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We thank the authors for their insightful and thoughtful commentary on our recent publication [...].

Abstract Background Cholesterol embolism causes various organ dysfunctions, including skin, kidney, and gastrointestinal tract dysfunction, as well as immunological abnormalities, such as hypocomplementemia and eosinophilia. However, only a few cases of vasculitis accompanied by cholesterol embolism have been reported. Case presentation We present the case of an 82-year-old man with cholesterol embolism who also developed small-vessel vasculitis of the skin and muscles. The patient had a persistent fever, and blood tests showed eosinophilia and hypocomplementemia. Two months later, the patient developed a skin rash and myalgia in the thighs. Magnetic resonance imaging of the thighs revealed diffuse intramuscular hyperintensities on T2-weighted images and short tau inversion recovery sequences in the hamstrings and quadriceps femoris. Histological findings of the skin and muscle revealed small-vessel vasculitis, and random skin biopsy revealed cholesterol embolism. We diagnosed the patient with cholesterol embolism accompanied by small-vessel vasculitis of the skin and femoral muscles. Methylprednisolone was administered intravenously, and oral prednisolone was initiated. Muscle tenderness improved rapidly after the initiation of glucocorticoid therapy. However, he developed superior mesenteric artery embolization and died. Conclusions Our case demonstrates that cholesterol embolism can be accompanied by small-vessel vasculitis of the skin and muscles.

This study examined the risk of intrauterine infection associated with radical trachelectomy (RT) in early‐stage cervical cancer patients. This procedure preserves fertility but is linked to increased risk of intrauterine infection due to cervical defects during pregnancy. DNA was extracted from the formalin‐fixed paraffin‐embedded (FFPE) placental specimens of 23 pregnant post‐RT patients and 16S rRNA gene sequencing was used for bacterial identification. The prevalence of Lactobacillus crispatus and Burkholderia stabilis was significantly higher in the non‐chorioamnionitis group. In contrast, alpha diversity analysis using the PD index showed significantly higher diversity in the chorioamnionitis group (P = 0.04). The demonstrated relationship between chorioamnionitis and microbial diversity affirms the importance of controlling the genital bacterial flora in pregnancies following RT.

Objective: Laser vaporization is less invasive than conization for cervical intraepithelial neoplasia (CIN). The outcome of laser vaporization for CIN is empirically known to depend on the colposcopic findings, especially localization of the lesion. In this study, we sought to identify factors involved in the outcome of laser vaporization. Materials and methods: We retrospectively investigated 290 cases of CIN (CIN2, n = 180; CIN3, n = 110) treated with laser evaporation at Nishikawa Women's Health Clinic between 2018 and 2021. All treatments were performed using a carbon dioxide laser under either colposcopic vision (n = 172) or direct vision using a vaginal speculum (n = 118). Risk factors were statistically examined for cure rate after treatment. Results: Multivariate analysis using a logistic regression model identified independent factors affecting the success of treatment to be high-risk human papillomavirus infection status preoperatively, CIN grade, presence of CIN lesions at the periphery of the cervix, and the surgical method used. Colposcopy-guided laser vaporization reduced the risk of treatment failure by 84% (odds ratio 0.16, 95% confidence interval 0.06–0.46; p = 0.001) compared with direct vision using a vaginal speculum. For lesions at the periphery of the cervix, most of the treatment failures were in the group that was not guided by colposcopy (p = 0.031). Conclusion: The presence of a peripheral CIN lesion was suggested to be a risk factor for treatment failure. Laser vaporization under colposcopic vision is recommended for treatment of peripheral CIN lesions.

Abstract Seasonal epidemics of influenza viruses are responsible for a significant global public health burden. Vaccination remains the most effective way to prevent infection; however, due to the persistence of antigenic drift, vaccines must be updated annually. The selection of vaccine strains occurs months in advance of the influenza season to allow adequate time for production in eggs. RNA vaccines offer the potential to accelerate production and improve efficacy of influenza vaccines. We leveraged the nucleoside-modified RNA (modRNA) platform technology and lipid nanoparticle formulation process of the COVID-19 mRNA vaccine (BNT162b2; Comirnaty®) to create modRNA vaccines encoding hemagglutinin (HA) (modRNA-HA) for seasonal human influenza strains and evaluated their preclinical immunogenicity and toxicity. In mice, a monovalent modRNA vaccine encoding an H1 HA demonstrated robust antibody responses, HA-specific Th1-type CD4+ T cell responses, and HA-specific CD8+ T cell responses. In rhesus and cynomolgus macaques, the vaccine exhibited durable functional antibody responses and HA-specific IFN-γ+ CD4+ T cell responses. Immunization of mice with monovalent, trivalent, and quadrivalent modRNA-HA vaccines generated functional antibody responses targeting the seasonal influenza virus(es) encoded in the vaccines that were greater than, or similar to, those of a licensed quadrivalent influenza vaccine. Monovalent and quadrivalent modRNA-HA vaccines were well-tolerated by Wistar Han rats, with no evidence of systemic toxicity. These nonclinical immunogenicity and safety data support further evaluation of the modRNA-HA vaccines in clinical studies.

Abstract Hematopoietic stem cells (HSCs) react to various stress conditions. However, it is unclear whether and how HSCs respond to severe anemia. Here, we demonstrate that upon induction of acute anemia, HSCs rapidly proliferate and enhance their erythroid differentiation potential. In severe anemia, lipoprotein profiles largely change and the concentration of ApoE increases. In HSCs, transcription levels of lipid metabolism-related genes, such as very low-density lipoprotein receptor (Vldlr), are upregulated. Stimulation of HSCs with ApoE enhances their erythroid potential, whereas HSCs in Apoe knockout mice do not respond to anemia induction. VldlrhighHSCs show higher erythroid potential, which is enhanced after acute anemia induction. VldlrhighHSCs are epigenetically distinct because of their low chromatin accessibility, and more chromatin regions are closed upon acute anemia induction. Chromatin regions closed upon acute anemia induction are mainly binding sites of Erg. Inhibition of Erg enhanced the erythroid differentiation potential of HSCs. Our findings indicate that lipoprotein metabolism plays an important role in HSC regulation under severe anemic conditions.

Abstract Osteoclasts are multinucleated bone-resorbing cells, and their formation is tightly regulated to prevent excessive bone loss. However, the mechanisms by which osteoclast formation is restricted remain incompletely determined. Here, we found that sterol regulatory element binding protein 2 (SREBP2) functions as a negative regulator of osteoclast formation and inflammatory bone loss. Cholesterols and SREBP2, a key transcription factor for cholesterol biosynthesis, increased in the late phase of osteoclastogenesis. The ablation of SREBP2 in myeloid cells resulted in increased in vivo and in vitro osteoclastogenesis, leading to low bone mass. Moreover, deletion of SREBP2 accelerated inflammatory bone destruction in murine inflammatory osteolysis and arthritis models. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor 7 (IRF7). Taken together, our study highlights a previously undescribed role of the SREBP2-IRF7 regulatory circuit as a negative feedback loop in osteoclast differentiation and represents a novel mechanism to restrain pathological bone destruction.

Carboxylato-bridged dinuclear and tetranuclear Mn(II) complexes 1–3 with ditopic ligands featuring two N3-terminal coordination sites connected by hexyl (tphn), octyl (tpon), and p-xylyl (tpxn) linkers have been synthesized and characterized through X-ray single-crystal structure analyses, infrared spectroscopy, and elemental analyses. Complex 1 is a μ-fluorido-bis-μ-acetato dinuclear Mn(II) complex where the ligand tphn coordinates to both terminal sides of a dinuclear Mn unit. In contrast, complexes 2 and 3 are tetranuclear Mn(II) complexes with a macrocyclic structure, in which two dinuclear Mn units are linked by ligands tpon or tpxn. The redox behaviors of 1 and 2 were elucidated by cyclic voltammetry, revealing two metal-centered redox processes corresponding to Mn2(II,II)/Mn2(II,III) and Mn2(II,III)/Mn2(III,III).

This study examined socially shared regulation of learning (SSRL) and motivation processes in a collaborative learning task that required creativity using the ICT tool of mind mapping. Thirty university students formed three groups, collaborating face-to-face to generate creative ideas. The following results were obtained from qualitative and quantitative data using psychological scales and utterance analysis. In the middle phase of the collaborative activity, there was a significant weak-to-moderate positive correlation between socially shared regulation of cognition, self-regulation, co-regulation, and socially shared regulation of intrinsic motivation and a deep level of regulation utterances. Moreover, there were significant weak-to-moderate correlations between behavioral and cognitive engagement, SSRL of monitoring and cognition, and the three modes of motivational regulation. Creative performance was significantly and moderately positively associated with socially shared regulation of cognition and total frequency of utterances in the group. Based on these findings, the implications for practice in university education are discussed from the perspective of socially shared regulation in collaborative learning.

Objective Reflux oesophagitis (RO) is one of the most common diseases encountered by gastroenterologists and primary care physicians. However, few epidemiological studies have investigated the association of medication use and RO. This study aimed to investigate the prevalence of RO and its risk factors, particularly with respect to medication use.Methods This retrospective, cross-sectional study included consecutive patients who underwent oesophagogastroduodenoscopy (OGD) and were assessed using questionnaires at the National Center for Global Health and Medicine (Shinjuku, Tokyo, Japan) between October 2015 and December 2021. The questionnaire collected data on patient characteristics, medical history, smoking and alcohol consumption, and medications that patients were taking at the time of OGD.Results Among the 13 993 eligible patients, the prevalence of RO was 11.8%. Multivariate logistic regression analysis indicated that male sex (OR=1.52 (95% CI 1.35 to 1.72), p

In coal gasification, soot forms from volatile matter (VM) and it influences the gasification efficiency. Recently, biomass or plastic wastes with higher VM than coal are used for gasification processes and the importance of soot is increasing. For predicting soot formation, elementary step models are often used. However, defining main reaction paths is difficult because the models include huge species and reactions. In this study, the polyaromatic hydrocarbon formation path was analyzed via an elementary step-like model with 257 species and 1107 reactions to understand soot formation. The main reaction paths were extracted. Initially, 257 species were classified into non-aromatic species, one-ring, two-ring, and three- or more-ring aromatics. Ten species in each group with high maximum concentrations were considered as the major species. The reactions were extracted as follows: extracting reactions according to their contribution to the major species mass balance; adding fast reactions; and identifying the main reaction path. Consequently, the main reaction path extracted (MRE) model for the combustor condition was reduced to under 100 reactions for two kinds of conditions. Simulation of coal gasification reaction with the MRE model successfully described soot formation behavior in experiments with a drop tube furnace.

This study examined a path model linking the providing and receiving of autonomy support to performance in intellectual group activities, through self-efficacy, social self-efficacy, and value, by comparing university students and working adults. Participants comprised 181 university students and 295 working adults who completed an online questionnaire consisting of psychological measurements. The students included 118 women and 63 men (first-year, 40; second-year, 40; third-year, 55; fourth-year, 46). The working adults were employed full-time and included 77 women, with an average of 12.68 years of employment. The hypothesized path model showed a good enough fit in the multi-group structural equation modeling analysis. The positive paths from providing of autonomy support to self-efficacy (student, β = 0.56; adults, β = 0.31), social self-efficacy (student, β = 0.37; adults, β = 0.37), and value (student, β = 0.39; adults, β = 0.33), and those from receiving autonomy support to social self-efficacy (student, β = 0.28; adults, β = 0.22) and value (student, β = 0.32; adults, β = 0.31), were significant for both groups. Moreover, significant positive paths were found from the receiving of autonomy support to self-efficacy (β = 0.29), and from values to performance levels (β = 0.18) in working adults. Positive paths from self-efficacy (student, β = 0.40; adults, β = 0.58) and social self-efficacy (β = 0.40) to performance levels were significant for both groups, and among university students, respectively. This suggests the possibility and necessity of implementing path model-based practices in universities and workplaces.

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. Methods A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. Results In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was − 1.07 (95% confidence interval [CI] − 1.29 to − 0.86; P

Respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection, especially in children and the elderly. Various vaccines containing the major transmembrane surface proteins of RSV (proteins F and G) have been tested; however, they have either afforded inadequate protection or are associated with the risk of vaccine-enhanced disease (VED). Recently, F protein-based maternal immunization and vaccines for elderly patients have shown promising results in phase III clinical trials, however, these vaccines have been administered by injection. Here, we examined the potential of using the ectodomain of small hydrophobic protein (SHe), also an RSV transmembrane surface protein, as a nasal vaccine antigen. A vaccine was formulated using our previously developed cationic cholesteryl-group-bearing pullulan nanogel as the delivery system, and SHe was linked in triplicate to pneumococcal surface protein A as a carrier protein. Nasal immunization of mice and cotton rats induced both SHe-specific serum IgG and mucosal IgA antibodies, preventing viral invasion in both the upper and lower respiratory tracts without inducing VED. Moreover, nasal immunization induced greater protective immunity against RSV in the upper respiratory tract than did systemic immunization, suggesting a critical role for mucosal RSV-specific IgA responses in viral elimination at the airway epithelium. Thus, our nasal vaccine induced effective protection against RSV infection in the airway mucosa and is therefore a promising vaccine candidate for further development.

Migraine is a chronic neurological disorder that frequently coexists with different vestibular and cochlear symptoms (sudden hearing loss, tinnitus, otalgia, aural fullness, hyperacusis, dizziness, imbalance, and vertigo) and disorders (recurrent benign positional vertigo, persistent postural perceptual dizziness, mal de debarquement, and Menière's disease). Despite evidence of an epidemiological association and similar pathophysiology between migraine and these vestibulocochlear disorders, patients suffering from migraine-related symptoms are usually underdiagnosed and undertreated. Current migraine treatment options have shown success in treating vestibulocochlear symptoms. Lifestyle and dietary modifications (reducing stress, restful sleep, avoiding migraine dietary triggers, and avoiding starvation and dehydration) and supplements (vitamin B2 and magnesium) offer effective first-line treatments. Treatment with migraine prophylactic medications such as tricyclic antidepressants (e.g., nortriptyline), anticonvulsants (e.g., topiramate), and calcium channel blockers (e.g., verapamil) is implemented when lifestyle and dietary modifications are not sufficient in improving a patient's symptoms. We have included an algorithm that outlines a suggested approach for addressing these symptoms, taking into account our clinical observations. Greater recognition and understanding of migraine and its related vestibular and cochlear symptoms are needed to ensure the appropriate diagnosis and treatment of affected patients.