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Mitral valve aneurysm (MVA) is a rare but life-threatening valvular pathologic entity most commonly associated with infective endocarditis (IE) of the aortic valve (AV). We describe a diabetic patient with ruptured anterior MVA secondary to capsular genotype V Streptococcus agalactiae (GBS) harboring novel ST1656 IE without AV involvement. Our patient presented with manifestations of various serious systemic and intracardiac complications, requiring early surgery, but ultimately died from non-cardiogenic causes. This case emphasizes the importance of treating MVA as a dangerous sequela of IE, of performing transesophageal echocardiography to make its accurate diagnosis and institute early surgical intervention, and of considering GBS as a rare but important causative agent of IE in elderly patients with comorbidities.

Maternal high-fat diet (HFD) modulates vascular remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) development. Female wild-type mice were fed an HFD or normal diet (ND). AAA was induced in eight-week-old pups using calcium chloride. Male offspring of HFD-fed dams (O-HFD) showed a significant enlargement in AAA compared with the offspring of ND-fed dams (O-ND). Positive-staining cells for tartrate-resistant acid phosphate (TRAP) and matrix metalloproteinase (MMP) activity were significantly increased in O-HFD. The pharmacological inhibition of osteoclastogenesis abolished the exaggerated AAA development in O-HFD. The in vitro tumor necrosis factor-α-induced osteoclast-like differentiation of bone marrow-derived macrophages showed a higher number of TRAP-positive cells and osteoclast-specific gene expressions in O-HFD. Consistent with an increased expression of nuclear factor of activated T cells 1 (NFATc1) in O-HFD, the nuclear protein expression of interferon regulatory factor 8 (IRF8), a transcriptional repressor, were much lower, with significantly increased H3K27me3 marks at the promoter region. The enhancer of zeste homolog 2 inhibitor treatment restored IRF8 expression, resulting in no difference in NFATc1 and TRAP expressions between the two groups. Our findings demonstrate that maternal HFD augments AAA expansion, accompanied by exaggerated osteoclast-like macrophage accumulation, suggesting the possibility of macrophage skewing via epigenetic reprogramming.

Background We retrospectively analyzed the articulation, mastication, and swallowing function of patients who underwent reconstruction or used a prosthesis after resection of the upper gingiva. Methods This study included patients who underwent resection of cancer of the upper gingiva from January 2014 to December 2018. Articulatory function was evaluated with Hirose’s conversational function evaluation criteria. Mastication function was evaluated with the Yamamoto’s occlusion table. Swallowing function was assessed with the MTF (Method of intake, Time, Food) score. Results The mean articulatory function score was 8 points in the Reconstruction Surgery Group (RSG) and 8.8 points in the Prosthesis Group (PG). The mean mastication function score was 2.8 points in the RSG and 3.3 points in the PG. The mean swallowing function score was M3T4F4 in the RSG and M4T4F4.3 in the PG. Conclusions The prosthesis depends on the remaining occlusal support area. Our study suggest that prosthesis is better indication when there is more than one occlusal support area.

Hypothesis We investigated the treatment effect of intratympanic insulin-like growth factor-1 (IGF-1) on severe facial paralysis in guinea pigs. Background The use of regenerative medicine involving growth factors has been reported in the treatment of peripheral nerve diseases. IGF-1 plays a crucial role in nerve regeneration. Methods We performed the following procedures on guinea pigs. In the normal group (n = 7), no procedure was performed. In the saline (n = 7) and IGF-1 (n = 7) groups, facial paralysis was induced by freezing of the facial canal. Subsequently, in the saline and IGF-1 groups, a gelatin hydrogel impregnated with 100 μL saline and 400 μg/100 μL IGF-1, respectively, was placed in the facial canal. Facial nerve functions were evaluated using three test batteries: facial movement observation, electrophysiological testing, and histological assessment. Results At 10 weeks postoperatively, the facial movement scores for the IGF-1 group were improved compared to those in the saline group. The conductive velocity was significantly faster in the IGF-1 group than in the saline group. There was a significant between-group difference in the nerve fiber number and myelin thickness. Conclusion Intratympanic IGF-1 administration improved facial nerve regeneration. This novel method could provide prompt ambulatory regenerative treatment and reduce the incidence of poor recovery in patients with severe facial paralysis.

Rhabdomyosarcoma (RMS) is a rare, rapidly growing and aggressive malignant neoplasm mainly affecting children. However, mean age at the diagnosis of patients with gingival RMS is 26.9 years. A 12-year-old girl presented to our clinic with a chief complaint of trismus. The examination findings indicated a malignant tumor in the left maxillary gingiva. We performed a biopsy of the tumor, and the histopathological diagnosis was RMS. We report a rare case of primary RMS of the maxillary gingiva in a child patient.

BACKGROUND: In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the “leaky gut,” reportedly contributes to pathologic processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear. METHODS: To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation. RESULTS: MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with K. oxytoca activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under K. oxytoca supernatant or IL-17 stimulation. Treatment with neutralizing anti–IL-17 antibody treatment had renoprotective effects. In contrast, LPS administration accelerated kidney injury in the murine diabetic kidney disease model. CONCLUSIONS: Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.

In this report, we propose a deep learning technique for high-accuracy estimation of the intensity class of a typhoon from a single satellite image, by incorporating meteorological domain knowledge. By using the Visual Geometric Group’s model, VGG-16, with images preprocessed with fisheye distortion, which enhances a typhoon’s eye, eyewall, and cloud distribution, we achieved much higher classification accuracy than that of a previous study, even with sequential-split validation. Through comparison of t-distributed stochastic neighbor embedding (t-SNE) plots for the feature maps of VGG with the original satellite images, we also verified that the fisheye preprocessing facilitated cluster formation, suggesting that our model could successfully extract image features related to the typhoon intensity class. Moreover, gradient-weighted class activation mapping (Grad-CAM) was applied to highlight the eye and the cloud distributions surrounding the eye, which are important regions for intensity classification; the results suggest that our model qualitatively gained a viewpoint similar to that of domain experts. A series of analyses revealed that the data-driven approach using only deep learning has limitations, and the integration of domain knowledge could bring new breakthroughs., 論文

Aspergillus oryzae is a safe microorganism that is commonly used in food production. We constructed a self-cloning vector capable of high expression in A. oryzae. Using the vector, three putative pectin methylesterase (PME) genes belonging to Carbohydrate Esterase family 8 derived from A. oryzae were expressed, and several characteristics of the gene products were examined. The effects of temperature and pH on the three enzymes (AoPME1, 2, and 3) were similar, with optimal reaction temperatures of 50 - 60 °C and optimal reaction pH range of 5 - 6. The specific activities of AoPME1, 2, and 3 for apple pectin were significantly different (34, 7,601, and 2 U/mg, respectively). When the substrate specificity was examined, AoPME1 showed high activity towards pectin derived from soybean and pea. Although AoPME2 showed little activity towards these pectins, it showed very high activity towards apple- and citrus-derived pectins. AoPME3 showed low specific activity towards all substrates tested. Sugar composition analysis revealed that apple- and citrus-derived pectins were rich in homogalacturonan, while soybean- and pea-derived pectins were rich in xylogalacturonan. When pea pectin was treated with endo-polygalacturonase or endo-xylogalacturonase in the presence of each PME, specific synergistic actions were observed (endo-polygalacturonase with AoPME1 or AoPME2 and endo-xylogalacturonase with AoPME1 or AoPME3). Thus, AoPME1 and AoPME3 hydrolyzed the methoxy group in xylogalacturonan. This is the first report of this activity in microbial enzymes. Our findings on the substrate specificity of PMEs should lead to the determination of the distribution of methoxy groups in pectin and the development of new applications in the field of food manufacturing.

It is not feasible to continuously observe ecological succession in lakes because of the long time-scales generally involved. Thus, the process has been inductively deduced by comparing many lakes with different succession states, or indirectly simulated by tracking studies of smaller water bodies, experiments using microcosms or mesocosms, and reconstruction of lake history by sediment analysis. However, the reality of succession processes in large lakes with slow succession is not well understood, and new approaches are needed. Theoretically, in a group of large and small lakes of similar ages and with similar initial and watershed environments, the rate of nutrient accumulation in each lake depends on the ratio of watershed area to lake size, and the lakes are predicted to evolve to different trophic levels over time. Here, we tested this hypothesis on the 10 lakes of varying sizes in Akan Caldera, Japan, which were formed thousands of years ago by fragmentation due to volcanic eruptions within the caldera. Topographic and water quality studies showed that the ratio of accumulated watershed area to lake size (area and volume), expressed logarithmically, had a positive linear regression with the total phosphorus concentration, an indicator of trophic level. The trophic levels of the lakes were diverse, including oligotrophic, mesotrophic, and eutrophic types in the traditional “lake type” classification based on total phosphorus and chlorophyll-a concentrations. Furthermore, 21 species of aquatic macrophytes were observed by a diving survey, and the plant species composition was classified into five groups corresponding to the trophic status of the lakes, indicating a conventional “hydrarch succession”. The diversity of water quality and aquatic vegetation in a group of lakes with similar origins paves the way for new comparative studies of lakes, including large lakes.

ObjectiveRecently, podocytes have been recognised not only as a physical barrier to prevent urinary protein loss but also as producers of proinflammatory cytokines. However, the roles of podocytes in the pathogenesis of lupus nephritis (LN) remain largely unknown. This study aims to determine the roles of suppressor of cytokine signalling (SOCS) family members expressed in glomeruli in the regulation of LN.MethodsWe investigated the expression of SOCS family members in glomeruli in murine lupus model induced by repeated epicutaneous administration of the TLR7/8 agonist imiquimod. We also investigated the roles of SOCS3 expressed in podocytes in the imiquimod-induced glomerulonephritis and systemic autoimmunity by using podocyte-specific SOCS3-deficient mice (podocin-Cre x SOCS3fl/fl mice (SOCS3-cKO mice)). Finally, we investigated the expression of proinflammatory cytokines and chemokines in SOCS3-deficient podocyte cell lines.ResultsqPCR analysis revealed that among SOCS family members, SOCS3 was preferentially induced in glomeruli on epicutaneous administration of imiquimod and that interleukin 6 (IL-6) induced SOCS3 expression in podocyte cell lines. SOCS3-cKO mice exhibited severe glomerulonephritis, high levels of serum creatinine and urine albumin and decreased survival rate compared with control SOCS3-WT mice. Levels of anti-double-strand DNA antibody, SOCS (GC) formation and the numbers of follicular helper T (Tfh) cells and GC B cells in the spleen were higher in SOCS3-cKO mice than those in SOCS3-WT mice. Serum IL-6 levels and expression of IL-6 mRNA in glomeruli were also elevated in SOCS3-cKO mice. IL-6-induced IL-6 expression was enhanced in SOCS3-deficient podocyte cell lines compared with that in SOCS3-sufficient podocyte cell lines.ConclusionSOCS3 expressed in podocytes plays protective roles for the development of glomerulonephritis and inhibits autoantibody production in the imiquimod-induced lupus model presumably by suppressing IL-6 production of podocytes.

Dynamics of rapid changes of intensity and structure in an eyewall replacement cycle of tropical cyclones remain an open question. To clarify the dynamics of the inner eyewall decaying, a quantitative estimation of inner-core wind fields based on highly frequent observation images with 2.5-min temporal resolution in the Himawari-8 satellite is applied to Typhoon Trami (2018) which had a clear concentric eyewall structure. A high tangential wind of 50 m s(-1) is estimated at a radius of 30 km, which is located in the inner edge of the inner eyewall, during an active stage of the inner eyewall. During the decaying stage of the inner eyewall, the estimated tangential wind rapidly decreases to about 20 m s(-1) at a radius of 24 km. The satellite-based tangential winds are validated with dropsondes around the inner core by an aircraft. Vorticity field retrieved by the satellite-based tangential winds during the decaying stage exhibits a rapid decrease in an outer part of the eye and the inner eyewall, and a slow decrease near the storm center. Examination on an absolute angular momentum coordinate indicates that the rapidly slow-down rotation in the outer edge of the eye and inner eyewall is faster than a slow-down rotation explained by surface friction. It suggests that asymmetric eddies transport angular momentum across the moat in the inner eyewall dissipation. This study is the first examination of dynamical contributions of asymmetric eddies to the inner-eyewall dissipation based on satellite-estimated tangential winds. Plain Language Summary Intense tropical cyclones often have the concentric secondary eyewall outside the original (primary) eyewall enclosing the eye (i.e., concentric eyewalls; CEs). The primary eyewall tends to decay after the secondary eyewall formation (i.e., eyewall replacement cycle; ERC). Dynamics of rapid changes of intensity and structure in an ERC remain an open question. To clarify the dynamics of the inner eyewall decaying, a quantitative estimation of tangential winds is applied to Typhoon Trami (2018) with CEs. The estimation is based on tracking of cloud motions associated with the tangential winds, using 2.5-min images in the Himawari-8 satellite. A high tangential wind of 50 m s(-1) is estimated in the inner edge of the inner eyewall in Trami during an active stage of the inner eyewall. During the decaying stage of the inner eyewall, the estimated tangential wind rapidly decreases to about 20 m s(-1) at a radius of 24 km. The satellite-based tangential winds are validated with dropsondes by an aircraft. Our results highlight that the tangential winds during the inner-eyewall decaying stage is mainly decelerated due to eddies superposed on annular cyclonic circulations in the inner eyewall. The process can be best illustrated on an absolute momentum coordinate.

Epilepsy and white matter abnormality have been reported in DYRK1A-related intellectual disability syndrome; however, the clinical course has yet to be elucidated. Here, we report the clinical course of an 18-year-old male with a novel heterozygous DYRK1A variant ({"type":"entrez-nucleotide","attrs":{"text":"NM_001396.4","term_id":"1113820482","term_text":"NM_001396.4"}}NM_001396.4: c.957C>G, p.Tyr319*); based on previous reports, epilepsy with this syndrome tends to be well controlled. Follow-up MRIs of the patient’s lesion revealed slightly reduced signal intensity compared to the first image.

Typhoons are extreme weather phenomena that inflict damages and casualties around globe. These phenomena are difficult to study because of their chaotic behaviour but the capacity to measure their intensity can help mitigate the hazards that they bring. In the past, several attempts have been done to relate typhoon's intensity with the structural evolution of its eye. This suggests the possible relation between the typhoon intensity with typhoon eye altitude. In this research, we visualize Typhoon Trami’s structure by reconstructing the three-dimensional model inside its eye and analyze the information of its cloud top altitude. An experiment was conducted under the SATREPS/ULAT project (SATREPS: Science and Technology Research Partnership for Sustainable Development, ULAT: Understanding Lightning and Thunderstorm) where images of Typhoon Trami were taken from an aircraft last September 26, 2018. Aircraft images were used to reconstruct the 3D model inside the typhoon eye because they provide closer views of the typhoon than that of geostationary satellite images, making it easier to reconstruct a 3D model. The 3D reconstruction generated covers 43 km region of the typhoon eye at 20.2 m/pixel spatial resolution. Three cross-sections of the 3D model were analyzed, and the resulting altitude distribution was compared with the cloud-top altitude estimated by mapping the brightness temperature of the Himawari Thermal Infrared Band 13 with cloud-top height as measured by NOAA sonde data. From the 3D model, the altitude distribution ranges from 5.3 km to 14.3 km which corresponds with the altitude estimated from the brightness temperature of 6.5 km to 14.3 km. However, regions of altitude difference can also be observed between the two methods. This study shows that a three-dimensional model could be a good mode of typhoon visualization as it shows a more detailed typhoon structure such as the stairstep structures that was detected at some regions within the typhoon eye. This research was supported by SATREPS, funded by Japan Science and Technology Agency (JST) / Japan International Cooperation Agency (JICA).

Osteomas are benign tumors characterized by bony growth that commonly occur in the sinuses. Peripheral osteomas in the jawbone are relatively uncommon, with only 8 cases, including the present case, reported in the mandibular sigmoid notch. The patient had a peripheral osteoma that developed from the sigmoid notch of the mandible to the condylar neck. We performed panoramic radiography and computed tomography (CT) for preoperative image analysis, and created a three-dimensional model based on the CT data. Using the model, we were able to explain the lesion to the patient in an easy-to-understand manner. The pathological diagnosis of the resected specimen was peripheral osteoma. At 21 months after the operation, no recurrence has been observed.

The effects of tedizolid (TZD) against multidrug-resistant Mycobacterium tuberculosis isolates were investigated. This is possibly the first study to evaluate the MIC of TZD against Japanese Mycobacterium tuberculosis isolates. As TZD had a significantly lower MIC than LZD (P0.01), it was suggested to be a better, non-toxic alternative to LZD.

This study investigates the causal effects of long-term PM2.5 exposure on COVID-19 deaths, fatality rates and cases in India by using an instrumental variables approach based on thermal inversion episodes. The estimation results indicate that a 1% increase in long-term exposure to PM2.5 leads to an increase in COVID-19 deaths by 5.7 percentage points and an increase in the COVID-19 fatality rate by 0.027 percentage points, but this exposure is not necessarily correlated with COVID-19 cases. People with underlying health conditions such as respiratory illness caused by exposure to air pollution might have a higher risk of death following SARS-CoV-2 infection. This finding might also apply to other countries where high levels of air pollution are a critical issue in terms of development and public health.

Mycobacterium avium subspecies hominissuis (MAH) is a pathogen that causes various non-tuberculous mycobacterial diseases in humans and animals worldwide. Among the genus, MAH is characterized by relatively slow growth. Here, we isolated a rapidly growing variant of the MAH 104 strain. The variant strain (named N104) exhibited an enhanced growth rate and higher motility compared to the parent MAH 104 strain (P104). Whole-genome sequencing analysis of N104 revealed the loss of the stop codon of MAV_RS14660 due to a single nucleotide replacement, resulting in the substitution of the codon for tryptophan. Notably, exclusion of the stop codon ligated the open reading frames and caused the fusion of two adjacent proteins. A revertant parent strain, in which a mutation was introduced to restore the stop codon, revealed that elimination of the stop codon in MAV_RS14660 was responsible for the N104 phenotype. Furthermore, we analysed the phenotypes of the parent and mutated strains by determining the functions of the MAV_RS14660 and MAV_RS14655 coding regions flanking the stop codon. The mutant strains, expected to express a fusion protein, exhibited increased resistance to antimicrobial drugs and exogenous copper toxicity compared to that of the parent strains. These findings suggest that the fusion of the MAV_RS14660- and MAV_RS14655-encoding regions in the mutant N104 strain could be related to the modified functions of these intrinsic proteins.

It is difficult to continuously observe ecological succession processes within lakes occurring over long-time spans. Thus, the process is generally shown as “lake types” or "hydrarch succession" reflected by trophic levels or differing aquatic vegetation, based on inductive inference by comparison of many lakes. Alternatively, long-term changes are simulated via microcosms or mesocosms in experimental systems, or lake history can be reconstructed by sediment analysis. Here, we try to demonstrate lake ecological succession processes over thousands of years by showing an example of lakes with diverse trophic levels and aquatic vegetation which were formed by segmentation inside Akan Caldera in eastern Hokkaido, Japan, due to volcanic eruptions. We found oligotrophic, mesotrophic, eutrophic and dystrophic lake systems in the caldera, despite similar ages and process of origin. Total water phosphorus concentration, defining trophic level, was significantly correlated with the ratio of accumulated watershed area to lake area and volume. Twenty-one species of aquatic macrophytes were classified into five groups clearly corresponding to respective or combinations of trophic level. This study is the first to visualize lake serial stages by documenting a series of trophic levels and associated aquatic vegetation groups as a result of differing eutrophication rates over time.

Background The collagen type IV alpha 1 chain (COL4A1) gene on 13q34 encodes one chain of collagen. COL4A1 mutations have been identified as the cause of a group of multisystemic conditions in humans, including the brain, eyes, kidneys, muscles, and other organs at any age. Brain imaging shows a wide spectrum of abnormalities, including porencephaly, schizencephaly, polymicrogyria focal cortical dysplasia, periventricular leukoencephalopathy, ventricular dysmorphisms, and multiple brain calcifications. However, there are no reports in the literature showing progressive radiological findings in consecutive follow-up scans. Herein, we report three cases of COL4A1 mutations with porencephaly from gestation to five years of age or longer, and describe their clinical and brain imaging findings. Case reports: We retrospectively reviewed the clinical symptoms and radiological findings, including brain magnetic resonance imaging (MRI) and computed tomography (CT), in three female patients with COL4A1 mutations. Their mutations were c.4843G>A (p.Glu1615Lys), c.1835G>A (p.Gly612Asp), and c.3556+1G>T respectively. All the three cases represented porencephaly in the fetal period; severe hemolytic anemia in the neonatal period; and drug-resistant epilepsy, global developmental delay, and spastic quadriplegia in their childhood. Results Brain MRI and CT showed progressive white matter atrophy from gestation to five-year follow-up or later. Minor cerebral hemorrhage without symptoms occasionally occurred in one patient. Despite brain changes, the clinical picture was stable during early childhood. Conclusions COL4A1 mutations may cause progressive cerebral atrophy beyond early childhood.

Background Mycobacterium abscessus subsp. abscessus (M. abscessus) is a rapidly growing mycobacterium that is resistant to most antibiotics. The number of patients with pulmonary disease caused by M. abscessus is increasing in several regions, and therapy involves long-term antibiotic combination treatments, although no standard treatment regimen has been established. Objectives To examine candidate regimens for maintenance of antimicrobial treatment against M. abscessus by measuring MIC using the three-drug chequerboard method. Methods We evaluated the drug susceptibility of 70 clinical isolates of M. abscessus using the three-drug chequerboard method. We tested the antimycobacterial agents bedaquiline, clofazimine, amikacin, and sitafloxacin (which showed a relatively low MIC range when used as single agents) alone and in combinations. Results The three-drug combinations of bedaquiline/clofazimine/amikacin, and bedaquiline/clofazimine/sitafloxacin were studied. Among isolates for which the fractional inhibitory concentration index (FICI) could be calculated, 29/70 isolates (41%) and 11/70 isolates (16%) showed a synergistic response (FICI ≤0.75) with combined use of bedaquiline/clofazimine/amikacin, or with bedaquiline/clofazimine/sitafloxacin, respectively. Conclusions The combination of bedaquiline with clofazimine plus either amikacin or sitafloxacin may be useful as maintenance regimens when treating pulmonary disease caused by M. abscessus.

Background: Although chyle leakage may occur in the neck when the thoracic duct is damaged during cervical dissection, it is extremely rare for the chylothorax alone to leak chyle into the thoracic cavity. Case presentation: We report a case of bilateral chylothorax without chyle cervical leakage after left neck dissection, wherein partial left upper jaw resection and left radical neck dissection were performed in a 46-year-old woman who was diagnosed with left upper gingival cancer. The thoracic duct was ligated and cut during surgery and, although no obvious leakage of lymph was observed, dyspnea and cough reflex during deep inhalation were observed from the 3rd postoperative day. Approximately 600 mL of yellowish-white pleural effusion was aspirated during bilateral thoracentesis, and chylothorax was diagnosed based on clinical findings and biochemical analysis results. The patient was put on a low-fat diet on the 4th postoperative day, and a total of 3 neck drains were removed 8 days after the operation. Conclusions: Pleural effusion disappeared on imaging examination 16 days after thoracentesis and 5 years and 6 months have passed since the operation. At this time, there has been no evidence of tumor recurrence, metastasis, or pleural effusion.

The Coronavirus disease 2019 (COVID‐19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J‐SSCG) 2020 Special Committee created the Japanese Rapid/Living recommendations on drug management for COVID‐19 using the experience of creating the J‐SSCGs. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on September 9, 2020, and this document is the revised edition (ver. 3.1) (released on March 30, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ‐2), hydroxychloroquine (CQ‐3), corticosteroids (CQ‐4), tocilizumab (CQ‐5), ciclesonide (CQ‐6), and anticoagulants (CQ‐7). Favipiravir is recommended for patients with mild COVID‐19 not requiring supplemental oxygen (GRADE 2C); remdesivir for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization (GRADE 2B); hydroxychloroquine is not recommended for all COVID‐19 patients (GRADE 1B); corticosteroids are recommended for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization (GRADE 1B) and severe COVID‐19 patients requiring ventilator management/intensive care (GRADE 1A); however, their administration is not recommended for mild COVID‐19 patients not requiring supplemental oxygen (GRADE 1B); tocilizumab is recommended for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization (GRADE 2B); and anticoagulant therapy for moderate COVID‐19 patients requiring supplemental oxygen/hospitalization and severe COVID‐19 patients requiring ventilator management/intensive care (GRADE 2C). We hope that these clinical practice guidelines will aid medical professionals involved in the care of COVID‐19 patients.

To clarify the applicability of the Gurson-Tvergaard-Needleman (GTN) model for impact ductile fracture behaviour, SHB test was reproduced by finite element analysis (FEA). The strain-rate dependence of the strength for austenitic stainless steel JIS SUS304L was obtained by tensile tests at quasi-static strain rate and impact strain rate. The CowperSymonds power law, which takes into the strain-rate dependence of strength, and the GTN model implemented in the commercial FEA code were used to simulate for impact ductile-fracture behaviour. GTN model parameters were determined by minimizing the difference between the simulated and measured stress-strain curve using response surface method. SHB test was simulated using GTN model obtained from quasi-static tensile test result. Simulation results did not occur the necking and fracture on the specimen. The fracture surfaces were observed by SEM micrograph. The appearance of ductile fracture since dimples are observed, regardless of the strain rate. It is necessary to adjust the parameter to accelerate the nucleation of the void. By identifying the GTN parameters in consideration of the strain rate dependence including impact strain rate. It would be possible to improve the simulation accuracy of impact ductile fracture behaviour.

Steel is widely used as a constituent material for various structures such as automobiles and ships. To perform high precision analysis including high strain rate behavior, an understanding for the strain rate dependence of material strength becomes very important. The purpose of this study is to evaluate the strain rate dependence of material strength with rolled steels for welded structure, JIS SM490B (ASTM E). We investigated the deformation characteristics at room temperature by performing compression tests at a wide range of strain rates and applied the obtained experimental results to the material constitutive model using an optimization method of Nelder-Mead method. The quasi-static tests were conducted using a universal testing machine at the strain rate of 10-3, 10-2 and 10-1 s-1. The impact test was conducted using a split Hopkinson pressure bar apparatus at the strain rate of approximately 103 s-1. As the results of the compression tests, it was confirmed that SM490B has a positive strain rate dependence of material strength. The Cowper-Symonds constitutive model showed good agreement with the experimental results up to the strain of 20%. However, the error became larger between experimental results and CS approximation as the strain increases to 20% or more.

In this study, we conducted experiments to analyze how different materials used in the pickguard affect the sound quality of electric guitars with the goal of establishing the design and production guidelines for the manufacturing of pickguards. First, we tested pickguards made of different materials; the difference in sound quality of each attached pickguard was compared with the conventional plastic pickguard. The material of the pickguard that we selected for further testing was copper with a thickness of 1.0 mm. Next, the vibrational characteristics of the pickguard and its effect on the sound quality was investigated. Finally, we examined the vibrational characteristics of the pickguard when each guitar string was played. Based on these experiments, it was determined that a metal pickguard caused the sound to decay quicker; moreover, it resulted in a sharper tone. In addition, the output voltage of each string and, indirectly, the vibrational characteristics of each string varied when using a metal pickguard. In conclusion, it was determined that the sound quality is affected by the vibrational characteristics; these can be adjusted by varying the means by which the pickguard is attached to the guitar body.

This study evaluated the interfacial adhesive strength between aluminium alloy and epoxy resin (Al/epoxy resin) over a wide range of strain rates (loading rates). We conducted three types of tests with different loading rate, i.e., a quasi-static tensile test for the range of lower loading rate, a Split Hopkinson Bar (SHB) for the range of middle loading rate, and Laser Shock Adhesion Test (LaSAT) for the range of higher loading rate. LaSAT is a unique test of adhesion evaluation, since laser induced shock wave is employed to lead interfacial fracture. In parallel, finite element method (FEM) is conducted in order to calculate stress distribution at the interface during LaSAT. As a result, it was found that the interface between the aluminium alloy and the epoxy resin interface shows significant loading rate dependency of the adhesion strength and this tendency is very similar to that of bulk epoxy materials.

Mycobacterium avium subspecies hominissuis (MAH) is a pathogen that causes various non-tuberculous mycobacterial diseases in humans and animals worldwide. Among the genus, MAH is characterized by relatively slow growth. Here, we isolated a rapidly growing variant of the MAH 104 strain. The variant strain (named N104) exhibited an enhanced growth rate and higher motility compared to the parent MAH 104 strain (P104). Whole-genome sequencing analysis of N104 revealed the loss of the stop codon of MAV_RS14660 due to a single nucleotide replacement, resulting in the substitution of the codon for tryptophan. Notably, exclusion of the stop codon ligated the open reading frames and caused the fusion of two adjacent proteins. A revertant parent strain, in which a mutation was introduced to restore the stop codon, revealed that elimination of the stop codon in MAV_RS14660 was responsible for the N104 phenotype. Furthermore, we analysed the phenotypes of the parent and mutated strains by determining the functions of the MAV_RS14660 and MAV_RS14655 coding regions flanking the stop codon. The mutant strains, expected to express a fusion protein, exhibited increased resistance to antimicrobial drugs and exogenous copper toxicity compared to that of the parent strains. These findings suggest that the fusion of the MAV_RS14660- and MAV_RS14655-encoding regions in the mutant N104 strain could be related to the modified functions of these intrinsic proteins.

Objectives X-linked hypophosphatemic rickets (XLH) is a congenital fibroblast growth factor (FGF)23-related metabolic bone disease that is treated with active vitamin D and phosphate as conventional therapies. Complications of these therapies include nephrocalcinosis (NC) caused by excessive urine calcium and phosphate concentrations. Recently, an anti-FGF23 antibody, burosumab, was developed and reported to be effective in poorly-controlled or severe XLH patients. This study aimed to reveal the impact of switching treatments in relatively well-controlled XLH children with the Rickets Severity Scale less than 2.0. Methods The effects of the two treatments in eight relatively well-controlled XLH children with a mean age of 10.4 ± 1.9 years were compared retrospectively for the same treatment duration (31 ± 11 months) before and after the baseline. Results Actual doses of alfacalcidol and phosphate as conventional therapy were 150.9 ± 43.9 ng/kg and 27.5 ± 6.3 mg/kg per day, respectively. Renal echography revealed spotty NC in 8/8 patients, but no aggravation of NC was detected by switching treatments. Switching treatments increased TmP/GFR (p=0.002) and %TRP (p Conclusions Our results suggest that a high dose of alfacalcidol was needed to control the disease, but it caused hypercalciuria and NC. We concluded that switching treatments in relatively well-controlled XLH children improved renal phosphate reabsorption and decreased urine calcium extraction, and may have the potential to prevent NC.

The destruction caused by ballistic ejecta from the phreatic eruptions of Mt. Ontake in 2014 and Mt. Kusatsu-Shirane (Mt. Moto-Shirane) in 2018 in Japan, which resulted in numerous casualties, highlighted the need for better evacuation facilities. In response, some mountain huts were reinforced with aramid fabric to convert them into shelters. However, a number of decisions must be made when working to increase the number of shelters, which depend on the location where they are to be built. In this study, we propose a method of using high-strength steel to reinforce wooden buildings for use as shelters. More specifically, assuming that ballistic ejecta has an impact energy of 9 kJ or more, as in previous studies, we developed a method that utilizes SUS304 and SS400 unprocessed steel plates based on existing impact test data. We found that SUS304 is particularly suitable for use as a reinforcing material because it has excellent impact energy absorption characteristics due to its high ductility as well as excellent corrosion resistance. With the aim of increasing the structural strength of steel shelters, we also conducted an impact test on a shelter fabricated from SS400 deck plates (i.e., steel with improved flexural strength provided by work-hardened trapezoidal corrugated plates). The results show that the shelter could withstand impact with an energy of 13.5 kJ (2.66 kg of simulated ballistic ejecta at 101 m/s on impact). In addition, from the result of the impact test using the roof-simulating structure, it was confirmed the impact absorption energy is further increased when artificial pumice as an additional protective layer installed on this structure. Observations of the shelter after the impact test show that there is still some allowance for deformation caused by projectile impact, which means that the proposed steel shelter holds promise, not only structurally, but also from the aspects of transportation and assembly. Hence, the usefulness of shelters that use steel was shown experimentally. However, shelter construction should be suitable for the target environment.

Background and Objective: Depression is an independent risk factor of cardiovascular disease and significantly associated with the prevalence of abdominal aortic aneurysm (AAA). We investigated the impact of repeated social defeat (RSD) on AAA formation. Methods and Results: Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same cage without physical contact. After social interaction test to confirm depressive-like behaviors, mice underwent application of 0.5M calcium chloride (CaCl 2 ) on the infrarenal aorta. At one-week, maximum diameter and circumference of external elastic membrane were comparable between the two groups. The number of F-4/80 and MMP-9-positive cells in immunofluorescent images were also comparable. Consistently, fluorescent image taken by IVIS revealed no difference in MMP activity, suggesting that acute inflammatory response was comparable between the two groups. In contrast, at two weeks, maximum diameter and circumference of external elastic membrane were significantly increased in defeated mice ( p < 0.01). Intriguingly, periaortic fibrotic area in aneurysmal portion was markedly decreased in defeated mice (12.5х10 3 μm 2 vs. 3.7х10 3 μm 2 , Control vs. Defeat, p < 0.01). Consistently, accumulation of α-SMA-positive cells in adventitia of aneurysmal portion was much lesser in defeated mice (876 cells/mm 2 vs. 319 cells/mm 2 , Control vs. Defeat, p < 0.05), whereas those in tunica media of non-aneurysmal portion did not show any difference between the two groups. LPS-induced iNOS gene and protein expressions in bone marrow-derived macrophages (BMDMs) were significantly decreased in defeated mice, whereas the TGF-β-induced phosphorylation of Smad2 and ERK1/2 in primary cultured aortic VSMCs were comparable between the two groups. Conclusions: Our findings demonstrate that RSD enhances AAA expansion by suppressing the periaortic fibrosis following inflammatory response, and suggest that decreased NO production from accumulated macrophages contributes to the reduced VSMCs proliferation and collagen deposition.

Background and Objective: Depression is an independent risk factor of cardiovascular disease (CVD). We have recently shown that repeated social defeat (RSD) exaggerates atherosclerosis development by enhancing neutrophil extracellular traps (NETs) formation. Here, we investigated the impact of RSD on arterial thrombosis. Methods and Results: Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same gage without physical contact. After social interaction test to confirm depressive-like behaviors, defeated mice (19 of 31) and control mice (12 of 14) were underwent arterial injury at 10 wks of age. A filter paper saturated with 10% FeCl3 was applied on the adventitial surface of left carotid artery for 3 min and analyzed 3 hrs later. The volume of thrombi was comparable between the two groups. However, fibrinogen/fibrin-positive areas in immunofluorescent images significantly increased in defeated mice (48.8% vs. 27.8%, p < 0.01). The number of Ly-6G-positive cells in thrombi was markedly higher in defeated mice (878/mm2 vs. 144/mm2, p < 0.05). Further, Ly-6G-positive cells were co-localized with neutrophil elastase, Cit-H3, and CD42b-positive staining. Percentage of CD42b-positive area in thrombi and in vitro platelets aggregations induced by ADP or collagen were comparable between the two groups. Treatment with DNase I completely diminished the exaggerated fibrin-rich clot formation in defeated mice to an extent similar to that in control mice (22.3% vs. 25.7%, p = ns), although the number of Ly-6G-positive cells in thrombi was not affected. We therefore examined the vulnerability to NETs formation induced by thrombin-activated platelets. Flow cytometric analysis showed that in vitro NETs formation assessed by Cit-H3/MPO double-positive cells was significantly higher in defeated mice (20.7% vs 12.5%, p < 0.01). Conclusions: Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NETs formation via platelet-neutrophil interactions, suggesting that NETosis could be a new therapeutic target in depression-related CVD development.

Background and objective Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Atherosclerotic vascular calcification is closely associated with the onset of cardiovascular event. We therefore investigated the impact of maternal HFD on calcification of atherogenic plaques. Methods and results Eight-week-old female apo-E−/− mice (C57BL/6) were fed an HFD or a normal diet (ND) one week prior to mating, and the diet was continued throughout gestation and lactation. Offspring of both groups were fed a high-cholesterol diet (HCD) from 8 weeks of age. Ex vivo osteogenic activity of aortic root and aortic arch was analyzed using in vivo imaging system (IVIS) with OsteoSense 680. Sixteen-week-old male offspring of HFD-fed dams (O-HFD) showed a 1.4-fold increase in fluorescent intensity compared with those of ND-fed dams (O-ND) (p Conclusion Our findings demonstrate that maternal HFD accelerates the development of atherogenic calcification independent of plaque size. In vitro transformation to osteochondrocytic-like cells is enhanced in VSMCs from offspring of HFD-fed dams. Inhibition of VSMCs skewing toward osteochondrocytic-like cells could be a potential therapeutic target for preventing the development of atherosclerotic vascular calcification. Funding Acknowledgement Type of funding source: None

A recent study proposed the novel classification of the family Mycobacteriaceae based on the genome analysis of core proteins in 150 Mycobacterium species. The results from these analyses supported the existence of five distinct monophyletic groups within the genus Mycobacterium. That is, Mycobacterium has been divided into two novel genera for rapid grower Mycobacteroides and Mycolicibacterium, and into three genera for slow grower Mycolicibacter, Mycolicibacillus, and an emended genus Mycobacterium, which include all the major human pathogens. Here, cryo-TEM examinations of 1,816 cells of 31 species (34 strains) belonging to the five novel genera were performed. The fundamental morphological properties of every single cell, such as cell diameter, cell length, cell perimeter, cell circularity, and aspect ratio were measured and compared between these genera. In 50 comparisons on the five parameters between any two genera, only five comparisons showed “non-significant” differences. That is, there are non-significant differences between slow grower genus Mycolicibacillus and genus Mycobacterium in average cell diameter (p = 0.15), between rapid grower genus Mycobacteroides and slow grower genus Mycobacterium in average cell length (p > 0.24), between genus Mycobacteroides and genus Mycobacterium (p > 0.68) and between genus Mycolicibacter and genus Mycolicibacillus (p > 0.11) in average cell perimeter, and between genus Mycolicibacterium and genus Mycobacterium in circularity (p > 0.73). The other 45 comparisons showed significant differences between the genera. Genus Mycobacteroides showed the longest average cell diameter, whereas the genus Mycolicibacter showed the shortest average diameter. Genus Mycolicibacterium showed the most extended average cell length, perimeter, and aspect ratio, whereas the genus Mycolicibacillus showed the shortest average cell length, perimeter, and aspect ratio. Genus Mycolicibacillus showed the highest average cell circularity, whereas genus Mycobacterium showed the lowest average cell circularity. These fundamental morphological data strongly support the new classification in the family Mycobacteriaceae, and this classification is rational and effective in the study of the members of the family Mycobacteriaceae. Because both the genus Mycolicibacterium and the genus Mycobacterium contain many species and showed larger significant standard deviations in every parameter, these genera may be divided into novel genera which show common genotype and phenotypes in morphology and pathogenicity.

Background and purpose In acute coronary syndrome (ACS) patients, major cardiovascular events during follow-up were equally attributable to recurrence at the site of culprit lesions and to non-culprit lesions, and mostly occurred within one year. Recent studies showed that Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor significantly reduces the risk of cardiovascular events. However, the rigorous effects of PCSK9 inhibitor in patients with ACS, especially for the stabilization of plaque in the non-culprit lesions has not been identified. The purpose of this study was to evaluate the efficacy of a PCSK9 inhibitor for the plaque stabilization in the non-culprit lesion of ACS patients. Methods We retrospectively analyzed the 10 ACS patients (STEMI:5 cases, NSTEMI:1 case, and UAP:4 cases) who had non-culprit lesions and were injected with a PCSK9 inhibitor. We analyzed 11 non-culprit lesions before and after PSCK9 injections by using a near-infrared intravascular ultrasonography (NIRS-IVUS). Results The follow up intervals were 229.4±82.9 days. Major cardiovascular events did not occur in all patients. The serum low-density lipoprotein (LDL) cholesterol levels were significantly decreased form 128±36.7 mg/dl to 26.7±7.4 mg/dl (P Conclusion This study suggested that the plaque morphology can be altered by the aggressive lipid lowering therapy by using a PCSK9 inhibitor, and NIRS-IVUS can detect these plaque stabilizations of non-culprit lesion in ACS patients. The authors have no financial conflicts of interest to disclose concerning the presentation. Figure 1 Funding Acknowledgement Type of funding source: None

Background and objective Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) formation. Methods and results Eight-week-old female wild-type mice (C57BL/6) were fed a HFD or normal diet (ND) one week prior to mating, and the diet was continued throughout gestation and lactation. In eight-week-old male offspring, AAA was induced with the application of 0.5 M calcium chloride (CaCl2) on the infrarenal aorta. Offspring of HFD-fed dams (O-HFD) showed a significant increase in maximum outer diameter of AAA at 1, 4 and 8 weeks after surgery compared with offspring of ND-fed dams (O-ND). The lengths of outer circumference assessed by histological analysis were increased in O-HFD (p Conclusion Our findings demonstrate that maternal HFD accelerates CaCl2-induced AAA expansion, accompanied by the exaggerated accumulation of osteoclast-like macrophages and augmented activity of MMPs. Inhibition of macrophages skewing toward osteoclast-like cells could be a potential therapeutic target for preventing AAA development. Funding Acknowledgement Type of funding source: None

Background and objective Depression is an independent risk factor of cardiovascular disease (CVD) and significantly associated with the prevalence of abdominal aortic aneurysm (AAA). We have recently shown that repeated social defeat (RSD) precipitates depressive-like behaviors in apoE−/− mice and exaggerates atherosclerosis development by enhancing leukocyte activation. Here, we investigated the impact of RSD on AAA formation. Methods and results Eight-week-old male WT mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. Control mice were housed in the same gage without physical contact. After social interaction test to confirm depressive-like behaviors, defeated mice (28 of 48) and control mice (31 of 36) underwent application of 0.5 M calcium chloride (CaCl2) on the infrarenal aorta to induce AAA. At 1 week after application, maximum diameter and circumference of external elastic membrane were comparable between the two groups. The number of F-4/80, MMP-9, and TNF-α-positive cells in immunofluorescent images were also comparable. Further, in vitro bone marrow derived macrophages stimulation by LPS did not show any difference in mRNA expression levels of inflammatory cytokines, suggesting no discernable difference in acute inflammatory response between the two groups. In contrast, at 2 weeks after application, at the time point when MMP-9 and TNF-α-positive cells were scarcely observed, maximum diameter and circumference of external elastic membrane were significantly increased in defeated mice (0.72 mm vs. 0.90 mm, 1.59 mm vs. 2.00 mm, respectively, Control vs. Defeat, p Conclusions Our findings demonstrate for the first time that RSD enhances AAA expansion by eliminating periaortic fibrosis in tissue repair phase, suggesting that the impaired resolution of acute inflammation after CaCl2 application contributes, at least in part, to the augmented expansion of AAA in defeated mice. Funding Acknowledgement Type of funding source: None