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ABSTRACT Aims/Introduction PIONEER REAL Japan was a non‐interventional prospective study of oral semaglutide in adults with type 2 diabetes in Japanese clinical practice. Materials and Methods Adults naïve to injectable glucose‐lowering therapies initiated oral semaglutide in routine clinical practice and were followed for 34–44 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study; the co‐primary endpoint was number of adverse events (AEs). Secondary endpoints included change in bodyweight from baseline to end of study. Analyses were also carried out for subgroups aged

Abstract Aims Catheter ablation (CA) of atrial fibrillation (AF) improves left ventricular ejection fraction (LVEF) in patients with heart failure with reduced ejection fraction (HFrEF). The impact of ST‐segment depression before CA on LVEF recovery and clinical outcomes remains unknown. In the present study, we aimed to investigate the relationship between ST‐segment depression during AF rhythm before CA and improvement in the LVEF and clinical outcomes in persistent atrial fibrillation (PerAF) patients with HFrEF. Methods and results The present study included 122 PerAF patients (male; 98 patients, 80%, mean age: 69 [56, 76] years) from the Osaka Rosai Atrial Fibrillation ablation (ORAF) registry who had LVEF

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a rare adverse event following the coronavirus disease 2019 (COVID-19) vaccination. We report a case of neuropsychiatric symptoms and refractory HLH in a woman with systemic lupus erythematosus (SLE) after receiving her COVID-19 vaccine treated with belimumab, later found to have intravascular large B-cell lymphoma (IVLBCL) at autopsy. A 61-year-old woman with SLE was referred to our hospital because of impaired consciousness and fever. One month prior to consulting, she received her second COVID-19 vaccine dose. Afterward, her consciousness level decreased, and she developed a high fever. She tested negative for SARS-CoV-2. Neuropsychiatric SLE was suspected; therefore, glucocorticoid pulse therapy was initiated on day 1 and 8. She had thrombocytopenia, increased serum ferritin levels and hemophagocytosis. The patient was diagnosed with HLH and treated with etoposide, dexamethasone and cyclosporine. Despite treatment, the patient died on day 75; autopsy report findings suggested IVLBCL as the underlying cause of HLH. Differentiating comorbid conditions remains difficult; however, in the case of an atypical clinical presentation, other causes should be considered. Therefore, we speculate that the COVID-19 vaccination and her autoimmune condition may have expedited IVLBCL development.

Abstract Aims Low‐density lipoprotein cholesterol (LDL‐C), anaemia and low platelets have been associated with worse clinical outcomes in heart failure patients. We investigated the relationship between the combination of these three components and clinical outcome in patients with heart failure with preserved ejection fraction (HFpEF). Methods and results We examined the data of 1021 patients with HFpEF hospitalized with acute decompensated heart failure (HF) from the PURSUIT‐HFpEF registry, a prospective, multicenter observational study. The enrolled patients were classified into four groups by an LEP (LDL‐C, Erythrocyte, and Platelet) score of 0 to 3 points, with 1 point each for LDL‐C, erythrocyte and platelet values less than the cut‐off values as calculated by receiver operating characteristic curve analysis. The endpoint, a composite of all‐cause death and HF readmission, was evaluated among the four groups. Median follow‐up duration was 579 [300, 978] days. Risk of the composite endpoint significantly differed among the four groups (P

Exposure of water to ionizing radiation induces OH radical formation. Within cellular environments, the presence of OH radicals can stimulate the abstraction of hydrogen atoms from the sugar backbone of DNA. Subsequent damage to DNA structures leads to various diseases. Multiple studies have elucidated this phenomenon, especially computational studies examining the differences in the degree of abstraction between the sugar hydrogens (H1′, H2′, H2″, H3′, H4′, H5′, and H5″). However, the details of this phenomenon have not yet been clarified. It is rare for OH radicals to approach DNA within the simulation time, making it difficult to adequately sample the configurations in which OH radicals immediately precede the abstraction of the hydrogen atoms. To address this problem, we performed molecular dynamics simulation to calculate the relative accessibility by putting a potential on nucleotides and OH radicals. As a result, we found that the accessibility of OH radicals to each hydrogen atom differs from that of water molecules as solvents. A more detailed accessibility analysis revealed that the angle of the OH radicals approaching the hydrogen atoms of ribose and the energy barrier for abstracting the hydrogen atoms can be considered to improve the correspondence with the experimental data. Moreover, we found that the behavior of water molecules and OH radicals toward accessibility to DNA differs significantly and showed that the factors are related to the physicochemical properties of water molecules and OH radicals, as well as the structure of DNA.

Abstract Focal segmental glomerulosclerosis (FSGS) shares podocyte damage as an essential pathological finding. Several mechanisms underlying podocyte injury have been proposed, but many important questions remain. Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) is a serine/threonine kinase responsible for a wide array of cellular functions. We found that ROCK2 is activated in podocytes of adriamycin (ADR)-induced FSGS mice and cultured podocytes stimulated with ADR. Conditional knockout mice in which the ROCK2 gene was selectively disrupted in podocytes (PR2KO) were resistant to albuminuria, glomerular sclerosis, and podocyte damage induced by ADR injection. In addition, pharmacological intervention for ROCK2 significantly ameliorated podocyte loss and kidney sclerosis in a murine model of FSGS by abrogating profibrotic factors. RNA sequencing of podocytes treated with a ROCK2 inhibitor proved that ROCK2 is a cyclic nucleotide signaling pathway regulator. Our study highlights the potential utility of ROCK2 inhibition as a therapeutic option for FSGS.

Summary: Background: Emergence of SARS-CoV-2 variants that escape neutralising antibodies hampers the development of vaccines and therapeutic antibodies against SARS-CoV-2. IGHV3-53/3-66-derived public antibodies, which are generally specific to the prototype virus and are frequently induced in infected or vaccinated individuals, show minimal affinity maturation and high potency against prototype SARS-CoV-2. Methods: Monoclonal antibodies isolated from a Delta breakthrough infection case were analysed for cross-neutralising activities against SARS-CoV-2 variants. The broadly neutralising antibody K4-66 was further analysed in a hamster model, and the effect of somatic hypermutations was assessed using the inferred germline precursor. Findings: Antibodies derived from IGHV3-53/3-66 showed broader neutralising activity than antibodies derived from IGHV1-69 and other IGHV genes. IGHV3-53/3-66 antibodies neutralised the Delta variant better than the IGHV1-69 antibodies, suggesting that the IGHV3-53/3-66 antibodies were further maturated by Delta breakthrough infection. One IGHV3-53/3-66 antibody, K4-66, neutralised all Omicron subvariants tested, including EG.5.1, BA.2.86, and JN.1, and decreased the viral load in the lungs of hamsters infected with Omicron subvariant XBB.1.5. The importance of somatic hypermutations was demonstrated by the loss of neutralising activity of the inferred germline precursor of K4-66 against Beta and Omicron variants. Interpretation: Broadly neutralising IGHV3-53/3-66 antibodies have potential as a target for the development of effective vaccines and therapeutic antibodies against newly emerging SARS-CoV-2 variants. Funding: This work was supported by grants from AMED (JP23ym0126048, JP22ym0126048, JP21ym0126048, JP23wm0125002, JP233fa627001, JP223fa627009, JP24jf0126002, and JP22fk0108572), and the JSPS (JP21H02970, JK23K20041, and JPJSCCA20240006).

Abstract In this study, we aimed to separately evaluate the relationship between waist circumference and the incidence of hyperuricemia in men and women in the general Japanese population. We performed a population-based longitudinal study using data from the annual health examination of residents of Iki City, Japan. A total of 5567 participants without hyperuricemia at baseline were included in the analysis. The men and women were placed into groups according to the tertile of waist circumference. The outcome was incident hyperuricemia (uric acid > 416 µmol/L [7.0 mg/dL]). The relationship between waist circumference and the incidence of hyperuricemia was investigated using Cox proportional hazards models. During the follow-up period, hyperuricemia developed in 697 people (551 men and 146 women). The incidence (per 1000 person-years) of hyperuricemia increased with increasing waist circumference in the men (34.9 for tertile 1, 49.9 for tertile 2 and 63.3 for tertile 3; P trend

Abstract Hydrogen serves as a renewable, clean energy carrier, and the critical development of technologies for safer and simpler storage and transportation is imperative for addressing global warming. There is also a growing demand for efforts to capture and utilize CO2 to tackle similar issues. Consequently, considerable attention has been drawn to carriers that chemically store hydrogen. Hydrogen can be stored and released through hydrogenation and dehydrogenation. Notably, the storage and release of hydrogen via CO2 hydrogenation and subsequent dehydrogenation of its hydrogenation product could potentially bolster the future hydrogen economy, rendering it an appealing option as a CO2 circulation hydrogen carrier (CCHC). To leverage CCHC for various applications, a catalytic process enabling the reversible storage and release of hydrogen is essential. This review focuses on CCHC candidates, such as methanol (MeOH), dimethyl ether (DME), and formic acid (FA), summarizing recent catalytic approaches for hydrogen production through pivotal dehydrogenation processes within the CCHC cycle.

Abstract Metazoans use silicon traces but rarely develop extensive silica skeletons, except for the early-diverging lineage of sponges. The mechanisms underlying metazoan silicification remain incompletely understood, despite significant biotechnological and evolutionary implications. Here, the characterization of two proteins identified from hexactinellid sponge silica, hexaxilin and perisilin, supports that the three classes of siliceous sponges (Hexactinellida, Demospongiae, and Homoscleromorpha) use independent protein machineries to build their skeletons, which become non-homologous structures. Hexaxilin forms the axial filament to intracellularly pattern the main symmetry of the skeletal parts, while perisilin appears to operate in their thickening, guiding extracellular deposition of peripheral silica, as does glassin, a previously characterized hexactinellid silicifying protein. Distant hexaxilin homologs occur in some bilaterians with siliceous parts, suggesting putative conserved silicifying activity along metazoan evolution. The findings also support that ancestral Porifera were non-skeletonized, acquiring silica skeletons only after diverging into major classes, what reconciles molecular-clock dating and the fossil record.

Abstract Objectives The aims of this study were (1) to develop a decision-making aid for couples hesitant about transitioning from infertility treatment to advanced assisted reproductive technology, (2) to examine the adequacy of this aid, and (3) to evaluate its usability. After the first version of the decision-making aid was created, the first version was supervised and finally a prototype of the decision-making aid was completed. We conducted a feasibility study from February to March 2022. We used a quantitative cross-sectional descriptive design involving 22 medical professionals and infertility survivors recruited. Results Twenty-two participants (3 reproductive medical specialists, 11 nurses who specialize in reproductive medicine, and 8 infertility survivors) were included in the final analysis (91.7% valid response rate). Of these participants, 81.8% answered Agree regarding “Easy-to-read degree of charts”, 17 (77.3%) answered It is just the right amount regarding “Appropriateness of information volume”, 81.8% answered Agree regarding “Ease of understanding content”, and 90.9% answered Good regarding “Overall performance”. From the opinions received, we extracted 4 categories: “Useful for decision making,” “Suitable for providing information,” “Useful in clinical practice,” and “Needs improvement.” Certain degrees of surface validity and content validity were confirmed for the trial version of the decision-making aid.

Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2i-preceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: −3.5 ± 9.4 mL/min/1.73 m2/year, post: −0.4 ± 6.3 mL/min/1.73 m2/year, p < 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: −2.0 ± 10.9 mL/min/1.73 m2/year, post: −1.8 ± 5.4 mL/min/1.73 m2/year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits—especially annual eGFR decline—of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug.

Abstract Background Mother-to-infant bonding (MIB) is critical for the health and well-being of the mother and child. Furthermore, MIB has been shown to boost the social-emotional development of infants, while also giving mothers a sense of happiness in raising their children. Nausea and vomiting during pregnancy (NVP) is a normal complication of pregnancy, occurring in approximately 50–90% of pregnant women in the early stages of pregnancy. Despite widespread knowledge of MIB and postpartum depression, little research attention has been given to the effects of NVP on MIB. This study aimed to investigate the relationship between NVP and MIB and the mediating effects of postpartum depression. Methods We analyzed the data of 88,424 infants and 87,658 mothers from the Japan Environment and Children’s Study (JECS), which is a government-funded nationwide birth prospective cohort study. The Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) was used to assess MIB, and the Edinburgh Postpartum Depression Scale (EPDS) was utilized to assess postpartum depression. We divided participants into four groups according to a self-reported questionnaire assessing NVP (No NVP, Mild NVP, Moderate NVP, and Severe NVP). MIB disorder was defined as a MIBS-J score ≥ 5. Logistic analysis was performed to evaluate the effect of NVP on MIB disorder at one year after delivery. A mediation analysis was conducted to examine whether postpartum depression mediated the association between NVP and MIBS-J scores. Results The logistic regression analysis results revealed reduced risks of MIB disorder among mothers with Moderate NVP (adjusted OR 0.93; 95% confidence interval, 0.86–0.99) and Severe NVP (adjusted OR 0.81; 95% confidence interval, 0.74–0.89), compared to those with No NVP. The mediation analysis revealed that NVP positively correlated with MIBS-J score in the indirect effect via postpartum depression, while NVP (Mild NVP, Moderate NVP, and Severe NVP) negatively correlated with MIBS-J score in the direct effect. Conclusion The risks of MIB disorder were reduced in the Moderate NVP and Severe NVP mothers, although NVP inhibited the development of MIB via postpartum depression. The development of effective interventions for postpartum depression is important to improve MIB among mothers with NVP.

Fiber-reinforced soils have been increasingly used in geotechnical engineering. Over the years, research has sought to understand and investigate the influences of fibers as reinforcement in soil–fiber mixtures. This study assessed the behavior of clayey soil in the city of Curitiba (Paraná, Brazil), adding rice husk fiber (RHF), an industrial waste from Cooperativa Agroindustrial in Alegrete (Rio Grande do Sul, Brazil). To evaluate the effect of the presence of natural RHF on the mechanical behavior of compacted soil, aspects such as the influence of fiber content and the drained and undrained behaviors of the soil were evaluated through unconfined triaxial compression tests. The following tests were realized: soil granulometry, specific mass of solids and Atterberg limits. Specimens were produced in quadruplicate for the soil and mixtures using the RHF contents of 0.5%, 0.75%, 1% and 1.5% to determine the unconfined compressive strength (UCS). Triaxial tests were realized on a pure soil specimen and the specimens with 1% RHF under confining pressures of 50 kPa, 100 kPa, 200 kPa and 400 kPa. The interactions at the interface between husk surface and soil were analyzed using scanning electron microscopy (SEM). In UCS tests, specimens with RHF percentages of 1% and 1.5% presented the highest results, with an increment of 36% compared to the soil without RHF. The results of the consolidated drained triaxial compression tests show that in terms of effective stress, there was a small difference in the strength of the compacted pure soil and soil with the addition of RHF. For the undrained tests, the strength increased with the inclusion of husk, with a reduction of 50% in cohesion and an increment of 22% in friction angle for specimens containing RHF compared to the soil without RHF additions.

Mast cells take up extracellular latent heparanase and store it in secretory granules. The present study examined whether the enzymatic activity of heparanase regulates its uptake efficiency. Recombinant mouse heparanase mimicking both the latent and mature forms (L-Hpse and M-Hpse, respectively) was internalized into mastocytoma MST cells, peritoneal cell-derived mast cells, and bone marrow-derived mast cells. The internalized amount of L-Hpse was significantly higher than that of M-Hpse. In MST cells, L-Hpse was continuously internalized for up to 8 h, while the uptake of M-Hpse was saturated after 2 h of incubation. L-Hpse and M-Hpse are similarly bound to the MST cell surface. The expression level of cell surface heparan sulfate was reduced in MST cells incubated with M-Hpse. The internalized amount of M-Hpse into mast cells was significantly increased in the presence of heparastatin (SF4), a small molecule heparanase inhibitor that does not affect the binding of heparanase to immobilized heparin. Enzymatically quiescent M-Hpse was prepared with a point mutation at Glu335. The internalized amount of mutated M-Hpse was significantly higher than that of wild-type M-Hpse but similar to that of wild-type and mutated L-Hpse. These results suggest that the enzymatic activity of heparanase negatively regulates the mast cell-mediated uptake of heparanase, possibly via the downregulation of cell surface heparan sulfate expression.

Abstract Objectives In this study, we aimed to implement and evaluate a Web-based partnership support program to enhance the QoL of male patients undergoing infertility treatment. We conducted a pilot study involving 41 infertile couples from September to October of 2021. We used a quasi-experimental design (pre-test and post-test with comparison) involving purposive sampling. A subgroup analysis was conducted to determine which demographics of the participants would benefit from the program. Results Thirty-four participants (mean age 37.3 years; duration of infertility treatment 14.5 months) were included in the final analysis (follow-up rate 82.9%). Although there was no significant increase in the participants’ QoL under the Web-based partnership support program, the assisted reproductive technology group (P = 0.03), the no medical history group (P = 0.032), and the with experience of changing hospital group (P = 0.027) showed a significant increase in the relational subscale scores of the QoL before and after the program. The majority of the participants (n = 29; 85.3%) expressed satisfaction with the support program. Participation in the Web-based partnership support program may improve the QoL of some men undergoing infertility treatment. Trial registration Retrospectively registered at the University Hospital Medical Information Network on 26 January 2023 (ID: UMIN0000 000050153).