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We report the discovery in TMC-1 of two cyano derivatives of the PAH acenaphthylene (C12H8). We have found two series of lines with the QUIJOTE line survey that we assign to 1-C12H7CN and 5-C12H7CN. For the 1-isomer, we have detected and assigned 173 rotational transitions with J up to 46 and Ka up to 9, corresponding to 107 independent frequencies. For the 5-isomer, the identification is based on 56 individual lines, corresponding to 117 rotational transitions with J up to 40 and Ka up to 8. Identification of the carriers was achieved through a careful analysis of the derived rotational constants, which permit us to focus on molecules larger than naphthalene but smaller than anthracene and phenanthrene. Moreover, the derived rotational constants indicate that the species are planar; this allows us to discard derivatives of fluorene and acenaphthene, which are non-planar species. Quantum chemical calculations and subsequent chemical synthesis of these molecules, as well as the observation of their rotational transitions in the laboratory, unequivocally support our identifications. We also confirm, via a robust line-by-line detection, the previous claimed detection of 1- and 2-cyanonaphthalene, which were obtained through statistical stacking techniques. The column densities of 1- and 5-cyanoacenaphthylene are (9.5 ± 0.9) × 1011 cm−2, while those of 1- and 2-cyanonapthalene are (5.5 ± 0.5) × 1011 cm−2. Hence, it seems that acenaphthylene could be a factor of 1.7 more abundant than naphthalene. These results support a scenario in which PAHs grow in cold dark clouds based on fused five- and six-membered carbon rings. [ABSTRACT FROM AUTHOR]

The presence in the interstellar medium of several imines suggests that other molecules of the same family could be present as well. The propargylimine molecule (HCCCHNH), which arises from CCH substitution on the C atom of methanimine (H2CNH), the simplest imine, has been recently detected in space. Therefore, the analogous CCH derivative substituted on the N atom, known as N-ethynylmethanimine (H2CNCCH), is a good candidate to be observed as well. To allow for its astronomical detection we have investigated its laboratory rotational spectra. The species has been produced by an electric discharge of acetonitrile (CH3CN) and acetylene (HCCH) in argon, and its rotational spectrum between 9 and 40 GHz has been characterized using a Balle–Flygare narrow band-type Fourier-transform microwave spectrometer. The spectral analysis allowed us to derive accurate spectroscopic parameters to obtain reliable frequency predictions for astronomical searches in different sources. We searched for H2CNCCH in several molecular clouds, G+0.693−0.027, L483, and TMC-1, but did not detect it. The upper limits to its abundance derived are consistent with a preference of the CCH substitution of H2CNH on the C atom rather than on the N atom, in line with quantum chemical calculations on the reaction between CCH and H2CNH. [ABSTRACT FROM AUTHOR]

Takashi Shigematsu,1 Shinji Asada,2 Yuichi Endo,3 Takehisa Kawata,2,3 Masafumi Fukagawa,4 Tadao Akizawa5 1Department of Nephrology, Wakayama Medical University, Wakayama, Japan; 2Medical Affairs Department, Kyowa Kirin Co., Ltd., Tokyo, Japan; 3R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan; 4Division of Nephrology, Endocrinology, and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan; 5Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, JapanCorrespondence: Takashi ShigematsuDepartment of Nephrology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, JapanTel +81-73-441-0638Fax +81-73-441-0639Email taki@wakayama-med.ac.jpPurpose: Evocalcet is a novel oral calcimimetic drug that has demonstrated similar efficacy to cinacalcet in regulating serum parathyroid hormone (PTH), calcium, and phosphate levels, with fewer upper gastrointestinal tract-related adverse drug reactions (ADRs) in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. We investigated the efficacy and safety of once-daily oral evocalcet under different dialysate calcium concentrations.Patients and Methods: A post hoc analysis by dialysate calcium concentration (2.5, 2.75, and 3.0 mEq/L) was performed using data from a previous Phase 3 study that included cinacalcet as an active control. Efficacy endpoints were the proportion of patients who achieved the target intact PTH levels of ≥ 60 and ≤ 240 pg/mL between Week 28 and Week 30; time-course changes in serum intact PTH; calcium and phosphorus levels, bone turnover markers, and fibroblast growth factor 23 (FGF23) over the 30-week study period. Safety endpoints were overall ADRs and hypocalcemia- and upper gastrointestinal tract-related ADRs.Results: A total of 634 patients were included in the analysis. Levels of intact PTH, calcium, phosphate, bone turnover markers, and FGF23 showed improvement in all sub-groups, irrespective of dialysate calcium concentration. The incidence of upper gastrointestinal tract-related ADRs was significantly lower in the evocalcet group than the cinacalcet group with dialysate calcium concentrations of 2.75 and 3.0 mEq/L (p< 0.05 for both concentrations).Conclusion: Evocalcet was effective and safe in regulating the levels of serum intact PTH, calcium, and phosphate in patients with secondary hyperparathyroidism undergoing hemodialysis, irrespective of dialysate calcium concentration.Keywords: hypocalcemia, intact parathyroid hormone, oral calcimimetic, post hoc analysis, upper gastrointestinal tract

Objective: The optimal strategy for difficult-to-treat (D2T) rheumatoid arthritis (RA) has not been identified, and the ultrasound characteristics of D2T RA have not been reported. We investigated the clinical characteristics and factors contributing to the outcome in D2T RA in a multicentre RA ultrasound observational cohort. Method: We reviewed 307 Japanese patients diagnosed with RA who underwent treatment with biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). We compared the differences in patient characteristics between the D2T RA and non-D2T RA groups. We examined the factors contributing to a good response [defined as b/tsDMARD continuation and Clinical Disease Activity Index (CDAI) ≤ 10 at 12 months] in the D2T RA patient group. Results: Forty-three patients (14%) were categorized as D2T RA and the remaining 264 (86%) as non-D2T RA at baseline. The grey-scale (GS) score, disease duration, and CDAI at the initiation of treatment were significantly higher in the D2T RA group than in the non-D2T RA group. In contrast, the power Doppler (PD) score was not significantly different between the two groups. Of the 43 D2T RA patients, 20 achieved a good response. The introduction of CTLA4-Ig (n = 5) was significantly associated with a good response in analysis based on inverse probability weighting with propensity score. GS and PD scores at baseline were not significantly associated with therapeutic response at 12 months in D2T RA patients. Conclusions: Patients with D2T RA had high clinical and ultrasound activity and poor responses to treatment with b/tsDMARDs. CTLA4-Ig was associated with a good response at 12 months in D2T RA patients. [ABSTRACT FROM AUTHOR]

Satoshi Kubota,1 Yutaka Endo,1 Mitsue Kubota,1 Tomohiko Shigemasa2 1School of Nursing and Rehabilitation Sciences at Odawara, International University of Health and Welfare, Odawara, Kanagawa, Japan; 2Department of Cardiology, International University of Health and Welfare Atami Hospital, Atami, Shizuoka, Japan Background: Downward shifts in blood volume with changing position generally cause tachycardic responses. Age-related decreases in vagal nerve activity could contribute to orthostatic hypotension in older individuals. Fowler’s position is a reclined position with the back between 30° and 60°, used to facilitate breathing, eating, and other routine daily activities in frail and elderly patients. Objective: This study examined whether stroke volume (SV) was higher and heart rate (HR) lower in Fowler’s position with an upright upper trunk than in Fowler’s position with the whole trunk upright in both older and younger subjects, based on the assumption that lower HR would result from reduced sympathetic activation in older individuals. Methods: We assessed hemodynamics and HR variability from electrocardiography, noninvasive arterial pressure and impedance cardiography in 11 younger male subjects (age range, 20–22 years) and 11 older male subjects (age range, 64–79 years), using three positions: supine, or Fowler’s positions with either 30° of lower trunk inclination and 60° of upper trunk inclination (UT60) or 60° of whole trunk inclination (WT60). Comparisons were then made between age groups and between positions. Results: Reductions in SV and tachycardic response were smaller with UT60 than with WT60, in both younger and older subjects. In addition, reduced tachycardic response with upright upper trunk appeared attributable to decreased vagal withdrawal in younger subjects and to reduced sympathetic activation in older subjects. Conclusion: Our findings indicate that an upright upper trunk during Fowler’s position allowed maintenance of SV and inhibited tachycardic response compared to an upright whole trunk regardless of age, although the autonomic mechanisms underlying tachycardic responses differed between younger and older adults. An upright upper trunk in Fowler’s position might help to reduce orthostatic stress and facilitate routine activities and conversation in frail patients. Keywords: aging, cardiovascular regulation, hemodynamics, Fowler’s position, stroke volume

Manabu Suno,1,* Yuriko Endo,1,* Hiroyuki Nishie,2 Makoto Kajizono,3 Toshiaki Sendo,3 Junji Matsuoka4 1Department of Oncology Pharmaceutical Care and Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 3Department of Pharmacy, Okayama University Hospital, 4Faculty of Health Sciences, Okayama University Medical School, Okayama, Japan *These authors contributed equally to this work Background: An appropriate plasma concentration of fentanyl is the key to achieving good pain control in cancer patients. Cachexia, a multifactorial syndrome, is known to affect drug-metabolizing enzymes. However, the fentanyl concentrations in the blood of patients with cachexia have not been analyzed. The aim of this study was to evaluate the influence of cancer cachexia on dose-adjusted plasma fentanyl concentrations in cancer patients.Methods: Blood was collected from 21 Japanese cancer patients treated with a 24-hour transdermal fentanyl patch during the steady state of fentanyl plasma concentration. Plasma fentanyl concentrations were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the levels were adjusted with the dose of fentanyl. Laboratory data were collected, and the cachexia stage was determined, based on study by Fearon et al. Multiple regression analysis was performed to identify the factors that affected fentanyl plasma concentrations.Results: Eight patients were classified as precachexia, nine as cachexia, and four as refractory cachexia, and the median dose-adjusted fentanyl concentrations (ng/mL per mg/kg/day) were 27.5, 34.4, and 44.5, respectively. The dose-adjusted fentanyl concentration in patients with refractory cachexia was higher than that in patients with precachexia (Kruskal–Wallis test and post hoc Mann–Whitney U-test, P

Over the last few decades, Pd-based three-way catalysts (TWCs) have been more extensively used than Pt-based TWCs because of their higher thermal stability. In this study, the addition of CeO2 to a Pt-based TWC was performed to improve the reductivity and dispersion of Pt particles after aging at 1000 °C. The aged dispersion of the Pt-loaded CeO2 was much higher than that of a commonly used La2O3–CeO2–ZrO2 catalyst. Furthermore, the hydrogen temperature-programmed reduction conducted on Pt/CeO2 revealed that the Pt-loaded highly crystalline CeO2 (HC–CeO2) exhibited a higher reductivity as compared with that of the high surface area CeO2 (HS–CeO2). Adding a small amount of HC–CeO2 to the Pt-based TWC increased both the Pt dispersion and reductivity after aging. Owing to the high dispersion and reductivity of Pt, Rh/Pt-based TWCs with HC–CeO2 used as an additive to the Pt catalyst layer demonstrated a higher catalytic activity than that of the Rh/Pd-based TWCs even after aging at 1000 °C in an exhaust gas. [ABSTRACT FROM AUTHOR]

We found four series of harmonically related lines in IRC +10216 with the Yebes 40m and IRAM 30m telescopes. The first series corresponds to a molecule with a rotational constant, B, of 1448.5994±0.0013MHz and a distortion constant, D, of 63.45±1.15 Hz and covers upper quantum numbers from Ju = 11 up to 33 (B1449). The second series is fitted with B= 1446.9380±0.0098MHz and D= 91±23 Hz and covers upper quantum numbers from Ju = 11 up to 17 (B1447). The third series is fitted with B= 598.7495±0.0011MHz and D= 6.13±0.43 Hz and covers quantum numbers from Ju = 26 up to 41 (B599). Finally, the frequencies of the last series of lines can be reproduced with B= 594.3176±0.0026MHz and D= 4.92±1.16 Hz (B594). The large values of D point toward four metal-bearing carriers. After exploring all plausible candidates containing Na, Al, Mg, and other metals, our ab initio calculations indicate that the cations MgC4H+, MgC3N+, MgC6H+, and MgC5N+ must be the carriers of B1449, B1447, B599, and B594, respectively. These cations could be formed by the radiative association of Mg+ with C4H, C3N, C6H, and C5N, respectively. We calculated the radiative association rate coeffcient of Mg+ with C4H, C3N, C6H, and C5N and incorporated them in our chemical model. The results confirm that the Mg-bearing cations can be formed through these radiative association reactions in the outer layers of IRC +10216. This is the first time that cationic metal-bearing species have been found in space. These results provide a new paradigm on the reactivity of ionized metals with abundant radicals and open the door for further characterization of similar species in metal-rich astrophysical environments. [ABSTRACT FROM AUTHOR]

Heat illness is the primary cause of morbidity and mortality among young athletes and people engaged in outdoor activities in hot environments, including military and industrial applications. Heat illness presents on a spectrum from relatively mild heat exhaustion to the most severe, exertional heat stroke (EHS). EHS is a life-threatening emergency that requires rapid cooling and immediate medical assistance, leading to severe organ damage and sometimes death. EHS is a complicated disease resulting from interactions of several contributing factors, including aberrant calcium dynamics in skeletal muscle. This assertion is based on the fact that human and mouse models with abnormalities in skeletal muscle excitation-contraction (EC) coupling have been associated with the onset of heat stroke. However, a complete understanding of the pathogenesis of EHS remains elusive. To further investigate the pathomechanisms in EHS related to the EC-coupling abnormality, we generated zebrafish models with knocking-in an R615C mutation in the zebrafish ryr1b gene using CRISPR/Cas9 system. Zebrafish with homozygous and heterozygous mutations showed normal development and no motor abnormalities under standard husbandry conditions. When exposed to elevated temperatures, severe muscle damage was observed, which was the same manifestation as our previously reported zebrafish model of EHI and malignant hyperthermia (junctin fish). In addition, we observed that caffeine stimulation enhanced muscle dysfunction, providing a more sensitive assessment of disease severity. The platform we have developed will be useful for drug screening and for evaluating new causative genes that may be discovered in the future. [ABSTRACT FROM AUTHOR]

Ξ− atomic X-ray spectroscopy is one of the most useful methods for investigation of the Ξ–nucleus strong interaction. Since the X-ray energy is shifted and/or broadened due to the Ξ–nucleus strong interaction compared to those calculated from electromagnetic interaction alone, the measurement of the energy shift, Δ E , and the width, Γ, give us information on the Ξ–nucleus potential. A serious problem in the measurement is the significant background derived from in-flight Ξ− decay. A novel method of identifying stopped Ξ− events using the nuclear emulsion was developed to realize the first Ξ− atomic X-ray spectroscopy experiment as the J-PARC E07 experiment, which also aimed at searching for ΛΛ and Ξ− hypernuclei in the emulsion. The X-rays emitted from Ξ− Br and Ξ− Ag atoms were measured using germanium detectors. No clear peaks were observed in the obtained spectra. However, we succeeded in reducing the background to 1/170 by this method employing coincidence measurements using nuclear emulsion and X-ray detectors. [ABSTRACT FROM AUTHOR]

Latent space exploration is a technique that discovers interpretable latent directions and manipulates latent codes to edit various attributes in images generated by generative adversarial networks (GANs). However, in previous work, spatial control is limited to simple transformations (e.g., translation and rotation), and it is laborious to identify appropriate latent directions and adjust their parameters. In this paper, we tackle the problem of editing the StyleGAN image layout by annotating the image directly. To do so, we propose an interactive framework for manipulating latent codes in accordance with the user inputs. In our framework, the user annotates a StyleGAN image with locations they want to move or not and specifies a movement direction by mouse dragging. From these user inputs and initial latent codes, our latent transformer based on a transformer encoder‐decoder architecture estimates the output latent codes, which are fed to the StyleGAN generator to obtain a result image. To train our latent transformer, we utilize synthetic data and pseudo‐user inputs generated by off‐the‐shelf StyleGAN and optical flow models, without manual supervision. Quantitative and qualitative evaluations demonstrate the effectiveness of our method over existing methods. [ABSTRACT FROM AUTHOR]