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Emraclidine is a novel, highly selective positive allosteric modulator of M4 muscarinic acetylcholine receptors currently in development for the treatment of schizophrenia and Alzheimer’s disease psychosis. By selectively activating M4 receptors, emraclidine may reduce excess dopamine signaling in the striatum, potentially leading to a reduction in psychotic symptoms. Unlike current antipsychotics, emraclidine does not interfere with signaling at dopamine, serotonin, or histamine receptors, which can lead to adverse events. A previous phase 1b study supports further investigation of emraclidine. The phase 2 EMPOWER program will fully evaluate the efficacy, safety, tolerability, and dose-range of once-daily (QD) emraclidine in schizophrenia.
Methods
EMPOWER-1 and EMPOWER-2 are two adequately powered, multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week inpatient studies of emraclidine monotherapy (10 mg QD, 15 mg QD, 30 mg QD). The trials are enrolling adult participants with schizophrenia who are experiencing an acute exacerbation of psychosis. Eligible participants will have a Positive and Negative Syndrome Scale (PANSS) Total Score between ≥85 and ≤120 and a Clinical Global Impression – Severity (CGI-S) score ≥4 at baseline. Both de novo participants and those who complete EMPOWER-1 or EMPOWER-2 will be eligible to participate in EMPOWER-3, a 52-week open label extension trial to evaluate the long-term safety and tolerability of emraclidine in adult participants with stable schizophrenia.
Results
Detailed study designs for the EMPOWER program will be presented. Primary outcome measure for EMPOWER 1 and 2 is change from baseline in PANSS total score at week 6. Other outcome measures include change from baseline in CGI-S score at week 6. Data from EMPOWER-3 will contribute to the overall evaluation of safety and tolerability of emraclidine in adult participants with schizophrenia.
Conclusions
The development of emraclidine is promising, as it selectively activates M4, a novel target that has been implicated in reducing psychotic symptoms while potentially avoiding many of the side effects currently associated with antipsychotics. The EMPOWER program aims to establish the efficacy, safety, tolerability, and appropriate dose-range of emraclidine in the treatment of schizophrenia.
Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs).
Methods
We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons.
Results
Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus (p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type (p < 0.01, FDR correction).
Conclusion
Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.
The configuration of hydroxyl groups around the octahedral cations of 2:1 phyllosilicate minerals has long been an important question in clay science. In the present study, 27Al multiple quantum (MQ) magic angle spinning nuclear magnetic resonance (MAS NMR) was applied to the local structural analysis of octahedral Al positions in a purified Na-montmorillonite. Three octahedral Al sites ([6]Ala, [6]Alb, and [6]Alc) are distinguished by 27Al 5QMAS NMR, whereas these sites are not differentiated by 27Al MAS and 3QMAS NMR. The isotropic chemical shift (δcs) and the quadrupolar product (PQ) were estimated to be 5.8 ppm and 2.6 MHz for [6]Ala, 6.2 ppm and 3.0 MHz for [6]Alb, and 6.7 ppm and 3.7 MHz for [6]Alc, respectively. The three Al sites originated from geometric isomers with cis and trans structures, which have mutually different configurations of the OH groups around the central Al3+ ions. From the view point of symmetry for the OH groups, [6]Ala and [6]Alb in the upfield region were assigned to cis sites, and [6]Alc in the downfield region was assigned to a trans site. The occurrence of multiple Al sites implies that Na-montmorillonite used in the present study has cis-vacant structure in the octahedral sheet. This is a reasonable insight, supported by the chemical composition and the differential thermal analysis data of the Na-montmorillonite.
Mycobacterium lentiflavum is a slow-growing nontuberculous mycobacterium that is widely distributed in soil and water systems, but it is sometimes pathogenic to humans. Although cases of M. lentiflavum infections are rare, 22 isolates of M. lentiflavum were identified at a single hospital in Japan. We suspected a nosocomial outbreak; thus, we conducted transmission pattern and genotype analyses.
Methods:
Cases of M. lentiflavum isolated at Kushiro City General Hospital in Japan between May 2020 and April 2021 were analyzed. The patient samples and environmental culture specimens underwent whole-genome sequencing (WGS). Additionally, we retrospectively collected clinical data from patient medical records.
Results:
Altogether, 22 isolates of M. lentiflavum were identified from sputum and bronchoalveolar lavage samples. Clinically, the instances with M. lentiflavum isolates were considered contaminants. In the WGS analysis, 19 specimens, including 18 patient samples and 1 environmental culture from the hospital’s faucet, showed genetic similarity. The frequency of M. lentiflavum isolation decreased after we prohibited the use of taps where M. lentiflavum was isolated.
Conclusions:
WGS analysis identified that the cause of M. lentiflavum pseudo-outbreak was the water used for patient examinations, including bronchoscopy.
The present study sought to examine the impact of physical symptoms, facial disfigurement, adequacy of preoperative information, and social support on anxiety and depression in Japanese patients with head and neck cancer (HNC) who had undergone surgery.
Method:
A cross-sectional study with 194 patients was conducted using a self-administered questionnaire. This instruments included the Hospital Anxiety and Depression Scale (HADS), the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck cancer module (QLQ–H&N35), and a Social Support Scale developed by Okabayashi et al. (1997).
Results:
The majority (56.7%) had surgery two or more years before completing the questionnaire. More than 25% of respondents showed anxiety or depression. Higher levels of perceived social support were associated with lower rates of anxiety and depression (p < 0.01). Sensory problems were associated with anxiety, and reduced sexuality was associated with depression (p < 0.01). Perceived disfigurement and adequacy of preoperative information were not associated with anxiety or depression.
Significance of Results:
Survivors of HNC experience anxiety and depression for an extended period of time. Social support may alleviate the severity of these disorders. More research is needed to confirm the impact of facial disfigurement and that of the preoperative information provided by surgeons on psychological distress in HNC patients.
This study assessed the factor structure, internal consistency, and concurrent and discriminant validity of a scale used to measure social distress in Japanese head and neck cancer outpatients with facial disfigurement.
Method:
The sample included 225 Japanese outpatients with head and neck cancer, including 129 patients with facial disfigurement. Participants' level of social distress was assessed through our scale, the European Organization for Research and Treatment Cancer questionnaire (EORTC) QLQ-H&N35 and the Hospital Anxiety and Depression scale (HADS).
Results:
Factor analyses confirmed the structure of two subscales of the social distress scale. Social distress was significantly correlated with the social contact subscale of the EORTC QLQ-H&N35 and the HADS.
Significance of results:
Results demonstrated preliminary reliability and validity of the social distress scale. This scale may extend social adjustment research by revealing its determinants and effects for head and neck cancer with facial disfigurement in Japan.
A one-stage repair was performed for correction of the intracardiac malformations associated with coarctation of aorta in five pateints or interrupted aortic arch in eight patients. The ages ranged from four to 294 (median 35) days. The anomalies within the heart were a ventricular septal defect with or without subaortic stenosis (n=7), an aortopulmonary window (n=2), common arterial trunk (n=2), aortic valvar stenosis (n=1) and the TaussigBing anomaly (n=1). Surgery was performed through a median sternotomy employing cardiopulmonary bypass with moderate to deep hypothermia. In terms of the aortic reconstruction, an extended direct anastomosis was performed in 10 patients, while a vascular graft was interposed in three. So long as the aortic cannula did not interfere with the proximal anastomotic site on the aorta, circulatory arrest was avoided. As for surgery within the heart, the ventricular septal defects were closed via the right atrium with myotomy and myectomy if a morphological substrate for subaortic stenosis was confirmed (n=4). There were two hospital deaths (15.4%) due to low cardiac output. In patients who underwent myotomy and myectomy for subaortic stenosis, the postoperative pressure gradient across the aortic valve was negligible. We conclude that surgical results of one-stage repair for the intracardiac malformations associated with interrupted aortic arch or aortic coarctation are reasonable. We suggest that the early relief of obstruction within the left ventricular outflow tract may have played some role in the favorable outcome.
Hydrogen Affinity of Silica-based Nanocomposite for High Temperature Hydrogen Separation Membranes Japan Fine Ceramics Center, 2-4-1, Mutsuno, Nagoya, 456-8587, Japan Yumi H. Ikuhara, Tomohiro Saito, Koji Hataya, Yuji Iwamoto and Seiji Takahashi Because of concerns about global warming, increasing attention is being directed to find an alternative to fossil hydrocarbon fuels and hydrogen is rapidly becoming one of the leading candidates. For hydrogen production, high temperature membrane reactor is applicable by simplify the process of producing hydrogen from natural gas and purifying it by combining these process into single step. Among the materials, ceramic membranes with molecular sieve-like properties have been expected for application in membrane reactors for conversion enhancement in dehydrogenation and methane reforming reactions. Amorphous silica (Si-O) membranes prepared by sol-gel method have been intensively studied as molecular sieve membranes for gas separation at high temperature. To enhance the hydrogen permselectivity, we have developed Ni nanoparticle-dispersed amorphous Si-O based composite membrane through the precursor solution method and achieved higher hydrogen permeance compared to helium and nitrogen at 573K to 773K. In order to understand the phenomenon of the high hydrogen permeance of the novel nanocomposite membrane, it is important to clarify the expected high temperature hydrogen affinity, i.e., hydrogen adsorption properties. Here, the relationship between microstructure and hydrogen affinity of the nanocomposite was intensively studied from the view point of concentration of Ni nanoparticle in the amorphous Si-O matrix and reversible hydrogen adsorption property. Ni nanoparticles with about 3 to 5 nm in size were homogeneously dispersed in the amorphous Si-O matrix, and the Ni nanoparticles reached to saturate in the Si-O matrix with Ni/(Si+Ni) ratio of 0.2. The reversibly adsorbed hydrogen was hardly detected on the amorphous Si-O and Ni at 573 K, while Ni nanoparticle-dispersed amorphous silica apparently exhibited reversible hydrogen adsorption property. There was appreciable pressure dependence of the reversible hydrogen adsorption on the composite. Further study of the relationship between the increase amount of the reversibly adsorbed hydrogen (Vr) and Ni content on the composite powders revealed that the Vr gradually increased with increasing the Ni content and the highest Vr was ascertained for the composite with the Ni/(Si+Ni) ratio of 0.2. Combining the results of the unique hydrogen permeance through the composite membrane and the hydrogen affinity in the composite powder, we conclude that the existence of reversibly adsorbed hydrogen due to the extensive dispersion of Ni nanoparticles in the Si-O-based membrane involve the enlargement of the number of solubility site for hydrogen, which resulted in the selective enhancement in the hydrogen permeance of the nanocomposite membrane. Contact persons: Y
Using the most advanced anisotropic (2D) Fokker-Planck (FP) models, we calculate the evolution of the mass functions of the Galactic globular cluster system (GCMF). Our models include two-body relaxation, binary heating, tidal shocks, dynamical friction, stellar evolution, and realistic cluster orbits. We perform 2D-FP simulations for a large number of virtual globular clusters and synthesize these results to study the relation between the initial and present GCMFs. We found two probable IGCMFs that eventually evolve into the Milky Way GCMF : truncated power-law, and log-normal model with higher initial low mass limit and peak mass than the earlier studies.
Crack-healing of structural ceramics is a most valuable technique to overcome their weak point such as surface cracks. Crack-healing ability appeared by admixing SiC to ceramics, because this function is to use the oxidation of SiC. Endowment of crack-healing ability as well as improvement in fracture toughness was expected to be achieved by compositing SiC whiskers. For this purpose, alumina / 30 vol% SiC whiskers and alumina/ 20vol% SiC whiskers/ 10 vol% SiC particles multi-composites were developed. Crack-healing ability and fracture toughness of these composites were investigated. Alumina/ 20 vol% SiC whiskers/ 10 vol% SiC particles multi-composite and alumina/ 30vol% SiC whiskers composite were found to have 1.43 times and 1.65 times higher fracture toughness than monolithic alumina, respectively. From the results of the strength recovery by crack-healing, alumina/ 20 vol% SiC whiskers/ 10 vol% SiC particles multi-composite and alumina / 30vol% SiC whiskers composite were found to be able to heal the pre-crack below 0.250 μm and 0.200 μm in surface length, respectively. In spite of the same SiC content, SiC particles and SiC whiskers multi-compositing enlarged the limit crack size to be able to crack-heal. On the other hand, increasing SiC whiskers content enhanced strength recovery of the specimen with the large crack above limit crack-size.
Council Regulation 44/2001 on jurisdiction and the recognition and enforcement of Judgments in Civil Commercial Matters1 replaced the 1968 Brussels Convention on 1 March 2002 for Member States of the European union Except Denmark.2 This has given the European Community exclusive competence in matters relating to jurisdiction and the recognition and enforcement of judgments. As a result individual Member States can no longer freely ratify conventions which, in relation to specific matters, govern jurisdiction or the recognition or enforcement of judgments.3 This is reflected in the deletion of ‘or will be’ from the text of Article 71(1) of the Regulation,4 a phrase which previously found in the equivalent provision in the Brussels Convention.5
We investigate the dynamical evolution of clusters of galaxies in virial equilibrium by using Fokker–Planck models and self-consistent N-body models. In particular we focus on the growth of the common halos and the development of the central density cusps in the clusters. We find good agreement between the Fokker–Planck and N-body models. At the cluster center the cusp approximated by a power law, ρ(r) ∝ r-α (α ∼ 1), develops. We conclude that this shallow cusp results from the combined effects of two-body relaxation and tidal stripping. The cusp steepness α weakly depends on the relative importance of tidal stripping.
The world's first microstereolithography named “IH process” was developed by Ikuta et al. in 1992. Several types of micro stereo lithography including Hybrid-IH process, Super-IH process and Two-photon IH process, have been also developed. Three-dimensional (3D) resolution has reached to 140 nm in the two-photon IH process. The super-IH process and the two-photon process enable direct writing of movable micromechanisms without assembling process or sacrificial layer technique. The hybrid-IH process provides various types of composite devices with other functional elements such as actuators and sensors. These IH processes can be widely used for making polymeric microdevices. We have applied these techniques to create new micro chemical device named “Biochemical IC Chip” proposed by Ikuta et al. in 1994. IH process enables to make the biochemical IC chip including real 3D micro fluidic channels. Various kinds of Biochemical IC chip such as micro pumps, switching valves, reactors, concentrators, have already been fabricated. In chip cell-free protein synthesis has been demonstrated by using biochemical IC chips. The biochemical IC chips will open new bioscience and medicine based on innovative technology. In this paper, we introduce several types of IH process and its application to biochemical IC chips.
Third party procedure has the merits of saving time and expenses and of preventing inconsistent decisions through eliminating the duplication of proceedings. Because of these procedural merits, third party proceedings (called ‘Part 20 proceedings’1 in the Civil Procedure Rules 1998 (CPR)) are often instituted to bring a claim for contribution. In English law, contribution claims are allowed under the Civil Liability (Contribution) Act 1978 (hereafter the 1978 Act) between wrongdoers such as tortfeasors and defaulters in contracts. Not all legal systems allow contribution claims in such wide circumstances. A third party claim form (called a ‘Part 20 claim form’ in the CPR) may be served out of the jurisdiction under the CPR Rule 6.20(3 A),2 which provides for a special base of jurisdiction for third party proceedings in the case where the third party is a ‘necessary or proper party’ to the claim against the Part 20 claimant. The service is, however, subject to the permission of the court which will not be given unless England is judged to be clearly the most appropriate forum under the forum conveniens discretion.
If a defendazCnt to legal proceedings conceals or dissipates his assets before a judgment is given, the execution of the ensuing judgment may become impossible. To preserve the possibility that a future judgment will be executed, both English and Japanese courts have power to grant interim relief freezing a defendant's assets. As is well known, this is achieved in England by the Mareva injunction, which is now called simply “freezing injunction” with the implementation of the new Civil Procedure Rules. In Japan, it is the kari-sashiosae order available under the Civil Interim Relief Law (Minji Hozen Ho)1 which serves this purpose.
Recent N-body simulations have shown that there is a serious discrepancy between the results of N-body simulations and the results of Fokker-Planck simulations for the evolution of globular and rich open clusters under the influence of the galactic tidal field. In some cases, the lifetime obtained from Fokker-Planck calculations is more than an order of magnitude smaller than those from N-body simulations. In this paper we show that the principal cause for this discrepancy is an oversimplified treatment of the tidal field used in previous Fokker-Planck simulations. We performed new Fokker-Planck calculations using a more appropriate implementation for the boundary condition of the tidal field. The implementation is only possible with anisotropic Fokker-Planck models, while all previous Fokker-Planck calculations rely on the assumption of isotropy. Our new Fokker-Planck results agree well with N-body results. Comparison of the two types of simulations gives a better understanding of the evolution of such clusters.
In the dynamical study of globular star clusters, five types of dynamical models are in current use. The following list includes recent highlights, some of which are developed in these proceedings by other authors.
The evolution of spherical single-mass star clusters was followed by numerically solving the orbit-averaged two-dimensional Fokker-Planck equation in energy-angular momentum space. Velocity anisotropy is allowed in the two-dimensional Fokker-Planck model. The development of the anisotropy is discussed in detail.
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