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Yasutomo Tanaka,1,2 Masatoshi Hanada,1,2 Chika Kitagawa,3 Kazuaki Suyama,4 Ryota Shiroishi,5 Naoto Rikitomi,3 Toru Tsuda,6 Yoshiaki Utsunomiya,5 Takako Tanaka,1 Kazuya Shingai,1 Yorihide Yanagita,7 Ryo Kozu1,2 1Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 2Department of Rehabilitation Medicine, Nagasaki University Hospital, Nagasaki, Japan; 3Nagasaki Pulmonary Rehabilitation Clinic, Nagasaki, Japan; 4Tagami Hospital, Nagasaki, Japan; 5Utsunomiya Medical Clinic, Fukuoka, Japan; 6Kirigaoka Tsuda Hospital, Fukuoka, Japan; 7Department of Physical Therapy, School of Health Science, Toyohashi Sozo University, Aichi, JapanCorrespondence: Ryo Kozu, Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8520, Japan, Tel/Fax +81 95 819 7963, Email ryokozu@nagasaki-u.ac.jpPurpose: Assessment for frailty is important as it enables timely intervention to prevent or delay poor prognosis in chronic obstructive pulmonary disease (COPD). The aims of this study, in a sample of outpatients with COPD, were to (i) assess the prevalence of physical frailty using the Japanese version of the Cardiovascular Health Study (J-CHS) criteria and the Short Physical Performance Battery (SPPB) and the degree of agreement between the findings of the two assessments and (ii) identify factors associated with the disparity in the results obtained with these instruments.Patients and Methods: This was a multicenter cross-sectional study of individuals with stable COPD enrolled in four institutions. Frailty was assessed using the J-CHS criteria and the SPPB. Weighted Cohen’s kappa (k) statistic was performed to investigate the magnitude of agreement between the instruments. We divided participants into two groups depending on whether there was agreement or non-agreement between the results of the two frailty assessments. The two groups were then compared with respect to their clinical data.Results: A total of 103 participants (81 male) were included in the analysis. The median age and FEV1 (%predicted) were 77 years and 62%, respectively. The prevalence of frailty and pre-frail was 21% and 56% with the J-CHS criteria and 10% and 17% with the SPPB. The degree of agreement was fair (k = 0.36 [95% CI: 0.22– 0.50], P< 0.001). There were no significant differences in the clinical characteristics between the agreement group (n = 44) and the non-agreement group (n = 59).Conclusion: We showed that the degree of agreement was fair with the J-CHS criteria detecting a higher prevalence than the SPPB. Our findings suggest that the J-CHS criteria may be useful in people with COPD with the aim of providing interventions to reverse frailty in the early stages.Keywords: cardiovascular health study, Short Physical Performance Battery, chronic lung disease, physical function

Purpose of Review: Hypertension-induced cardiac hypertrophy is widely known as a major risk factor for increased cardiovascular morbidity and mortality. Although exercise is proven to exert overall beneficial effects on hypertension and hypertension-induced cardiac hypertrophy, there are some concerns among providers about potential adverse effects induced by intense exercise, especially in hypertensive athletes. We will overview the underlying mechanisms of physiological and pathological hypertrophy and delineate the beneficial effects of exercise in young people with hypertension and consequent hypertrophy., Recent Findings: Multiple studies have demonstrated that exercise training, both endurance and resistance types, reduces blood pressure and ameliorates hypertrophy in hypertensives, but certain precautions are required for hypertensive athletes when allowing competitive sports: Elevated blood pressure should be controlled before allowing them to participate in high-intensity exercise. Non-vigorous and recreational exercise are always recommended to promote cardiovascular health. Exercise-induced cardiac adaptation is a benign and favorable response that reverses or attenuates pathological cardiovascular remodeling induced by persistent hypertension. Exercise is the most effective nonpharmacological treatment for hypertensive individuals. Distinction between recreational-level exercise and competitive sports should be recognized by medical providers when allowing sports participation for adolescents and young adults., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Becker muscular dystrophy (BMD) is an X-linked recessive disorder responsible for mild skeletal muscle involvement and variable degree of cardiomyopathy. The characteristics of cardiac phenotype of BMD in childhood remain elusive. Clinical manifestations, genotype, serum biomarkers, and echocardiogram were retrospectively reviewed in BMD patients. Cardiac phenotype was classified into acute progressive (AP), chronic persistent (CP), and latent (L) groups based upon symptoms and echocardiographic findings. Twenty-five BMD patients were studied over 9.5 ± 2.5 years. Sixteen patients presented initially with variable degree of muscle weakness whereas 9 were asymptomatic. Three patients developed medically refractory heart failure by age 18 with progressive dilated cardiomyopathy (DCM) (AP). Six patients developed mild to moderate left ventricular (LV) systolic dysfunction with LV dilatation but remained asymptomatic (CP). Although 16 patients continued to show normal LV function (L), they demonstrated variable degrees of skeletal muscle involvement. The AP groups presented with significantly larger LV size and LV mass index (LVMI) at the initial encounter than groups CP or L, suggesting early myocardial remodeling predicts rapid disease progression. None presented with atrophic myocardial phenotype commonly observed in Duchenne muscular dystrophy (DMD). Wide availability of genetic testing has changed the scope of clinical presentation of BMD. Cardiomyopathy in BMD presents with a diverse clinical spectrum with variable progression of DCM where larger LV dimension and mass at the time of diagnosis may predict the progressiveness of cardiomyopathy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Eosinophilic chronic rhinosinusitis (ECRS) is an allergic inflammatory disease characterized by chronic inflammation of the sinus mucosa, and sometimes, osteitis. This study aimed to investigate the pattern of osteitis in ECRS and the relationship between bony thickening of the middle turbinate and recurrence of ECRS., Methods: A total of 246 patients with paranasal diseases were included in the study. The patients' data on bone thickening level, mucosal thickening, polyp score, clinical severity, and laboratory data were retrospectively evaluated., Results: In total, 38, 186, and 22 patients had ECRS, non-ECRS (NECRS), and odontogenic sinusitis, respectively. The Lund-Mackey (LM) score and Global Osteitis Scoring Scale (GOSS) scores in patients with ECRS were higher than those in patients with other paranasal diseases. There was a significant positive correlation between the GOSS score and ECRS clinical disease severity. Postoperative recurrence was significantly increased in patients with ECRS associated with bony thickening of the middle turbinate., Conclusion: Both mucosal inflammation and osteitis were more severe in patients with ECRS than in patients with other diseases, and clinical disease severity was correlated with osteitis. Furthermore, the postoperative recurrence rate tended to increase in patients with ECRS who had bony thickening of the middle turbinate., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Congenital cystic eye (CCE) is a rare congenital ocular disease, which has been suggested to be caused by problems with optic vesicle invagination. This is characterized by the formation of intraorbital cystic lesions lined by undifferentiated neuroepithelium. However, cases involving ocular structures with varying degrees of differentiation have also been reported as CCE in humans and animals. In horses, CCE have only been reported as a case presenting as neuroepithelial-lined cysts without the formation of ocular structures. This paper describes large bilateral intraorbital cysts in a 1-day-old horse. The histopathological findings revealed that the cysts were covered by neuroepithelium with formation of the lens, ciliary body, and optic nerve, and it was diagnosed as CCE. This report provides further variations of CCE in horses.

The present paper reports the fabrication of novel types of hybrid fibrous photocatalysts by combining block copolymer (BCP) templating, sol-gel processing, and coaxial electrospinning techniques. Coaxial electrospinning produces core-shell nanofibers (NFs), which are converted into hollow porous TiO 2 NFs using an oxidative calcination step. Hybrid BCP micelles comprising a single plasmonic nanoparticle (NP) in their core and thereof derived silica-coated core-shell particles are utilized as precursors to generate yolk-shell type particulate inclusions in photocatalytically active NFs. The catalytic and photocatalytic activity of calcined NFs comprising different types of yolk-shell particles is systematically investigated and compared. Interestingly, calcined NFs comprising silica-coated yolk-shells demonstrate enhanced catalytic and photocatalytic performance despite the presence of silica shell separating plasmonic NP from the TiO 2 matrix. Electromagnetic simulations indicate that this enhancement is caused by a localized surface plasmon resonance and a confinement effect in silica-coated yolk-shells embedded in porous TiO 2 NFs. Utilization of the coaxially electrospun TiO 2 NFs in combination with yolk-shells comprising plasmonic NPs reveals to be a potent method for the photocatalytic decomposition of numerous pollutants. It is worth noting that this study stands as the first occurrence of combining yolk-shells (Au@void@SiO 2 ) with porous electrospun NFs (TiO 2 ) for photocatalytic purposes and gaining an understanding of plasmon and confinement effects for photocatalytic performance. This approach represents a promising route for fabricating highly active and up-scalable fibrous photocatalytic systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study investigated the tibiofemoral contact point (CP) on standing lateral radiographs in knee osteoarthritis and assessed the relationship between CP and pre- and postoperative knee kinematics in total knee arthroplasty (TKA)., Methods: The intraoperative knee status of 46 knees with varus deformity that underwent bicruciate stabilized TKA using a navigation system was investigated. The intraoperative anteroposterior (AP) position of the femur relative to the tibia at maximum extension, 15°, 30°, 45°, 60° and 90° was evaluated by the navigation system before and after TKA. The CP, defined as the CP between the femur and tibia, was assessed on standing lateral radiographs at the maximum extension of the knee before and 1 year after TKA. CP was expressed as the ratio of tibial plateau distance on a scale of 0-1, with 0 indicating the most anterior position of the femur relative to the tibia., Results: The mean CP on standing lateral radiographs was 0.54 ± 0.12 and 0.46 ± 0.08 before and after TKA, respectively. The postoperative CP was significantly more anterior than the preoperative CP ( p  = 0.0002). The mean AP position of the femur relative to the tibia moved anteriorly during early knee flexion both before and after TKA, representing nonanatomical AP movement. The preoperative posterior CP group (CP > 0.54) showed more nonanatomical AP movement from 15° to 60° before and after TKA compared with the preoperative anterior CP group (CP < 0.54)., Conclusion: Preoperative posterior deviation of the femur relative to the tibia in the standing position was a predictive factor for nonanatomical AP knee kinematics. Biomechanical analysis of postoperative knees will be necessary; however, surgeons should focus on preoperative tibiofemoral CP on standing lateral radiographs to predict knee kinematics., Level of Evidence: Level Ⅲ., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Aim: Oral anticoagulants (OACs) reduce the risk of ischemic stroke but may increase the risk of major bleeding in patients with non-valvular atrial fibrillation (NVAF). Various risk scores, such as HAS-BLED, ATRIA, ORBIT, and DOAC, have been proposed to assess the risk of major bleeding in patients with NVAF receiving OACs. However, limited data are available regarding bleeding risk stratification in Japanese patients with NVAF., Methods: Of the 16,098 NVAF patients from the J-RISK AF study, the combined data of the five major AF registries in Japan (J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry), we analyzed 11,539 patients receiving OACs (median age, 71 years old; women, 29.6%; median CHA 2 DS 2 -VASc score, 3)., Results: During the 2-year follow-up period, major bleeding occurred in 274 patients (1.3% per patient-year). In a multivariate Cox proportional hazards analysis, an advanced age, hypertension (systolic blood pressure ≥ 150 mmHg), bleeding history, anemia, thrombocytopenia, and concomitant antiplatelet agents were significantly associated with a higher incidence of major bleeding. We developed a novel risk stratification system, HED-[EPA] 2 -B 3 score, which had a better predictive performance for major bleeding (C-statistics 0.67, [95% confidence interval, 0.63-0.70]) than the HAS-BLED (0.64, [0.60-0.67], P for difference 0.02) and ATRIA (0.63, [0.60-0.66], P for difference ＜0.01) scores. Furthermore, it was non-significantly higher than the ORBIT (0.65, [0.62-0.68], P for difference 0.07) and DOAC (0.65, [0.62-0.68], P for difference 0.17) scores., Conclusion: Our novel risk stratification system, the HED-[EPA] 2 -B 3 score, may be useful for identifying Japanese patients receiving OACs at a risk of major bleeding.

Context: Repeated ankle sprains can lead to injuries, including those of the anterior talofibular ligament (ATFL); however, the extent to which these ligament injuries are associated with symptoms of chronic ankle instability (CAI) remains unclear., Objective: To examine the influence of ATFL injury and ankle anterior displacement on symptoms of CAI., Design: Case-control study., Setting: University laboratory., Patients or Other Participants: A total of 122 of 426 college students who completed a questionnaire on the history of ankle sprain were enrolled in healthy (n = 34; 24 men, 10 women; age = 20.6 ± 0.5 years), coper (n = 49; 38 men, 11 women; age = 20.2 ± 1.2 years), and CAI groups (n = 39; 24 men, 15 women; age = 20.1 ± 1.1 years)., Main Outcome Measure(s): One examiner measured the ATFL delineation using ultrasound and anterior ankle displacement using a capacitance-type sensor device. The Cumberland Ankle Instability Tool was applied to assess pain and perceived instability., Results: The ATFL was normal more frequently in the healthy group and abnormal more frequently in the CAI group (χ2 = 18.45, P < .001). Anterior ankle displacement was greater in the coper and CAI groups than in the healthy group (both, P < .001), but no difference was observed between the coper and CAI groups (P = .16). We observed no correlation between the anterior ankle displacement and Cumberland Ankle Instability Tool scores (r = -0.004, P = .71) in participants with previous ankle sprains., Conclusions: Observation of an abnormal ATFL on ultrasonography was associated with anterior displacement of the ankle joint. However, the influence of anterior ankle displacement due to damage to the ATFL on the pain and perceived instability in CAI was assumed to be small., (© by the National Athletic Trainers’ Association, Inc.)

We propose a method for integrating confocal amplitude and phase images obtained through dual-comb microscopy (DCM). DCM combines the benefits of confocal laser microscopy and quantitative phase microscopy, offering high axial resolution and scan-less imaging. By leveraging the coherence between confocal amplitude and phase images within the same DCM system, we accurately determine the number of phase wrapping iterations, thereby eliminating ambiguity in phase wrapping. We demonstrate this approach using samples with micrometer-range optical thickness and nanometer-scale surface roughness. The results demonstrate an expanded axial range, spanning from micrometers to millimeters, while maintaining nanometer-level axial resolution. This integrated DCM imaging technique enables the simultaneous acquisition of confocal amplitude image and absolute phase image, thus enhancing its potential for wide-axial-dynamic-range imaging across various applications., (© 2024. The Author(s).)

Background: Head and neck small-cell carcinoma (HNSmCC) is a rare and aggressive cancer with a high tendency for distant metastasis. It is treated with multimodal treatment involving chemotherapy. Occasionally, surgery is performed for the management of locoregional HNSmCC. However, the benefits of surgery in this context have not yet been elucidated. Therefore, in this study, we aimed to investigate whether surgery could improve the survival of patients with HNSmCC., Patients and Methods: We obtained data from patients with locoregional HNSmCC treated with chemoradiation therapy (CRT) from the Surveillance, Epidemiology, and End Results database. Patients who did and did not undergo surgery were matched using propensity scores. The overall survival (OS) and disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios (HRs) were calculated using the Cox proportional hazard model., Results: The 5-year OS rates of the patients who did and did not undergo surgery were 57.2% and 50.6%, respectively (P = 0.689); the corresponding 5-year DSS rates were 61.0% and 57.5% (P = 0.769). The adjusted HRs for surgery were 0.85 (95% confidence interval [CI]: 0.54-1.33) for OS and 0.87 (95% CI: 0.51-1.49) for DSS., Conclusion: The addition of surgery to CRT did not improve the survival of patients with locoregional HNSmCC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hosokawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Skin barrier dysfunction initiates or deteriorates various cutaneous problems, such as atopic dermatitis. At high concentrations, the nonreducing disaccharide trehalose (α-d-glucopyranosyl α-d-glucopyranoside) induces a transient senescence-like state in fibroblasts and promotes wound repair. In this study, we investigated the effect of trehalose on normal human keratinocytes and demonstrated its specific role in the skin barrier. RNA-sequencing analysis revealed that trehalose regulates the expression of many skin barrier-associated genes. T helper 2 cytokines IL-4/IL-13 were observed to downregulate several differentiation markers (FLG, loricrin, keratin 1, and keratin 10) and epidermal antimicrobial proteins in monolayer-cultured keratinocytes and living skin equivalents and impaired skin barrier function in living skin equivalents, all of which were significantly upregulated or restored by trehalose. Trehalose inhibited IL-33 expression and reduced nuclear IL-33 levels by activating MAPK/extracellular signal-regulated kinase kinase 5-extracellular signal-regulated kinase 5 and suppressing extracellular signal-regulated kinase kinase 1/2-extracellular signal-regulated kinase pathway. It also increased NRF2 activation to trigger antioxidant enzyme production through JNK, thus neutralizing IL-4/IL-13-mediated oxidative stress. Trehalose prevented IL-4/IL-13-mediated signal transducer and activator of transcription 3/signal transducer and activator of transcription 6 activation and restored IL-4/IL-13-suppressed skin barrier molecules through IL-33 downregulation and NRF2 activation. This study demonstrated that trehalose may play a role in skin barrier repair in atopic dermatitis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Myocardial infarction is rare in children but frequently occurs unexpectedly with atypical presentation. It can cause a progressive lethal course unless prompt treatment is initiated., Methods: Paediatric cases of myocardial infarction diagnosed by the presence of ischaemic myocardial insults and symptomatic ventricular dysfunction were reviewed retrospectively., Results: Eighteen patients (5 days to 14 years of age; median 3 months) with myocardial infarction were studied. The aetiology was variable, including congenital coronary anomalies: anomalous left coronary artery from pulmonary artery (five patients), pulmonary atresia with intact ventricular septum with right ventricle-dependent coronary circulation (four), anomalous aortic origin of left coronary artery (three), and Williams syndrome with supravalvar aortic stenosis (one). Two acquired coronary anomalies occurred in one patient with undiagnosed Kawasaki disease with complete thrombotic obstruction of the left coronary artery and another with post-transplant cardiac allograft microangiopathy. Three patients developed thromboembolic coronary artery incidents in normal coronary anatomy. Fourteen patients were less than 1 year of age (78%). Electrocardiographic abnormalities were noted in all patients. Four patients required extracorporeal membrane oxygenation support for severe ventricular dysfunction, none of whom survived. Five patients underwent heart transplant. Five patients died during the same hospitalisation, and one patient died after discharge (overall mortality 33%). Transplant-free survival was 39%., Conclusion: Most myocardial infarction occurred in infants who presented with abrupt onset of non-specific clinical manifestations with progressively deteriorating haemodynamic status resulting in poor transplant-free survival rate. Early diagnosis and treatment are essential to prevent catastrophic outcomes.

Background: The ductus arteriosus (DA) is critical in maintaining postnatal circulation in neonates with obstructed systemic circulation (OSC) and pulmonary circulation (OPC). We hypothesized that the size of the DA and aortic isthmus (AoI) undergoes adaptive growth in utero to counteract the hemodynamic challenges in these congenital heart diseases (CHD)., Methods: Postnatal echocardiograms of neonates diagnosed prenatally with ductal-dependent CHD who were started on prostaglandins within 24 h of birth were reviewed. We assessed the cross-sectional area of the aortic valve opening, pulmonary valve opening, AoI, and DA by calculating (diameter) 2 /body surface area. Neonates were classified into OSC or OPC then subgrouped depending upon the patency of semilunar valves: OSC with and without aortic atresia (OSC-AA and OSC-nAA, respectively) and OPC with and without pulmonary atresia (OPC-PA and OPC-nPA, respectively)., Results: Ninety-four cases were studied. The DA in OSC was significantly larger than OPC, and the DA in OSC-AA was significantly larger than OSC-nAA. The size of the AoI was significantly larger in OPC than OSC and larger in OSC-AA than OSC-nAA. Within the OSC-nAA group, there was no significant difference in the size of the DA, AoI, or pulmonary valve opening between those with retrograde flow (RF) at the AoI and without (nRF) except the aortic valve opening was significantly larger in nRF. All groups had comparable cross-sectional areas of systemic output., Conclusions: Our findings suggest that DA and AoI show compensatory growth to maintain critical blood flow to vital organs against primary anatomical abnormalities in ductus-dependent CHD. (249 words)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Chronic rhinosinusitis (CRS) is a common disease with mucosal inflammation, and may sometimes be accompanied by bone thickening. The disease is usually bilateral; when it is unilateral, there may be a specific disease. This study aimed to investigate the association between unilateral sinus opacification and osteitis., Methods: In total, 104 patients with computed tomography revealing unilateral sinus opacification were included in this study. Patients were retrospectively evaluated using the Global Osteitis Scoring Scale (GOSS) score, Lund-Mackey (LM) score, polyp score, and blood tests., Results: In total, 47, 11, 9, 17, and 20 patients had CRS, paranasal sinus cyst, inverted papilloma, mycetoma, and odontogenic sinusitis, respectively. The GOSS score in patients with mycetoma was higher than that in patients with CRS. However, no significant differences in the GOSS scores between patients with mycetoma, inverted papilloma, and odontogenic sinusitis existed. 10 of the 104 patients had osteitis with extensive bone thickening and a GOSS score of 4 or higher. Patients with CRS and mycetoma tended to have a higher GOSS score for the maxillary sinus than for the other sinuses. There was a significant positive correlation between the GOSS score and LM score in patients with diseases other than paranasal sinus cyst., Conclusions: Mycetoma is more likely to cause osteitis than CRS, and a unique mechanism of osteitis exacerbation is predicted. As there is a positive correlation between bone thickening and sinus inflammation, a close association between osteitis and mucosal inflammation is inferred in diseases involving unilateral sinus opacification., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aberrant subclavian artery (ASCA) is frequently observed in interrupted aortic arch (IAA) with aortic/subaortic obstruction. Developmental significance of ASCA in IAA in utero remains elusive. Newborns with prenatally diagnosed isolated IAA under continuous prostaglandin E1 infusion were studied. Cross-sectional areas of aortic valve opening (AVO CSA ) and patent ductus arteriosus (PDA CSA ) were represented by echocardiographic measurement of (diameter) 2 indexed by body surface area (m 2 ). Types of IAA and presence of ASCA were examined in relation to sizes of AVO CSA and PDA CSA . Twenty-four newborns with IAA (six type A and 18 type B) were reviewed. Male dominance was seen in type B (male 72%). Twenty-three patients had left aortic arch. No type A patients had ASCA, but 50% of type B had ASCA; AVO CSA was significantly smaller in type B than in type A (p = 0.003). In type B, PDA CSA was significantly larger in those with ASCA than without (p = 0.003), but AVO CSA exhibited no significant size difference between these two subgroups. Chromosome 22q11 deletion was only seen in type B (56%) and showed no significant correlation with the presence of ASCA. In type B IAA, the presence of ASCA was associated with larger PDA CSA , suggesting an adaptive enlargement of the ductus arteriosus and ASCA in response to reduced antegrade flow across small AVO CSA , which may be augmenting cerebral blood flow. Preservation of cerebral blood flow may be another important determinant affecting embryonic cardiovascular development., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic rhinosinusitis (CRS) is a persistent inflammatory disease affecting the nasal and paranasal sinus tissues, classified into two main categories: one associated with nasal polyps (CRSwNP) and one without them (CRSsNP). A particular form of CRSwNP, known as eosinophilic CRS (ECRS), is distinguished by the excessive presence of eosinophils in the affected tissues. While surgical intervention and corticosteroids are the standard treatments, high relapse rates have led to increasing interest in biological treatments. Inverted papilloma (IP), a benign yet recurrent tumor with potential for malignancy, often complicates diagnosis when concurrent inflammation is present. We present a case of a 56-year-old man with a long-standing history of ECRS, initially suspected to have experienced a recurrence. Imaging suggested the possibility of IP, but biopsy results showed a marked increase in eosinophil levels. Following surgery, the diagnosis of IP was confirmed, and no malignancy was found. A year after surgery, the patient remained free of recurrence. This case emphasizes the difficulty of differentiating ECRS from IP due to their overlapping histological features. To ensure accurate diagnosis, a thorough evaluation combining radiological, endoscopic, and pathological methods is crucial., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics committee of Osaka University issued approval No. 16329. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tsuda et al.)

We describe the transition-metal-free coupling for polyfluoroalkoxy arenes using polyfluoroalkoxy borates, which serve as counterions to diaryliodonium salts and transferring mediators of polyfluoroalkoxy groups. This strategy demonstrates high functional group compatibility owing to the low nucleophilicity of the borate mediator, thus offering a practical approach for synthesizing diverse polyfluoroalkoxy arenes.

Background: The autonomic nervous system (ANS) is critical in regulating involuntary bodily functions, including heart rate. Heart rate variability (HRV) reflects the complex interplay between the ANS and humoral factors, making it a valuable noninvasive tool for assessing autonomic function. While HRV has been extensively studied in adults, normative data for HRV in children, primarily based on long-term rhythm recordings, are limited., Objective: This study aimed to establish comprehensive normative data for HRV in children., Methods: In this retrospective study, we examined 24-h Holter monitors of children aged 1 day to 18 years, divided into six age groups, at Nemours Children's Health in Orlando, Florida, spanning the years 2013-2023. HRV analysis encompassed time-domain, frequency-domain, and nonlinear indices., Results: Holter data for a total of 247 patients in six age groups were included. An age-related uptrend was observed in all time- and frequency-domain variables except the normalized unit of low-frequency power. Entropy analysis revealed contradictory results among different entropy techniques. Sample and approximate entropy analyses were consistent and showed less complexity and more predictability of HRV with decreasing heart rate, while Shannon entropy analysis showed the opposite. Fractal detrended fluctuation analysis exhibited significant decreases across the age groups, suggestive of diminishing self-similarity of HRV patterns., Conclusion: Control of heart rate and HRV is a highly complex process and requires further study for a better understanding. It seems that no single parameter can fully elucidate the entire process. A combination of time-domain, frequency-domain, and nonlinear indices may be necessary to explain HRV behavior in the growing body., (© 2024. Springer-Verlag GmbH Germany.)

Background: Pulmonary sarcomatoid carcinoma is a rare tumor that is resistant to cytotoxic agents. This observational study aimed to evaluate the detection rate of driver gene alteration and the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma., Methods: We established a database of patients with pulmonary sarcomatoid carcinoma and their clinical information, including EGFR mutation, ALK fusion gene, ROS1 fusion gene, BRAF mutation, and MET exon 14 skipping mutation. The present study retrieved and analyzed the data of patients with pulmonary sarcomatoid carcinoma in whom driver gene alterations were evaluated, and the survival duration after the initiation of treatment with targeted therapy was examined., Results: A total of 44 patients were included in the present study. The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in 2/43 patients (4.7%), 2/34 patients (5.9%), and 2/16 patients (12.5%), respectively. The ROS1 fusion gene (0/18 patients) and BRAF mutation (0/15 patients) were not detected. Female patients (P = 0.063, Fisher's exact test) and patients without smoking history (P = 0.025, Fisher's exact test) were the dominant groups in which any driver mutation was detected. Five patients with driver gene alterations were treated with targeted therapy. Progression-free survival (PFS) was 1.3 months and 1.6 months in 2 of the patients treated with gefitinib. Two patients with the ALK fusion gene showed 2.1 and 14.0 months of PFS from the initiation of treatment with crizotinib, and a patient with the MET exon 14 skipping mutation showed 9.7 months of PFS from the initiation of treatment with tepotinib., Conclusion: The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in patients with pulmonary sarcomatoid carcinoma in clinical practice, and some patients achieved long survival times after receiving targeted therapy. Further investigation is necessary to evaluate the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma., (© 2024. The Author(s).)

Background: Anemia, a common comorbidity in older patients with heart failure (HF) and atrial fibrillation (AF), is associated with an increased risk of adverse events. This study evaluated the prognostic effects of longitudinal changes in anemia status on clinical outcomes in patients with AF., Methods and Results: We prospectively evaluated data of 1,388 patients with AF from the Hokuriku-Plus AF Registry (1,010 men; mean [±SD] age 72.3±9.7 years) and recorded the incidence of death, HF, thromboembolism, and major bleeding. Of these patients, the 1,233 for whom hemoglobin levels were available at baseline and at the 1-year follow-up were further evaluated. Patients were categorized into 3 groups based on longitudinal changes in 1-year anemia status: Group 1, AF without anemia; Group 2, AF with improved anemia; and Group 3, AF with sustained or new-onset anemia. Over the 1-5 years of follow up, the incidences of death, HF, thromboembolism, and major bleeding were significantly higher among patients with than without anemia. In addition, the incidence of death or HF was significantly higher in Group 3 than in Groups 1 and 2. Multivariate analysis revealed no anemia or improvement in anemia in 1 year as an independent predictor for a favorable prognosis for cardiovascular death and HF., Conclusions: Recovery from anemia may be associated with a favorable clinical course of AF.

Objectives/hypothesis: To determine the presence of sex differences in difficult laryngeal exposure and the Laryngoscore, validate the Laryngoscore, mini-Laryngoscore, and Clarysse's model for predicting difficult laryngeal exposure, and modify the Laryngoscore for improved prediction accuracy., Study Design: Retrospective study., Methods: This study included 153 patients who underwent laryngeal microsurgery at a tertiary laryngology center and university hospital. Patients were evaluated using the 11 items of the Laryngoscore, mini-Laryngoscore, and Clarysse's model to predict difficult laryngeal exposure. Difficult laryngeal exposure was defined as the inability to view the anterior commissure through a rigid laryngoscope under counterpressure to the anterior neck. Descriptive statistics and receiver-operating characteristic curve analysis were used to assess the diagnostic performance of the predictive models and variables, including sex., Results: The prevalence of difficult laryngeal exposure was significantly higher in men than in women, despite higher Laryngoscore values in females. The Laryngoscore, mini-Laryngoscore, and Clarysse's model demonstrated good diagnostic performance with C-indexes of 0.751, 0.727, and 0.783, respectively. Based on these findings, we proposed a modified Laryngoscore, including treatment history, interincisors gap, upper jaw dental status, thyro-mental distance, degree of neck flexion-extension, and sex, achieving a C-index of 0.835., Conclusions: Inclusion of sex in the Laryngoscore and related predictive models enhances the accuracy of predicting difficult laryngeal exposure. These findings support the inclusion of sex as a factor in future modifications of these models to improve their predictive performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

This study investigates the significance of quantifying amino acids in minute sweat volumes using high-performance liquid chromatography with fluorescence detection. Sweat, a valuable biofluid for non-invasive health monitoring, provides real-time insights into physiological changes. Amino acids, which are critical for various physiological processes, are key to protein synthesis and cellular regulation. Therefore, analyzing sweat's amino acid profiles can offer insights into metabolic states, exercise-induced stress, and potential biomarkers for health conditions. For sensitive analysis, amino acids were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), followed by liquid chromatographic separation on an octadecylsilyl column and fluorescence detection. The developed method was validated and applied to human sweat samples, enabling the quantification of 14 amino acids. The most abundant amino acids in the samples were serine, glycine, and alanine, which aligns with prior studies. This method offers a non-invasive and efficient way to screen for diseases by detecting amino acids in sweat, even with minimal sweat volumes. The approach could also be used to analyze other biomolecules in sweat, expanding its potential applications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Differences in the efficacy and safety between the preclose and postclose suture-mediated vascular closure systems for femoral vein access have not been adequately studied., Objectives: This study aimed to evaluate the efficacy and safety of these 2 suturing techniques in femoral vein access., Methods: Patients subjected to elective catheter ablation via the femoral vein using a sheath of 8- to 13-F inner diameter (n = 282) were randomized to the preclose or postclose groups for the single-suture technique using ProGlide/ProStyle (Abbott Vascular). Duplex ultrasound was performed on days 1 and 90 after the procedure to evaluate vascular complications. The primary efficacy endpoint was rebleeding requiring recompression, and the primary safety endpoint was any major complication occurring within 90 days. The secondary efficacy endpoints included time to hemostasis and time to ambulation, and the secondary safety endpoint was any minor complication occurring within 90 days., Results: The preclose group demonstrated a significantly lower rebleeding rate (5 of 141 [3.5%] vs 15 of 141 [10.6%]; P = 0.03) and shorter time to hemostasis (254.0 ± 120.4 seconds vs 299.8 ± 208.2 seconds; P = 0.02) compared with the postclose group. Five patients in each group were lost to follow-up at 90 days. Incidence of major complications were similar in both groups (1 of 136 [0.7%]; P = 1.00), whereas minor complications were observed in 18 of 136 (13.2%) and 21 of 136 (15.4%) patients in the preclose and postclose groups, respectively, without a significant difference (P = 0.73)., Conclusions: In femoral vein access using the single-suture technique with ProGlide/ProStyle, the preclose technique presented a higher hemostasis rate than the postclose technique, without compromising safety., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Granulomatous lesions in the nasal sinuses are associated with a variety of diseases, including immune disorders such as sarcoidosis, vasculitis, immunoglobulin G4 (IgG4)-related diseases, malignant lymphomas, and microbial infections. Here, we report a rare case of fungal granuloma that occurred exclusively within the nasal septum. The patient presented to the Department of Surgery with the chief complaint of nasal obstruction associated with nasal septal deviation. A bulge was found below the right nasal septum. Initially, it was diagnosed as mucosal swelling associated with rhinitis, and surgery was performed. A granulomatous lesion with bone destruction was found under the mucosa of the nasal septum, which led to the diagnosis of fungal granulation based on postoperative pathology. Though bacterial and fungal infections of the nasal septum are occasionally observed, this is the first reported instance of a fungal granuloma confined to the nasal septum. Infection within the nasal septum, although rare, should also be considered as a differential diagnosis for morphological abnormalities of the nasal septum., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Ethics Committee of Osaka University issued approval 16329. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tamura et al.)

Background: In this study, we aimed to investigate the preoperative and postoperative anteroposterior position (AP) of the femur relative to the tibia in total knee arthroplasty (TKA) and assess the influence of change in the AP position on clinical outcomes., Methods: We evaluated 49 knees that underwent bi-cruciate-substituted TKA using a navigation system. The preoperative and postoperative AP position of the femur relative to the tibia at maximum extension, 15°, 30°, 45°, 60°, 90°, 105°, and 120° and maximum flexion angles were calculated. The 2011 Knee Society Score was evaluated preoperatively and 1 year postoperatively. The Wilcoxon signed rank and Spearman's rank correlation tests were performed, with statistical significance set at P < 0.05., Results: The postoperative AP position was significantly correlated with the preoperative AP position at each measured angle. The postoperative AP positions were statistically more anterior than those preoperatively. Furthermore, the changes in the AP position after TKA negatively correlated with the symptom (P = 0.027 at 30°, P = 0.0018 at 45°, P = 0.0003 at 60°, P = 0.01 at 90°, and P = 0.028 at 105°) and patient satisfaction (P = 0.018 at 60° and P = 0.009 at 90°) scores at 1 year postoperatively., Conclusion: The postoperative AP position of the femur relative to the tibia was strongly influenced by the preoperative those in TKA. Postoperative anterior deviation of the femur relative to the tibia from mid-flexion to deep flexion could worsen clinical outcomes., (© 2024. The Author(s).)

Background: Low vaccination coverage among travelers poses a critical challenge to global health security. Indeed, public concerns regarding vaccines can lead to vaccine reluctance and refusal, but evidence about the impacts of concerns regarding vaccines on the uptake of travel vaccinations remains sparse. We examined the associations between concerns about vaccines and vaccination behavior among travelers., Methods: Japanese travelers aged 18 years or older, who stayed at a guesthouse in New Delhi, India, were targeted (n = 153). We conducted cross-sectional surveys from August 23 to September 2, 2019, and from February 19 to March 5, 2020. We examined the associations of three concerns regarding vaccines (5-point scale)-serious side effects from vaccines, vaccine safety, and vaccine effectiveness-with the uptake of travel vaccinations., Results: In total, 60 participants (39.2 %) had been vaccinated for this or a past trip. After adjusting for all potential confounding variables, concerns about serious side effects from vaccines and vaccine safety were negatively associated with the uptake of travel vaccinations. The ORs (95 % CIs) for 1-point increases in concerns about serious side effects from vaccines and vaccine safety were 0.72 (0.52, 0.99) and 0.71 (0.52, 0.96), respectively. Sensitivity analyses did not change the results substantially., Conclusions: Concerns about vaccine safety issues were negatively associated with the uptake of travel vaccinations among the participants, with no corresponding association observed for vaccine effectiveness. Addressing concerns about vaccine safety issues, rather than vaccine effectiveness may contribute to an increased uptake of travel vaccinations., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Kazuhiko Watanabe,1 Ayumi Onoue,1 Kenichi Kubota,2 Noritaka Higashi,2 Toshinari Hayashi,3 Tohru Tsuda,4 Hisamitsu Omori1 1Department of Biomedical Laboratory Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0976, Japan; 2Department of Respiratory Medicine, Japanese Red Cross Kumamoto Health Care, Kumamoto 861-8528, Japan; 3Tokorozawa Respiratory Clinic, Tokorozawa, Saitama, Japan; 4Kirigaoka Tsuda Hospital, Kitakyusyu, Fukuoka, JapanCorrespondence: Hisamitsu OmoriDepartment of Biomedical Laboratory Sciences, Faculty of Life Sciences, Kumamoto University, 4-24-1 Kuhonji, Chuo-ku Kumamoto, Kumamoto 862-0976, JapanTel +81 96 373 5462Fax +81 96 373 5462Email omorih@gpo.kumamoto-u.ac.jpIntroduction: This study aimed to assess the association between airflow limitation (AL) severity and reduced bone mineral density (BMD) in Japanese men.Subjects and methods: This cross-sectional study included 290 subjects aged over 40 years (mean age 72.0, SD 11.6), who underwent a comprehensive health examination, including spirometry and measurement of BMD at the left femoral neck using dual-energy X-ray absorptiometry (DXA), between 2016 and 2017 at Japanese Red Cross Kumamoto Health Care Center. AL was defined as forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) of −2.5 SD]), or osteoporosis (YAM ≦ 70% [≦ −2.5 SD]). Reduced BMD was defined as osteopenia, osteoporosis, or medication used for osteoporosis. Logistic regression analysis was used to assess the association between AL severity and the reduced BMD.Results: The prevalence of reduced BMD in subjects with moderate-to-severe AL (76.2%) was significantly higher than in those without AL (47.9%) (p=0.030). In logistic regression models adjusted for age, body mass index, pack-years, physical activity, and alcohol drinking, the risk of reduced BMD (odds ratio: 3.87; 95% confidence interval: 1.20–12.49; p=0.024) was significantly higher in subjects with moderate-to-severe AL than in those with normal pulmonary function.Conclusion: Present results suggest that reduced BMD is associated with AL severity in Japanese men.Keywords: chronic obstructive pulmonary disease, comorbidity, bone mineral density, osteoporosis, airflow limitation, pulmonary function

Kentaro Machida,1,* Tomotaka Kawayama,2,* Masaharu Kinoshita,3,* Masakazu Ichinose,4 Tohru Tsuda,5 Shohei Takata,6 Hiroshi Koto,7 Makoto Yoshida,8 Yoshinori Ashihara,9 Masaru Kawashima,10 Hideaki Suna,10 Hiromasa Inoue1 1Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; 2Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; 3Nagata Hospital, Yanagawa 832-0059, Japan; 4Department of Respiratory Medicine, Tohoku University, Graduate School of Medicine, Sendai 980-8574, Japan; 5Kirigaoka Tsuda Hospital, Kitakyushu 802-0052 Japan; 6Division of Respiratory Medicine, National Hospital Organization Fukuoka-Higashi Medical Center, Koga 811-3195, Japan; 7Division of Respiratory Medicine, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka 815-8588, Japan; 8Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka 811-1394, Japan; 9Division of Respiratory Medicine, Oita Nakamura Hospital, Oita 870-0022, Japan; 10ONO Pharmaceutical Co. Ltd., Osaka 541-8564, Japan*These authors contributed equally to this workCorrespondence: Hiromasa InoueDepartment of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, JapanTel +81 99 275 6481Fax +81 99 275 6482Email inoue-pulm@umin.netBackground: Although long-acting muscarinic receptor antagonists are central to the management of chronic obstructive pulmonary disease (COPD), inhaled medicines may have technical difficulty in some patients and adherence barriers.Methods: A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase II trial was performed to evaluate the efficacy and safety of oral administration of the antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD patients with % forced expiratory volume in 1 s (FEV1) ≥30% and

Norimasa Fujimoto,1 Hikaru Nakamura,2 Tetsuya Tsuda,3 Yosuke Wakutani,4 Takeo Takao4 1Department of Rehabilitation, Kurashiki Heisei Hospital, Kurashiki, Okayama, Japan; 2Department of Health and Welfare Science, Okayama Prefectural University, Soja, Okayama, Japan; 3Department of Communication Sciences and Disorders, Prefectural University of Hiroshima, Mihara, Hiroshima, Japan; 4Department of Neurology, Kurashiki Heisei Hospital, Kurashiki, Okayama, Japan Background: Brain-damaged patients often have difficulty understanding non-literal language. However, whether patients with Alzheimer’s disease (AD) have comprehension deficits of metaphorical expressions, in contrast with non-metaphorical (literal) expressions, remains unclear.Patients and methods: The subjects were 40 AD patients; 20 had mild AD (17–23 points on the Mini-Mental State Examination [MMSE]), and 20 had very mild AD (≥24 points). Twenty normal elderly controls were also enrolled as a control group. Thirty sentences that contained novel similes (Items) were prepared. For each Item, four explanatory choices, consisting of one correct response and three foils, were provided. The participants were asked to choose the written statement that best represented the Item’s meaning. In addition, all the subjects completed the Token Test.Results: The patients with mild AD had significantly lower scores than the normal controls on both the simile comprehension test and the Token Test. However, the patients with very mild AD exhibited significantly lower scores on the simile comprehension test, but not on the Token Test. The distributions of error types for the simile test differed between the mild AD group and the other groups. The mild AD patients made more errors that were “far” from the correct responses.Conclusion: Patients with AD are more likely to have comprehension deficits of metaphorical expressions than comprehension deficits of non-metaphorical expressions. Pragmatic language dysfunction may precede formal language dysfunction during the progression of AD.Keywords: non-literal language, simile, multiple-choice, pragmatics

Metal nanoparticle-based electrocatalysts are widely used in electronic devices, which serve for electrochemical reactions like oxygen reduction reaction, alcohol oxidation and CO 2 reduction reaction. These catalyst-dependent reactions are the key of the emerging clean energy systems. Catalyst design and synthesis therefore have received keen attention in past decades. We are motivated to study synthesis approaches of metal nanoparticle-based electrocatalysts using ionic liquids (ILs), which are promising solvents for the nanoparticle preparation because of their unique physicochemical properties. In this personal account, we review our previous and present works on nanoparticle preparation in IL and utilization of the obtained nanoparticles as electrocatalysts., (© 2023 The Chemical Society of Japan & Wiley-VCH GmbH.)

Eosinophilic chronic rhinosinusitis (ECRS) is a refractory type 2 inflammation-based airway allergic disease that is prone to complications such as bronchial asthma. Pott's puffy tumor (PPT) is a rare clinical entity characterized by osteomyelitis of the frontal bone accompanied by a subperiosteal abscess. A 56-year-old female with a history of cranial surgery and bronchial asthma presented to an otolaryngology clinic with nasal obstruction and loss of smell, later developing swelling and redness on her forehead. She was diagnosed and treated for ECRS and was thought to have developed PPT during her course. Nasal endoscopy reveals bilateral polyp formation originating from the middle meatus. Paranasal computed tomography (CT) indicates substantial swelling extending from the opening of the frontal sinus to the adjacent subcutaneous tissue, accompanied by a defect in the frontal bone and osteolysis at the base of the frontal skull. Her management included conservative antibiotic therapy adjusted due to a drug eruption and, subsequently, endoscopic sinus surgery (ESS). The case was complicated by the patient's medical history and the absence of detailed surgical records, which limited the use of enhanced imaging techniques. This underscores the complexity of diagnosing and managing PPT in adults, particularly those with prior surgeries, emphasizing the need for a tailored diagnostic and therapeutic approach that integrates detailed patient history with current clinical indicators to effectively guide treatment. This case contributes to the limited literature on adult PPT and underscores the critical need for careful patient monitoring and detailed surgical history., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Tatsuki et al.)

Objective Pembrolizumab plus platinum and pemetrexed (Pemb-Plt-PEM) combination therapy is an effective first-line treatment for advanced non-squamous non-small-cell lung cancer (NSCLC), regardless of programmed death ligand 1 expression. However, the effectiveness and feasibility of first-line Pemb-Plt-PEM therapy in elderly patients (≥75 years old) remain unclear. Therefore, this study investigated the safety and efficacy of first-line Pemb-Plt-PEM in elderly patients with nonsquamous NSCLC. Methods We retrospectively evaluated the data of patients ≥75 years old with non-squamous NSCLC who were treated with first-line Pemb-Plt-PEM from December 2018 to December 2020 at 10 institutes in Japan. Data on patient characteristics, efficacy of pemb-Plt-PEM therapy, and the type and severity of adverse events were reviewed. Results Thirty patients [20 men and 10 women; median age: 76 (range: 75-82) years old] were included in the analysis. The overall response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 40.0%, 66.7%, and 7.5 and 24.0 months, respectively. The treatment-related deaths were caused by pneumonitis. First-line Pemb-Plt-PEM was associated with the PFS, based on the neutrophil-to-lymphocyte ratio (NLR). The PFS for low and high NLR values was 10.1 and 2.0 months, respectively. Furthermore, the sex and NLR influenced the association between Pemb-Plt-PEM and the OS. The OS for low and high NLR values was 32.8 and 2.6 months, respectively. Conclusion First-line pemb-Plt-PEM therapy is effective and feasible in elderly patients with non-squamous NSCLC.

Recent reports have focused on the usefulness of conversion surgery, in which chemotherapy is given to patients with unresectable advanced gastric cancer (GC), and radical surgery is subsequently performed if resection becomes possible; however, no consensus has been reached regarding the usefulness of this strategy. We report on a 74-year-old man who was diagnosed with esophagogastric junction cancer (T3N3M1 (LYM): stage IV). Chemotherapy was chosen and seven courses of S1 + cisplatin (SP) + trastuzumab (HCN) and two courses of S1 + HCN were administered. Approximately 10 months after the start of chemotherapy, the tumor had almost disappeared and we therefore decided to perform conversion surgery. Pathologic examination of the specimen and dissected lymph nodes showed no cancer. Postoperatively, the patient underwent chemotherapy until the second postoperative year, and no metastasis or recurrence was observed for nine years after surgery. Conversion surgery after chemotherapy resulted in recurrence-free survival in this case; however, further studies are needed to elucidate the effect of surgery after chemotherapy for patients with stage IV GC, as chemotherapy continues to evolve., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Enomoto et al.)

Background: An epicardial connection (EC) through the intercaval bundle (EC-ICB) between the right pulmonary vein (RPV) and right atrium (RA) is one of the reasons for the need for carina ablation for PV isolation and may reduce the acute and chronic success of PV isolation. We evaluated the intra-atrial activation sequence during RPV pacing after failure of ipsilateral RPV isolation and sought to identify specific conduction patterns in the presence of EC-ICB., Methods and Results: This study included 223 consecutive patients who underwent initial catheter ablation of atrial fibrillation. If the RPV was not isolated using circumferential ablation or reconnected during the waiting period, an exit map was created during mid-RPV carina pacing. If the earliest site on the exit map was the RA, the patient was classified into the EC-ICB group. The exit map, intra-atrial activation sequence, and RPV-high RA time were evaluated. First-pass isolation of the RPV was not achieved in 36 patients (16.1%), and 22 patients (9.9%) showed reconnection. Twelve and 28 patients were classified into the EC-ICB and non-EC-ICB groups, respectively, after excluding those with multiple ablation lesion sets or incomplete mapping. The intra-atrial activation sequence showed different patterns between the 2 groups. The RPV-high RA time was significantly shorter in the EC-ICB than in the non-EC-ICB group (69.2±15.2 versus 148.6±51.2 ms; P <0.001), and RPV-high RA time<89.0 ms was highly predictive of the existence of an EC-ICB (sensitivity, 91.7%; specificity, 89.3%)., Conclusions: An EC-ICB can be effectively detected by intra-atrial sequencing during RPV pacing, and an RPV-high RA time of <89.0 ms was highly predictive.

Background: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear., Objective: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis., Patients and Methods: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020., Results: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03)., Conclusions: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge., (© 2024. The Author(s).)

T cell-based immunotherapies for solid tumors have not achieved the clinical success observed in hematological malignancies, partially due to the immunosuppressive effect promoted by the tumor microenvironment, where PD-L1 and TGF-β play a pivotal role. However, durable responses to immune checkpoint inhibitors remain limited to a minority of patients, while TGF-β inhibitors have not reached the market yet. Here, we describe a bispecific antibody for dual blockade of PD-L1 and TFG-β, termed AxF (scFv) 2 , under the premise that combination with T cell redirecting strategies would improve clinical benefit. The AxF (scFv) 2 antibody was well expressed in mammalian and yeast cells, bound both targets and inhibited dose-dependently the corresponding signaling pathways in luminescence-based cellular reporter systems. Moreover, combined treatment with trispecific T-cell engagers (TriTE) or CAR-T cells significantly boosted T cell activation status and cytotoxic response in breast, lung and colorectal (CRC) cancer models. Importantly, the combination of an EpCAMxCD3×EGFR TriTE with the AxF (scFv) 2 delayed CRC tumor growth in vivo and significantly enhanced survival compared to monotherapy with the trispecific antibody. In summary, we demonstrated the feasibility of concomitant blockade of PD-L1 and TGF-β by a single molecule, as well as its therapeutic potential in combination with different T cell redirecting agents to overcome tumor microenvironment-mediated immunosuppression., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Coronary microvascular dysfunction (CMD) encompasses a spectrum of structural and functional alterations in coronary microvasculature resulting in impaired coronary blood flow and consequent myocardial ischemia without obstruction in epicardial coronary artery. The pathogenesis of CMD is complex involving both functional and structural alteration in the coronary microcirculation. In adults, CMD is predominantly discussed in context with anginal chest pain or existing ischemic heart disease and its risk factors. The presence of CMD suggests increased risk of adverse cardiovascular events independent of coronary atherosclerosis. Coronary microvascular dysfunction is also known in children but is rarely recognized due to paucity of concommitent coronary artery disease. Thus, its clinical presentation, underlying mechanism of impaired microcirculation, and prognostic significance are poorly understood. In this review article, we will overview variable CMD reported in children and delineate its emerging clinical significance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC)., Methods: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival., Results: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients., Conclusions: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber syndrome, is a rare autosomal dominant disorder characterized by vascular malformations. This comprehensive review aimed to provide an overview and summarize various aspects of HHT, including the genetic abnormalities, complications associated with visceral arteriovenous malformations (AVMs), prognosis of HHT, quality of life (QOL), and treatment of epistaxis. In addition, this review highlights the challenges in diagnosing HHT and emphasizes the critical role of otolaryngologists in the early detection of HHT. Otolaryngologists can refer patients with refractory epistaxis for AVM screening to expedite intervention. Mutation of the genes involved in the transforming growth factor-β signaling pathway leads to the incidence of HHT, resulting in the formation of abnormal blood vessel formation. These vascular malformations commonly manifest as telangiectasia on the skin and mucous membranes; however, epistaxis remains the hallmark symptom of HHT. The impact of HHT goes beyond the visible symptoms and often includes the formation of life-threatening visceral AVMs in the lungs, liver, and brain. The prognosis of patients with HHT is closely related to the development of these complications, necessitating timely diagnosis and intervention. Refractory epistaxis diminishes the QOL of patients with HHT. The management of epistaxis ranges from conservative measures to advanced interventions such as prevention, conservative treatments, ablation, surgical procedures, and the administration of anti-angiogenic agents. However, effective management requires a multidisciplinary approach. The diagnosis of HHT remains challenging due to its variable presentation and lack of awareness among physicians. This review highlights the importance of reducing the duration between symptom onset and diagnosis. Otolaryngologists who are experienced in the management of refractory epistaxis can aid in identifying potential cases of HHT. They can facilitate the initiation of screening for visceral AVMs via prompt recognition of the signs and symptoms of HHT, contributing to improved patient outcomes. Early detection and intervention through screening can extend the life expectancy of patients with HHT to levels comparable with that of the general population. In conclusion, this review provides insight into various aspects of HHT and emphasizes the importance of timely diagnosis and intervention in the mitigation of the potentially life-threatening complications associated with this disorder. Otolaryngologists play a critical role in this process, serving as gatekeepers to the identification of cases of HHT and implementation of appropriate screening and management pathways, thereby improving the life expectancy and QOL of patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Identification of paediatric coronary artery abnormalities is challenging. We studied whether coronary artery CT angiography can be performed safely and reliably in children., Materials: Retrospective analysis of consecutive coronary CT angiography scans was performed for image quality and estimated radiation dose. Both factors were assessed for correlation with electrocardiographic-gating technique that was protocoled on a case-by-case basis, radiation exposure parameters, image noise artefact parameters, heart rate, and heart rate variability., Results: Sixty scans were evaluated, of which 96.5% were diagnostic for main left and right coronaries and 91.3% were considered diagnostic for complete coronary arteries. Subjective image quality correlated significantly with lower heart rate, increasing patient age, and higher signal-to-noise ratio. Estimated radiation dose only correlated significantly with choice of electrocardiographic-gating technique with median doses as follows: 2.42 mSv for electrocardiographic-gating triggered high-pitch spiral technique, 5.37 mSv for prospectively triggered axial sequential technique, 3.92 mSv for retrospectively gated technique, and 5.64 mSv for studies which required multiple runs. Two scans were excluded for injection failure and one for protocol outside the study scope. Five non-diagnostic cases were attributed to breathing motion, scanning prior to peak contrast enhancement, or scan acquisition during the incorrect portion of the R-R interval., Conclusions: Diagnostic-quality coronary CT angiography can be performed reliably with a low estimated radiation exposure by tailoring each scan protocol to the patient's body habitus and heart rate. We propose coronary CT angiography is a safe and effective diagnostic modality for coronary artery abnormalities in children.

Evidence suggests that atrial fibrillation (AF) could increase the risk of worsening kidney function (WKF) which is linked to an increased risk of stroke, bleeding, and death in AF patients. However, limited data exist regarding the factors that could lead to WKF in these patients. Therefore, we sought to identify the potential factors associated with the development of WKF in patients with non-valvular AF (NVAF). We analyzed prospectively recruited 1122 NVAF patients [men 71.9%, median age 73.0 years (interquartile range: 66.0-79.0)] with a baseline estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m 2 from the Hokuriku-Plus AF Registry. The primary outcome was incident WKF, defined as the %eGFR change from the baseline ≥ 30% during the follow-up period. We evaluated the association between baseline variables and incident WKF using univariate and multivariate Cox proportional hazard models. We also evaluated the non-linear association between the identified factors and incident WKF. During a median follow-up period of 3.0 years (interquartile range: 2.7-3.3), incident WKF was observed in 108 patients (32.6 per 1000 person-years). Compared to the patients without incident WKF, the patients with incident WKF were older and had a higher prevalence of heart failure (HF), diabetes mellitus (DM), and vascular disease at baseline. Those who experienced incident WKF also had higher diastolic blood pressure, lower hemoglobin, lower eGFR, higher B-type natriuretic peptide (BNP) and used warfarin more frequently. Upon multivariate analysis, age ≥ 75 years, HF, DM, and anemia were independently associated with incident WKF. Additionally, age and hemoglobin were linearly associated with the risk of incident WKF, whereas a J- or U-shaped association was observed for HbA1c and BNP. Age ≥ 75 years, HF, DM, and anemia were associated with the development of WKF in Japanese patients with NVAF. In patients with these risk factors, a careful monitoring of the kidney function and appropriate interventions may be important when possible., (© 2022. Springer Japan KK, part of Springer Nature.)

Background: Despite the positive impact of implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) on prognosis, their implantation is often withheld especially in Japanese heart failure patients with reduced left ventricular ejection fraction (HFrEF) who have not experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) for uncertain reasons. Recent advancements in heart failure (HF) medications have significantly improved the prognosis for HFrEF. Given this context, a critical reassessment of the treatment and prognosis of ICDs and WCDs is essential, as it has the potential to reshape awareness and treatment strategies for these patients., Methods: We are initiating a prospective multicenter observational study for HFrEF patients eligible for ICD in primary and secondary prevention, and WCD, regardless of device use, including all consenting patients. Study subjects are to be enrolled from 31 participant hospitals located throughout Japan from April 1, 2023, to December 31, 2024, and each will be followed up for 1 year or more. The planned sample size is 651 cases. The primary endpoint is the rate of cardiac implantable electronic device implementation. Other endpoints include the incidence of VT/VF and sudden death, all-cause mortality, and HF hospitalization, other events. We will collect clinical background information plus each patient's symptoms, Clinical Frailty Scale score, laboratory test results, echocardiographic and electrocardiographic parameters, and serial changes will also be secondary endpoints., Results: Not applicable., Conclusion: This study offers invaluable insights into understanding the role of ICD/WCD in Japanese HF patients in the new era of HF medication., Competing Interests: YOk received research funding from Bayer Healthcare and Biosense Webster, Inc, and received scholarship grant from Boston Scientific Japan, and received speaker honoraria from Daiichi‐Sankyo, Bayer Healthcare, and Bristol‐Meyers Squibb, Ono Pharmaceutical, and Medtronic Japan, and affiliated with endowed courses from Boston Scientific Japan, Japan Lifeline, Fukuda Denshi, Abbott Medical Japan, BIOTRONIK Japan, and Medtronic Japan. RKo is affiliated with an endowed division supported by BIOTRONIK Japan, Abbott Medical Japan, Japan Lifeline and Medtronic Japan. KN received research funding from Johnson & Johnson K.K. TN received lecture fees from Abbott Medical Japan, Medtronic Japan, and BIOTRONIK Japan. TKat received lecture fees from Daiichi‐Sankyo, Bristol‐Myers Squibb, Bayer Healthcare, Boston Scientific Japan, Abbott Japan, Nihon Kohden and Medtronic Japan. HF received speaker honoraria from Daiichi‐Sankyo, Bayer Yakuhin, Nippon Boehringer Ingelheim, Johnson & Johnson K.K., Abbott Medical Japan, Medtronic Japan and Japan Lifeline. SK received research funding from Johnson & Johnson K.K. SN received speaker honoraria from Bayer Healthcare, Daiichi‐Sankyo, Bristol‐Meyers Squibb and Medtronic Japan. MH received research funding from BIOTRONIK Japan, Medtronic Japan, Abbott Medical Japan, Japan Lifeline, Nihon Kohden and Boston Scientific Japan, and received speaker honoraria from Nippon Boehringer Ingelheim, Daiichi‐Sankyo, Bristol‐Meyers Squibb, Medtronic Japan, Japan Lifeline, and Abbott Medical Japan. MM received speaker honoraria from Medtronic Japan and Boston Scientific Japan. WS received grants from Daiichi Sankyo and Nippon Boehringer Ingelheim, and received remuneration for lectures, presentations, speakers bureaus, manuscript writing or educational events from Daiichi Sankyo, Nippon Boehringer Ingelheim, Bristol‐Meyers Squibb, K.K., Bayer Yakuhin, Pfizer, Ono Pharmaceutical and Medtronic Japan. KKu received speaker honoraria from Daiichi‐Sankyo, Ltd., Bayer Yakuhin, and Medtronic Japan, and received research grants from Medtronic Japan, HITACHI, and JSR. KI received speaker honoraria from Medtronic Japan and BIOTRONIK Japan. TH received speaker honoraria from Medtronic Japan, BIOTRONIK Japan and Bayer Yakuhin. IN has received speaking honoraria from Medtronic Japan. MS is affiliated with an endowed division supported by BIOTRONIK Japan, Boston Scientific Japan K.K, Medtronic Japan and Abbott Medical Japan. SHi is affiliated with an endowed division supported by BIOTRONIK Japan, Boston Scientific Japan K.K., Medtronic Japan and Abbott Medical Japan. IM received speaker honoraria from Daiichi‐Sankyo and Abbott Medical Japan. RKa received speaker honoraria from Daiichi‐Sankyo and Medtronic Japan, and received research grants from Boston Scientific Japan and Abbott Medical Japan. YIked received speaker honoraria from Bayer Yakuhin and Medtronic Japan. KKa has received research grants from Omron Healthcare Co., Ltd., A&D Co., Ltd., and Fukuda Denshi Co., Ltd. SS is affiliated with an endowed division supported by BIOTRONIK Japan, and received speaker honoraria from Medtronic Japan, Abbott Medical Japan, BIOTRONIK Japan, Boston Scientific Japan, and Japan Lifeline. YKo received speaker honoraria from Daiichi‐Sankyo, Bayer, Abbott Medical Japan, BIOTRONIK Japan, Boston Scientific Japan, Japan Lifeline, and received research funding from Daiichi‐Sankyo. KM has received honoraria for Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, MSD, Kyowa Kirin, Yakult Pharmaceutical, and Boehringer Ingelheim. Other authors have no conflict of interest., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Objectives: Intrapulpal calcifications can occur in the dental pulp of patients with diabetes. We focused on the association between ectopic calcifications in the dental pulp and advanced glycation end products (AGEs) in Spontaneously Diabetic Torii (SDT)-fatty rats, an obese type 2 diabetic rat model, to determine the mechanism of calcification with pulp stone in the dental pulp., Materials and Methods: Pathologic calcification in the dental pulp of SDT-fatty rats was observed using electron microscopy and immunohistochemical analysis. Moreover, mechanical analysis of periapical region of molar tooth against occlusal force was performed., Results: In SDT-fatty rats, pathogenic pulpal calcifications occurred during blood glucose elevation after 6 weeks, and granular calcification was observed in the dental pulp after 11 weeks. Pentosidine, a major AGE, and the receptor for AGEs were strongly expressed in the dental pulp of SDT-fatty rats. S100A8, TNF-α, and IL-6 also showed positive response in the dental pulp of the SDT-fatty rat, which indicated pulpal inflammation. Blood flow disorder and hypoxic dental pulp cells were also observed. In silico simulation, strain from occlusal force concentrates on the root apex., Conclusions: Glycation makes blood vessels fragile, and occlusal forces damage the vessels mechanically. These are factors for intrapulpal calcification of diabetes., (© 2023 Wiley Periodicals LLC.)

Immune checkpoint inhibitors (ICIs) are indicated for a diverse range of cancer types, and characterizing the tumor immune microenvironment is critical for optimizing therapeutic strategies, including ICIs. T cell infiltration and activation status in the tumor microenvironment greatly affects the efficacy of ICIs. Here, we show that semaphorin 6D (Sema6D) forward signaling, which is reportedly involved in coordinating the orientation of cell development and migration as a guidance factor, impaired the infiltration and activation of tumor-specific CD8+ T cells in murine oral tumors. Sema6D expressed by nonhematopoietic cells was responsible for this phenotype. Plexin-A4, a receptor for Sema6D, inhibited T cell infiltration and partially suppressed CD8+ T cell activation and proliferation induced by Sema6D stimulation. Moreover, mouse oral tumors, which are resistant to PD-1-blocking treatment in wild-type mice, showed a response to the treatment in Sema6d-KO mice. Finally, analyses of public data sets of human head and neck squamous cell carcinoma, pan-cancer cohorts, and a retrospective cohort study showed that SEMA6D was mainly expressed by nonhematopoietic cells such as cancer cells, and SEMA6D expression was significantly negatively correlated with CD8A, PDCD1, IFNG, and GZMB expression. Thus, targeting Sema6D forward signaling is a promising option for increasing ICI efficacy.

Chronic rhinosinusitis (CRS) is a persistent inflammatory disease of the nasal cavity and paranasal sinuses. Traditional classification is denoted by the presence (CRSwNP) or absence of nasal polyps (CRSsNP). Particularly, CRSwNP is distinguished by the presence of infiltrating cells and inflammatory markers in the nasal mucosa. Patients with CRSwNP in Western countries predominantly display a type 2 endotype, whereas those in Asian regions display a mixed type 2 endotype. Nevertheless, recent transcriptome analyses have revealed two types of nasal polyps - type 2 and non-type 2 polyps, suggesting that geographical differences in endotypes likely resulted from the different proportions of each endotype. Moreover, various endotypes of CRSsNP have been identified, making phenotype a crucial factor for predicting treatment efficacy. Type 2 endotypes, designated as eosinophilic CRS (ECRS) in Japan, are characterized by severe eosinophilic infiltration into the paranasal sinus tissue and are particularly refractory. In this review, we discuss the latest developments in ECRS. We also provide recent findings on the involvement of nasal epithelial cells in pathogenesis., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

Sweat is an essential protection system for the body, but its failure can result in pathologic conditions, including several skin diseases, such as palmoplantar pustulosis (PPP). As reduced intraepidermal E-cadherin expression in skin lesions was confirmed in PPP skin lesions, a role for interleukin (IL)-1-rich sweat in PPP has been proposed, and IL-1 has been implicated in the altered E-cadherin expression observed in both cultured keratinocytes and mice epidermis. For further investigation, live imaging of sweat perspiration on a mouse toe-pad under two-photon excitation microscopy was performed using a novel fluorescent dye cocktail (which we named JSAC). Finally, intraepidermal vesicle formation which is the main cause of PPP pathogenesis was successfully induced using our "LASER-snipe" technique with JSAC. "LASER-snipe" is a type of laser ablation technique that uses two-photon absorption of fluorescent material to destroy a few acrosyringium cells at a pinpoint location in three-dimensional space of living tissue to cause eccrine sweat leakage. These observatory techniques and this mouse model may be useful not only in live imaging for physiological phenomena in vivo such as PPP pathomechanism investigation, but also for the field of functional physiological morphology., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)