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Abstract FtsZ is highly conserved among bacteria and plays an essential role in bacterial cell division. The tense conformation of FtsZ bound to GTP assembles into a straight filament via head-to-tail associations, and then the upper subunit of FtsZ hydrolyzes GTP bound to the lower FtsZ subunit. The subunit with GDP bound disassembles accompanied by a conformational change in the subunit from the tense to relaxed conformation. Although crystal structures of FtsZ derived from several bacterial species have been determined, the conformational change from the relaxed to tense conformation has only been observed in Staphylococcus aureus FtsZ (SaFtsZ). Recent cryo-electron microscopy analyses revealed the three-dimensional reconstruction of the protofilament, in which tense molecules assemble via head-to-tail associations. However, the lower resolution of the protofilament suggested that the flexibility of the FtsZ protomers between the relaxed and tense conformations caused them to form in less-strict alignments. Furthermore, this flexibility may also prevent FtsZs other than SaFtsZ from crystalizing in the tense conformation, suggesting that the flexibility of bacterial FtsZs differs. In this study, molecular dynamics simulations were performed using SaFtsZ and Bacillus subtilis FtsZ in several situations, which suggested that different features of the FtsZs affect their conformational stability.

Abstract Background Left ventricular enlargement (LVE) is a common manifestation of cardiac remodeling that is closely associated with cardiac dysfunction, heart failure (HF), and arrhythmias. This study aimed to propose a machine learning (ML)-based strategy to identify LVE in HF patients by means of pulse wave signals. Method We constructed two high-quality pulse wave datasets comprising a non-LVE group and an LVE group based on the 264 HF patients. Fourier series calculations were employed to determine if significant frequency differences existed between the two datasets, thereby ensuring their validity. Then, the ML-based identification was undertaken by means of classification and regression models: a weighted random forest model was employed for binary classification of the datasets, and a densely connected convolutional network was utilized to directly estimate the left ventricular diastolic diameter index (LVDdI) through regression. Finally, the accuracy of the two models was validated by comparing their results with clinical measurements, using accuracy and the area under the receiver operating characteristic curve (AUC-ROC) to assess their capability for identifying LVE patients. Results The classification model exhibited superior performance with an accuracy of 0.91 and an AUC-ROC of 0.93. The regression model achieved an accuracy of 0.88 and an AUC-ROC of 0.89, indicating that both models can quickly and accurately identify LVE in HF patients. Conclusion The proposed ML methods are verified to achieve effective classification and regression with good performance for identifying LVE in HF patients based on pulse wave signals. This study thus demonstrates the feasibility and potential of the ML-based strategy for clinical practice while offering an effective and robust tool for diagnosing and intervening ventricular remodeling.

Abstract Direct conversion from terahertz photon to charge current is a key phenomenon for terahertz photonics. Quantum geometrical description of optical processes in crystalline solids predicts existence of field-unbiased dc photocurrent arising from terahertz-light generation of magnetic excitations in multiferroics, potentially leading to fast and energy-efficient terahertz devices. Here, we demonstrate the dc charge current generation from terahertz magnetic excitations in multiferroic perovskite manganites with spin-driven ferroelectricity, while keeping an insulating state with no free carrier. It is also revealed that electromagnon, which ranges sub-terahertz to 2 THz, as well as antiferromagnetic resonance shows the giant conversion efficiency. Polar asymmetry induced by the cycloidal spin order gives rise to this terahertz-photon-induced dc photocurrent, and no external magnetic and electric bias field are required for this conversion process. The observed phenomena are beyond the conventional photovoltaics in semi-classical regime and demonstrate the essential role of quantum geometrical aspect in low-energy optical processes. Our finding establishes a paradigm of terahertz photovoltaic phenomena, paving a way for terahertz photonic devices and energy harvesting.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has changed our lifestyle by imposing restrictions, such as physical distancing. The effect of COVID-19 prevalence on seasonal variations in glycemic control in patients with diabetes mellitus (DM) remains unknown. Methods This single-center retrospective cohort study evaluated glycemic control in patients with type 2 DM who visited Sugi Cardiovascular Hospital in December 2021. We evaluated the clinical findings of all patients treated regularly between March 1, 2019, and December 31, 2021, including the periods both before and after the COVID-19 pandemic. All the standard treatments were approved. Furthermore, seasonal changes in hemoglobin A1c (HbA1c) levels were evaluated using stratified analyses based on age. Results This study analyzed 86 patients (mean age, 69.6 ± 9.2 years; men, 57). Median HbA1c (National Glycohemoglobin Standardization Program [Union of Clinical Chemistry]) levels in spring (March) were 7.70% (interquartile range (IQR):7.23%–8.30%) [60.6 mmol/mol (IQR:55.4–67.2 mmol/mol)], 7.35% (IQR:6.90%–7.90%) [56.8 mmol/mol (IQR:51.9–62.8 mmol/mol)], and 7.50% (IQR:7.10%–8.00%) [58.5 mmol/mol (IQR:54.1–63.9 mmol/mol)] in 2019, 2020, and 2021, respectively. During these periods, HbA1c levels and body mass index (BMI) revealed significant seasonal variations “high in spring” and “low in autumn.” Median HbA1c levels in spring (March) and autumn (September) were 7.86% [61.2 mmol/mol] and 7.48% [57.4 mmol/mol] in 2019 (P

Abstract Giant cell myocarditis (GCM) is a rare but fatal disease that can lead to cardiac failure. Survival with a cardiac standstill requires mechanical circulatory support or a biventricular assist device (BiVAD) and prolonged survival is extremely rare. Drug‐induced hypersensitivity syndrome (DIHS) is a severe cutaneous adverse reaction. Some cases of DIHS are reportedly associated with the onset of GCM. We present a case of a 28‐year‐old woman who developed GCM during steroid tapering after DIHS. She went into continuous cardiac standstill but survived for 74 days under BiVAD support. Our case is noteworthy because the histopathologic specimens obtained on three occasions contributed to the diagnosis of this particular condition over time. We also reviewed previous literature on concomitant cases of GCM and DIHS. We found that two are potentially associated and most cases of GCM occur within 3 months of DIHS during steroid tapering.

Abstract The Bangkok Metropolitan Region (BMR), located in the Chao Phraya River basin delta, is particularly vulnerable to floods, with susceptibility heightened by geographical aspects and rapid urbanization. This study aimed to assess spatiotemporal flood exposure and allow proper flood‐risk recognition among all stakeholders through a three‐phase flood exposure assessment. First, land use and land cover (LULC) changes were identified based on a 30‐year Landsat time series. Second, built‐up areas that overlapped with past flood inundation maps were designated as flood exposure areas. Third, a rainfall‐runoff inundation (RRI) model simulated the 2011 Thailand Flood, the largest on record, by analyzing inundation depth implications across three decades. The findings revealed a dramatic increase in the use of built‐up areas and the associated flood exposure. In 1992, built‐up areas accounted for approximately 20% of the total area, sharply increasing to nearly 45% by 2022, according to the LULC classification. The flood exposure increased from 648.83 km2 in 1992 to 1681.26 km2 by 2022, demonstrating a linear trend. Notably, the catastrophic 2011 flood did not inhibit urbanization in flood‐prone areas, highlighting the need for robust policies, such as the segmentation of flood‐risk zones, to mitigate future exposure in the region.

Introduction Reducing neonatal deaths in premature infants in low- and middle-income countries is key to reducing global neonatal mortality. International neonatal networks, along with patient registries of premature infants, have contributed to improving the quality of neonatal care; however, the involvement of low-to-middle-income countries was limited. This project aims to form an international collaboration among neonatal networks in Asia (AsianNeo), including low-, middle- and high-income countries (or regions). Specifically, it aims to determine outcomes in sick newborn infants, especially very low birth weight (VLBW) infants or very preterm infants, with a view to improving the quality of care for such infants.Methods and analysis Currently, AsianNeo comprises nine neonatal networks from Indonesia, Japan, Malaysia, Philippines, Singapore, South Korea, Sri Lanka, Taiwan and Thailand. AsianNeo will undertake the following four studies: (1) institutional questionnaire surveys investigating neonatal intensive care unit resources and the clinical management of sick newborn infants, with a focus on VLBW infants (nine countries/regions); (2) a retrospective cohort study to describe and compare the outcomes of VLBW infants among Asian countries and regions (four countries/regions); (3) a prospective cohort study to develop the AsianNeo registry of VLBW infants (six countries/regions); and (4) implementation and evaluation of educational and quality improvement projects in AsianNeo countries and regions (nine countries/regions).Ethics and dissemination The study protocol was approved by the Research Ethics Board of the National Center for Child Health and Development, Tokyo, Japan (reference number 2020–244, 2022–156). The study findings will be disseminated through educational programmes, quality improvement activities, conference presentations and medical journal publications.

The nonlinear massive plane wave solution of the classical scalar field in the Higgs potential is revisited to study the mass generation and particle creation. In particular, by assuming that the Higgs system is in the slightly excited state in early universe and it is described by the nonlinear solution, we study the mass generation mechanism for massive vector bosons and a heavy fermion in the quantum field theory around the nonlinear massive classical field. The nonlinear massive classical solution gives the transition from the vacuum to a pair of vector bosons and fermions. We present the new formulae of the probability density of the production process for particles in the standard model of elementary particle physics. The probability densities of the particle productions vanish when the nonlinear massive solution reduces to the constant solution (the classical vacuum expectation value); while the probability densities are expressed as the function of the free parameter in the classical solution in general case. We discuss the behavior of the probability densities for the three oscillating modes in the classical solution.

Abstract Background We aimed to evaluate the length of hospital stay following total knee arthroplasty to determine the impact of relevant factors using data from the Diagnosis Procedure Combination database. Methods This was a retrospective observational study. The study cohort included 5,831 patients who had osteoarthritis of the knee and had undergone total knee replacement between February 2018 and October 2022 at 38 hospitals. Results Multivariate analysis showed that the factors influencing the length of stay included: age (p

Abstract The emergence of COVID-19 dramatically changed social behavior across societies and contexts. Here we study whether social norms also changed. Specifically, we study this question for cultural tightness (the degree to which societies generally have strong norms), specific social norms (e.g. stealing, hand washing), and norms about enforcement, using survey data from 30,431 respondents in 43 countries recorded before and in the early stages following the emergence of COVID-19. Using variation in disease intensity, we shed light on the mechanisms predicting changes in social norm measures. We find evidence that, after the emergence of the COVID-19 pandemic, hand washing norms increased while tightness and punishing frequency slightly decreased but observe no evidence for a robust change in most other norms. Thus, at least in the short term, our findings suggest that cultures are largely stable to pandemic threats except in those norms, hand washing in this case, that are perceived to be directly relevant to dealing with the collective threat.

Abstract This study aimed to investigate the lesion and endoscopist factors associated with unintentional endoscopic piecemeal mucosal resection (uniEPMR) of colorectal lesions ≥ 10 mm. uniEPMR was defined from the medical record as anything other than a preoperatively planned EPMR. Factors leading to uniEPMR were identified by retrospective univariate and multivariate analyses of lesions ≥ 10 mm (adenoma including sessile serrated lesion and carcinoma) that were treated with endoscopic mucosal resection (EMR) at three hospitals. Additionally, a questionnaire survey was conducted to determine the number of cases treated by each endoscopist. A learning curve (LC) was created for each lesion size based on the number of experienced cases and the percentage of uniEPMR. Of 2557 lesions, 327 lesions underwent uniEPMR. The recurrence rate of uniEPMR was 2.8%. Multivariate analysis showed that lesion diameter ≥ 30 mm (odds ratio 11.83, 95% confidence interval 6.80–20.60, p

Background/Aims Endoscopic activity confirmed by enteroscopy is associated with poor clinical outcome in Crohn’s disease (CD). We investigated which of the existing biomarkers best reflects endoscopic activity in CD patients including the small bowel, and whether their combined use can improve accuracy. Methods One hundred and four consecutive patients with ileal and ileocolonic type CD who underwent balloon-assisted enteroscopy (BAE) from October 2021 to August 2022 were enrolled, with clinical and laboratory data prospectively collected and analyzed. Results Hemoglobin, platelet count, C-reactive protein, leucine-rich alpha-2 glycoprotein (LRG), fecal calprotectin, and fecal hemoglobin all showed significant difference in those with ulcers found on BAE. LRG and fecal calprotectin showed the highest areas under the curve (0.841 and 0.853) for detecting ulcers. LRG showed a sensitivity of 78% and specificity of 80% at a cutoff value of 13 μg/mL, whereas fecal calprotectin showed a sensitivity of 91% and specificity of 67% at a cutoff value of 151 μg/g. Dual positivity for LRG and fecal calprotectin, as well as LRG and fecal hemoglobin, both predicted ulcers with an improved specificity of 92% and 100%. A positive LRG or fecal calprotectin/hemoglobin showed an improved sensitivity of 96% and 91%. Positivity for LRG and either of the fecal biomarkers was associated with increased risk of hospitalization, surgery, and relapse. Conclusions The biomarkers LRG, fecal calprotectin, and fecal hemoglobin can serve as noninvasive and accurate tools for assessing activity in CD patients confirmed by BAE, especially when used in combination.

Abstract Pulse wave, as a message carrier in the cardiovascular system (CVS), enables inferring CVS conditions while diagnosing cardiovascular diseases (CVDs). Heart failure (HF) is a major CVD, typically requiring expensive and time-consuming treatments for health monitoring and disease deterioration; it would be an effective and patient-friendly tool to facilitate rapid and precise non-invasive evaluation of the heart’s blood-supply capability by means of powerful feature-abstraction capability of machine learning (ML) based on pulse wave, which remains untouched yet. Here we present an ML-based methodology, which is verified to accurately evaluate the blood-supply capability of patients with HF based on clinical data of 237 patients, enabling fast prediction of five representative cardiovascular function parameters comprising left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), left atrial dimension (LAD), and peripheral oxygen saturation (SpO2). Two ML networks were employed and optimized based on high-quality pulse wave datasets, and they were validated consistently through statistical analysis based on the summary independent-samples t-test (p > 0.05), the Bland–Altman analysis with clinical measurements, and the error-function analysis. It is proven that evaluation of the SpO2, LAD, and LVDd performance can be achieved with the maximum error

Abstract Genome Editing is widely used in biomedical research and medicine. Zinc finger nucleases (ZFNs) are smaller in size than transcription activator‐like effector (TALE) nucleases (TALENs) and CRISPR‐Cas9. Therefore, ZFN‐encoding DNAs can be easily packaged into a viral vector with limited cargo space, such as adeno‐associated virus (AAV) vectors, for in vivo and clinical applications. ZFNs have great potential for translational research and clinical use. However, constructing functional ZFNs and improving their genome editing efficiency is extremely difficult. Here, the efficient construction of functional ZFNs and the improvement of their genome editing efficiency using AlphaFold, Coot, and Rosetta are described. Plasmids encoding ZFNs consisting of six fingers using publicly available zinc‐finger resources are assembled. Two functional ZFNs from the ten ZFNs tested are successfully obtained. Furthermore, the engineering of ZFNs using AlphaFold, Coot, or Rosetta increases the efficiency of genome editing by 5%, demonstrating the effectiveness of engineering ZFNs based on structural modeling.

Abstract Transient creep in olivine aggregates has been studied by stress‐relaxation experiments at pressures of 1.7–3.6 GPa and at temperatures of ≤1020 K in a DIA apparatus. Time‐dependent deformation of olivine at small strains (

Abstract Background and Aim To date, no randomized trials have compared the efficacy of 7‐day vonoprazan, amoxicillin, and metronidazole triple therapy (VAM) versus 7‐day vonoprazan, amoxicillin, and clarithromycin triple therapy (VAC) as a first‐line treatment for Helicobacter pylori eradication. This study was performed to compare the efficacy of VAM and VAC as first‐line treatments. Methods This prospective multicenter randomized trial was performed in Japan and involved 124 H. pylori‐positive patients without a history of eradication. Patients without antibiotic resistance testing of H. pylori were eligible. The patients were randomized to receive either VAC (vonoprazan 20 mg + amoxicillin 750 mg + clarithromycin 200 or 400 mg twice a day) or VAM (vonoprazan 20 mg + amoxicillin 750 mg + metronidazole 250 mg twice a day) for 7 days, with stratification by age and sex. Eradication success was evaluated using the 13C‐urea breath test. We evaluated safety using patient questionnaires (UMIN000025773). Results The intention‐to‐treat and per‐protocol eradication rates of VAM were 91.3% (95% confidence interval [CI], 82.0–96.7%) and 92.6% (95% CI, 83.7–97.6%), respectively, and those of VAC were 89.1% (95% CI, 77.8–95.9%) and 96.1% (95% CI, 86.5–99.5%), respectively. No significant difference was observed between VAM and VAC in either analysis (P = 0.76 and P = 0.70, respectively). Abdominal fullness was more frequent in patients who received VAM than VAC. Conclusions These findings suggest that VAM as a first‐line treatment in Japan can be categorized as grade B (intention‐to‐treat cure rate of 90–95%) and have potential as a first‐line national insurance ‐approved regimen.

Abstract The method used to cultivate the popular Japanese mushroom Grifola frondosa (maitake), called 'wood log cultivation', comprised two steps: (1) the mycelium is grown around a wood log in a plastic bag, and (2) the mycelium that has spread on the wood log is transferred into casing substrates in a forest. This method is still popular in Japan due to its low cost and high-quality crop production. The importance of the microbiome that inhabits mushroom-cultivation surroundings has recently attracted attention, but no study of the microbial communities in maitake cultivation has been published. We investigated how the bacterial communities changed in wood logs in comparison with a control group (without inoculation) and their interaction with maitake during the first to fourth years of maitake wood log cultivation. A maitake biomass was detected by quantitative PCR in wood logs but not in the casings, and we thus decided to investigate the bacterial communities in wood log samples for control and first- to fourth-year cultivation. The results indicate that the phyla Proteobacteria, Firmicutes, and Gemmatimonadota play key roles in changes of the microbiome composition for maitake wood log cultivation. In a functional profile, bacteria communities in the wood logs during maitake cultivation showed higher relative abundance in cellulolysis, glycolysis, TCA cycle, and many biosynthesis pathways, whereas the control group showed higher relative abundance in fermentation. These results suggested that (i) the bacterial communities which inhabited maitake cultivated wood logs may help the maitake degrade wood cellulose, and (ii) part of the glucose from the cellulose degraded by both maitake and bacteria was used for the bacterial TCA cycle instead of fermentation. Bacteria also produce some chemicals that maitake mycelium may need. It is also likely that some potential intracellular parasites dwell with maitake. The different cultivation stages showed different network structures. A network analysis indicated that Class Gammaproteobacteria is a potential keystone taxon for the microbiome network stability of maitake cultivated wood logs. These results contribute to the understanding of the microbiome in maitake-cultivation surroundings and will improve maitake wood log cultivation.

Abstract While polymorphism is prevalent in crystalline solids, polyamorphism draws increasing interest in various types of amorphous solids. Recent studies suggested that supercooling of liquid phase-change materials (PCMs) induces Peierls-like distortions in their local structures, underlying their liquid-liquid transitions before vitrification. However, the mechanism of how the vitrified phases undergo a possible polyamorphic transition remains elusive. Here, using high-energy synchrotron X-rays, we can access the precise pair distribution functions under high pressure and provide clear evidence that pressure can reverse the Peierls-like distortions, eliciting a polyamorphic transition in GeTe and GeSe. Combined with simulations based on machine-learned-neural-network potential, our structural analysis reveals a high-pressure state characterized by diminished Peierls-like distortion, greater coherence length, reduced compressibility, and a narrowing bandgap. Our finding underscores the crucial role of Peierls-like distortions in amorphous octahedral systems including PCMs. These distortions can be controlled through pressure and composition, offering potentials for designing properties in PCM-based devices.

Abstract Background/objective Few reports have directly compared the outcomes of patients with acute ischemic stroke (AIS) who are managed in a stroke care unit (SCU) with those who are managed in an intensive care units (ICU). This large database study in Japan aimed to compare in-hospital mortality between patients with AIS admitted into SCU and those admitted into ICU. Methods Patients with AIS who were admitted between April 1, 2014, and March 31, 2019, were selected from the administrative database and divided into the SCU and ICU groups. We calculated the propensity score to match groups for which the admission unit assignment was independent of confounding factors, including the modified Rankin scale (mRS) score. The primary outcome was in-hospital mortality, and secondary outcomes were the mRS score at discharge, length of stay (LOS), and total hospitalization cost. Results Overall, 8,683 patients were included, and 960 pairs were matched. After matching, the in-hospital mortality rates of the SCU and ICU groups were not significantly different (5.9% vs. 7.9%, P = 0.106). LOS was significantly shorter (SCU = 20.9 vs. ICU = 26.2 days, P

Abstract The associations among Kellgren–Lawrence (KL) grade, medial meniscus extrusion (MME), and cartilage thickness in knee osteoarthritis (OA) remain insufficiently understood. Our aim was to determine these associations in early to moderate medial tibiofemoral knee OA. We included 469 subjects with no lateral OA from the Kanagawa Knee Study. KL grade was assessed using artificial intelligence (AI) software. The MME was measured by MRI, and the cartilage thickness was evaluated in 18 subregions of the medial femorotibial joint by another AI system. The median MME width was 1.4 mm in KL0, 1.5 mm in KL1, 2.4 mm in KL2, and 6.0 mm in KL3. Cartilage thinning in the medial femur occurred in the anterior central subregion in KL1, expanded inwardly in KL2, and further expanded in KL3. Cartilage thinning in the medial tibia occurred in the anterior and middle external subregions in KL1, expanded into the anterior and middle central subregions in KL2, and further expanded in KL3. The absolute correlation coefficient between MME width and cartilage thickness increased as the KL grade increased in some subregions. This study provides novel insights into the early stages of knee OA and potentially has implications for the development of early intervention strategies.

Abstract Background Autoantibodies develop in autoimmune diseases, cancer, diabetes mellitus (DM), and atherosclerosis-related diseases. However, autoantibody biomarkers have not been successfully examined for diagnosis and therapy. Methods Serological identification of antigens through recombinant cDNA expression cloning (SEREX) was used for primary screening of antigens. The cDNA product was expressed in bacteria and purified. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) was used to evaluate antibody levels in serum samples. Results Phosphoenolpyruvate carboxykinase 1 (PCK1) was recognized as an antigen by serum IgG antibodies in the sera of patients with atherosclerosis. AlphaLISA showed significantly higher serum antibody levels against recombinant PCK1 protein in patients with DM and cardiovascular disease than in healthy donors, but not in those with acute ischemic stroke, transient ischemic attack, or obstructive sleep apnea syndrome. The area under the receiver operating characteristic curve for anti-PCK1 antibodies was 0.7024 for DM. The serum anti-PCK1 antibody levels were associated with age, platelet count, and blood pressure. Anti-PCK1-antibody-positive patients showed significantly lower overall survival than the negative patients. Conclusions Serum anti-PCK1 antibody levels were found to be associated with DM. The anti-PCK1 antibody marker is useful for predicting the overall survival of patients with DM.

Ezrin‐radixin‐moesin‐binding phosphoprotein 50 (EBP50) is a scaffold protein that is required for epithelial polarity. Knockout (KO) of membranous EBP50 (Me‐EBP50) in ovarian clear cell carcinoma (OCCC) cells induced an epithelial–mesenchymal transition (EMT)‐like phenotype, along with decreased proliferation, accelerated migration capability, and induction of cancer stem cell (CSC)‐like properties. Shotgun proteomics analysis of proteins that co‐immunoprecipitated with EBP50 revealed that Me‐EBP50 strongly interacts with myosin 9 (MYH9). Specific inhibition of MYH9 with blebbistatin phenocopied Me‐EBP50 KO, and blebbistatin treatment potentiated the effects of Me‐EBP50 KO. In OCCC cells from clinical samples, Me‐EBP50 and MYH9 were co‐localized at the apical plasma membrane. Patients with a combination of Me‐EBP50‐high and MYH9‐high scores had the best prognosis for overall and progression‐free survival. Our data suggest that Me‐EBP50 has tumor‐suppressive effects through the establishment and maintenance of epithelial polarization. By contrast, loss of Me‐EBP50 expression induces EMT‐like phenotypes, probably due to MYH9 dysfunction; this results in increased cell mobility and enhanced CSC‐like properties, which in turn promote OCCC progression.

Although patients with hyperuricemia and gout often have dyslipidemia, the effects of febuxostat, a xanthine oxidase inhibitor, on their lipid profiles are unclear. Thus, we performed a sub-analysis of the randomized PRIZE study in which the effects of febuxostat on carotid atherosclerosis were investigated in patients with hyperuricemia. The participants were randomized to the febuxostat or control group. The primary endpoint of this sub-analysis was changes in the patients’ non-high-density lipoprotein cholesterol (HDL-C) levels from baseline to 6-month follow-up. Correlations between the changes in lipid profiles and cardiometabolic parameters were also evaluated. In total, 456 patients were included. From baseline to 6 months, non-HDL-C levels were significantly reduced in the febuxostat group (−5.9 mg/dL, 95% confidence interval [CI]: −9.1 to −2.8 mg/dL, p < 0.001), but not in the control group (−1.3 mg/dL, 95% CI: −4.4 to 1.8, p = 0.348). The reduction in non-HDL-C levels was more pronounced in women and correlated with changes in serum uric acid and estimated glomerular filtration rate levels only in the febuxostat group. In patients with hyperuricemia, febuxostat treatment was associated with reduced non-HDL-C levels from baseline to the 6-month follow-up compared to the control treatment, suggesting that the lipid-lowering effect of febuxostat should be considered when targeting dyslipidemia.

Enterovirus A71 (EV-A71) infection involves a variety of receptors. Among them, two transmembrane protein receptors have been investigated in detail and shown to be critical for infection: P-selectin glycoprotein ligand-1 (PSGL-1) in lymphocytes (Jurkat cells), and scavenger receptor class B member 2 (SCARB2) in rhabdomyosarcoma (RD) cells. PSGL-1 and SCARB2 have been reported to be expressed on the surface of Jurkat and RD cells, respectively. In the work reported here, we investigated the roles of PSGL-1 and SCARB2 in the process of EV-A71 entry. We first examined the expression of SCARB2 in Jurkat cells, and detected it within the cytoplasm, but not on the cell surface. Further, using PSGL-1 and SCARB2 knockout cells, we found that although both PSGL-1 and SCARB2 are essential for virus infection of Jurkat cells, virus attachment to these cells requires only PSGL-1. These results led us to evaluate the cell surface expression and the roles of SCARB2 in other EV-A71-susceptible cell lines. Surprisingly, in contrast to the results of previous studies, we found that SCARB2 is absent from the surface of RD cells and other susceptible cell lines we examined, and that although SCARB2 is essential for infection of these cells, it is dispensable for virus attachment. These results indicate that a receptor other than SCARB2 is responsible for virus attachment to the cell and probably for internalization of virions, not only in Jurkat cells but also in RD cells and other EV-A71-susceptible cells. SCARB2 is highly concentrated in lysosomes and late endosomes, where it is likely to trigger acid-dependent uncoating of virions, the critical final step of the entry process. Our results suggest that the essential interactions between EV-A71 and SCARB2 occur, not at the cell surface, but within the cell.

Background: Although guidelines recommend intracoronary acetylcholine (ACh) and ergonovine (ER) provocation testing for diagnosis of vasospastic angina, the feasibility and safety of sequential (combined) use of both pharmacological agents during the same catheterization session remain unclear. Objectives: In this study, we investigated the feasibility and safety of sequential intracoronary ACh and ER administration for coronary spasm provocation testing. Methods: The study included 235 patients who showed positive results on ACh and ER provocation testing. Initial intracoronary ACh administration was followed by ER administration for left coronary artery (LCA) spasm provocation testing. Subsequently, the right coronary artery (RCA) was subjected to sequential ACh and ER administration for provocation testing. The primary outcome of the study was the safety of sequential intracoronary ACh and ER provocation testing, which was assessed based on a composite of all-cause death, sustained ventricular tachycardia and fibrillation, and cardiogenic shock. Results: Even in patients with negative results on sequential intracoronary ACh and ER provocation testing in the LCA and only ACh administration into the RCA, additional administration of ER into the RCA showed a positive provocation test result in 33 of 235 (14.0%) patients; three (1.3%) patients developed adverse effects (cardiogenic shock occurred in all cases) during LCA provocation testing. We observed no deaths attributable to spasm provocation testing. Conclusion: Sequential administration of intracoronary ACh and ER was associated with a relatively low major complication rate and may be safe and potentially useful for diagnosis of vasospastic angina.

Summary: The pandemic HIV-1, HIV-1 group M, emerged from a single spillover event of its ancestral lentivirus from a chimpanzee. During human-to-human spread worldwide, HIV-1 diversified into multiple subtypes. Here, our interdisciplinary investigation mainly sheds light on the evolutionary scenario of the viral budding system of HIV-1 subtype C (HIV-1C), a most successfully spread subtype. Of the two amino acid motifs for HIV-1 budding, the P(T/S)AP and YPxL motifs, HIV-1C loses the YPxL motif. Our data imply that HIV-1C might lose this motif to evade immune pressure. Additionally, the P(T/S)AP motif is duplicated dependently of the level of HIV-1 spread in the human population, and >20% of HIV-1C harbored the duplicated P(T/S)AP motif. We further show that the duplication of the P(T/S)AP motif is caused by the expansion of the CTG triplet repeat. Altogether, our results suggest that HIV-1 has experienced a two-step evolution of the viral budding process during human-to-human spread worldwide.

One of the severe complications of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is myocarditis. However, the characteristics of fulminant myocarditis with SARS-CoV-2 infection are still unclear. We systematically reviewed the previously reported cases of fulminant myocarditis associated with SARS-CoV-2 infection from January 2020 to December 2022, identifying 108 cases. Of those, 67 were male and 41 female. The average age was 34.8 years; 30 patients (27.8%) were ≤20 years old, whereas 10 (9.3%) were ≥60. Major comorbidities included hypertension, obesity, diabetes mellitus, asthma, heart disease, gynecologic disease, hyperlipidemia, and connective tissue disorders. Regarding left ventricular ejection fraction (LVEF) at admission, 93% of the patients with fulminant myocarditis were classified as having heart failure with reduced ejection fraction (LVEF ≤ 40%). Most of the cases were administered catecholamines (97.8%), and mechanical circulatory support (MCS) was required in 67 cases (62.0%). The type of MCS was extracorporeal membrane oxygenation (n = 56, 83.6%), percutaneous ventricular assist device (Impella®) (n = 19, 28.4%), intra-aortic balloon pumping (n = 12, 12.9%), or right ventricular assist device (n = 2, 3.0%); combination of these devices occurred in 20 cases (29.9%). The average duration of MCS was 7.7 ± 3.8 days. Of the 76 surviving patients whose cardiac function was available for follow-up, 65 (85.5%) recovered normally. The overall mortality rate was 22.4%, and the recovery rate was 77.6% (alive: 83 patients, dead: 24 patients; outcome not described: 1 patient).

Abstract The effect of prehospital factors on favorable neurological outcomes remains unclear in patients with witnessed out-of-hospital cardiac arrest (OHCA) and a shockable rhythm. We developed a decision tree model for these patients by using prehospital factors. Using a nationwide OHCA registry database between 2005 and 2020, we retrospectively analyzed a cohort of 1,930,273 patients, of whom 86,495 with witnessed OHCA and an initial shockable rhythm were included. The primary endpoint was defined as favorable neurological survival (cerebral performance category score of 1 or 2 at 1 month). A decision tree model was developed from randomly selected 77,845 patients (development cohort) and validated in 8650 patients (validation cohort). In the development cohort, the presence of prehospital return of spontaneous circulation was the best predictor of favorable neurological survival, followed by the absence of adrenaline administration and age. The patients were categorized into 9 groups with probabilities of favorable neurological survival ranging from 5.7 to 70.8% (areas under the receiver operating characteristic curve of 0.851 and 0.844 in the development and validation cohorts, respectively). Our model is potentially helpful in stratifying the probability of favorable neurological survival in patients with witnessed OHCA and an initial shockable rhythm.

Abstract Pyropia is a genus comprising red algae of the Bangiaceae family that is commonly found in intertidal zones worldwide. However, understanding of Pyropia species that are prone to tropical regions remains limited despite recent breakthroughs in genomic research. Within the realm of Pyropia species thriving in tropical regions, P. vietnamensis stands out as a widely recognized species. In this study, we aimed to investigate Pyropia species in the southwest coast of Myanmar using physiological and molecular approaches, culture-based analyses, chloroplast rbcL and nuclear SSU gene sequencing, and whole chloroplast and mitochondrial genome sequencing. Physiological analysis showed that the Myanmar samples were more heat-tolerant than their Japanese counterparts, including those of subtropical origin. Additionally, molecular characterization revealed that the Myanmar samples were closely related to P. vietnamensis from India. This study is the first to sequence the chloroplast and mitochondrial genomes of Pyropia species from tropical regions. A unique deletion event was observed within a ribosomal RNA gene cluster in the chloroplast genome of the studied Pyropia species, which is a deviation from the usual characteristics of most Pyropia species. This study improves current understanding of the physiological and molecular characteristics of this comparatively understudied Pyropia species that grows in tropical regions.

Abstract Many molecular targeted agents, including biologics, have emerged for inflammatory bowel diseases (IBD), but their high prices have prevented their widespread use. This study aimed to reveal the changes in patient characteristics and the therapeutic strategies of IBD before and after the implementation of biologics in Japan, where the unique health insurance system allows patients with IBD and physicians to select drugs with minimum patient expenses. The analysis was performed using a prospective cohort, including IBD expert and nonexpert hospitals in Japan. In this study, patients were classified into two groups according to the year of diagnosis based on infliximab implementation as the prebiologic and biologic era groups. The characteristics of therapeutic strategies in both groups were evaluated using association analysis. This study analyzed 542 ulcerative colitis (UC) and 186 Crohn’s disease (CD). The biologic era included 53.3% of patients with UC and 76.2% with CD, respectively. The age of UC (33.9 years vs. 38.8 years, P

Abstract Hyperuricemia is reportedly associated with the progression of carotid intima-media thickness (IMT), a surrogate of cardiovascular risks and events. However, factors associated with carotid IMT progression in patients with asymptomatic hyperuricemia are largely unknown. In this post-hoc analysis of the multicenter, randomized PRIZE study, we analyzed data from a total of 326 patients who underwent carotid ultrasonography in a blind manner at baseline and 24 months to evaluate carotid IMT. Mean and maximum IMT at the common carotid artery (CCA) were measured at a central core laboratory. Factors related to the absolute change in mean and maximum IMT from baseline to 24 months were explored. Overall, the adjusted mean [0.0032 (− 0.0214 to 0.0278) mm] and maximum [0.0011 (− 0.0327 to 0.0351) mm] CCA-IMT increased numerically from baseline to 24 months. Multivariable analysis identified higher body mass index, history of atherosclerotic cardiovascular disease (ASCVD), and lower mean CCA-IMT at baseline as significant factors associated with the increase in mean CCA-IMT. In addition, older age and lower mean CCA-IMT at baseline were significant factors for an increased absolute change in the maximum CCA-IMT at 24 months. The present sub-analysis of the PRIZE study showed higher body mass index, history of ASCVD, and older age as significant factors associated with CCA-IMT progression in patients with asymptomatic hyperuricemia. These factors may be considered when identifying the possible risk of atherosclerotic progression in this specific patient population of hyperuricemia. Trial registration: UMIN000012911 and UMIN000041322.

In the present study, we conducted a placebo-controlled, double-blind, parallel-group comparison trial in which an extract of Cordyceps militaris (CM) mycelium was administered to long-distance runners for 16 weeks during the pre-season training period and blood test markers for anemia were investigated. The results indicated that the change rates of serum ferritin levels were moderately increased in the CM group (n = 11) but decreased in the placebo group (n = 11) during the study period, and the levels were significantly increased in the CM group compared with those in the placebo group at 4 weeks and 8 weeks after the test food intake (p < 0.05). Moreover, the change rates of hemoglobin and hematocrit were significantly increased in the CM group compared with those in the placebo group at 8 weeks after the test food intake (p < 0.05). These observations suggest that the intake of test food containing Cordyceps militaris mycelium extract is expected to effectively maintain the hemoglobin and hematocrit levels in long-distance runners, possibly via the suppression of the decrease in iron storage, which is reflected by serum ferritin, during pre-season training. Furthermore, the levels of creatine kinase were increased above the normal range in both the placebo and CM groups at registration. Interestingly, the creatine kinase levels were significantly decreased in the CM group compared with those in the placebo group at 16 weeks after the test food intake (p < 0.05). These results suggest that Cordyceps militaris mycelium extract exhibits a protective action on the muscle damage observed in long-distance runners and may suppress muscle injury. Together, these observations suggest that Cordyceps militaris mycelium extract exhibits an improving effect on the markers for not only anemia, but also muscle injury in long-distance runners during pre-season training.

Background: Although takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV), the time course and mechanism of LV function recovery remain elusive. The aim of this study is to evaluate cardiac functional recovery in TTS via serial cardiac magnetic resonance feature tracking (CMR-FT). Methods: In this Japanese multicenter registry, patients with newly diagnosed TTS were prospectively enrolled. In patients who underwent serial cardiovascular magnetic resonance (CMR) imaging at 1 month and 1 year after the onset, CMR-FT was performed to determine the global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS). We compared LV ejection fraction, GCS, GRS and GLS at 1 month and 1 year after the onset of TTS. Results: Eighteen patients underwent CMR imaging in one month and one year after the onset in the present study. LV ejection fraction had already normalized at 1 month after the onset, with no significant difference between 1 month and 1 year (55.8 ± 9.2% vs. 58.9 ± 7.3%, p = 0.09). CMR-FT demonstrated significant improvement in GCS from 1 month to 1 year (−16.7 ± 3.4% vs. −18.5 ± 3.2%, p < 0.01), while there was no significant difference in GRS and GLS between 1 month and year (GRS: 59.6 ± 24.2% vs. 59.4 ± 17.3%, p = 0.95, GLS: −12.8 ± 5.9% vs. −13.8 ± 4.9%, p = 0.42). Conclusions: Serial CMR-FT analysis revealed delayed improvement of GCS compared to GRS and GLS despite of rapid recovery of LV ejection fraction. CMR-FT can detect subtle impairment of LV systolic function during the recovery process in patients with TTS.

Inflammation is closely associated with cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers, and it is accompanied by the development of autoantibodies in the early stage of inflammation-related diseases. Hence, it is meaningful to discover novel antibody biomarkers targeting inflammation-related diseases. In this study, Jumonji C-domain-containing 6 (JMJD6) was identified by the serological identification of antigens through recombinant cDNA expression cloning. In particular, JMJD6 is an antigen recognized in serum IgG from patients with unstable angina pectoris (a cardiovascular disease). Then, the serum antibody levels were examined using an amplified luminescent proximity homogeneous assay-linked immunosorbent assay and a purified recombinant JMJD6 protein as an antigen. We observed elevated levels of serum anti-JMJD6 antibodies (s-JMJD6-Abs) in patients with inflammation-related diseases such as ischemic stroke, acute myocardial infarction (AMI), diabetes mellitus (DM), and cancers (including esophageal cancer, EC; gastric cancer; lung cancer; and mammary cancer), compared with the levels in healthy donors. The s-JMJD6-Ab levels were closely associated with some inflammation indicators, such as C-reactive protein and intima–media thickness (an atherosclerosis index). A better postoperative survival status of patients with EC was observed in the JMJD6-Ab-positive group than in the negative group. An immunohistochemical analysis showed that JMJD6 was highly expressed in the inflamed mucosa of esophageal tissues, esophageal carcinoma tissues, and atherosclerotic plaques. Hence, JMJD6 autoantibodies may reflect inflammation, thereby serving as a potential biomarker for diagnosing specific inflammation-related diseases, including stroke, AMI, DM, and cancers, and for prediction of the prognosis in patients with EC.

Background: We previously developed a risk-scoring system for heart failure (HF) in patients with acute myocardial infarction (MI), namely “HF time-points (HFTPs)”. In the original HFTPs, the presence of HF on admission, during hospitalization, and at short-term follow-up was individually scored. This study examined whether the revised HFTPs, with additional scoring of previous HF, provide better predictivity. Methods: This multicenter registry included a total of 1331 patients with acute MI undergoing percutaneous coronary intervention. HF was evaluated at four time-points before and after acute MI onset: (1) a history of HF; (2) elevated natriuretic peptide levels on admission; (3) in-hospital HF events; and (4) elevated natriuretic peptide levels at a median of 31 days after the onset. When HF was present at each time-point, one point was assigned to a risk scoring system, namely the original and revised HFTPs, ranging from 0 to 3 and from 0 to 4. The primary endpoint was a composite of cardiovascular death and HF rehospitalization after discharge. Results: Of the 1331 patients, 65 (4.9%) had the primary outcome events during a median follow-up period of 507 (interquartile range, 335–1106) days. The increase in both original and revised HFTPs was associated with an increased risk of the primary outcomes in a stepwise fashion with similar diagnostic ability. Conclusions: The original and revised HFTPs were both predictive of long-term HF-related outcomes in patients with acute MI undergoing percutaneous coronary intervention. Yet, the original HFTPs may be sufficient to estimate HF risks after MI.

Background: Coronary artery calcification score (CACS) on electrocardiography (ECG)-gated computed tomography (CT) is used for risk stratification of atherosclerotic cardiovascular disease, which requires dedicated analytic software. In this study, we evaluated the diagnostic ability of manual calcification length assessment on non-ECG-gated CT for epicardial coronary artery disease (CAD). Methods: A total of 100 patients undergoing both non-ECG-gated plain CT scans with a slice interval of 1.25 mm and invasive coronary angiography were retrospectively included. We manually measured the length of the longest calcified lesions of coronary arteries on each branch. The relationship between the number of coronary arteries with the length of coronary calcium > 5, 10, or 15 mm and the presence of epicardial CAD on invasive angiography was evaluated. Standard CACS was also evaluated using established software. Results: Of 100 patients, 49 (49.0%) had significant epicardial CAD on angiography. The median standard CACS was 346 [7, 1965]. In both manual calcium assessment and standard CACS, the increase in calcium burden was progressively associated with the presence of epicardial CAD on angiography. The receiver operating characteristic curve analysis showed similar diagnostic abilities of the two diagnostic methods. The best cut-off values for CAD were 2, 1, and 1 for the number of vessels with calcium > 5, 10, and 15 mm, respectively. Overall, the diagnostic ability of manual calcium assessment was similar to that of standard CACS > 400. Conclusions: Manual assessment of coronary calcium length on non-ECG-gated plain CT provided similar diagnostic ability for the presence of significant epicardial CAD on invasive angiography, as compared to standard CACS.

Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage erosion, structural changes, and inflammation. Synovial fibroblasts play a crucial role in OA pathophysiology, with abnormal fibroblastic cells contributing significantly to joint pathology. Fibrocytes, expressing markers of both hematopoietic and stromal cells, are implicated in inflammation and fibrosis, yet their marker and role in OA remain unclear. ENTPD1, an ectonucleotidase involved in purinergic signaling and expressed in specific fibroblasts in fibrotic conditions, led us to speculate that ENTPD1 plays a role in OA pathology by being expressed in fibrocytes. This study aimed to investigate the phenotype of ENTPD1+CD55+ and ENTPD1−CD55+ synovial fibroblasts in OA patients. Proteomic analysis revealed a distinct molecular profile in ENTPD1+CD55+ cells, including the upregulation of fibrocyte markers and extracellular matrix-related proteins. Pathway analysis suggested shared mechanisms between OA and rheumatoid arthritis. Correlation analysis revealed an association between ENTPD1+CD55+ fibrocytes and resting pain in OA. These findings highlight the potential involvement of ENTPD1 in OA pain and suggest avenues for targeted therapeutic strategies. Further research is needed to elucidate the underlying molecular mechanisms and validate potential therapeutic targets.

Abstract In this study, we developed and investigated a small‐diameter, low‐profile, wideband orthogonal‐polarisation multiple‐input multiple‐output (MIMO) antenna. A polarisation MIMO antenna is a combination of a modified sleeve antenna for vertical polarisation and a halo antenna with four parasitic elements for horizontal polarisation. Four parasitic elements vertically were loaded above and below the halo antenna, and a sleeve antenna with an upper sleeve structure was inserted inside the halo antenna to achieve a low profile, wideband antenna with a small diameter. Simulation and measurement results showed that the proposed antenna achieved a relative bandwidth of 10.1% (|S11| and |S22| ≤ −10 dB). For the lower frequency wavelength (λmin) in the required bandwidth, the diameter and height of the proposed antenna are 0.14λmin and 0.57λmin respectively. Additionally, it is capable of orthogonal‐polarisation isolation of approximately 20 dB within the operating frequency bandwidth.

Objectives We aimed to investigate the regional variations in the number of interventions and surgeries for peripheral artery disease (PAD) and explore the major determinants of the variations.Design Cross-sectional study.Setting The Japanese Ministry of Health, Labour and Welfare National Database and Diagnostic Procedure Combination database in 2018.Data The rates of endovascular treatment (EVT), bypass surgery per 100 000 individuals in the population were calculated for all 47 prefectures in Japan. The total annual changes in the rates of EVT and bypass surgery in Japan from 2012 to 2019 were calculated.Analysis A linear regression model was developed with rates of EVT and bypass surgery as dependent variables and regional medical supply in each prefecture as explanatory variables. These regional factors included the rate of percutaneous coronary intervention (PCI) for angina, the numbers of cardiovascular specialists, specialists in cardiac surgery, interventional radiology (IVR) training facilities and cardiovascular surgery training facilities, per 100 000, respectively.Results There was a 5.7-fold difference (143 and 25 per 100 000 individuals aged ≥40 years) in the highest and lowest EVT rates. The highest and lowest rates of bypass surgery were 34 and

Considering the role of epidermal keratinocytes, they occupy more than 90% of the epidermis, form a physical barrier, and also function as innate immune barrier. For example, epidermal keratinocytes are capable of recognizing various cytokines and pathogen-associated molecular pattern, and producing a wide variety of inflammatory cytokines, chemokines, and antimicrobial peptides. Previous basic studies have shown that the immune response of epidermal keratinocytes has a significant impact on inflammatory skin diseases. The purpose of this review is to provide foundation of knowledge on the cytokines which are recognized or produced by epidermal keratinocytes. Since a number of biologics for skin diseases have appeared, it is necessary to fully understand the relationship between epidermal keratinocytes and the cytokines. In this review, the cytokines recognized by epidermal keratinocytes are specifically introduced as “input cytokines”, and the produced cytokines as “output cytokines”. Furthermore, we also refer to the existence of biologics against those input and output cytokines, and the target skin diseases. These use results demonstrate how important targeted cytokines are in real skin diseases, and enhance our understanding of the cytokines.

Abstract Background The number of patients with heart disease who can benefit from treatment is continuing to increase due to the widespread use of cardiac implantable devices. Accordingly, the number of cardiac device-related infective endocarditis (CDRIE) cases has been increasing year by year. We report a very rare experience of performing an autopsy on a patient who died of CDRIE at the site of MitraClip ® implantation, which has recently been developed as a treatment option for severe mitral regurgitation. In addition to hematoxylin–eosin (H-E) staining, Elastica-Masson staining in the present case revealed destruction of all of the atrial, trabecular, fiber and myocardial layers. Case presentation The patient was hemodialyzed with a dialysis catheter. Hemodialysis treatment was difficult due to functional mitral regurgitation caused by cardiac dysfunction, and the MitraClip® procedure was performed. However, he subsequently developed a fever and dialyzation became difficult again, and he was admitted to the cardiology department. Echocardiography revealed a large vegetation at the site of MitraClip® implantation and a diagnosis of CDRIE was made. Guidelines recommend removal of the device and surgical intervention. However, considering the patient's general condition, a decision was made at a heart team conference to give priority to antibiotic therapy. However, the patient did not respond to antibiotic therapy and died of septic shock. Conclusion To our knowledge, this is the first reported case of CDRIE and death after MitraClip® implantation that resulted in an autopsy. Furthermore, not only H-E staining but also Elastica-Masson staining was performed, and it was confirmed that there was significant valve tissue destruction. In the future, the MitraClip® procedure, even though it is minimally invasive, should be carefully considered in immunocompromised patients.