose a classification framework based on three fundamental structural dimensions (length scale, complexity and symmetry) to aid categorising, comparing and designing various types of Au NPs. Their novel functions and potential for biomedical applications will also be discussed, featuring point-of-care diagnostics by advanced optical spectroscopy and assays, as well as minimally invasive surgeries and targeted drug delivery using multifunctional nano-robots.

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat. In the context of viral infections, sncRNAs have been shown to regulate the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK-RNA-seq, a modified next-generation sequencing (NGS), we found that nasopharyngeal swabs (NPS) samples from SARS-CoV-2 positive and negative subjects show a significant difference in sncRNA profiles. There are about 166 impacted sncRNAs. Among them, tRFs are the most significantly affected and almost all impacted tRFs are derived from the 5′-end of tRNAs (tRF5). Using qRT-PCR, we validated that tRF5s derived from tRNA GluCTC (tRF5-GluCTC), LysCTT (tRF5-LysCTT), ValCAC (tRF5-ValCAC), CysGCA (tRF5-CysGCA) and GlnCTG (tRF5-GlnCTG) are enhanced in NPS samples of SARS-CoV2 patients and SARS-CoV2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several sncRNAs derived from the virus (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3′-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs

This study was performed to examine and clarify the cause of hindlimb ataxia and neuropathy seen in the South Korean horse population. Fifty horses diagnosed with hindlimb ataxia and neuropathy were referred for this study. Neurological examination was performed on 47 horses while necropsy was performed in all 50 animals. The occurrence of neurological diseases increased rapidly in the summer and 47 out of 50 horses were referred after the end of July. The incidence of neurological diseases started from the southern part of Korea in July and proceeded northward in August and September. Although there was no correlation with age, Thoroughbred and Warmblood horses showed a higher incidence rate than Halla and Jeju horses. The incidence rate was 5 times higher in geldings than in mares and stallions. Of the 20 cases, 16 were diagnosed with eosinophilic meningoencephalomyelitis in 2015. The most common lesions observed in 2016 were parasitic meningoencephalomyelitis (10 cases, 33%) and eosinophilic meningomyelitis (7 cases, 23%). Histopathological analysis of the brain and spinal cord revealed nematodes of approximately 100–200 µm in diameter, microcavitation and infiltrates of eosinophils, and brown pigmented macrophage infiltrates. The nematodes were identified as Setaria digitata via DNA sequencing, performed subsequent to polymerase chain reaction using DNA isolated from formalin-fixed paraffin-embedded tissue sections of the spinal cord. These results show that aberrant migration of Setaria digitata larva in the brain and spinal cord was a major cause for neurological signs in horses.

Bladder cancer (BC) is the main disease in the urinary tract with a high recurrence rate and it is diagnosed by cystoscopy (CY). To train the CY procedures, a realistic bladder phantom with correct anatomy and physiological properties is highly required. Here, we report a soft bladder phantom (FlexBlad) that mimics many important features of a human bladder. Under filling, it shows a large volume expansion of more than 300% with a tunable compliance in the range of 12.2 ± 2.8 - 32.7 ± 5.4 mL cmH2O-1 by engineering the thickness of the bladder wall. By 3D printing and multi-step molding, detailed anatomical structures are represented on the inner bladder wall, including sub-millimeter blood vessels and reconfigurable bladder tumors. Endoscopic inspection and tumor biopsy were successfully performed. A multi-center study was carried out, where two groups of urologists with different experience levels executed consecutive CYs in the phantom and filled in questionnaires. The learning curves reveal that the FlexBlad has a positive effect in the endourological training across different skill levels. The statistical results validate the usability of the phantom as a valuable educational tool, and the dynamic feature expands its use as a versatile endoscopic training platform., Cyber Valley Research Fund, Bundesministerium für Bildung und Forschung, Projekt DEAL, Max Planck Society

On 5 May 2017, MMS observed a crater‐type flux rope on the dawnside tailward magnetopause with fluctuations. The boundary‐normal analysis shows that the fluctuations can be attributed to nonlinear Kelvin‐Helmholtz (KH) waves. Reconnection signatures such as flow reversals and Joule dissipation were identified at the leading and trailing edges of the flux rope. In particular, strong northward electron jets observed at the trailing edge indicated midlatitude reconnection associated with the 3‐D structure of the KH vortex. The scale size of the flux rope, together with reconnection signatures, strongly supports the interpretation that the flux rope was generated locally by KH vortex‐induced reconnection. The center of the flux rope also displayed signatures of guide‐field reconnection (out‐of‐plane electron jets, parallel electron heating, and Joule dissipation). These signatures indicate that an interface between two interlinked flux tubes was undergoing interaction, causing a local magnetic depression, resulting in an M‐shaped crater flux rope, as supported by reconstruction., Key Points MMS observed a magnetic flux rope formed on the boundary of a nonlinear Kelvin‐Helmholtz (KH) waveBoth in‐plane and midlatitude reconnection associated with the 3‐D structure of the KH vortex‐inducedflux rope were identifiedA current sheet at the flux rope center supported by reconstruction indicates two flux tubes interlinked to form a crater‐type flux rope

One of the most important transient phenomena affecting the solar wind-Earth’s magnetosphere coupling is non-steady dayside magnetic reconnection, observationally evidenced by a transient structure consisting of a bipolar magnetic-field component normal to the magnetopause. This signature, termed a flux-transfer-event (FTE), has been recently found to often consist of two interlinked flux tubes. The recent observations, particularly from the MMS spacecraft, showed a reconnecting current sheet between the interlaced flux tubes. However, local kinetic processes between the flux tubes have not been understood in the context of the broader FTE structure and evolution. An FTE observed by MMS on 18 December, 2017 comprised two flux tubes of different topology. One includes field lines with their ends connected to the northern and southern hemispheres while the other includes field lines that are connected to the magnetosheath (and ultimately the Sun). Evidence for reconnection occurring at the interface of the two flux tubes indicates how interacting flux tubes evolve into a flux rope having helical magnetic topology connecting either both to the Earth or being completely open. This study proposes a new aspect of how micro-to-meso-scale dynamics occurring within FTEs determines the macroscale characteristics and evolution of the structures.

Purpose Despite the availability of molecular methods, identification of the causative virus in children with acute respiratory infections (ARIs) has proven difficult as the same viruses are often detected in asymptomatic children. Methods Multiplex reverse transcription polymerase chain reaction assays were performed to detect 15 common respiratory viruses in children under 15 years of age who were hospitalized with ARI between January 2013 and December 2015. Viral epidemiology and clinical profiles of single virus infections were evaluated. Results Of 3,505 patients, viruses were identified in 2,424 (69.1%), with the assay revealing a single virus in 1,747 cases (49.8%). While major pathogens in single virus-positive cases differed according to age, human rhinovirus (hRV) was common in patients of all ages. Respiratory syncytial virus (RSV), influenza virus (IF), and human metapneumovirus (hMPV) were found to be seasonal pathogens, appearing from fall through winter and spring, whereas hRV and adenovirus (AdV) were detected in every season. Patients with ARIs caused by RSV and hRV were frequently afebrile and more commonly had wheezing compared with patients with other viral ARIs. Neutrophil-dominant inflammation was observed in ARIs caused by IF, AdV, and hRV, whereas lymphocyte-dominant inflammation was observed with RSV A, parainfluenza virus, and hMPV. Monocytosis was common with RSV and AdV, whereas eosinophilia was observed with hRV. Conclusion In combination with viral identification, recognition of virus-specific clinical and laboratory patterns will expand our understanding of the epidemiology of viral ARIs and help us to establish more efficient therapeutic and preventive strategies.

Atomically dispersed Co(II) cations coordinated to nitrogen in a carbon matrix (Co-N-C) catalyze oxidative dehydrogenation of benzyl alcohol in water with a specific activity approaching that of supported Pt nanoparticles. Whereas Cu(II) cations in N-doped carbon also catalyze the reaction, they are about an order of magnitude less active compared with Co(II) cations. Results from X-ray absorption spectroscopy suggest that oxygen is also bound to N-coordinated Co(II) sites but that it can be partially removed by H2 treatments at 523–750 K. The N-coordinated Co(II) sites remained cationic in H2 up to 750 K, and these stable sites were demonstrated to be active for propane dehydrogenation. In situ characterization of Cu(II) in N-doped carbon revealed that reduction of the metal in H2 started at about 473 K, indicating a much lower thermal stability of Cu(II) in H2 relative to Co(II). The demonstrated high catalytic activity and thermal stability of Co-N-C in reducing environments suggests that this material...

In this study, novel benzo[b]thieno[2,3-d]thiophene (BTT) derivatives, 2-(thiophene-2-yl)benzo[b]thieno[2,3-d]thiophene (compound 1), 2-(5-(2-ethylhexyl)thiophene-2-yl)benzo[b]thieno[2,3-d]thiohpene (compound 2), and 2-(5-octylthiophene-2-yl)benzo[b]theino[2,3-d]thiohpene (compound 3), were synthesized and characterized as solution-processable organic semiconductors (OSCs) for organic field-effect transistors (OFETs). Developed organic compounds were analyzed by thermogravimetric analysis (TGA), differential scanning calorimeter (DSC), UV–vis spectroscopy, and cyclic voltammetry for physicochemical characteristics. All BTT-derivatives were coated by solution-shearing method and fabricated films were characterized by atomic force microscopy (AFM) and θ-2θ X-ray diffraction (XRD). To investigate the electrical performance of newly synthesized BTT-derivatives, bottom-gate/top-contact OFETs were fabricated and characterized in ambient conditions. All compounds exhibited p-channel activity and especially, the resulting OFETs based on films of compound 3 showed the highest hole mobility of 0.11 cm2/Vs and current on/off ratio of 8.7 × 106.

Plasmonic molecules are building blocks of metallic nanostructures that give rise to intriguing optical phenomena with similarities to those seen in molecular systems. The ability to design plasmonic hybrid structures and molecules with nanometric resolution would enable applications in optical metamaterials and sensing that presently cannot be demonstrated, because of a lack of suitable fabrication methods allowing the structural control of the plasmonic atoms on a large scale. Here we demonstrate a wafer-scale "lithography-free" parallel fabrication scheme to realize nanogap plasmonic meta-molecules with precise control over their size, shape, material, and orientation. We demonstrate how we can tune the corresponding coupled resonances through the entire visible spectrum. Our fabrication method, based on glancing angle physical vapor deposition with gradient shadowing, permits critical parameters to be varied across the wafer and thus is ideally suited to screen potential structures. We obtain billions of aligned dimer structures with controlled variation of the spectral properties across the wafer. We spectroscopically map the plasmonic resonances of gold dimer structures and show that they not only are in good agreement with numerically modeled spectra, but also remain functional, at least for a year, in ambient conditions.

Remotely controlled, automated actuation and manipulation at the microscale is essential for a number of micro-manufacturing, biology, and lab-on-a-chip applications. To transport and manipulate micro-objects, arrays of remotely-controlled micro-actuators are required, which, in turn, typically require complex and expensive solid-state chips. Here, we show that a continuous surface can function as a highly-parallel, many-degree of freedom, wirelessly-controlled micro-actuator with seamless deformation. The soft continuous surface is based on a hydrogel that undergoes a volume change in response to applied light. The fabrication of the hydrogels and the characterization of their optical and thermomechanical behaviors are reported. The temperature-dependent localized deformation of the hydrogel is also investigated by numerical simulations. Static and dynamic deformations are obtained in the soft material by projecting light fields at high spatial resolution onto the surface. By controlling such deformations in open loop and especially closed loop, automated photoactuation is achieved. The surface deformations are then exploited to examine how inert microbeads can be manipulated autonomously on the surface. We believe that the proposed approach suggests ways to implement universal 2D micromanipulation schemes that can be useful for automation in microfabrication and lab-on-a-chip applications.

Microrheology is a key technique to characterize soft materials at small scales. The microprobe is wirelessly actuated and therefore typically only low forces or torques can be applied, which limits the range of the applied strain. Here, we report a new magnetic actuation system for microrheology consisting of an array of rotating permanent magnets, which achieves a rotating magnetic field with a spatially homogeneous high field strength of ~100 mT in a working volume of~20 × 20× 20 mm 3 , Compared to a traditional electromagnetic coil system, the permanent magnet assembly is portable and does not require cooling, and it exerts a large magnetic torque on the microprobe that is an order of magnitude higher than previous setups. Experimental results demonstrate that the measurement range of the soft gels' elasticity covers at least five orders of magnitude. With the large actuation torque, it is also possible to study the fracture mechanics of soft biomaterials at small scales.

Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation by T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a potential approach for the tailored treatment of autoimmune disorders. Gene modulation can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using short interfering ribonucleic acid (siRNA) or by inhibiting cytokine signaling using small molecules. In addition, gene modulation delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for gene or immunomodulation in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.

International audience; We report MMS observations of the ion-scale flux transfer events (FTEs) that may involve two main X lines and tearing instability between the two X lines. The four spacecraft detected multiple isolated regions with enhanced magnetic field strength and bipolar B n signatures normal to the nominal magnetopause, indicating FTEs. The currents within the FTEs flow mostly parallel to B, and the magnetic tension force is balanced by the total pressure gradient force. During these events, the plasma bulk flow velocity was directed southward. Detailed analysis of the magnetic and electric field and plasma moments variations suggests that the FTEs were initially embedded within the exhaust region north of an X line but were later located southward/downstream of a subsequent X line. The cross sections of the individual FTEs are in the range of~2.5-6.8 ion inertial lengths. The observations suggest the formation of multiple secondary FTEs. The presence of an X line in the exhaust region southward of a second X line results from the southward drift of an old X line and the reformation of a new X line. The current layer between the two X lines is unstable to the tearing instability, generating multiple ion-scale flux-rope-type secondary islands.