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Abstract Aims Congestive heart failure (HF) is a common complication in patients with acute myocardial infarction (AMI). The estimated plasma volume status [ePVS = (100 − haematocrit)/haemoglobin] is used as the blood plasma volume index to determine the presence of congestion in patients with HF. However, the clinical impact of ePVS at discharge in patients with AMI remains unclear. This study aimed to investigate whether ePVS at discharge could determine the long‐term prognosis in patients with AMI. Methods and results We retrospectively identified patients with AMI with ePVS measured at discharge between January 2012 and December 2020. The primary endpoint was post‐discharge all‐cause death. The patients were divided into two groups according to an ePVS cut‐off value of 5.5%, which is commonly used in HF. In total, 1012 patients with AMI were included. The median age was 70 years (range, 61–78 years), and 76.4% of the patients were male. The ePVS > 5.5% (high‐ePVS) group included 365 patients (36.1%), and the all‐cause mortality rate in the total cohort was 17.7%. The log‐rank test revealed that the high‐ePVS group had a significantly higher rate of all‐cause death than the ePVS ≤ 5.5% (low‐ePVS) group (P

Abstract Background The current status of wearable cardiovascular defibrillators (WCD) use in Japan is unclear. Methods Using a nationwide claims database of Japan, we assessed characteristics of patients using WCD and factors influencing subsequent implantable cardioverter‐defibrillator (ICD) implantation. Results In 1049 cases, those with prior cardiopulmonary arrest (CPA) or ventricular arrhythmia, cardiomyopathy, or device‐related issues were more likely to require permanent ICDs, whereas females were less likely. Conclusions Prior CPA or fatal arrhythmia, underlying cardiomyopathy, or device‐related issues were associated with future permanent ICD implantation. These findings offer insights into the current status of WCD use in Japan.

Abstract Background In 2019, the shortage of cefazolin led to the demand for cefotiam and cefmetazole exceeding the supply. The Department of Nephro-urology at Nagoya City University Hospital used fosfomycin as a substitute for perioperative prophylaxis. This retrospective preliminary study evaluated the efficacy of fosfomycin and cefotiam for preventing infections following ureterorenoscopy. Methods The study included 182 patients who underwent ureterorenoscopy between January 2018 and March 2021). Perioperative antibacterial treatment with fosfomycin (n = 108) or cefotiam (n = 74) was administered. We performed propensity score matching in both groups for age, sex, preoperative urinary catheter use, and preoperative antibiotic treatment. Results The fosfomycin and cefotiam groups (n = 69 per group) exhibited no significant differences in terms of patients’ median age, operative duration, preoperative urine white blood cell count, preoperative urine bacterial count, and the rate of preoperative antibiotic treatment. In the fosfomycin and cefotiam groups, the median duration of postoperative hospital stay was 3 and 4 days, respectively; the median maximum postoperative temperature was 37.3 °C and 37.2 °C, respectively. The fosfomycin group had lower postoperative C-reactive protein levels and white blood cell count than the cefotiam group. However, the frequency of fever > 38 °C requiring additional antibiotic administration was similar. Conclusions During cefotiam shortage, fosfomycin administration enabled surgeons to continue performing ureterorenoscopies without increasing the complication rate.

Abstract Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Fluoride(F-) is present in wastewater produced by various industries, such as semiconductor, glass processing, mining and smelting. Development of high-efficient and low-cost treatment processes of wastewater is desirable. In this study, Seashells sorbents for F- removal were synthesized by phosphate solution treatment of seashells (oyster, scallop, sea urchin and barnacle) waste at room temperature. The seashells sorbents could remove F- in water to below effluent standard (8 mg/L) in Japan. The optimal initial pH range for seashells sorbents synthesis was below pH6. The phosphate consumptions for synthesis could be estimated by specific surface area of seashells. F- sorption isotherms of seashells sorbents were fitted well by the Langmuir model. The synthesis reaction of seashell sorbents at room temperature was that calcium hydrogen phosphate was produced to the surface of calcium carbonate contained in seashells. Dominant mechanism of F- removal of seashell sorption was identified as to form fluorapatite from the calcium hydrogen phosphate and F-.

Abstract Background Lipocalin-2 (LCN2) is a secretory glycoprotein upregulated by oxidative stress; moreover, patients with idiopathic pulmonary fibrosis (IPF) have shown increased LCN2 levels in bronchoalveolar lavage fluid (BALF). This study aimed to determine whether circulatory LCN2 could be a systemic biomarker in patients with IPF and to investigate the role of LCN2 in a bleomycin-induced lung injury mouse model. Methods We measured serum LCN2 levels in 99 patients with stable IPF, 27 patients with acute exacerbation (AE) of IPF, 51 patients with chronic hypersensitivity pneumonitis, and 67 healthy controls. Further, LCN2 expression in lung tissue was evaluated in a bleomycin-induced lung injury mouse model, and the role of LCN2 was investigated using LCN2-knockout (LCN2 -/-) mice. Results Serum levels of LCN2 were significantly higher in patients with AE-IPF than in the other groups. The multivariate Cox proportional hazards model showed that elevated serum LCN2 level was an independent predictor of poor survival in patients with AE-IPF. In the bleomycin-induced lung injury mouse model, a higher dose of bleomycin resulted in higher LCN2 levels and shorter survival. Bleomycin-treated LCN2 -/- mice exhibited increased BALF cell and protein levels as well as hydroxyproline content. Moreover, compared with wild-type mice, LCN2-/- mice showed higher levels of circulatory 8-isoprostane as well as lower Nrf-2, GCLC, and NQO1 expression levels in lung tissue following bleomycin administration. Conclusions Our findings demonstrate that serum LCN2 might be a potential prognostic marker of AE-IPF. Moreover, LCN2 expression levels may reflect the severity of lung injury, and LCN2 may be a protective factor against bleomycin-induced acute lung injury and oxidative stress.

Objective: Transurethral bipolar enucleation of the prostate (BipolEP) is a cost-effective surgical procedure for benign prostatic hyperplasia that is highly curable. However, the surgery has a learning curve in the early stages of implementation. We named an enucleation method that utilizes the beak-like shape of the tip of a resectoscope as the “beak technique''. Our aim was to establish this new surgical technique at our hospital and to examine subsequent surgical results, including those performed by surgeons without experience in enucleation. Patients and surgical procedure: The study participants included 102 patients who underwent BipolEP at our hospital over a 14-month period from June 2022 to August 2023. The median age of patients was 75 (55–88) years, and 50 (49 %) cases involved preoperative urinary retention. The surgery was performed by two surgeons with experience in transurethral prostate enucleation (54 cases) and five surgeons with no experience (48 cases). We shared a video explaining the Beek Technique methodology with the novice enucleation doctors in our hospital and performed the procedure. Results: Times for median surgery, enucleation, and morcellation were 79 (37–157), 28 (8–93), and 13 (2–98) min, respectively. The median enucleation weight was 42 (6–151) g, and the median postoperative hospital stay was 4 days. Incidental prostate cancer was found in 12 cases. For those surgeons who had no prior experience with transurethral enucleation, the median surgical time was 88 (64–194) min, and the median enucleation time was 38 (16–193) min. Conclusions: Using the beak technique, we were able to safely introduce BipolEP in a relatively short period of time, even to surgeons with no experience in enucleation surgery. We believe this method should be recommended for beginners in prostate enucleation. In addition, once proficient, a surgeon can aim for an enucleation efficiency of 2 g/min or higher.

Abstract This study aimed to evaluate the prognostic impact and predictors of persistent renal dysfunction in acute kidney injury (AKI) after an emergency percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). A total of 877 patients who underwent emergency PCI for AMI were examined. AKI was defined as serum creatinine (SCr) ≥ 0.3 mg/dL or ≥ 50% from baseline within 48 h after PCI. Persistent AKI was defined as residual impairment of SCr ≥ 0.3 mg/dL or ≥ 50% from baseline 1 month after the procedure. The primary outcome was the composite endpoints of death, myocardial infarction, hospitalization for heart failure, stroke, and dialysis. AKI and persistent AKI were observed in 82 (9.4%) and 25 (2.9%) patients, respectively. Multivariate Cox proportional hazards analysis demonstrated that persistent AKI, but not transient AKI, was an independent predictor of primary outcome (hazard ratio, 4.99; 95% confidence interval, 2.30–10.8; P 75 years, left ventricular ejection fraction

Abstract Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

Introduction As an aggressive adenocarcinoma phenotype, primary signet ring cell carcinoma of the urinary bladder is an extremely rare variant. The prognosis of metastatic signet ring cell carcinoma of the urinary bladder is extremely poor and the clinical course for its specific pathogenesis remains unelucidated. Case presentation A 64‐year‐old Japanese male patient was diagnosed with invasive urothelial carcinoma with glandular differentiation of a signet ring cell–type with pT4aN0M0, and he was eventually diagnosed with metastatic signet ring cell carcinoma of the urinary bladder. He was initially responsive to systemic combination induction chemotherapy of S‐1 and cisplatin followed by avelumab switch maintenance therapy; however, signet ring cell carcinoma of the urinary bladder relapse occurred in the pathological findings of a biopsy from the right thigh. Immunohistochemical analysis of this specimen identified strong positive staining for nectin‐4 and, following enfortumab–vedotin treatment, the patient showed a good response. Conclusion We thus describe a rare case of metastatic signet ring cell carcinoma of the urinary bladder with nectin‐4 expression diagnosed by a biopsy of a metastatic site.

Introduction The bladder exstrophy‐epispadias complex is a rare congenital disease. Urothelial carcinomas rarely occur in patients with this disease, and there have been few reports on its treatment. Case presentation We report the case of a 44‐year‐old man with a hemorrhage from the external urethral meatus. He was diagnosed with bladder exstrophy‐epispadias complex and underwent urinary diversion with substitution cystoplasty and Mitrofanoff appendicovesicostomy. Because computed tomography and magnetic resonance imaging suggested invasive bladder carcinoma in the defunctionalized bladder, we performed a cystectomy. The patient was diagnosed with urothelial carcinoma with glandular differentiation. One month after the surgery, nivolumab adjuvant chemotherapy was administered. The patient showed no signs of recurrence or metastasis after the treatment. Conclusion This is the first case of adjuvant nivolumab therapy for urothelial carcinoma with the bladder exstrophy‐epispadias complex.

Background S100A9 is a damage-associated molecular pattern protein that may play an important role in the inflammatory response and fibrotic processes. Paquinimod is an immunomodulatory compound that prevents S100A9 activity. Its safety and pharmacokinetics have been confirmed in human clinical trials. In this study, we investigated the effects of paquinimod in preventing the development of lung fibrosis in vivo and examined the prognostic values of circulatory and lung S100A9 levels in patients with idiopathic pulmonary fibrosis (IPF).Methods The expression and localisation of S100A9 and the preventive effect of S100A9 inhibition on fibrosis development were investigated in a mouse model of bleomycin-induced pulmonary fibrosis. In this retrospective cohort study, the S100A9 levels in the serum and bronchoalveolar lavage fluid (BALF) samples from 76 and 55 patients with IPF, respectively, were examined for associations with patient survival.Results S100A9 expression was increased in the mouse lungs, especially in the inflammatory cells and fibrotic interstitium, after bleomycin administration. Treatment with paquinimod ameliorated fibrotic pathological changes and significantly reduced hydroxyproline content in the lung tissues of mice with bleomycin-induced pulmonary fibrosis. Additionally, we found that paquinimod reduced the number of lymphocytes and neutrophils in BALF and suppressed endothelial–mesenchymal transition in vivo. Kaplan-Meier curve analysis and univariate and multivariate Cox hazard proportion analyses revealed that high levels of S100A9 in the serum and BALF were significantly associated with poor prognoses in patients with IPF (Kaplan-Meier curve analysis: p=0.037 (serum) and 0.019 (BALF); multivariate Cox hazard proportion analysis: HR=3.88, 95% CI=1.06 to 14.21, p=0.041 (serum); HR=2.73, 95% CI=1.05 to 7.10, p=0.039 (BALF)).Conclusions The present results indicate that increased S100A9 expression is associated with IPF progression and that the S100A9 inhibitor paquinimod is a potential treatment for IPF.

Abstract We elucidated the efficacy of gut microbiome–altering drugs on pembrolizumab efficacy in patients with metastatic urothelial carcinoma (mUC). Clinical data were analyzed retrospectively from 133 patients with mUC who received second-line pembrolizumab therapy between January 2018 and January 2021, following failed platinum-based chemotherapy. We evaluated the effects of gut microbiome–altering drugs (proton pump inhibitors [PPI]/potassium-competitive acid blockers [P-CAB], H2 blockers, antibiotics, non-steroidal anti-inflammatory drugs [NSAIDs], metformin, antipsychotics, steroids, and opioids), taken by patients within 30 days before/after pembrolizumab treatment, on progression-free survival (PFS) and overall survival (OS). Fifty-one patients received PPI/P-CAB (37/14, respectively); H2 blockers, 7; antibiotics, 35; NSAIDs, 22; antipsychotics, 8; metformin, 3; steroids, 11; and opioids, 29. Kaplan–Meier curves revealed PPI or P-CAB users showed shorter PFS than non-PPI-P-CAB users (p = 0.001, p = 0.005, respectively). Multivariate analysis highlighted PPI/P-CAB use as the only independent prognostic factor for disease progression (hazards ratio: 1.71, 95% confidence interval: 1.14–2.07, p = 0.010) but not death (p = 0.177). Proton pump inhibitors/potassium-competitive acid blockers may decrease the efficacy of pembrolizumab therapy for mUC, possibly via gut microbiome modulation.

Abstract Background The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first‐line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non‐small cell lung cancer (NSCLC). Methods Our study comprised 288 patients with advanced NSCLC who received RD as the second‐line treatment after first‐line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum‐based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. Results Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression‐free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD‐L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. Conclusion Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second‐line RD treatment in patients with advanced NSCLC.

Purpose: Knee joint line orientation (KJLO), an essential component of knee kinematics, has recently been of interest as a clinical parameter, but the factors that determine this are unknown. This study aims to clarify the effect of mechanical axis inclination of the lower limb on KJLO after total knee arthroplasty. Methods: The study included 95 knees of 95 patients who underwent kinematically aligned total knee arthroplasty in which two postoperative whole-leg standing radiographs (open and closed stance) were evaluated. We measured hip-knee-ankle angle, mechanical lateral distal femoral angle, medial proximal tibial angle, KJLO, joint line convergence angle, ankle joint line orientation and the inclination angle of lower limb mechanical axis (θ); the amount of change in each measurement was defined as delta (Δ). The correlation between ΔKJLO and each measured value was analysed, and a multiple linear regression analysis was performed to identify significant factors related to ΔKJLO. Results: The open and closed stance radiographs had differences in KJLO (3.4 ​± ​2.2° vs. −0.2 ​± ​2.3°,p ​

Purpose: To radiographically evaluate the ankle and foot complications in preoperative patients for total knee arthroplasty (TKA) in Japan. Methods: This study included 500 legs of 500 patients who planned to undergo primary TKA in affiliated hospitals of our university from August 2020 to November 2021. Hip to calcaneus view, anterior view of the ankle joint, and anterior and lateral views of the foot were taken within 1 month preoperatively. We measured hip-knee-ankle angle (HKA), mechanical ankle joint axis point (MAJAP), lateral distal tibial angle (LDTA), tibio-plafound inclination (TPI), talar inclination (TI), ankle joint line convergence angle (A-JLCA), talo-first metatarsal angle (TMA), calcaneal pitch angle (CPA), hallux valgus angle (HVA), first-second intermetatarsal angle (M1M2A), first fifth intermetatarsal angle (M1M5A), talonavicular coverage angle (TNCA), and percentage of Takakura Tanaka classification. Results: Mean measured values were as follows: HKA: 11.0°; MAJAP, 39.6%; LDTA: 92.2°; TPI: 6.9°; TI: 7.2°; A-JLCA: 0.3°; TMA:−4.3° (9° in 373 feet, 74.6%); M1M5A: 31.1°(≥30° in 321 feet, 64.2%); TNCA: 10.6° (≥7° in 375 feet, 75.0%); Takakura Tanaka classification Stage ​≥ ​IIIa in 108 feet, 21.6%. Conclusions: Mild-to-severe hallux valgus was noted in 26.5% of patients and Stage IIIa or higher ankle osteoarthritis in 21.6%, and abnormal alignment—including flat feet—was indicated in some patients. Patient's knee, foot, and ankle symptoms should be considered before TKA.

Abstract Background Immune checkpoint inhibitors (ICIs) can cause severe immune‐related adverse events (irAEs). However, biomarkers for irAEs common to different types of ICIs and cancers have not been reported. This study examined whether eosinophils can be used as a predictor of irAEs. Methods Six hundred fourteen patients with cancer (esophageal, gastric, head and neck, lung, melanoma, renal cell, urothelial, and other cancer) received anti‐PD‐1, anti‐PD‐L1, or anti‐CTLA‐4 plus anti‐PD‐1 therapy. The patients were divided into two groups depending on whether they experienced irAEs (irAE group) or not (non‐irAE group). Eosinophils were examined before the two‐course treatment. Results Patients in the irAE group who received anti‐PD‐1 or anti‐CTLA‐4 plus anti‐PD‐1 therapy had higher eosinophils before the two‐course treatment than those in the non‐irAE group (p

Abstract Objectives The objective was to investigate the details of the attachments of the mylohyoid muscle to the mandible anterior to the hyoid and mylohyoid lines to understand the positional relationship between the sublingual space and the mylohyoid, knowledge that is essential for dental implant surgery in the incisal region, as well as the routes of communication between the sublingual space and other spaces. Methods While evaluating the presence or absence of an anterior mylohyoid muscle fiber attachment to the mandible, sublingual gland herniation, spaces between muscle fascicles were also recorded as sites of penetration. The mean muscle thickness in each of these areas was also calculated. Results In all specimens, the mylohyoid originated not only from the mylohyoid line but also from the lingual surface of the center of the mandibular body (the mandibular symphysis) below the mental spines. The mylohyoid muscle fascicles were thickest in the posterior region, and further anterior to this, they tended to become thinner. Sublingual gland herniations passing through the mylohyoid were noted in the anterior and central regions, but not in the posterior region. Penetration between the muscle fascicles was most common in the central region, and no such penetration was evident in the posterior region. Conclusions These results suggest that the mylohyoid functions only incompletely as a septum, and that routes of communication from the sublingual space to the submandibular space may be present in both the anterior and central muscle fascicles of the mylohyoid. Therefore, bleeding complications during dental implant placement in the anterior mandible can be serious issues. There is a potential for sublingual hematoma that could compromise the airway by pressing the tongue against the soft palate into the pharynx.

Abstract Background The prognosis of patients with lung cancer accompanied by interstitial pneumonia is poorer than that of patients with lung cancer but without interstitial pneumonia. Moreover, the available therapeutic interventions for lung cancer patients with interstitial pneumonia are limited. Therefore, a new treatment strategy for these patients is required. The aim of the present study was to investigate the pathophysiological relationship between interstitial pneumonia and lung cancer and explore potential therapeutic agents. Methods A novel hybrid murine model of lung cancer with interstitial pneumonia was established via bleomycin-induced pulmonary fibrosis followed by orthotopic lung cancer cell transplantation into the lungs. Changes in tumor progression, lung fibrosis, RNA expression, cytokine levels, and tumor microenvironment in the lung cancer with interstitial pneumonia model were investigated, and therapeutic agents were examined. Additionally, clinical data and samples from patients with lung cancer accompanied by interstitial pneumonia were analyzed to explore the potential clinical significance of the findings. Results In the lung cancer with interstitial pneumonia model, accelerated tumor growth was observed based on an altered tumor microenvironment. RNA sequencing analysis revealed upregulation of the hypoxia-inducible factor 1 signaling pathway. These findings were consistent with those obtained for human samples. Moreover, we explored whether ascorbic acid could be an alternative treatment for lung cancer with interstitial pneumonia to avoid the disadvantages of hypoxia-inducible factor 1 inhibitors. Ascorbic acid successfully downregulated the hypoxia-inducible factor 1 signaling pathway and inhibited tumor progression and lung fibrosis. Conclusions The hypoxia-inducible factor 1 pathway is critical in lung cancer with interstitial pneumonia and could be a therapeutic target for mitigating interstitial pneumonia-mediated lung cancer progression.

In patients with Parkinson’s disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

ABSTRACTMacrolide antibiotics such as clarithromycin (CLR) and azithromycin are the key drugs used in multidrug therapy for Mycobacterium avium complex (MAC) diseases. For these antibacterial drugs, drug susceptibility has been correlated with clinical response in MAC diseases. We have previously demonstrated the correlation between drug susceptibility and mutations in the 23S rRNA gene, which confers resistance to macrolides. Herein, we developed a rapid detection method using the amplification refractory mutation system (ARMS)–loop-mediated isothermal amplification (LAMP) technique to identify mutations in the 23S rRNA gene of M. avium. We examined the applicability of the ARMS–LAMP method to genomic DNA extracted from six genotypes of M. avium clinical isolates. The M. avium isolates were classified into 21 CLR-resistant and 9 CLR-susceptible strains based on the results of drug susceptibility tests; the 23S rRNA genes of these strains were sequenced and analyzed using the ARMS–LAMP method. Sequence analysis revealed that the 9 CLR-sensitive strains were wild-type strains, whereas the 21 CLR-resistant strains comprised 20 mutant-type strains and one wild-type strain. Using ARMS–LAMP, no amplification from genomic DNAs of the 10 wild-type strains was observed using the mutant-type mismatch primer sets (MTPSs); however, amplification from the 20 mutant-type strain DNAs was observed using the MTPSs. The rapid detection method developed by us integrates ARMS–LAMP with a real-time turbidimeter, which can help determine drug resistance in a few hours. In conclusion, ARMS–LAMP might be a new clinically beneficial technology for rapid detection of mutations.IMPORTANCEMultidrug therapy for pulmonary Mycobacterium avium complex disease is centered on the macrolide antibiotics clarithromycin and azithromycin, and resistance to macrolides is an important prognosticator for clinical aggravation. Therefore, it is important to develop a quick and easy method for detecting resistance to macrolides. Drug resistance is known to be correlated with mutations in macrolide resistance genes. We developed a rapid detection method using amplification refractory mutation system (ARMS)–loop-mediated isothermal amplification (LAMP) to identify a mutation in the 23S rRNA gene, which is a macrolide resistance gene. Furthermore, we examined the applicability of this method using M. avium clinical isolates. The rapid method developed by us for detection of the macrolide resistance gene by integrating ARMS–LAMP and a real-time turbidimeter can help in detection of drug resistance within a few hours. Since this method does not require expensive equipment or special techniques and shows high analytical speed, it would be very useful in clinical practice.

Protein phosphorylation, a key regulator of cellular processes, plays a central role in brain function and is implicated in neurological disorders. Information on protein phosphorylation is expected to be a clue for understanding various neuropsychiatric disorders and developing therapeutic strategies. Nonetheless, existing databases lack a specific focus on phosphorylation events in the brain, which are crucial for investigating the downstream pathway regulated by neurotransmitters. To overcome the gap, we have developed a web-based database named “Kinase-Associated Neural PHOspho-Signaling (KANPHOS).” This paper presents the design concept, detailed features, and a series of improvements for KANPHOS. KANPHOS is designed to support data-driven research by fulfilling three key objectives: (1) enabling the search for protein kinases and their substrates related to extracellular signals or diseases; (2) facilitating a consolidated search for information encompassing phosphorylated substrate genes, proteins, mutant mice, diseases, and more; and (3) offering integrated functionalities to support pathway and network analysis. KANPHOS is also equipped with API functionality to interact with external databases and analysis tools, enhancing its utility in data-driven investigations. Those key features represent a critical step toward unraveling the complex landscape of protein phosphorylation in the brain, with implications for elucidating the molecular mechanisms underlying neurological disorders. KANPHOS is freely accessible to all researchers at https://kanphos.jp.

The unraveling of the regulatory mechanisms that govern neuronal excitability is a major challenge for neuroscientists worldwide. Neurotransmitters play a critical role in maintaining the balance between excitatory and inhibitory activity in the brain. The balance controls cognitive functions and emotional responses. Glutamate and γ-aminobutyric acid (GABA) are the primary excitatory and inhibitory neurotransmitters of the brain, respectively. Disruptions in the balance between excitatory and inhibitory transmission are implicated in several psychiatric disorders, including anxiety disorders, depression, and schizophrenia. Neuromodulators such as dopamine and acetylcholine control cognition and emotion by regulating the excitatory/inhibitory balance initiated by glutamate and GABA. Dopamine is closely associated with reward-related behaviors, while acetylcholine plays a role in aversive and attentional behaviors. Although the physiological roles of neuromodulators have been extensively studied neuroanatomically and electrophysiologically, few researchers have explored the interplay between neuronal excitability and cell signaling and the resulting impact on emotion regulation. This review provides an in-depth understanding of “cell signaling crosstalk” in the context of neuronal excitability and emotion regulation. It also anticipates that the next generation of neurochemical analyses, facilitated by integrated phosphorylation studies, will shed more light on this topic.

Abstract Background Left bundle branch area pacing (LBBAP) is a novel conduction system pacing technique. In this multicenter study, we aimed to evaluate the procedural success, safety, and preoperative predictors of procedural failure of LBBAP. Methods LBBAP was attempted in 285 patients with pacemaker indications for bradyarrhythmia, which were mainly atrioventricular block (AVB) (68.1%) and sick sinus syndrome (26.7%). Procedural success and electrophysiological and echocardiographic parameters were evaluated. Results LBBAP was successful in 247 (86.7%) patients. Left bundle branch (LBB) capture was confirmed in 54.7% of the population. The primary reasons for procedural failure were the inability of the pacemaker lead to penetrate deep into the septum (76.3%) and failure to achieve shortening of stimulus to left ventricular (LV) activation time in lead V6 (18.4%). Thickened interventricular septum (odds ratio [OR], 2.48; 95% confidence interval [CI], 1.15–5.35), severe tricuspid regurgitation (OR, 8.84; 95% CI, 1.22–64.06), and intraventricular conduction delay (OR, 8.16; 95% CI, 2.32–28.75) were preoperative predictors of procedural failure. The capture threshold and ventricular amplitude remained stable, and no major complications occurred throughout the 2‐year follow‐up. In patients with ventricular pacing burden >40%, the LV ejection fraction remained high regardless of LBB capture. Conclusions Successful LBBAP was affected by abnormal cardiac anatomy and intraventricular conduction. LBBAP is feasible and safe as a primary strategy for patients with AVB, depending on ventricular pacing.

Abstract Background Nestin, an intermediate filament protein, participates in various pathophysiological processes, including wound healing, angiogenesis, endothelial–mesenchymal transition (EndoMT), and fibrosis. However, the pathophysiological roles of lung nestin-expressing cells remain unclear due to conflicting reports. The objective of this study is to elucidate the characteristics and functions of lung nestin-expressing cells. Methods We conducted a series of in vitro and in vivo experiments using endothelial cell line MS1 and nestin-GFP mice. This animal model allows for nestin-expressing cell detection without the use of anti-nestin antibodies. Results Lung nestin-expressing cells occurred in approximately 0.2% of CD45− cells and was co-expressed with epithelial, endothelial, and mesenchymal cell-surface markers. Importantly, virtually all nestin-expressing cells co-expressed CD31. When compared to lung nestin-nonexpressing endothelial cells, nestin-expressing endothelial cells showed robust angiogenesis with frequent co-expression of PDGFRβ and VEGFR2. During TGFβ-mediated EndoMT, the elevation of Nes mRNA expression preceded that of Col1a1 mRNA, and nestin gene silencing using nestin siRNA resulted in further upregulation of Col1a1 mRNA expression. Furthermore, Notch3 expression was regulated by nestin in vitro and in vivo; nestin siRNA resulted in reduced Notch3 expression accompanied with enhanced EndoMT. Contrary to previous reports, neither Nes mRNA expression nor nestin-expressing cells were increased during pulmonary fibrosis. Conclusions Our study showed that (1) lung nestin-expressing cells are an endothelial lineage but are distinct from nestin-nonexpressing endothelial cells; (2) nestin regulates Notch3 and they act collaboratively to regulate angiogenesis, collagen production, and EndoMT; and (3) nestin plays novel roles in lung angiogenesis and fibrosis. Video Abstract

Background/Objectives: Immuno-oncology plus tyrosine kinase inhibitor (IO+TKI) combination therapy is an essential first-line therapy for advanced renal cell carcinoma (RCC). However, reports of its efficacy and safety as late-line therapy are lacking. This study aimed to examine the efficacy and safety of IO+TKI combination therapy as a late-line therapy for patients with RCC. Methods: We retrospectively examined 17 patients with RCC who received IO+TKI combination therapy as a second-line therapy or beyond (pembrolizumab plus axitinib, n = 10; avelumab plus axitinib, n = 5; nivolumab plus cabozantinib, n = 2). Results: The overall response and disease control rates of IO+TKI combination therapy were 29.4% and 64.7%, respectively. The median overall survival was not attained. Progression-free survival was 552 days, and 94.1% of patients (n = 16) experienced adverse effects (AEs) of any grade; moreover, 41.2% of patients (n = 7) experienced grade ≥ 3 immuno-related AEs. Conclusions: IO+TKI combination therapy may be a late-line therapy option for RCC.

Dielectric barrier discharge plasma actuators (DBD-PAs) have the potential to improve the performance of fluid machineries such as aircrafts and wind turbines by preventing flow separation. In this study, to identify the multiple flow control mechanisms in high Reynolds number flow, parametric experiments for an actuation parameter F+ with a wide range of Re values (105–106) for NACA0015 airfoil was conducted. We conducted wind tunnel tests by applying a DBD-PA to the flow field around a wing model at the leading edge. Lift characteristics, turbulent kinetic energy in the flow field, shear layer height, and the separation point of the boundary layer were evaluated based on pressure distributions on the wing surface and velocity of the flow field, with the effect of DBD-PA on the post-stall flow around the wing and the mechanism behind the increase in the lift coefficient CL analyzed based on these evaluation results. The following phenomena contributed to the increase in CL: (1) increase in turbulent kinetic energy; (2) increase in circulation; and (3) acceleration of the flow near the leading edge. Thus, this study effectively investigated the dependence of the increase in lift on F+ and the lift-increasing mechanism for a wide range of Re values.

Background: Chemotherapy is a common treatment for pediatric cancer. Although life prognosis is improving because of advances in medical science, it is important to deal with late effects such as dental abnormalities. We investigated the association between dental abnormalities and chemotherapy by age and tooth type. Methods: Among the 568 patients referred to the pediatric dentistry department of our hospital, we selected 32 patients (21 male and 11 female) who received chemotherapy between the ages of 0 and 6 and underwent panoramic examination after the age of 7. We recorded the age of chemotherapy commencement, diagnosis of systemic disease, and dental abnormalities such as congenital absence, microdonts, and short-rooted teeth. Results: Almost half of the patients had dental abnormalities such as congenital absence, microdonts, and short-rooted teeth, but there were no significant differences in the incidence of these abnormalities by age. When we analyzed the incidence of abnormal teeth by tooth type, the incidence of congenital absence was significantly higher in premolars (5.5%) and second molars (3.9%) than in incisor or canine or 1st molar (0.4%) (p < 0.01). The incidence of microdonts was significantly higher in premolars (3.9%) than in incisor or canine or 1st molar (0.2%) and second molars (0.0%) (p < 0.05). Conclusions: Patients who received chemotherapy had a high prevalence of dental abnormalities, and the incidence of abnormalities varied by tooth type. It is important to maintain long-term oral care for patients who have undergone chemotherapy even after the treatment is completed.

Various surgical treatments are available for occlusive subclavian and common carotid artery diseases. Nevertheless, to date, when cerebral endovascular treatment is utilized, revascularization via direct surgery may be required. This study reported five symptomatic cases of revascularization for CCA and SCA occlusive and stenotic lesions that were expected to be challenging to treat with endovascular treatment. We performed subclavian artery-common carotid artery or internal carotid artery bypass using artificial blood vessels or saphenous vein grafts in five patients with subclavian steal syndrome, symptomatic common carotid artery occlusion, and severe proximal common carotid artery stenosis. In this study, good bypass patency was achieved in all five cases. Although there were no intraoperative complications, one patient had a postoperative lymphatic leak. Moreover, there was no recurrence of stroke during postoperative follow-up for an average of 2 years. Conclusively, subclavian artery-common carotid artery bypass can be an effective surgical treatment for common carotid artery occlusion, proximal common carotid artery stenosis, and subclavian artery occlusion.

Abstract Fever is a common symptom of influenza and coronavirus disease 2019 (COVID-19), yet its physiological role in host resistance to viral infection remains less clear. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C increases host resistance to viral pathogens including influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High heat-exposed mice increase basal body temperature over 38 °C to enable more bile acids production in a gut microbiota-dependent manner. The gut microbiota-derived deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G-protein-coupled receptor 5 (TGR5) signaling increase host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage. Furthermore, the DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamsters from lethal SARS-CoV-2 infection. Moreover, we demonstrate that certain bile acids are reduced in the plasma of COVID-19 patients who develop moderate I/II disease compared with the minor severity of illness group. These findings implicate a mechanism by which virus-induced high fever increases host resistance to influenza virus and SARS-CoV-2 in a gut microbiota-dependent manner.

Abstract Flapping flight of animals has captured the interest of researchers due to their impressive flight capabilities across diverse environments including mountains, oceans, forests, and urban areas. Despite the significant progress made in understanding flapping flight, high-altitude flight as showcased by many migrating animals remains underexplored. At high-altitudes, air density is low, and it is challenging to produce lift. Here we demonstrate a first lift-off of a flapping wing robot in a low-density environment through wing size and motion scaling. Force measurements showed that the lift remained high at 0.14 N despite a 66% reduction of air density from the sea-level condition. The flapping amplitude increased from 148 to 233 degrees, while the pitch amplitude remained nearly constant at 38.2 degrees. The combined effect is that the flapping-wing robot benefited from the angle of attack that is characteristic of flying animals. Our results suggest that it is not a simple increase in the flapping frequency, but a coordinated increase in the wing size and reduction in flapping frequency enables the flight in lower density condition. The key mechanism is to preserve the passive rotations due to wing deformation, confirmed by a bioinspired scaling relationship. Our results highlight the feasibility of flight under a low-density, high-altitude environment due to leveraging unsteady aerodynamic mechanisms unique to flapping wings. We anticipate our experimental demonstration to be a starting point for more sophisticated flapping wing models and robots for autonomous multi-altitude sensing. Furthermore, it is a preliminary step towards flapping wing flight in the ultra-low density Martian atmosphere.

Abstract Aims Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a poor prognosis. Phenotyping is required to identify subtype‐dependent treatment strategies. Phenotypes of Japanese HFpEF patients are not fully elucidated, whose obesity is much less than Western patients. This study aimed to reveal model‐based phenomapping using unsupervised machine learning (ML) for HFpEF in Japanese patients. Methods and results We studied 365 patients with HFpEF (left ventricular ejection fraction >50%) as a derivation cohort from the Nara Registry and Analyses for Heart Failure (NARA‐HF), which registered patients with hospitalization by acute decompensated HF. We used unsupervised ML with a variational Bayesian–Gaussian mixture model (VBGMM) with common clinical variables. We also performed hierarchical clustering on the derivation cohort. We adopted 230 patients in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Registry as the validation cohort for VBGMM. The primary endpoint was defined as all‐cause death and HF readmission within 5 years. Supervised ML was performed on the composite cohort of derivation and validation. The optimal number of clusters was three because of the probable distribution of VBGMM and the minimum Bayesian information criterion, and we stratified HFpEF into three phenogroups. Phenogroup 1 (n = 125) was older (mean age 78.9 ± 9.1 years) and predominantly male (57.6%), with the worst kidney function (mean estimated glomerular filtration rate 28.5 ± 9.7 mL/min/1.73 m2) and a high incidence of atherosclerotic factor. Phenogroup 2 (n = 200) had older individuals (mean age 78.8 ± 9.7 years), the lowest body mass index (BMI; 22.78 ± 3.94), and the highest incidence of women (57.5%) and atrial fibrillation (56.5%). Phenogroup 3 (n = 40) was the youngest (mean age 63.5 ± 11.2) and predominantly male (63.5 ± 11.2), with the highest BMI (27.46 ± 5.85) and a high incidence of left ventricular hypertrophy. We characterized these three phenogroups as atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups, respectively. At the primary endpoint, Phenogroup 1 demonstrated the worst prognosis (Phenogroups 1–3: 72.0% vs. 58.5% vs. 45%, P = 0.0036). We also successfully classified a derivation cohort into three similar phenogroups using VBGMM. Hierarchical and supervised clustering successfully showed the reproducibility of the three phenogroups. Conclusions ML could successfully stratify Japanese HFpEF patients into three phenogroups (atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups).

Abstract Atopic dermatitis (AD) patients with skin barrier dysfunction are considered to be at a higher risk of allergic contact dermatitis (ACD), although previous studies showed that attenuated ACD responses to strong sensitizers in AD patients compared to healthy controls. However, the mechanisms of ACD response attenuation in AD patients are unclear. Therefore, using the contact hypersensitivity (CHS) mouse model, this study explored the differences in CHS responses to hapten sensitization between NC/Nga mice with or without AD induction (i.e., non-AD and AD mice, respectively). In this study, ear swelling and hapten-specific T cell proliferation were significantly lower in AD than in non-AD mice. Moreover, we examined the T cells expressing cytotoxic T lymphocyte antigen-4 (CTLA-4), which is known to suppress T cell activation, and found a higher frequency of CTLA-4+ regulatory T cells in draining lymph node cells in AD than in non-AD mice. Furthermore, the blockade of CTLA-4 using a monoclonal antibody eliminated the difference in ear swelling between non-AD and AD mice. These findings suggested that CTLA-4+T cells may contribute to suppressing the CHS responses in AD mice.

Abstract Clinical scenario 1 (CS1) is acute heart failure (HF) characterized by transient systolic blood pressure (SBP) elevation and pulmonary congestion. Although it is managed by vasodilators, the molecular mechanism remains unclear. The sympathetic nervous system plays a key role in HF, and desensitization of cardiac β-adrenergic receptor (AR) signaling due to G protein-coupled receptor kinase 2 (GRK2) upregulation is known. However, vascular β-AR signaling that regulates cardiac afterload remains unelucidated in HF. We hypothesized that upregulation of vascular GRK2 leads to pathological conditions similar to CS1. GRK2 was overexpressed in vascular smooth muscle (VSM) of normal adult male mice by peritoneally injected adeno-associated viral vectors driven by the myosin heavy chain 11 promoter. Upregulation of GRK2 in VSM of GRK2 overexpressing mice augmented the absolute increase in SBP (+ 22.5 ± 4.3 mmHg vs. + 36.0 ± 4.0 mmHg, P

A 63-year-old Japanese female presented with fever. Computed tomography showed multiple nodules in both lungs. Corticosteroids and antibiotics were administered to treat suspected organizing and bacterial pneumonia, resulting in no improvement and respiratory failure worsened. Surgical lung biopsy revealed infiltration of CD3, CD56, Granzyme B, and EBV-encoded RNA-ISH-positive atypical lymphocytes. She was diagnosed with primary pulmonary extranodal NK/T-cell lymphoma (ENKL) and died two months after diagnosis with only a temporary effectiveness of chemotherapy. We should consider the possibility of ENKL and perform prompt and appropriate biopsy for early diagnosis in cases where empiric therapy is ineffective for suspected pneumonia.

Abstract The aging of patients with tuberculosis and better therapeutic management for them are recent concerns. This study aimed to identify risk factors for adverse drug reactions (ADRs) or death in very elderly patients with pulmonary tuberculosis and to assess the association between the dosage of antituberculosis drugs and outcomes. We conducted a multicenter retrospective study at two hospitals. Hospitalized patients (≥ 80 years old) with pulmonary tuberculosis who were treated with antituberculosis drugs were enrolled. Multivariate analysis was performed to assess factors associated with ADRs or death within 60 days after treatment initiation. In total, 632 patients were included. The primary endpoint occurred in 268 patients (190 ADRs and 78 deaths). A serum albumin level

Abstract The lineage of periodontal ligament (PDL) stem cells contributes to alveolar bone (AB) and cementum formation, which are essential for tooth-jawbone attachment. Leptin receptor (LepR), a skeletal stem cell marker, is expressed in PDL; however, the stem cell capacity of LepR+ PDL cells remains unclear. We used a Cre/LoxP-based approach and detected LepR-cre-labeled cells in the perivascular around the root apex; their number increased with age. In the juvenile stage, LepR+ PDL cells differentiated into AB-embedded osteocytes rather than cementocytes, but their contribution to both increased with age. The frequency of LepR+ PDL cell-derived lineages in hard tissue was

Abstract Preserved ratio impaired spirometry (PRISm) is defined by reduced FEV1 with a preserved FEV1/FVC ratio; some individuals with PRISm can also have restrictive ventilatory abnormality. The aim of this study was to clarify clinical features of restrictive and non-restrictive PRISm. In total, 11,246 participants (mean, 49.1 years; range, 35–65 years) from five healthcare centres were included in this study. We evaluated baseline characteristics of participants with restrictive PRISm (FEV1/FVC ≥ 0.7, FEV1

Primary pleural angiosarcoma (PPA) is a rare and clinically fatal pleural tumor originating from vascular endothelial cells. Herein, we presented the case of a 73-year-old man who was referred to our emergency room with complaints of right chest and back pain for a few days. Chest computed tomography revealed massive pleural effusion and a large mass in the right chest cavity. Thoracoscopic examination demonstrated a large hemorrhagic tumor on the parietal pleura whose pathological analysis indicated PPA. The patient received immunotherapy combined with nivolumab and ipilimumab. A cycle of nivolumab and ipilimumab improved his hemorrhagic anemia and reduced the pleural effusion and tumor size. This treatment outcome suggests that nivolumab and ipilimumab comprise a vital treatment option for PPA.