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Background. The aquaculture industry is driven by the need to develop novel interspecific hybrids with improved culture characteristics, however currently no molecular markers are available for the validation of F1 hybrids in the case of groupers. The presently reported study was directed toward the development of molecular markers for F1 hybrids obtained by artificial spawning of eggs derived from orange-spotted grouper, Epinephelus coioides (Hamilton, 1822), with sperm from giant grouper, E. lanceolatus (Bloch, 1790). Materials and methods. DNA was extracted and purified from the fin clip of a single F1 hybrid of E. coioides × E. lanceolatus. Small insert shotgun genomics libraries were constructed, 40 positive transformants were sequenced, and the sequences deposited at the GenBank. Thirty locus-specific primer pairs were designed and tested across 64 F1 hybrid specimens as well as DNA samples extracted from coral grouper, Epinephelus corallicola (Valenciennes, 1828), and brown-marbled grouper, E. fuscoguttatus (Forsskål, 1775). Results. A panel of thirty molecular markers was developed to verify parentage, of these eleven and six of the markers were inherited from the sire and dam respectively. Two markers were specific to the F1 hybrid and none of the markers could be assigned to the closely related groupers E. corallicola and E. fuscoguttatus. Conclusion. The markers developed can be applied to assign parentage and determine the degree of introgression in interspecific grouper hybrids developed from E. coioides and E. lanceolatus. The methods developed in this study can be extended to characterize Quantitative Trait Loci (QTLs) and to identify interspecific F1 hybrids in the wild.

Background: Contrast extravasation ("blush") on contrast-enhanced computed tomography (CECT) indicates active bleeding, but diagnostic angiography (AG) following CECT sometimes differs from the CECT findings in patients with pelvic fractures. This study aimed to evaluate the concordance rate between blush on CECT and AG based on pelvic anatomical location., Methods: This retrospective single-center study included patients (18 years or older) with pelvic fractures between 2015 and 2023 who had AG after CECT. Angiography was performed in patients with blush or hematoma on CECT, or unstable hemodynamics due to pelvic fracture. Pelvic bleeding regions were categorized separately into left and right as anterior internal iliac artery and posterior internal iliac artery based on pelvic arterial anatomy. The concordance rate between blush on CECT and AG was assessed using the k statistic., Results: A total of 87 patients with pelvic fractures were included. Among these, 75 (86%) had blush on CECT, and 12 (14%) had no blush on CECT. The concordance rate was 83% (95% confidence interval, 0.03-0.57; k = 0.30) when assessed on an individual patient basis and 53% (95% confidence interval, 0.24-0.44; k = 0.34) when evaluated by anatomical regions on a unilateral half of the pelvis. The concordance rate for the anatomical hemipelvis evaluation was significantly lower compared with the individual evaluation ( p < 0.001). Thirty-three percent of patients with unilateral blush on CECT showed new contralateral blushes during AG., Conclusion: The location of active bleeding often differs between CECT and AG, indicating that bleeding may change intermittently and at various sites over time. This suggests the importance of evaluating both sides of the pelvic arteries during AG rather than solely relying on CECT findings., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 American Association for the Surgery of Trauma.)

Background: There are cases of idiopathic interstitial pneumonias (IIPs) that do not meet the diagnostic criteria for connective tissue disease but have clinical features suggestive of autoimmune process. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept for these patients. Although several prospective studies on IPAF have been conducted, its clinical significance in cryptogenic organizing pneumonia (COP) remains unclear. Methods : Patients aged ≥20 years with suspected COP were prospectively enrolled between June 2018 and December 2022. Among the enrolled patients, those diagnosed with COP based on computed tomography (CT) and bronchoalveolar lavage (BAL) findings were compared between the IPAF and non-IPAF groups. Results : A total of 56 patients were enrolled in this study. Of these, 30 were diagnosed with COP and included in the analysis. Clinical and serological features were positive in two and six patients, respectively. Each feature was exclusive, and eight patients (26.7%) were diagnosed with IPAF. There were no differences between the IPAF and non-IPAF groups in terms of clinical features, including BAL findings, laboratory data, CT findings, and clinical course. During the one-year follow-up period, the frequency of COP exacerbation did not differ between the IPAF and non-IPAF groups, and no cases of systemic autoimmune disease or death occurred in either group. Conclusions : The COP characteristics of the IPAF and non-IPAF groups are similar in all aspects, and distinguishing between the two groups may be of little significance.

Background: Because exacerbation of severe asthma decreases patients' quality of life, this study aimed to identify predictive factors for asthma exacerbation., Methods: Japanese patients with severe asthma requiring treatment according to the Global Initiative for Asthma (GINA) guidelines ≥ Step 4 between January 2018 and August 2021 were prospectively enrolled and followed up for one year at facilities participating in the Okayama Respiratory Disease Study Group (Okayama Severe Asthma Research Program)., Results: A total of 85 patients (29 men and 56 women) were included. The median age was 64 (interquartile range [IQR], 51-72) years. Treatment according to GINA Steps 4 and 5 was required in 29 and 56 patients, respectively, and 44 patients (51.8%) were treated with biologics. The median peripheral-blood eosinophil count, fractional exhaled nitric oxide, IgE level, and percent predicted FEV 1 (%FEV 1 ) at enrollment were 204 (IQR, 49-436)/μL, 28 (IQR, 15-43) ppb, 172 (IQR, 56-473) IU/mL, and 80.0 (IQR, 61.1-96.1) %, respectively. Exacerbation during the previous year, asthma control test (ACT) score <20, %FEV 1 <60%, and serum IL-10 level >6.7 pg/mL were associated with exacerbation during the observation period., Conclusions: Exacerbation during the previous year, low ACT score, and low %FEV 1 were predictive factors of future exacerbation, even in a cohort with >50% of patients treated with biologics. Furthermore, high serum IL-10 levels might be a new predictive factor., Competing Interests: Declaration of competing interest HH has received grants from Novartis Pharma K.K., outside the submitted work. AK received speaker fees from AstraZeneca K.K., GlaxoSmithKline K.K., Novartis Pharma K.K., and Sanofi K.K., NM received speaker fees from AstraZeneca K.K., Boehringer Ingelheim K.K., GlaxoSmithKline K.K., Novartis Pharma K.K., and Sanofi K.K.. The rest of the authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Owing to the miniaturization of diagnostic ultrasound scanners and their spread of their bedside use, ultrasonography has been actively utilized in emergency situations. Ultrasonography performed by medical personnel with focused approaches at the bedside for clinical decision-making and improving the quality of invasive procedures is now called point-of-care ultrasonography (POCUS). The concept of POCUS has spread worldwide; however, in Japan, formal clinical guidance concerning POCUS is lacking, except for the application of focused assessment with sonography for trauma (FAST) and ultrasound-guided central venous cannulation. The Committee for the Promotion of POCUS in the Japanese Association for Acute Medicine (JAAM) has often discussed improving the quality of acute care using POCUS, and the "Clinical Guidance for Emergency and Point-of-Care Ultrasonography" was finally established with the endorsement of JAAM. The background, targets for acute care physicians, rationale based on published articles, and integrated application were mentioned in this guidance. The core points include the fundamental principles of ultrasound, airway, chest, cardiac, abdominal, and deep venous ultrasound, ultrasound-guided procedures, and the usage of ultrasound based on symptoms. Additional points, which are currently being considered as potential core points in the future, have also been widely mentioned. This guidance describes the overview and future direction of ultrasonography for acute care physicians and can be utilized for emergency ultrasound education. We hope this guidance will contribute to the effective use of ultrasonography in acute care settings in Japan., Competing Interests: Dr. Akio Kimura is an Editorial Board member of AMS Journal and a co‐author of this article. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication. The Japanese version of this paper was published in the July 2022 issue of the Journal of the Japanese Association for Acute Medicine (JJAAM). The authors have obtained permission for the secondary publication of the English version of the editors of the JJAAM., (© 2024 The Author(s). Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Filamentous fungi produce numerous industrially important enzymes. Among them, Aspergillus oryzae-derived enzymes are widely used in various fermentation applications. In this study, we constructed self-cloning strains that overproduce multiple biomass-degrading enzymes under the control of a strong promoter of α-amylase-coding gene (amyB) using the industrial strain A. oryzae AOK11. Two strains (strains 2-4 and 3-26) were introduced with different combinations of genes encoding xylanase (xynG1), phytase (phyA), pectin lyase (pelA), and polygalacturonase (pgaB). These strains had at least one copy of each enzyme gene derived from the expression cassette in the genome. The transcription levels of enzyme-coding genes introduced were more than 100-fold higher than those in the parent strain. Reflecting the high transcription levels, the activities of the enzymes derived from the expression cassettes of these two strains were significantly higher than those of the parent strain in both liquid and solid-state cultures. Even in ventilated solid-state cultures that were scaled up using mechanical equipment for practical applications, the two strains showed significantly higher enzyme activity than the parent strain. These results indicate that these strains constructed using a safe self-cloning technique represent industrially valuable practical strains that can be used in the food and livestock industries., (Copyright © 2023 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Objective: Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality., Methods: Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome., Results: Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not., Conclusion: A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population., Competing Interests: K.M. have received personal fees from Nippon Shinyaku Co td and AstraZeneca. N.T. have received grants and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer-Ingelheim Japan, and Ono Pharmaceutical; grants from Kyowa Hakko Kirin, Nippon Kayaku Co. Ltd., and Takeda Pharmaceutical Co. Ltd.; and personal fees from MSD and Bristol-Myers Squibb Company Japan outside the submitted work. None declared (S.S., R. S., J. I., G. K., T. K., T. T., K. K., T. K., Y. N., H. H., D. H., N. M.) This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Miyake 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.)

The endocardial anchoring technique is a novel modification of total anomalous pulmonary venous return repair that involves creation of an L-shaped flap of the pulmonary venous confluence, subsequently anchoring it to the endocardium. A wide and smooth pathway can be expected from the theoretical advantages of this technique, namely, a smooth inner surface of the anchored flap and traction force to extend the orifice of the connection. An application of this technique for a rare variant of supracardiac total anomalous pulmonary venous return suggests its potential to be an alternative to the conventional repair, especially in patients with a curved pulmonary venous confluence., (© 2024 The Author(s).)

Fibrosis of the lung can occur in idiopathic pulmonary fibrosis, collagen vascular diseases, and hypersensitivity pneumonitis, among other diseases. Transforming growth factor (TGF)-β, vascular epithelial growth factor, fibroblast growth factor, and platelet-derived growth factor contribute to the pathophysiology of fibrosis. TGF-β and other cytokines, including interleukin (IL)-1β, IL-6, and IL-23, activate type-17 immunity, which is involved in pulmonary fibrosis. The components of type-17 immunity include type-17 helper T cells, γδT cells, IL-17A-producing CD8-positive T cells, invariant NKT cells, and group 3 innate lymphoid cells. IL-17A, the main cytokine of type-17 immunity, is able to induce the epithelial-mesenchymal transition in epithelial cells via a production of TGF-β, directly stimulate fibroblasts and fibrocytes, and inhibit autophagy, which otherwise protects against pulmonary fibrosis. IL-23 induces type-17 immunity and plays an important role in the acute exacerbation of pulmonary fibrosis. Clinical studies have also linked type-17 immunity to the pathogenesis of pulmonary fibrosis. Consequently, targeting type-17 immunity may serve as a new therapeutic strategy to prevent the development or exacerbation of pulmonary fibrosis., Competing Interests: Conflict of Interest Satoru Senoo, Hisao Higo, and Akihiko Taniguchi have no conflict of interest. Katsuyuki Kiura reports lecture fees from MSD K.K. outside of the submitted work. Katsuyuki Kiura also reports grants from Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Bristol-Myers Squibb K.K. outside of the submitted work. Yoshinobu Maeda reports lecture fees from Novartis Pharma K.K. outside of the submitted work. Yoshinobu Maeda also reports grants from Novartis Pharma K·K./AstraZeneca K·K./Astellas Pharma/Chugai Pharmaceutical Co., Ltd./Nippon Shinyaku Co., Ltd./Otsuka Pharmaceutical Co., Ltd./Eisai Co., Ltd./Chugai Pharmaceutical Co., Ltd./Nippon Shinyaku Co., Ltd./Takeda Pharmaceutical Company Limited/Kyowa Kirin Co., Ltd./Astellas Pharma outside of the submitted work. Nobuaki Miyahara reports grants from Novartis Pharma K·K, AstraZeneca K·K., Boehringer Ingelheim Co., Ltd., and GlaxoSmithKline Pharmaceuticals Co., Ltd./ROHTO Pharmaceutical Co., Ltd. outside of the submitted work., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Dupilumab is a fully humanized monoclonal antibody that blocks interleukin-4 and interleukin-13 signals. Several large clinical trials have demonstrated the efficacy of dupilumab in patients with severe asthma. However, few studies have examined a switch to dupilumab from other biologics., Methods: This retrospective, multi-center observational study was conducted by the Okayama Respiratory Disease Study Group. Consecutive patients with severe asthma who were switched to dupilumab from other biologics without a treatment interval between May 2019 and September 2021 were enrolled. Patients with a treatment interval of more than twice the standard dosing interval for the previous biologic prior to dupilumab administration were excluded., Results: The median patient age of the 27 patients enrolled in this study was 57 years (IQR, 45-68 years). Eosinophilic chronic rhinosinusitis (ECRS)/chronic rhinosinusitis with nasal polyp (CRSwNP) was confirmed in 23 patients. Previous biologics consisted of omalizumab (n = 3), mepolizumab (n = 3), and benralizumab (n = 21). Dupilumab significantly improved FEV 1 (median improvement: +145 mL) and the asthma control test score (median improvement: +2). The overall response rate in patients receiving dupilumab for asthma as determined using the Global Evaluations of Treatment Effectiveness (GETE) was 77.8%. There were no significant differences in the baseline characteristics of the GETE-improved group vs. the non-GETE-improved group. ECRS/CRSwNP improved in 20 of the 23 patients (87.0%). Overall, 8 of the 27 patients (29.6%) developed transient hypereosinophilia (>1500/μL), but all were asymptomatic and able to continue dupilumab therapy., Conclusions: Dupilumab was highly effective for the treatment of severe asthma and ECRS/CRSwNP, even in patients switched from other biologics without a treatment interval.

Background: Older individuals increasingly require emergency abdominal surgeries. They are susceptible to surgical stress and loss of independence in performing daily activities. We hypothesized that the psoas muscle volume would be significantly associated with postoperative functional decline (FD) in older patients undergoing emergency abdominal surgery and aimed to evaluate the use of the psoas muscle volume on computed tomography (CT) scans., Methods: A retrospective, single-center study of patients aged ≥ 65 years who had undergone emergency abdominal surgery between January 2019 and June 2021 was performed. We assessed patients' activities of daily living using the Barthel Index. FD was defined as a ≥ 5-point decrease between preoperative and 28-day postoperative values. The psoas muscle volume was measured by CT, which was used for diagnosis, and normalized by height to calculate total psoas muscle index (TPI). We evaluated associations between FD and TPI using receiver operating characteristics (ROC) analysis and multiple logistic regression analysis., Results: Of 238 eligible patients, 71 (29.8%) had clinical postoperative FD. Compared to the non-FD group, the FD group was significantly older and had a higher proportion of females, higher Charlson Comorbidity Index, lower body mass index, higher American Society of Anesthesiology score, lower serum albumin level, and lower TPI. ROC analyses revealed that TPI had the highest area under the curve (0.802; 95% confidence interval [CI], 0.75-0.86). A multivariable logistic regression model revealed that low TPI was an independent predictor of postoperative FD (odds ratio, 0.14; 95% CI, 0.06-0.32)., Conclusions: TPI can predict postoperative FD due to emergency abdominal surgery. Identification of patients who are at high risk of FD before surgery may be useful for enhancing the regionalized system of care for emergency general surgery., (© 2023. The Author(s).)

Neuropeptide Y (NPY), a 36 amino acid residue polypeptide distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of NPY on pulmonary fibrosis. NPY-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine concentrations, and morphological morphometry of the lungs were analyzed. Serum NPY concentrations were also measured in patients with idiopathic pulmonary fibrosis and healthy control subjects. NPY-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1β concentrations in the lungs compared with wild-type mice. Exogenous NPY treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1β concentrations in the lungs. Moreover, IL-1β neutralization in NPY-deficient mice attenuated the fibrotic changes. NPY decreased IL-1β release, and Y1 receptor antagonists inhibited IL-1β release and induced epithelial-mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower NPY and greater IL-1β concentrations in the serums compared with healthy control subjects. NPY expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that NPY plays a protective role against pulmonary fibrosis by suppressing IL-1β release, and manipulating the NPY-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression.

Anti-asparaginyl transfer RNA (tRNA) synthetase (KS) antibodies, detected in <5% patients with anti-aminoacyl-tRNA synthetase antibody syndrome, are strongly associated with interstitial pneumonia but not myositis and skin symptoms. A recent report suggested that most patients with interstitial pneumonia and anti-KS antibody (KS-ILD) may present with chronic disease. We herein report a rare case of severe acute respiratory failure in a KS-ILD patient requiring extracorporeal membrane oxygenation (ECMO). ECMO is useful for facilitating not only lung rest until recovery but also the definitive diagnosis and treatment of ILD. KS-ILD can develop acutely with fulminant respiratory failure, as observed in this case.

Robust and automated image segmentation in high-throughput image-based plant phenotyping has received considerable attention in the last decade. The possibility of this approach has not been well studied due to the time-consuming manual segmentation and lack of appropriate datasets. Segmenting images of greenhouse and open-field grown crops from the background is a challenging task linked to various factors such as complex background (presence of humans, equipment, devices, and machinery for crop management practices), environmental conditions (humidity, cloudy/sunny, fog, rain), occlusion, low-contrast and variability in crops and pose over time. This paper presents a new ubiquitous deep learning architecture ThelR547v1 (Thermal RGB 547 layers version 1) that segmented each pixel as crop or crop canopy from the background (non-crop) in real time by abstracting multi-scale contextual information with reduced memory cost. By evaluating over 37,328 augmented images (aug1: thermal RGB and RGB), our method achieves mean IoU of 0.94 and 0.87 for leaves and background and mean Bf scores of 0.93 and 0.86, respectively. ThelR547v1 has a training accuracy of 96.27%, a training loss of 0.09, a validation accuracy of 96.15%, and a validation loss of 0.10. Qualitative analysis further shows that despite the low resolution of training data, ThelR547v1 successfully distinguishes leaf/canopy pixels from complex and noisy background pixels, enabling it to be used for real-time semantic segmentation of horticultural crops.

Neuropeptide Y (NPY) is a neuropeptide widely expressed in not only the central nervous system but also immune cells and the respiratory epithelium. Patients with chronic obstructive pulmonary disease (COPD) reportedly exhibit decreased NPY expression in the airway epithelium, but the involvement of NPY in the pathophysiology of COPD has not been defined. We investigated the role of NPY in elastase-induced emphysema. NPY-deficient (NPY -/- ) mice and wild-type (NPY +/+ ) mice received intratracheal instillation of porcine pancreas elastase (PPE). The numbers of inflammatory cells and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates were determined along with quantitative morphometry of lung sections. Intratracheal instillation of PPE induced emphysematous changes and increased NPY levels in the lungs. Compared with NPY +/+ mice, NPY -/- mice had significantly enhanced PPE-induced emphysematous changes and alveolar enlargement. Neutrophilia seen in BAL fluid of NPY +/+ mice on day 4 after PPE instillation was also enhanced in NPY -/- mice, and the enhancement was associated with increased levels of neutrophil-related and macrophage-related chemokines and IL-17A as well as increased numbers of type 3 innate lymphoid cells in the airways. Treatment with NPY significantly reduced PPE-induced emphysematous changes. Conversely, treatment with a NPY receptor antagonist exacerbated PPE-induced emphysematous changes. These observations indicate that NPY has protective effects against elastase-induced emphysema and suggest that targeting NPY in emphysema has potential as a therapeutic strategy for delaying disease progression.

Aim: Limited information exists on the factors associated with prolonged procedural time in embolization for trauma patients. We clarified the clinical application of embolization in trauma patients and factors associated with a prolonged procedure time., Methods: Medical records of 162 trauma patients who underwent embolization between January 2007 and December 2020 at a regional trauma care center were reviewed retrospectively. Patients were divided into four embolized body regions: chest, abdomen, pelvis, and other. Patient demographics, trauma mechanism, physiology, trauma severity, embolization procedures, and 30-day mortality were examined. The outcomes were identifying an embolized body region, embolized arteries, and procedure time. Multiple regression model was created to investigate the factors associated with prolonged procedural time in embolization., Results: Embolization was mainly undertaken in pelvic fractures ( n  = 96, 59%) and abdominal organ injuries ( n  = 57, 35%) and extended to the chest ( n  = 17, 10%), and other ( n  = 20, 12%). Approximately 13% ( n  = 21) of patients underwent embolization in two or more regions. Embolization was more strictly performed in minor artery injuries, for example, external iliac ( n  = 15, 16%) and lumbar artery ( n  = 22, 23%) branches in pelvic fractures, and inferior phrenic artery ( n  = 2, 3.5%) branches in liver injuries. Multiple regression model indicated that the number of embolized arteries ( P  = 0.021) and number of embolized regions ( P  < 0.001) were associated with prolonged procedural time in embolization., Conclusions: Embolization for trauma patients extended to various trauma regions. In time-sensitive embolization, emergency interventional radiologists showed superior knowledge of expected embolizing arteries and factors associated with procedure time., (© 2022 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF)., Methods: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC)., Results: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions., Conclusions: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF., (© 2022. The Author(s).)

Acute exacerbation of idiopathic pulmonary fibrosis has a poor prognosis associated with neutrophilic inflammation. Interleukin-23 is a proinflammatory cytokine involved in neutrophilic inflammation. However, little is known about its role in acute exacerbation of pulmonary fibrosis. This study was performed to determine the role of interleukin-23 in acute exacerbation of pulmonary fibrosis. For assessment of acute exacerbation of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Inflammatory cells, cytokine levels, and morphological morphometry of the lungs were analyzed. Cytokine levels were measured in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients with or without acute exacerbation. Interleukin-23, -17A, and -22 levels were increased in the airway of mice with acute exacerbation of pulmonary fibrosis. Interleukin-23p19-deficient mice with acute exacerbation of pulmonary fibrosis had markedly reduced airway inflammation and fibrosis associated with decreased levels of interleukin-17A and -22 compared with wild-type mice. Treatment with an anti-interleukin-23 antibody attenuated airway inflammation and fibrosis and reduced interleukin-17A and -22 levels in mice with acute exacerbation of pulmonary fibrosis. T-helper type 17 cells were the predominant source of interleukin-17A in mice with acute exacerbation of pulmonary fibrosis. Interleukin-23 levels in bronchoalveolar lavage fluid tended to be higher in idiopathic pulmonary fibrosis patients with than without acute exacerbation. The data presented here suggest that interleukin-23 is essential for the development of acute exacerbation of pulmonary fibrosis and that blockade of interleukin-23 may be a new therapeutic strategy for acute exacerbation of pulmonary fibrosis.

Mucinous cystic neoplasm (MCN) of the pancreas is a rare cystic tumor occurring in the pancreatic body and tail in young to middle-aged women that is pathologically characterized by an ovarian-like stroma. Chemotherapy for recurrent/advanced pancreatic MCN has been based on chemotherapy regimens for pancreatic ductal adenocarcinoma, but the prognosis is poor. We herein report a 37-year-old woman with pancreatic mucinous cystadenocarcinoma with liver metastasis that responded dramatically to carboplatin plus paclitaxel therapy (CBDCA+PTX). CBDCA+PTX may be a treatment option for recurrent/advanced pancreatic MCN with an ovarian-like stroma.

Background: IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear., Methods: We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33 -/- mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again., Results: Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33 -/- mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33 -/- and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33 -/- mice than WT mice. IL-33 -/- mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE., Conclusion: These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor ( EGFR ), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult., (Copyright © 2020, Spandidos Publications.)

Quercetin is a flavonol that is known to have numerous beneficial biological effects such as an anti-fibrotic effect. Epithelial-mesenchymal transition (EMT) of alveolar type II epithelial cells is one of major causes of pulmonary fibrosis. However, the effect of quercetin on drug-induced EMT in alveolar type II cells is not known. In this study, we examined the effect of quercetin on bleomycin (BLM)-induced EMT using RLE/Abca3 cells having alveolar type II cell-like phenotype. BLM induced EMT-like morphological changes, downregulation of an epithelial marker E-cadherin, and upregulation of a mesenchymal marker α-smooth muscle actin in RLE/Abca3 cells. In addition, BLM increased the levels of phosphorylated Smad2 and Slug mRNA expression, and enhanced nuclear translocation of β-catenin, suggesting that BLM induced EMT in RLE/Abca3 cells via Smad and β-catenin signaling pathways. However, when the cells were co-treated with quercetin, quercetin suppressed all of these EMT-related changes induced by BLM. Furthermore, BLM increased the intracellular level of reactive oxygen species, which was also suppressed by quercetin. These results suggest that quercetin may be a possible candidate for preventing pulmonary fibrosis caused by drugs., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%., Methods: This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months., Results: 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib., Conclusions: Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment., Competing Interests: Takuo Shibayama has received research funding from Nippon Boeringer Ingerheim Co., Ltd. Kanehiro Arihiko has received honoria from Nippon Boeringer Ingerheim Co., Ltd. Katsuyuki Kiura has received research funding and donation from Nippon Boeringer Ingerheim Co., Ltd. The other authors have nothing to declare.