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The status of dupilumab self-injection at home is not well understood. We therefore aimed to identify the barriers to adherence to dupilumab self-injection. This non-interventional open-label study was conducted between March 2021 and July 2021. Patients with atopic dermatitis, bronchial asthma, and chronic rhinosinusitis with nasal polyps receiving dupilumab, from 15 sites, were requested to complete a self-administered questionnaire regarding the frequency and effectiveness of dosing as well as their use and satisfaction with dupilumab. Barriers to adherence were assessed using the Adherence Starts with Knowledge-12. We included 331 patients who used dupilumab for atopic dermatitis (n = 164), chronic rhinosinusitis with nasal polyps (n = 102), and bronchial asthma (n = 65). The median efficacy of dupilumab scored 9.3 on the visual analog scale. Overall, 85.5% of the patients self-injected dupilumab, and 70.7% perfectly complied with the established injection dates. The pre-filled pen was significantly superior to the conventional syringe in terms of usability, operability, ease of pushing the plunger, and patient satisfaction. However, the pre-filled pen caused more pain during self-injection than did the syringe. Multivariate logistic regression analysis showed that adherence decreased with longer dupilumab treatment duration (p = 0.017) and was not associated with age, sex, underlying disease, or device type. There was a difference in responses related to \"inconvenience/forgetfulness\" between the good and poor adherence groups. The pre-filled dupilumab pen was superior to the syringe in terms of usability, operability, ease of pushing the plunger, and satisfaction. Repetitive instructions are recommended for preventing poor adherence to dupilumab self-injection.

Objective: To determine whether the plantar perceptual learning task, using a hardness discrimination training, efficiently improves walking stability in the elderly. Design: A randomized controlled trial. Setting: Elder day-care center. Participants: Eighty-six elderly people (73.84 SD 5.98 years) who went to an elder day-care center were randomly assigned evenly to either an intervention or a control group. Intervention: The intervention group performed a task to discriminate hardness differences while standing on sponge mats of different levels of hardness. The control group underwent the same task except that they were not instructed to discriminate hardness levels of the mats. The tasks were carried out over a four-week period for 10 days for both groups. Outcome measures: Outcome was assessed by determining root mean squares of trunk acceleration during walking. Results: Plantar perception was significantly improved in the intervention group after training (F = 26.24, p < 0.01). In addition, changes in root mean square values of acceleration were significantly greater after training in the intervention group (medial–lateral, 0.36 SD 0.26; vertical, 0.32 SD 0.24; anterio–posterior, 0.26 SD 0.24) than in the control group (medial–lateral, 0.14 SD 0.28, vertical, 0.16 SD 0.35, anterio–posterior, 0.12 SD 0.29) (p < 0.05). Changes in walking speed were not significantly different (p = 0.13) between the intervention (0.06 SD 0.13) and control groups (0.02 SD 0.14). Conclusion: The plantar perceptual learning task might efficiently stabilize postural control during walking in the elderly.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Lenvatinib is approved as a first-line treatment for unresectable HCC. The therapeutic duration of lenvatinib is limited by resistance, but the underlying mechanism is unclear. To establish lenvatinib-resistant cells, Hep3B cells were initially treated with 3 µM lenvatinib. The concentration was gradually increased by 1 µM or 0.5 µM per week and it reached to 7.5 µM 2 months after the initial exposure to lenvatinib. The biological characteristics of these cells were analyzed by ERK activation in the MAPK signaling pathway and a human phospho‐receptor tyrosine kinase (RTK) antibody array. Factors possibly related to lenvatinib resistance were analyzed using inhibitors, and cell proliferation was analyzed. We established lenvatinib-resistant HCC cells (LR cells) by long-term exposure to lenvatinib. Lenvatinib reduced ERK activation in the parent cells, but not in the LR cells. RTK array analysis showed that the activities of EGFR and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) were significantly increased in LR cells, whereas the activities of other RTKs were unchanged. Erlotinib, a widely used EGFR inhibitor, downregulated ERK activation in LR cells. The proliferation of LR cells will also be affected when lenvatinib is combined with erlotinib to treat LR cells. In contrast, inhibition of IGFR/INSR did not affect ERK activation or cell proliferation. Scavenging of reactive oxygen species (ROS) ameliorated the enhanced EGFR activation in LR cells. Lenvatinib resistance was induced by enhanced EGFR activation, possibly via ROS accumulation, in lenvatinib- resistant cells. These findings may enable the development of lenvatinib combination therapies for HCC.

The voltage-controlled magnetic anisotropy (VCMA) effect is a key to realising high-speed, ultralow-power consumption spintronic devices. The fcc-Co-(111)-based stack is a promising candidate for the achievement of large VCMA coefficients. However, only a few studies on the fcc-Co-(111)-based stack have been reported and the VCMA effect has not been well understood. Previously, we observed a significant increase in the voltage-controlled coercivity (VCC) in the Pt/Ru/Co/CoO/TiO x structure upon post-annealing. However, the mechanism underlying this enhancement remains unclear. This study performs multiprobe analyses on this structure before and after post-annealing and discusses the origin of the VCMA effect at the Co/oxide interface. X-ray magnetic circular dichroism measurement revealed an increase in the orbital magnetic moment owing to post-annealing, accompanied by a significant increase in VCC. We speculate that the diffusion of Pt atoms into the vicinity of Co/oxide interface enhances the interfacial orbital magnetic moment and the VCMA at the interface. These results provide a guideline for designing structures to obtain a large VCMA effect in fcc-Co-(111)-based stacks.

There is urgent need for spintronics materials exhibiting a large voltage modulation effect to fulfill the great demand for high-speed, low-power-consumption information processing systems. Fcc-Co (111)-based systems are a promising option for research on the voltage effect, on account of their large perpendicular magnetic anisotropy (PMA) and high degree of freedom in structure. Aiming to observe a large voltage effect in a fcc-Co (111)-based system at room temperature, we investigated the voltage-induced coercivity ( H c ) change of perpendicularly magnetized Pt/heavy metal/Co/CoO/amorphous TiO x structures. The thin CoO layer in the structure was the result of the surface oxidation of Co. We observed a large voltage-induced H c change of 20.2 mT by applying 2 V (0.32 V/nm) to a sample without heavy metal insertion, and an H c change of 15.4 mT by applying 1.8 V (0.29 V/nm) to an Ir-inserted sample. The relative thick Co thickness, Co surface oxidation, and large dielectric constant of TiO x layer could be related to the large voltage-induced H c change. Furthermore, we demonstrated the separate adjustment of H c and a voltage-induced H c change by utilizing both upper and lower interfaces of Co.

ObjectivesTo evaluate complex CSF movements and shear stress in patients with idiopathic normal pressure hydrocephalus (iNPH) on four-dimensional (4D) flow MRI.MethodsThree-dimensional velocities and volumes of the reciprocating CSF movements through 12 ROIs from the foramen of Monro to the upper cervical spine were measured in 41 patients with iNPH, 23 patients with co-occurrence of iNPH and Alzheimer’s disease (AD), and 9 age-matched controls, using 4D flow imaging and application. Stroke volume, reversed-flow rate, and shear stress were automatically calculated. Relationships between flow-related parameters and morphological measurements were also assessed.ResultsStroke volumes, reversed-flow rates, and shear stress at the cerebral aqueduct were significantly higher in patients with iNPH than in controls. Patients with pure iNPH had significantly higher shear stress at the ventral aspect of the cerebral aqueduct than those with co-occurrence of iNPH and AD. The stroke volume at the upper end of the cerebral aqueduct had the strongest association with the anteroposterior diameter of the lower end of the cerebral aqueduct (r = 0.52). The stroke volume at the foramen of Monro had significant associations with the indices specific to iNPH. The shear stress at the dorsal aspect of the cerebral aqueduct had the strongest association with the diameter of the foramen of Magendie (r = 0.52).ConclusionsStroke volumes, reversed-flow rates, and shear stress through the cerebral aqueduct on 4D flow MRI are useful parameters for iNPH diagnosis. These findings can aid in elucidating the mechanism of ventricular enlargement in iNPH.Key Points• The CSF stroke volume and bimodal shear stress at the cerebral aqueduct were considerably higher in patients with iNPH.• The patients with pure iNPH had significantly higher shear stress at the ventral aspect of the cerebral aqueduct than those with co-occurrence of iNPH and AD.• The shear stress at the cerebral aqueduct was significantly associated with the diameter of the foramen of Magendie.

Polylactide (PLA) exhibits various types of crystal modifications depending on the preparation conditions, including the components. To solve the open question, a reliable calculation method for crystallinity, crystal forms, and composition in neat PLA and PLA composites was developed on the basis of temperature-dependent synchrotron wide-angle X-ray diffraction results. The relative composition of amorphous, α-form, and α’-form phases of PLA and its composites filled with halloysite nanotubes during heating was successfully obtained. It was found that only 47–56% of α’-form crystals transform into α-form crystals during a 2 °C/min heating process for PLA with a molecular weight of 54,300 g/mol. The loading of halloysite nanotubes decreases the cold crystallization and starting transition (α’ crystals transform into α-form crystals) temperatures of PLA. The crystallinity and the main diffraction peak intensity as a function of temperature were also analyzed. These results suggest that the α’-to-α form transition is a solid-solid phase transition.Polylactide (PLA) exhibits various types of crystal modifications depending on the preparation conditions, including the components. To solve the open question, a reliable calculation method for crystallinity, crystal forms and composition in neat PLA and PLA composites was developed on the basis of temperature-dependent synchrotron wide-angle X-ray diffraction results. The relative composition of amorphous, α-form, and α’-form phases of PLA and its composites filled with halloysite nanotubes during heating was successfully obtained.

MgO tunnel barrier is a key material in spintronics. MgO-based magnetic tunnel junctions (MTJs) are widely used in magnetic sensors and magnetoresistive random access memory (MRAM) applications. The MgO tunnel barrier also plays a central role in research on the voltage control of magnetic anisotropy (VCMA) effect, which enables an emerging magnetization control technique with ultralow power consumption. However, the value of the dielectric constant ( ε r ), which is a basic physical quantity of the MgO tunnel barrier, has not been experimentally investigated due to the difficulty in measuring the ε r of small and thin MgO tunnel barriers. In this study, we measured ε r for a MgO tunnel barrier in epitaxial stacks and systematically investigated the relationships among ε r , epitaxial strain, and the VCMA effect. We showed that the MgO tunnel barrier in the epitaxial stacks was subjected to ~1.5% compressive strain and exhibited an enhanced ε r (>15), which is more than 50% greater than that of bulk MgO. Our results indicate that the compressive strain in the thin MgO tunnel barrier enhances ε r and thus the VCMA coefficient. Such strain engineering makes simple rocksalt tunnel barriers more attractive for spintronics applications. This study clarified a large dielectric constant of MgO tunnel barriers in epitaxial magnetic tunnel junction (MTJ). The MgO tunnel barrier is subjected to compressive strain because of restraint from the underlying layers. We demonstrated that the dielectric constant of the MgO tunnel barrier and voltage controlled magnetic anisotropy (VCMA) coefficient of the epitaxial MTJ enhanced with increasing the compressive strain. Such strain engineering in epitaxial stacks makes simple rocksalt tunnel barriers more attractive for spintronics applications.

Nucleophilic, anionic boryl compounds are long-sought but elusive species. We report that reductive cleavage of the boron-bromine bond in N,N'-bis(2,6-diisopropylphenyl)-2-bromo-2,3-dihydro-1H-1,3,2-diazaborole by lithium naphthalenide afforded the corresponding boryllithium, which is isoelectronic with an N-heterocyclic carbene. The structure of the boryllithium determined by x-ray crystallography was consistent with sp2 boron hybridization and revealed a boron-lithium bond length of 2.291 ± 0.006 angstroms. The structural similarity between this compound and the calculated free boryl anion suggests that the boron atom has an anionic charge. The 11B nuclear magnetic resonance spectrum also supports the boryl anion character. Moreover, the compound behaves as an efficient base and nucleophile in its reactions with electrophiles such as water, methyl trifluoromethanesulfonate, 1-chlorobutane, and benzaldehyde.

In volvocine algae, gametogenesis is triggered by different cues depending on the species and their sexual systems. In isogamous unicellular organisms such as Chlamydomonas reinhardtii , which produce gametes of equal size and morphology, nitrogen depletion induces gametogenesis. In contrast, in oogamous multicellular species of the genus Volvox , which produce large, immobile eggs and small motile sperm, male gametogenesis is induced by a sex pheromone secreted by sperm packets (SPs), i.e., bundles of male gametes. Eudorina , an anisogamous multicellular volvocine alga that produces motile gametes of different sizes, is known to form SPs under nitrogen-depleted conditions. Intriguingly, a pheromone-like factor, present in male conditioned medium (CM), has also been implicated in SP formation. To clarify the relative contributions of nitrogen starvation and pheromone signaling, we conducted semi-quantitative analyses of SP induction using synchronously cultured male colonies of Eudorina . When CM was added to male cultures during an early maturation stage, most colonies formed SPs regardless of nitrogen availability. However, when the CM was diluted 100- to 100,000-fold, SP formation was significantly more efficient under nitrogen-depleted conditions than under nitrogen-replete conditions. Notably, SPs never formed without the addition of CM, even in a nitrogen-depleted medium. The SP-inducing activity of the CM was found to markedly decrease with protease treatment. These findings suggest that spermatogenesis in Eudorina is induced by a proteinaceous sex pheromone secreted by male colonies, and that nitrogen depletion, while not essential, enhances this pheromone activity.