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Abstract Aims A fourth heart sound (S4) was reported to be almost never present in patients with amyloid light‐chain cardiomyopathy. There have been no reports on S4 in patients with wild‐type transthyretin amyloid cardiomyopathy (ATTRwt‐CM). This study aimed to clarify the clinical implications of S4 in patients with ATTRwt‐CM. Methods and results Seventy‐six patients with ATTRwt‐CM (mean age: 80.4 ± 5.4 years, 68 males) who had undergone phonocardiography (PCG) were retrospectively assessed. We measured S4 amplitude on digitally recorded PCG. S4 was considered to be present when its amplitude was 1.0 mm or greater on the PCG. Distinct S4 was defined as S4 with an amplitude of 2.0 mm or greater, which is usually recognizable by auscultation. According to the rhythm and presence or absence of S4, the patients were divided into three groups, namely, sinus rhythm (SR) with S4, SR without S4, and non‐SR. Non‐SR consisted of atrial fibrillation, atrial flutter, and atrial tachycardia. Thirty‐six patients were in SR and the remaining 40 patients were in non‐SR. In the 36 patients in SR, S4 was shown by PCG to be present in 17 patients (47%), and distinct S4 was recognized in 7 patients (19%) by auscultation. In patients who were in SR, those with S4 had higher systolic blood pressure (124 ± 15 vs. 99 ± 8 mmHg, P

Abstract Ulcerative colitis (UC) is a refractory inflammatory bowel disease, which is known to cause psychiatric disorders such as anxiety and depression at a high rate in addition to peripheral inflammatory symptoms. However, the pathogenesis of these psychiatric disorders remains mostly unknown. While prior research revealed that the Enterococcus faecalis 2001 (EF-2001) suppressed UC-like symptoms and accompanying depressive-like behaviors, observed in a UC model using dextran sulfate sodium (DSS), whether it has an anxiolytic effect remains unclear. Therefore, we examined whether EF-2001 attenuates DSS-induced anxiety-like behaviors. Treatment with 2% DSS for seven days induced UC-like symptoms and anxiety-like behavior through the hole-board test, increased serum lipopolysaccharide (LPS) and corticosterone concentration, and p-glucocorticoid receptor (GR) in the prefrontal cortex (PFC), and decreased N-methyl-d-aspartate receptor subunit (NR) 2A and NR2B expression levels in the PFC. Interestingly, these changes were reversed by EF-2001 administration. Further, EF-2001 administration enhanced CAMKII/CREB/BDNF-Drebrin pathways in the PFC of DSS-treated mice, and labeling of p-GR, p-CAMKII, and p-CREB showed colocalization with neurons. EF-2001 attenuated anxiety-like behavior by reducing serum LPS and corticosterone levels linked to the improvement of UC symptoms and by facilitating the CAMKII/CREB/BDNF-Drebrin pathways in the PFC. Our findings suggest a close relationship between UC and anxiety.

Abstract Liquids crystallize as they cool; however, when crystallization is avoided in some way, they supercool, maintaining their liquidity, and freezing into glass at low temperatures, as ubiquitously observed. These metastable states crystallize over time through the classical dynamics of nucleation and growth. However, it was recently found that Coulomb interacting electrons on charge-frustrated triangular lattices exhibit supercooled liquid and glass with quantum nature and they crystallize, raising fundamental issues: what features are universal to crystallization at large and specific to that of quantum systems? Here, we report our experimental challenges that address this issue through the spatiotemporal observation of electronic crystallization in an organic material. With Raman microspectroscopy, we have successfully performed real-space and real-time imaging of electronic crystallization. The results directly capture strongly temperature-dependent crystallization profiles indicating that nucleation and growth proceed at distinctive temperature-dependent rates, which is common to conventional crystallization. However, the growth rate is many orders of magnitude larger than that in the conventional case. The temperature characteristics of nucleation and growth are universal, whereas unusually fast growth kinetics features quantum crystallization where a quantum-to-classical catastrophe occurs in interacting electrons.

Abstract Objective This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. Study Design Prospective cohort study. Setting A multicenter study involving 26 medical facilities in Japan. Methods Inclusion criteria were patients aged ≥18 years old with a confirmed COVID‐19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient‐reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. Results Patients with high albumin, low C‐reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282‐6.526) for taste disorders and 3.534 (95% CI, 1.382‐9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. Conclusion The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID‐19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

Abstract Aims We aim to clarify the prognosis on patients with hypertrophic cardiomyopathy (HCM) for a follow‐up period of more than 10 years. Methods and results We retrospectively analysed 102 consecutive patients with HCM diagnosed by 31 December 2000. Complete and detailed clinical records were obtained for 93 (91%) of the 102 patients. Sixty‐three (68%) of the 93 patients were men, and the mean age of the patients at the initial evaluation was 51.5 ± 13.0 years. During the mean follow‐up period of 19.6 ± 8.1 years (median 20.1 years), HCM‐related deaths occurred in 20 patients (21% [1.1%/year]). HCM‐related adverse events (including HCM‐related deaths and nonfatal HCM‐related events: hospitalization for heart failure, embolic stroke admission, and sustained ventricular tachycardia with haemodynamic instability or appropriate implantable cardioverter‐defibrillator discharge) occurred in 45 patients (48%). The first HCM‐related adverse events occurred in approximately 20% of the patients in every decade, the first decade to the third decade, from the initial evaluation. Forty‐seven patients (51%) had documentation of atrial fibrillation at the last follow‐up. There were seven patients in the end‐stage HCM group at the initial evaluation, and 22 patients (24%) had progression to end‐stage HCM during the follow‐up period. Conclusions In our cohort of patients, HCM‐related mortality was relatively favourable. However, approximately half of the patients suffered from HCM‐related adverse events during the follow‐up period of 20 years. It is important for HCM patients to be carefully followed up over the long‐term because HCM is a lifelong disease.

Genetic mechanisms influencing COVID-19 susceptibility are not well understood. Here, the authors analyzed whole blood RNA-seq data of 465 Japanese individuals with COVID-19, highlighting thousands of fine-mapped variants affecting expression and splicing of genes, as well as the presence of COVID-19 severity-interaction eQTLs.

Summary: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.

Background: The Japanese drug use system allowed the once-daily use of inhaled corticosteroid fluticasone furoate (FF) combined with a long-acting beta-2 agonist vilanterol (VI) and a long-acting muscarinic antagonist umeclidinium (UMEC) against asthma on 18 February 2021. We investigated the real-world effects of these drugs (FF/UMEC/VI) mainly on lung function tests.Methods: This was an open-label, uncontrolled, within-group time-series (before-after) study. Prior asthma treatment (inhaled corticosteroid with/without a long-acting beta-2 agonist with/without a long-acting muscarinic antagonist) was switched to FF/UMEC/VI 200/62.5/25 μg. Subjects were evaluated by lung function tests prior to, and 1–2 months after, initiation of FF/UMEC/VI 200/62.5/25 μg. Patients were asked questions regarding the asthma control test and preference for drugs.Results: Overall, 114 asthma outpatients (97% Japanese) were enrolled from February 2021 to April 2022: 104 subjects completed the study. Forced expiratory volume in 1 s, peak flow, and asthma control test score of FF/UMEC/VI 200/62.5/25 μg-treated subjects were significantly increased (p < 0.001, p < 0.001, and p < 0.01, respectively). In contrast with FF/VI 200/25 μg, instantaneous flow at 25% of the forced vital capacity and expiratory reserve volume were significantly increased by FF/UMEC/VI 200/62.5/25 μg (p < 0.01, p < 0.05, respectively). Sixty-six percent of subjects declared they wanted to continue FF/UMEC/VI 200/62.5/25 μg in the future. Adverse effects, mainly local, were seen in 30% of patients, but no serious adverse effects were seen.Conclusion: Once-daily FF/UMEC/VI 200/62.5/25 μg was effective against asthma without serious adverse events. This is the first report that demonstrated FF/UMEC/VI dilated peripheral airways using lung function tests. This evidence on drug effects may improve our understanding of pulmonary physiology and the pathophysiology of asthma.

Pulmonary arterial hypertension is a progressive fatal disease characterized by pathological pulmonary artery remodeling. Here the authors show that the dysregulation of the activin A-bone morphogenetic protein receptor type 2 link in the endothelium is involved in the progression of pulmonary hypertension.

A weird electronic state accompanied with an anomalous superconducting precursor and/or exotic orders, called the pseudogap state, arises prior to a superconducting condensate in underdoped cuprates that are situated near Mott transition. Another way to make the system approach the Mott transition is the variation of bandwidth or correlation strength, which gives a new dimension to exploring this exotic state. Here we report nuclear magnetic resonance (NMR) studies on layered organic superconductors with half-filled bands whose widths are pressure tuned near the Mott transition. The system situated on the verge of the Mott transition shows a pseudogap-like anomalous suppression of spin excitations on cooling from well above the superconducting critical temperature T_{c}. The pressure variation of the NMR relaxation rate shows that the pseudogap-like behavior is rapidly suppressed by applying pressure. The NMR experiments under various magnetic fields varied up to 18 T proves the absence of symmetry breaking orders that compete with superconductivity, such as charge orders, in the metallic phase. Remarkably, the pseudogap-like behavior above T_{c} and the superconducting condensate fade out in parallel under ascending magnetic fields with similar field-orientation dependence, indicating a superconducting precursor is the predominant origin of the pseudogap. Our further investigation of different materials, which take different “distances” from the Mott transition by chemical pressure, confirms that the superconducting precursor is not the conventional amplitude fluctuations arising from low dimensionality but unconventional preformation of Cooper pairs enhanced near the Mott transition. These findings conclude that preformed Cooper pairs persist up to twice as high as T_{c} on the verge of the bandwidth-controlled Mott transition.

Background The oxidized high-density lipoprotein (oxHDL) is a possible marker for cardiovascular diseases. This study investigated the effects of smoking cessation with varenicline (a partial agonist of nicotinic acetylcholine receptors) on the levels of oxHDL in the serum of subjects compared with those of high-density lipoprotein cholesterol (HDL-C). Methods Data of 99 nicotine-dependent adult subjects who visited the smoking cessation outpatient services at International University of Health and Welfare Shioya Hospital were reviewed. Each subject was treated with varenicline titrated up to 1.0 mg twice daily for 12 weeks. Serum levels of oxHDL and HDL-C were repeatedly measured by enzyme-linked immunosorbent assay and enzymatic method, respectively. Results The serum levels of oxHDL were significantly decreased from 163.2 ± 96.6 to 148.3 ± 80.7 U/mL (p = 0.034, n = 99). This effect was more prominent when the data of subjects in whom the treatment was objectively unsuccessful (exhaled carbon monoxide at 3 months ≥ 10 ppm) were omitted (from 166.6 ± 98.4 to 147.4 ± 80.6 U/mL; p = 0.0063, n = 93). In contrast, the serum levels of HDL-C were significantly increased (p = 0.0044, n = 99). There was a close relationship between the baseline levels of oxHDL and HDL-C (R = 0.45, p < 0.0001, n = 99). Changes in the levels of oxHDL were closely associated with changes in the levels of exhaled carbon monoxide in subjects in whom smoking cessation with varenicline was very effective (decrease in exhaled carbon monoxide by ≥ 15 ppm after treatment with varenicline; R = 0.42, p = 0.0052, n = 43). Conclusions Although there was a close relationship between the baseline serum concentrations of oxHDL and HDL-C, smoking cessation decreased oxHDL and increased HDL-C. This effect on oxHDL may be associated with the effectiveness of smoking cessation.

Obstructive sleep apnea (OSA) patients are at risk for increased blood pressure and carotid intima-media thickness (IMT), with pulmonary hypertension and right-sided heart failure potentially developing as well. Chronic intermittent hypoxia (IH) has been used as an OSA model in animals, but its effects on vascular beds have not been evaluated using objective unbiased tools. Previously published and current experimental data in mice exposed to IH were evaluated for IMT in aorta and pulmonary artery (PA) after IH with or without normoxic recovery using software for meta-analysis, Review Manager 5. Because IMT data reports on PA were extremely scarce, atherosclerotic area percentage from lumen data was also evaluated. IH significantly increased IMT parameters in both aorta and PA as illustrated by Forest plots (P < 0.01), which also confirmed that IMT values after normoxic recovery were within the normal range in both vascular beds. One-sided scarce lower areas in Funnel Plots were seen for both aorta and PA indicating the likelihood of significant publication bias. Forest and Funnel plots, which provide unbiased assessments of published and current data, suggest that IH exposures may induce IMT thickening that may be reversed by normoxic recovery in both aorta and PA. In light of the potential likelihood of publication bias, future studies are needed to confirm or refute the findings. In conclusion, OSA may induce IMT thickening (e.g., aorta and/or PA), but the treatment (e.g., nasal continuous positive airway pressure) will likely lead to improvements in such findings.

A number of materials have been proposed as realizations of exotic quantum spin liquids but many important properties are difficult to establish. Isono et al. show evidence for spin-lattice decoupling in an organic material, which may help resolve conflicting results about the existence of a spin-excitation gap.

Several organic materials exhibit spin liquid phases, which are predicted to host exotic spinon excitations that emerge from non-local quantum effects. Here, the authors identify a quasi-continuous phase transition in κ-(ET)2Cu2(CN)3 that may be associated with the presence of spinons.

Chronic stress is widely recognized as a risk factor for the development of major depression and anxiety disorders. Recently, we reported that yokukansan (YKS), a traditional Japanese herbal medicine, alleviated emotional abnormality in stress-maladaptive mice. The aim of the present study was to examine the effect of YKS on the expression of excitatory amino acid transporter (EAAT) 1–4 in the prefrontal cortex and hippocampus in stress-maladaptive mice. Mice were chronically exposed to inadaptable stress, i.e. repeated restraint stress for 240 min/day for 14 days. After the final exposure to stress, brains of mice were rapidly removed and the hippocampus and prefrontal cortex were dissected. Expressions of EAAT1-4 and glial fibrillary acidic protein (GFAP), a marker of astrocytes, in the brain tissues were analyzed by western blotting. Western blot analysis revealed that the expression level of EAAT2 was specifically decreased in the hippocampus of stress-maladaptive mice while there were no changes in the level of GFAP, and this change was inhibited by chronic treatment with YKS. In contrast, no changes were observed in the levels of EAAT1, EAAT3 or EAAT4 in stress-maladaptive mice. These results suggest that YKS may protect against the decrease in hippocampal EAAT2 expression induced by stress maladaptation, and this may contribute, at least in part, to the improvement of emotional abnormality.

It is expected that introducing charge carriers into an exotic quantum spin liquid state may lead to an unconventional metal but there are no clear realizations of a metallic spin liquid. Here, the authors present a spin liquid candidate that also shows evidence of strange metal behavior.

Pulmonary hypertension is a progressive lung disease with poor prognosis due to the consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction are culprits for pathologically increased pulmonary arterial pressure, but their underlying molecular mechanisms remain to be elucidated. Previous genome-wide association studies revealed a significant correlation between the genetic locus of family with sequence similarity 13, member A (FAM13A) and various lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis; however whether FAM13A is also involved in the pathogenesis of pulmonary hypertension remained unknown. Here, we identified a significant role of FAM13A in the development of pulmonary hypertension. FAM13A expression was reduced in the lungs of mice with hypoxia-induced pulmonary hypertension. We identified that FAM13A was expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated endothelial-to-mesenchymal transition potentially by inhibiting β-catenin signaling in pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in the development of pulmonary hypertension, and therefore increasing and/or preserving FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic strategy for the treatment of pulmonary hypertension.

In the field of respiratory clinical practice, the importance of measuring carbon dioxide (CO2) concentrations cannot be overemphasized. Within the body, assessment of the arterial partial pressure of CO2 (PaCO2) has been the gold standard for many decades. Non-invasive assessments are usually predicated on the measurement of CO2 concentrations in the air, usually using an infrared analyzer, and these data are clearly important regarding climate changes as well as regulations of air quality in buildings to ascertain adequate ventilation. Measurements of CO2 production with oxygen consumption yield important indices such as the respiratory quotient and estimates of energy expenditure, which may be used for further investigation in the various fields of metabolism, obesity, sleep disorders, and lifestyle-related issues. Measures of PaCO2 are nowadays performed using the Severinghaus electrode in arterial blood or in arterialized capillary blood, while the same electrode system has been modified to enable relatively accurate non-invasive monitoring of the transcutaneous partial pressure of CO2 (PtcCO2). PtcCO2 monitoring during sleep can be helpful for evaluating sleep apnea syndrome, particularly in children. End-tidal PCO2 is inferior to PtcCO2 as far as accuracy, but it provides breath-by-breath estimates of respiratory gas exchange, while PtcCO2 reflects temporal trends in alveolar ventilation. The frequency of monitoring end-tidal PCO2 has markedly increased in light of its multiple applications (e.g., verify endotracheal intubation, anesthesia or mechanical ventilation, exercise testing, respiratory patterning during sleep, etc.).

Quantum spin liquids emerge when quantum fluctuations suppress a magnetically ordered state. Here the authors measure magnetic torque inκ-(BEDT-TTF)2Cu2(CN)3, showing universal critical scaling in the magnetic susceptibilities, with critical exponents incompatible with known models for quantum spin liquids.

Strong electronic correlations are expected to generate novel behaviour in materials possessing exotic massless electrons with a relativistic nature. Here, the authors demonstrate the reshaping of tilted Dirac cones and ferrimagnetism associated with Coulombic interactions in a layered organic compound.

A deficiency in the superfluid density in overdoping cuprates is an unconventional feature of keen interest in superconductivity with an electron correlation and, likewise, it was previously suggested that pressure, which weakens the electron correlation, induces an increased deficiency in the superfluid density in an organic superconductor with a fixed band filling. Here, we report our magnetic penetration depth measurements of a layered organic superconductor situated near a Mott transition under various pressures to revisit the issue of superfluid density. The analyses of the results find no meaningful variation in superfluid density with increasing pressure, which greatly suppresses the superconducting transition temperature.

The orbital of electrons in a solid affects their mutual interaction, which is a key to emergent phenomena. Therefore, control of the interplay between distinct orbitals makes the behavior of solids fertile. Such a case is substantiated by the aggregation of the molecule, M(tmdt)_{2}, which contains π orbitals extended over the organic ligand, tmdt, and a level-tunable d orbital centered at the metal ion M. Among them, Au(tmdt)_{2} exemplifies the critical π-d mixing, which arguably causes an over-100 K antiferromagnetic metal whose nature remains elusive. Here, we track the π-d interplay in Au(tmdt)_{2} with dual orbital-resolved probes, ^{13}C NMR and synchrotron x-ray diffraction. We find substantial intramolecular (interorbital) redistribution of electrons on cooling, triggering a commensurate π-d antiferromagnetic metal to emerge, which invokes an orbital-selective doped Mott insulator caused by intramolecular self-doping. This demonstrates that vital traffic of electrons between distinct orbitals brings about an unique correlated phase.

Objective: The Japanese drug use system allowed the “once-daily use” of inhaled corticosteroid (ICS) fluticasone furoate (FF) combined with a long acting beta-2 agonist (LABA) vilanterol (VI) against asthma for the first time in 2013. Until then, patients with asthma had to use ICS at least twice-daily. We investigated the real-world efficacy and problems of this drug (FF/VI). Methods: This was an open-label, uncontrolled, within-group time-series (before-after) design. Prior treatments of asthma (twice-daily use of ICS with or without LABA) were switched to once-daily use of FF/VI (200 μg/25 μg). Subjects were evaluated by lung function tests prior to, and 2–3 months after, the initiation of FF/VI. Questions on the asthma control test (ACT) and preference of drugs were asked to patients. Results: One hundred and twenty-eight Japanese asthma outpatients were enrolled from 2014–2018 and 107 subjects completed the study. Peak flow, instantaneous flow at 75% of the forced vital capacity (V75), V50, maximum mid-expiratory flow rate, forced expiratory volume in 1 s, and ACT score in FF/VI-using subjects were significantly increased (all p

Abstract.: The ability to resist stress is an important defensive function of a living body. Thus, elucidation of the mechanisms by which the brain resists stress could help to pave the way for new therapeutic strategies for stress-related psychiatric disorders including depression. The present review focuses on the roles of brain 5-HT1A receptor–mediated epigenetic mechanisms in the development of resistance to emotional stress. Behavioral pharmacological studies have demonstrated that treatment with a 5-HT1A receptor agonist 24 h before testing suppressed the decrease in emotional behaviors induced by acute restraint stress. Studies with DNA microarray technology have revealed that histone deacetylase genes were decreased in the hippocampus of mice that had been pretreated with a 5-HT1A receptor agonist 24 h beforehand. This preliminary finding was supported by data that hippocampal acetylated histone H3 was increased in mice that had developed emotional resistance to acute restraint stress by 5-HT1A receptor agonist. Furthermore, the histone deacetylase inhibitor trichostatin A also protected against the emotional changes induced by acute restraint stress, accompanied by the induction of histone H3 acetylation. These findings suggest that epigenetic mechanisms that are functionally coupled with 5-HT1A receptors may play a key role in the development of resistance to emotional stress. Keywords:: 5-HT1A receptor, emotional stress resistance, epigenetic, histone acetylation

We present here the first accurate determination of the exact structure of κ-(BEDT-TTF)2Cu2(CN)3. Not only did we show that the room temperature structure used over the last twenty years was incorrect, but we were also able to correctly and precisely determine it. The results of our work provide evidence that the structure presents a triclinic symmetry with two non-equivalent dimers in the unit cell, which implies a charge disproportionation between the dimers. However, structural refinement shows that the charge disproportionation is quite weak at room temperature.