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Haruhiko Nishida,1 Katsuko Onishi,1 Satoshi Kurose,1 Hiromi Tsutsumi,1 Takumi Miyauchi,2 Nana Takao,2 Sawako Yoshiuchi,2 Aya Fujii,2 Yutaka Kimura1,2 1Department of Health Science, Kansai Medical University, Osaka, Japan; 2Health Science Center, Kansai Medical University, Osaka, JapanCorrespondence: Haruhiko NishidaDepartment of Health Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, JapanTel +81 72 804 2334Fax +81 72 804 2548Email nishidah@hirakata.kmu.ac.jpObjective: DNA methylation is an epigenetic mechanism that regulates gene expression. The obesity-related (FTO) gene is the first gene found to be associated with fat mass and obesity. However, no studies have examined the relationship between weight-loss intervention effect and FTO methylation in obese individuals with whole blood DNA. The purpose of this study was to quantify FTO whole blood DNA methylation and investigate the relationship between body composition, exercise capacity, and blood parameters with a 6-month weight-loss program intervention.Participants and Methods: Eighteen female participants (mean age, 50.6 ± 12.1 years, body mass index (BMI), 33.5 ± 6.2 kg/m2) who completed a 6-month weight-loss program at the obesity outpatient department at the Health Science Center of Kansai Medical University Hospital from March 2017 to October 2018 were included in the analysis. Participants were randomized into a normal treatment group (NTG) and a group with additional resistance training (RTG). Body composition, exercise tolerance and metabolic index were measured in each participant. DNA methylation status in whole blood samples was determined using pyrosequencing. All measurements were taken during the first visit and at the 6-month post-intervention visit.Results: The methylation rate was significantly decreased in the NTG in CpG1 (p=0.011) and total value of CpG (p=0.011), whereas in the treatment group containing resistance training (RTG), CpG3 (p=0.038) was increased significantly. Furthermore, the independent factors that determine %CpG3 of RTG were visceral fat area change rate (%VFA) (β = − 0.568, P = 0.007, R2 = 0.527) and resistance training (β = 0.517, P = 0.012, R2 = 0.527), which have been extracted.Conclusion: A 6-month weight-loss program, including resistance training, may be associated with decreased visceral fat area changes and increased RTG CpG3 methylation changes. However, further replication studies with larger sample sizes are warranted to verify the findings of this study.Keywords: epigenetics, obesity, body composition, resistance training

ObjectiveThe purpose of this study was to predict the four cold–heat patterns in patients who have the subjective symptoms of the cold–heat pattern described in the International Classification of Diseases Traditional Medicine Conditions – Module 1 by applying a machine learning algorithm.MethodsSubjects were first-visit Kampo outpatients at six institutions who agreed to participate in this multicenter prospective observational study. The cold pattern model and the heat pattern model were created separately with 148 symptoms, body mass index, blood pressure (systolic and diastolic), age, and sex. Along with a single cold or heat pattern, the tangled heat/cold pattern is defined as being predicted by both cold and heat patterns, while the moderate (heat/cold) pattern is defined as being predicted by neither the cold pattern nor the heat pattern.ResultsWe included 622 participants (mean age ±standard deviation, 54.4 ± 16.9; with female 501). The accuracy, macro-recall, precision, and F1-score of a combination of the two prediction models were 96.7%, 93.2%, 85.6%, and 88.5% respectively. The important items were compatible with the definitions of the cold–heat pattern.ConclusionWe developed a prediction model on cold–heat patterns with data from patients whose subjective cold/heat-related symptoms matched the cold–heat pattern diagnosis by the physician.

We previously reported that a high HbA1c level 3 months before vitrectomy for vitreous hemorrhage or a large preoperative decrease in the HbA1c level over 3 months tended to increase the risk of rebleeding in diabetic retinopathy patients evaluated between 2010 and 2014. Here, we aimed to confirm these results with an extended study period and an increased number of operated eyes. This study included 121 diabetic patients who were admitted to Osaka University Hospital between 2010 and 2019 and who underwent vitrectomy for vitreous hemorrhage. Binomial logistic regression analysis was performed with the presence of postoperative bleeding as the outcome. The present study showed that the duration of the operation was associated with rebleeding (odds ratio = 1.02, p = 0.0016). A high HbA1c level just before vitrectomy tended to be associated with the bleeding (odds ratio = 1.27, p = 0.05), while preoperative HbA1c changes were not associated with rebleeding. The results of this study suggest that a high preoperative HbA1c level just before vitrectomy, not a decrease in HbA1c levels, in addition to the duration of the operation may increase the risk of postoperative bleeding after vitrectomy in diabetic retinopathy patients.

Abstract Background The relationship between plasma tenofovir (TFV) concentration at the beginning of tenofovir disoproxil fumarate (TDF) administration and the development of renal dysfunction during long-term administration of TDF has not been demonstrated yet. The objective of the present study was to determine whether plasma TFV trough concentrations during early TDF administration could serve as an indicator of renal dysfunction when TDF is administered for long periods. Methods We included 149 HIV-1 infected Japanese patients who were prescribed TDF. We investigated the relationship between plasma TFV trough concentrations and the rate of discontinuation due to the development of renal dysfunction for up to five years after the start of TDF administration. We also examined how the decrease in renal function over time due to TDF administration was related to factors associated with high TFV levels and plasma TFV trough concentrations. Results The median TFV trough concentration in the TDF discontinuation group was 88 ng/mL, which was significantly higher (p = 0.0041), than that in the continuation group (72 ng/mL). Further, using an ROC curve, the cut-off value for TFV trough concentration at which TDF discontinuation was significantly high was found to be 98 ng/mL. Logistic multivariate analysis of factors associated with discontinuation of TDF due to renal function-related adverse events showed that being ≥ 50 years old (OR = 2.96; 95% CI, 1.01–8.64), having eGFR

Abstract Developing a safe and potent repellent of mosquitoes applicable to human skins is an effective measure against the spread of mosquito-borne diseases. Recently, we have identified that hydrophobic solutions such as low viscosity polydimethylsiloxane (L-PDMS) spread on a human skin prevent mosquitoes from staying on and biting it. This is likely due to the ability of L-PDMS in wetting mosquito legs and exerting a capillary force from which the mosquitoes attempt to escape. Here we show three additional functions of L-PDMS that can contribute to repel Aedes albopictus, by combining physicochemical analysis and behavioral assays in both an arm cage and a virtual flight arena. First, L-PDMS, when mixed with topical repellents and applied on a human skin, enhances the effect of topical repellents in reducing mosquito bites by efficiently transferring them to mosquito legs upon contact. Second, L-PDMS applied to mosquito tarsi compromises visual object tracking during flight, exerting an influence outlasting the contact. Finally, L-PDMS applied to mosquito tarsi acts as an aversive reinforcer in associative learning, making mosquitoes avoid the conditioned odor. These results uncover a multifaceted potential of L-PDMS in altering a sequence of mosquito behaviors from biting a human skin, visual object tracking following takeoff, to the response to an odor linked with L-PDMS.

Abstract Optogenetics enables precise regulation of intracellular signaling in target cells. However, the application of optogenetics to induce the differentiation of precursor cells and generate mature cells with specific functions has not yet been fully explored. Here, we focused on osteoclasts, which play an important role in bone remodeling, to develop a novel optogenetics tool, Opto-RANK, which can manipulate intracellular signals involved in osteoclast differentiation and maturation using blue light. We engineered Opto-RANK variants, Opto-RANKc and Opto-RANKm, and generated stable cell lines through retroviral transduction. Differentiation was induced by blue light, and various assays were conducted for functional analysis. Osteoclast precursor cells expressing Opto-RANK differentiated into multinucleated giant cells on light exposure and displayed upregulation of genes normally induced in differentiated osteoclasts. Furthermore, the differentiated cells exhibited bone-resorbing activities, with the possibility of spatial control of the resorption by targeted light illumination. These results suggested that Opto-RANK cells differentiated by light possess the features of osteoclasts, both morphological and functional. Thus, Opto-RANK should be useful for detailed spatiotemporal analysis of intracellular signaling during osteoclast differentiation and the development of new therapies for various bone diseases.

Abstract Background The sarcomatous variant of carcinoma is relatively rare in intrahepatic cholangiocarcinoma (ICC). Sarcomatous ICC (SICC) is associated with a poorer prognosis compared with ICC. SICC is rarely diagnosed before surgery due to non-descriptive findings; it progresses rapidly, resulting in miserable prognosis. Here, we report a case of rapidly progressing SICC that showed a clinically significant tumor growth rate. Case presentation A 77-year-old woman who had undergone ileocecal resection for cecal cancer 5 years previously was found to have elevated levels of the tumor marker carbohydrate antigen 19-9. Although an abdominal computed tomography (CT) scan did not detect any liver mass lesions until 3 months before this serum examination, the subsequent CT scan revealed a hypodensity 20 mm mass lesion in the right anterior section. Contrast-enhanced CT and magnetic resonance imaging revealed peripheral enhancement in the arterial-to-equilibrium phase. Fluorodeoxyglucose positron emission tomography revealed uptake in the lesion. None of the imaging modalities showed lymph node swelling or distant metastases. She underwent hepatectomy under the diagnosis of ICC or an atypical metastasis from previous cecal cancer. Although preoperative images showed no suspicious lymph node metastasis 3 weeks prior, the hilar lymph node swelled 3 cm and contained adenocarcinoma. Consequently, the patient underwent right anterior sectionectomy and lymph node dissection of the hepatoduodenal ligament. Histopathological examination revealed that the liver tumor was a poorly differentiated adenocarcinoma with sarcomatous pattern. While the patient received adjuvant gemcitabine and S-1 therapy, lymph node metastasis appeared in the mediastinum 13 months after the surgery. She received gemcitabine + cisplatin + S-1 therapy but died 20 months after surgery. Conclusion SICC and lymph node metastasis clinically appeared within 3 months and 3 weeks, respectively. Suspected ICC that rapidly progresses should be considered SICC and treated with early resection. SICC is often missed in clinical diagnosis and has a poor prognosis, even after curative resection. While an alternative strategy involving preoperative biopsy and neoadjuvant therapy may be beneficial, it should be approached with discretion due to the potential risks of tumor progression and peritoneal dissemination.

Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is a chronic disease that can rapidly deteriorate into circulatory collapse when complicated by comorbidities. We herein describe a case involving a 43‐year‐old woman with class III obesity (body mass index of 63 kg/m2) and severe CTEPH associated with total occlusion of the left main pulmonary artery who subsequently developed circulatory collapse along with multiple comorbidities, including acute kidney injury, pulmonary tuberculosis, and catastrophic antiphospholipid syndrome. The patient was successfully treated with two sessions of rescue balloon pulmonary angioplasty with veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support under local anesthesia without sedation, at cannulation and during the V‐A ECMO run, to avoid invasive mechanical ventilation. This case suggests the potential usefulness of rescue balloon pulmonary angioplasty under awake V‐A ECMO support for rapidly deteriorating, inoperable CTEPH in a patient with class III obesity complicated with multiple comorbidities.

Abstract The mechanisms of impaired glucose-induced insulin secretion from the pancreatic β-cells in obesity have not yet been completely elucidated. Here, we aimed to assess the effects of adipocyte-derived factors on the functioning of pancreatic β-cells. We prepared a conditioned medium using 3T3-L1 cell culture supernatant collected at day eight (D8CM) and then exposed the rat pancreatic β-cell line, INS-1D. We found that D8CM suppressed insulin secretion in INS-1D cells due to reduced intracellular calcium levels. This was mediated by the induction of a negative regulator of insulin secretion—NECAB1. LC–MS/MS analysis results revealed that D8CM possessed steroid hormones (cortisol, corticosterone, and cortisone). INS-1D cell exposure to cortisol or corticosterone increased Necab1 mRNA expression and significantly reduced insulin secretion. The increased expression of Necab1 and reduced insulin secretion effects from exposure to these hormones were completely abolished by inhibition of the glucocorticoid receptor (GR). NECAB1 expression was also increased in the pancreatic islets of db/db mice. We demonstrated that the upregulation of NECAB1 was dependent on GR activation, and that binding of the GR to the upstream regions of Necab1 was essential for this effect. NECAB1 may play a novel role in the adipoinsular axis and could be potentially involved in the pathophysiology of obesity-related diabetes mellitus.

Abstract The adeno-associated virus (AAV) is a potent vector for in vivo gene transduction and local therapeutic applications of AAVs, such as for skin ulcers, are expected. Localization of gene expression is important for the safety and efficiency of genetic therapies. We hypothesized that gene expression could be localized by designing biomaterials using poly(ethylene glycol) (PEG) as a carrier. Here we show one of the designed PEG carriers effectively localized gene expression on the ulcer surface and reduced off-target effects in the deep skin layer and the liver, as a representative organ to assess distant off-target effects, using a mouse skin ulcer model. The dissolution dynamics resulted in localization of the AAV gene transduction. The designed PEG carrier may be useful for in vivo gene therapies using AAVs, especially for localized expression.

Allyl isothiocyanate (AITC) activates transient receptor potential ankyrin 1 (TRPA1) channel, which is involved in the control of intestinal mucosal blood flow. However, the mechanism underlying the increased gastric mucosal blood flow (GMBF) in response to AITC remains unknown. We examined the effect of AITC on GMBF in the ex vivo stomachs of normal and sensory deafferented rats using a laser Doppler flowmeter. Mucosal application of AITC increased GMBF in a concentration-dependent manner. Repeated AITC exposure resulted in a marked desensitization. The increased GMBF response induced by AITC was entirely blocked by co-application of TRPA1 channel blockers HC-030031 or AP-18. Increased GMBF in response to AITC was significantly attenuated by chemical deafferentation following systemic capsaicin injections (total dose: 100 mg/kg). In contrast, increased GMBF responses to capsaicin, a transient receptor potential vanilloid 1 (TRPV1) activator, were completely abolished by chemical deafferentation. The increased GMBF response to AITC was markedly inhibited by BIBN 4096, a calcitonin gene-related peptide receptor (CGRP) antagonist, or AGP-8412, an adrenomedullin receptor antagonist. These results suggest that AITC-stimulated TRPA1 activation results in the increased GMBF through the release of CGRP and adrenomedullin.

Highlights We examined whether maximum body mass index (BMI) before the onset of diabetes (MBBO) affects histological findings of islet cells. We divided patients into two groups according to an MBBO cutoff of 25 kg/m2 or BMI cutoff of 21 kg/m2. We compared immunohistochemical parameters between the MBBO groups or BMI groups. The relative alpha‐cell area in the high MBBO group was significantly higher than that in the low MBBO group. There was no difference in the other parameters between the MBBO groups or BMI groups.

Abstract Mosquitoes carry lethal pathogens for humans and hundreds of thousands of people are killed by mosquito-borne diseases every year. Therefore, controlling mosquitoes is essential to protect the lives of people around the world. Insecticides are highly effective in controlling mosquitoes and have been used extensively worldwide. However, they have potentially harmful effects on biodiversity and environment, and some mosquitoes are resistant to insecticide ingredients and survive upon their application. Therefore, there is a demand for a method to control mosquitoes without using conventional insecticide ingredients. Here, we used Aedes albopictus to test whether solutions with low surface tension, particularly surfactant solutions can alter mosquito behavior by spreading over the hydrophobic cuticle of mosquitoes. We found that solutions with low surface tension indeed attached to mosquitoes flying or resting on the wall, and made them fall. In addition, solutions with yet lower surface tension covered the mosquito surface more quickly and widely, knocking down or killing mosquitoes. These results suggest that surfactants such as sodium dioctyl sulfosuccinate can be used to alter mosquito behavior without relying on conventional insecticides.

Our proposed ranking model ranks conversation partners based on self-reported rapport levels for each participant. The model is important for tasks that recommend interaction partners based on user rapport built in past interactions, such as matchmaking between a student and a teacher in one-to-one online language classes. To rank conversation partners, we can use a regression model that predicts rapport ratings. It is, however, challenging to learn the mapping from the participants’ behavior to their associated rapport ratings because a subjective scale for rapport ratings may vary across different participants. Hence, we propose a ranking model trained via preference learning (PL). The model avoids the subjective scale bias because the model is trained to predict ordinal relations between two conversation partners based on rapport ratings reported by the same participant. The input of the model is multimodal (acoustic and linguistic) features extracted from two participants’ behaviors in an interaction. Since there is no publicly available dataset for validating the ranking model, we created a new dataset composed of online dyadic (person-to-person) interactions between a participant and several different conversation partners. We compare the ranking model trained via preference learning with the regression model by using evaluation metrics for the ranking. The experimental results show that preference learning is a more suitable approach for ranking conversation partners. Furthermore, we investigate the effect of each modality and the different stages of rapport development on the ranking performance.

To automate operations in a logistic warehouse, a robot needs to extract items from the clutter on a shelf without collapsing the clutter. To address this problem, this study proposes a multi-step motion planner to stably extract an item by using the support relations of each object included in the clutter. This study primarily focuses on safe extraction, which allows the robot to choose the best next action based on limited observations. By estimating the support relations, we construct a collapse prediction graph to obtain the appropriate order of object extraction. Thus, the target object can be extracted without collapsing the pile. Furthermore, we show that the efficiency of the robot is improved if it uses one of its arms to extract the target object while the other supports a neighboring object. The proposed method is evaluated in real-world experiments on detecting support relations and object extraction tasks. This study makes a significant contribution because the experimental results indicate that the robot can estimate support relations based on collapse predictions and perform safe extraction in real environments. Our multi-step extraction plan ensures both better performance and robustness to achieve safe object extraction tasks from the clutter.

Abstract Sjögren's syndrome (SS) is an autoimmune disease characterized by dry mouth. The cause of SS is unknown, and its diverse symptoms make diagnosis difficult. The Saxon test, an intraoral examination, is used as the primary diagnostic method for SS, however, the risk of salivary infection is problematic. Therefore, we investigate the possibility of diagnosing SS by non-contact and imaging observation of the tongue surface. In this study, we obtained tongue photographs of 60 patients at the Tsurumi University School of Dentistry outpatient clinic to clarify the relationship between the features of the tongue and SS. We divided the tongue into four regions, and the color of each region was transformed into CIE1976L*a*b* space and statistically analyzed. To clarify experimentally the possibility of SS diagnosis using tongue color, we employed three machine-learning models: logistic regression, support vector machine, and random forest. In addition, we constructed diagnostic prediction models based on the Bagging and Stacking methods combined with three machine-learning models for comparative evaluation. This analysis used dimensionality compression by principal component analysis to eliminate redundancy in tongue color information. We found a significant difference between the a* value of the rear part of the tongue and the b* value of the middle part of the tongue in SS and non-SS patients. In addition to the principal component scores of tongue color, the support vector machine was trained using age, and achieved high accuracy (71.3%) and specificity (78.1%). The results indicate that the prediction of SS diagnosis by tongue color reaches a level comparable to machine learning models trained using the Saxon test. This is the first study using machine learning to predict SS diagnosis by non-contact tongue observation. Our proposed method can potentially support early SS detection simply and conveniently, eliminating the risk of infection at diagnosis, and it should be validated and optimized in clinical practice.

Abstract Background Primary spontaneous pneumothorax occasionally relapses, even after bullectomy; therefore, coverage of the bullectomy staple line for pleural reinforcement is common in Japan. However, the appropriate covering materials have not yet been determined. Methods This was a longitudinal prospective cohort study. Data were available for patients aged

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor–deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

BackgroundResearch on early psychosis has begun to identify psychiatric characteristics of the prodromal period of schizophrenia; however, subclinical characteristics of children in non-psychiatric fields have not been fully investigated. In our previous study, we developed the Child Psychosis-risk Screening System (CPSS).ObjectiveIn the present cross-sectional study, we attempted to identify the risk of developing psychosis in pediatric (n = 216) and psychiatric outpatients (n = 120), aged 6– 18 years, with the CPSS.MethodsAn analysis of variance of CPSS risk was performed in six diagnostic categories to examine specificity for each diagnosis. Receiver operating characteristic (ROC) curve analysis was conducted using the onset of schizophrenia spectrum as the outcome, and the discriminatory power and cut off values of the CPSS were determined. Logistic regression analysis was performed using clinical data to identify factors associated with the risk group (those at high risk of developing psychosis in the future) identified using the CPSS.ResultsThere were significant differences in risk variance among diagnostic categories (p

AimsThe excess deposition of intra-pancreatic fat deposition (IPFD) has been reported to be associated with type 2 diabetes, chronic pancreatitis, and pancreatic ductal adenocarcinoma. In the current study, we aimed to identify a relationship between lifestyle factors and IPFD.Materials and methods99 patients admitted to the Osaka University Hospital who had undergone abdominal computed tomography were selected. We evaluated the mean computed tomography values of the pancreas and spleen and then calculated IPFD score. Multiple regression analyses were used to assess the associations between IPFD score and lifestyle factors.ResultsFast eating speed, late-night eating, and early morning awakening were significantly associated with a high IPFD score after adjusting for age, sex, diabetes status and Body Mass Index (p=0.04, 0.01, 0.01, respectively).ConclusionThe current study has elucidated the significant associations of fast eating speed, late-night eating, and early morning awakening with IPFD.

Determining the inner structure of the molecular torus around an active galactic nucleus is essential for understanding its formation mechanism. However, spatially resolving the torus is difficult because of its small size. To probe the clump conditions in the torus, we therefore perform the systematic velocity-decomposition analyses of the gaseous ^12 CO rovibrational absorption lines ( v = 0 → 1, Δ J = ±1) at λ ∼ 4.67 μ m observed toward four (ultra)luminous infrared galaxies using the high-resolution ( R ∼ 5000–10,000) spectroscopy from the Subaru Telescope. We find that each transition has two to five distinct velocity components with different line-of-sight (LOS) velocities ( V _LOS ∼ −240 to +100 km s ^−1 ) and dispersions ( σ _V ∼ 15–190 km s ^−1 ), i.e., the components (a), (b), ⋯, beginning with the broadest one in each target, indicating that the tori have clumpy structures. By assuming a hydrostatic disk ( ${\sigma }_{V}\propto {R}_{\mathrm{rot}}^{-0.5}$ ), we find that the tori has dynamic inner structures, with the innermost component (a) outflowing with velocity ∣ V _LOS ∣ ∼ 160–240 km s ^−1 , and the outer components (b) and (c) outflowing more slowly or infalling with ∣ V _LOS ∣ ≲ 100 km s ^−1 . In addition, we find that the innermost component (a) can be attributed to collisionally excited hot (≳530 K) and dense ( $\mathrm{log}({n}_{{{\rm{H}}}_{2}}/{\mathrm{cm}}^{-3})\gtrsim 6$ ) clumps, based on the level populations. Conversely, the outer component (b) can be attributed to cold (∼30–140 K) clumps radiatively excited by a far-infrared-to-submillimeter background with a brightness temperature higher than ∼20–400 K. These observational results demonstrate the clumpy and dynamic structure of tori in the presence of background radiation.

We investigate the physical origins of the Balmer decrement anomalies in GS-NDG-9422 and RXCJ2248-ID galaxies at z ∼ 6 whose H α /H β values are significantly smaller than 2.7, the latter of which also shows anomalous H γ /H β and H δ /H β values beyond the errors. Because the anomalous Balmer decrements are not reproduced under the Case B recombination, we explore the nebulae with optical depths smaller and larger than the Case B recombination by physical modeling. We find two cases quantitatively explaining the anomalies: (1) density-bounded nebulae that are opaque only up to around Ly γ –Ly8 transitions and (2) ionization-bounded nebulae partly/fully surrounded by optically thick excited H i clouds. The case of (1) produces more H β photons via Ly γ absorption in the nebulae, requiring fine tuning in optical depth values, while this case helps ionizing photon escape for cosmic reionization. The case of (2) needs the optically thick excited H i clouds with N _2 ≃ 10 ^12 −10 ^13 cm ^−2 , where N _2 is the column density of the hydrogen atom with the principal quantum number of n = 2. Interestingly, the high N _2 values qualitatively agree with the recent claims for GS-NDG-9422 with the strong nebular continuum requiring a number of 2 s -state electrons and for RXCJ2248-ID with the dense ionized regions likely coexisting with the optically thick clouds. While the physical origin of the optically thick excited H i clouds is unclear, these results may suggest gas clouds with excessive collisional excitation caused by an amount of accretion and supernovae in the high- z galaxies.

Reducing the average Al composition of Al _x Ga _1− _x N/Al _y Ga _1− _y N multiple quantum wells (MQWs) is an effective approach to increase the current injection efficiencies of far-UV-C LEDs (far-UVC LEDs). A reduction can be realized by decreasing the Al-composition differentiation between the well and barrier layers. Compared to conventional MQWs, a 230 nm wavelength far-UVC LED equipped with a single-Al-composition and a 39 nm thick light-emitting layer exhibits a higher external quantum efficiency (EQE). The EQE of far-UVC LEDs with low Al-composition differentiation (∼1%) is enhanced to approximately 0.6% and 1.4% under continuous wave operations at 230 nm and 236 nm wavelengths, respectively.

We introduce a novel model to spectroscopically constrain the mid-infrared (MIR) extinction/attenuation curve from 3–17 μ m, using polycyclic aromatic hydrocarbon (PAH) emission drawn from an AKARI–Spitzer extragalactic cross-archival data set. Currently proposed MIR extinction curves vary significantly in their slopes toward the near-infrared, and the variation in the strengths and shapes of the 9.7 μ m and 18 μ m silicate absorption features make MIR spectral modeling and interpretation challenging, particularly for heavily obscured galaxies. By adopting the basic premise that PAH bands have relatively consistent intrinsic ratios within dusty starbursting galaxies, we can, for the first time, empirically determine the overall shape of the MIR attenuation curve by measuring the differential attenuation at specific PAH wavelengths. Our attenuation model shows PAH emission in most (ultra)luminous infrared galaxies is unambiguously subjected to attenuation, and we find strong evidence that PAH bands undergo differential attenuation as obscuration increases. Compared to preexisting results, the MIR attenuation curve derived from the model favors relatively gray continuum absorption from 3–8 μ m and silicate features with intermediate strength at 9.7 μ m but with stronger than typical 18 μ m opacity.

To evaluate the changes in respiratory syncytial virus (RSV) collected between 2019 and 2022, we analyzed RSV-A and RSV-B strains from various prefectures in Japan before and after the COVID-19 pandemic. RT-PCR-positive samples collected from children with rapid test positivity at outpatient clinics in 11 prefectures in Japan were sequenced for the ectodomain of the G gene to determine the genotype. Time-aware phylogeographic analyses were performed using the second hypervariable region (HVR) of the G gene from 2012 to 2022. Of 967 samples, 739 (76.4%) were found to be RSV-positive using RT-PCR. RSV peaked in September 2019 but was not detected in 2020, except in Okinawa. Nationwide epidemics occurred with peaks in July 2021 and 2022. The genotype remained the same, ON1 for RSV-A and BA9 for RSV-B during 2019–2022. Phylogeographic analysis of HVR revealed that at least seven clusters of RSV-A had circulated previously but decreased to two clusters after the pandemic, whereas RSV-B had a single monophyletic cluster over the 10 years. Both RSV-A and RSV-B were transferred from Okinawa into other prefectures after the pandemic. The RSV epidemic was suppressed due to pandemic restrictions; however, pre-pandemic genotypes spread nationwide after the pandemic.

To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom’s relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan–Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03–3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference −0.13, 95% CI −0.27–0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients.Clinical Trial Registration:https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020]

Abstract Background Treatment of congenital hemophilia A (HA) in Japan has greatly improved with the widespread adoption of prophylactic factor (F)VIII concentrates. However, it is unknown if this has translated into a real‐world reduction in disease and treatment burden. Objectives To describe HA disease burden in Japan based on information from two medical information databases, JMDC and Real World Data Co., Ltd. (RWD). Methods Eligible individuals were diagnosed with congenital HA and prescribed FVIII concentrates, bypassing agents, or emicizumab. Treatment patterns and disease burden data were derived from health insurance claims and electronic medical records. Results Data on 459 people with HA were retrospectively collected from 2005 to 2020 in the JMDC database (median [min, max] of 37 [2, 186] months of available records), and 229 people with HA from 1985 to 2020 in the RWD database (median [min, max] of 154 [0, 409] months of available records). Mean (standard deviation) ages at the time of the first record were 25.0 (16.8) years (JMDC) and 19.2 (20.3) years (RWD). In the JMDC database, mean monthly FVIII dose increased from 2201 IU in 2005 to 8239 IU in 2013 to 11,377 IU in 2019; HA‐related drug costs increased accordingly. Mean (95% confidence interval) annual outpatient and out‐of‐hours visits decreased slightly between 2013 and 2019 (outpatient visits: from 22.9 [16.8–29.0] to 14.3 [12.6–16.1] per person; out‐of‐hours visits: from 1.3 [0.2–2.5] to 0.6 [0–1.4]). There was no change in mean number of hospitalizations. Conclusions Challenges remain in HA, including treatment burden, outpatient visits, and hospitalizations.

Abstract Dietary soybean isoflavones (SIs) and soyasaponins (SSs) individually exert inhibitory effects on contact hypersensitivity (CHS), which is an animal model of allergic contact dermatitis (ACD); however, the beneficial effects of diets containing a mixture of SIs and SSs on CHS remain unclear. Here, we investigated the CHS‐suppressive effects of diets containing a mixture of SIs and SSs at physiologically relevant doses, and the role of the gut microbiota. The diets attenuated ear swelling and reduced the number of Gr‐1‐positive cells infiltrating the auricle tissues. Ear swelling was inhibited in the SI‐ and SS‐treated mice compared to the SI‐treated mice. Compared to the CHS controls, the levels of chemokine (C‐X‐C motif) ligand 2 and triggering receptor expressed on myeloid cells‐1 (TREM‐1) were lower in the auricle tissues of SI‐ and SS‐treated mice, whereas TREM‐1 production was not suppressed in SI‐ or SS‐treated mice. In addition, vancomycin treatment had little effect on the CHS‐inhibitory activity of SI and SS diets, whereas ciprofloxacin and metronidazole treatments blocked the effects of SI and SS diets. These antibiotics exhibited differing effects on the microbiota composition deduced from the bacterial 16S ribosomal RNA gene sequences. Therefore, consuming a mixture of SIs and SSs has ACD‐preventive effects and is affected by the gut microbiota.

Background and objectivePancreatic fat is a form of ectopic fat. Lipid droplets (LDs) are also observed in β cells; however, the pathophysiological significance, especially for β cell function, has not been elucidated. Our aim was to assess LD accumulation in β cells in various stages of glucose intolerance and to clarify its relationship with clinical and histological parameters.MethodsWe examined 42 Japanese patients who underwent pancreatectomy. The BODIPY493/503-positive (BODIPY-positive) area in β cells was measured in pancreatic sections from 32 patients. The insulin granule numbers were counted in an additional 10 patients using electron microscopy.ResultsThe BODIPY-positive area in β cells in preexisting type 2 diabetes patients was higher than that in normal glucose tolerance patients (p = 0.031). The BODIPY-positive area in β cells was positively correlated with age (r = 0.45, p = 0.0097), HbA1c (r = 0.38, p = 0.0302), fasting plasma glucose (r = 0.37, p = 0.045), and homeostasis model assessment insulin resistance (r = 0.41, p = 0.049) and negatively correlated with an increase in the C-peptide immunoreactivity level by the glucagon test (r = -0.59, p = 0.018). The ratio of mature insulin granule number to total insulin granule number was reduced in the patients with rich LD accumulation in β cells (p = 0.039).ConclusionsType 2 diabetes patients had high LD accumulation in β cells, which was associated with insulin resistance, hyperglycemia, aging and β cell dysfunction involving decreased mature insulin granules.

Introduction This study aimed to identify the associations between lifestyle factors and intrapancreatic fat deposition in patients with type 2 diabetes.Research design and methods The participants were 185 patients with type 2 diabetes who were hospitalized at Osaka University Hospital between 2008 and 2020 and underwent abdominal CT during hospitalization. Information regarding lifestyle factors, including the number of meals consumed per day, snacking habits, exercise habits, exercise at work, smoking habits, alcohol intake, insomnia, sleep apnea syndrome, and night-shift working, was acquired from self-administered questionnaires or medical records. We measured the mean CT values for the pancreas (P), liver (L), and spleen (S), and the visceral fat area (VFA), and quantified intrapancreatic and liver ectopic fat accumulation as P−S and L−S, respectively.Results After adjustment for age, sex, hemoglobin A1c, and body mass index (BMI), participants who consumed two meals per day had significantly lower P−S (higher intrapancreatic fat deposition, p=0.02) than those who consumed three meals per day. There were no significant associations between the number of meals consumed and liver ectopic fat accumulation and VFA (p=0.73 and p=0.67, respectively).Conclusions Patients with diabetes who consumed two meals per day showed greater intrapancreatic fat deposition than those who consumed three meals per day, even after adjustment for BMI. These findings support the current guideline for diabetes treatment that skipping meals should be avoided.

Olfactory dysfunction in the post COVID-19 condition reported worldwide are refractory for some patients. For this reason, appropriate treatment is desired. In this article, we describe two cases of olfactory dysfunction in the post COVID-19 condition that was improved by traditional acupuncture treatment. By using the Yingxiang point (LI20), which is said to improve the sense of smell since ancient times, acupuncture treatment was performed 1–2 times a week in two patients about 6 and 7 months after the diagnosis of COVID-19. Acupuncture needles with a body length of 30 mm and a body diameter of 0.16 mm were inserted about 10 mm deep into the skin. We stimulated LI20 of the right and left sides until the patients felt the de qi sensation (acupuncture resonance), and left needles in the points for about 15 min. Immediately after the acupuncture treatment, the symptoms of olfactory dysfunction were alleviated, and the improvement in olfactory dysfunction lasted for 2–4 days. As the number of acupuncture treatments increased, the time until the flareup of olfactory dysfunction was prolonged, and the symptoms tended to decrease. In our experience, the acupuncture treatment was effective in a short period for treating residual olfactory dysfunction of the post COVID-19 condition, suggesting that acupuncture may serve as an adjunct to modern medical treatment, and it may also be a new option for patients who are resistant to Western medical treatment or unable to continue treatment because of side effects. In conclusion, acupuncture may be a new option for patients who are resistant to modern medical treatment or who are unable to continue treatment because of side effects.

Abstract Background Although epidemiological and genetic studies have provided scientific evidence that places schizophrenia into the framework of early neurodevelopmental disorders, the psycho-behavioral characteristics of children that later go on to develop schizophrenia have not been sufficiently clarified. This study aimed to retrospectively identify characteristics specific to patients with schizophrenia during childhood via their guardians’ reporting of these characteristics. Methods Participants included 54 outpatients with schizophrenia in their twenties who fulfilled DSM-IV-TR criteria. Additionally, 192 normal healthy subjects participated as sex- and age-matched controls. The guardians of all participants were recruited to rate participants’ childhood characteristics from 6 to 8 years of age on a modified version of the Child Behavior Checklist (CBCL), which was used as a retrospective assessment questionnaire. Using t-tests, logistic regression, and Receiver Operating Characteristic (ROC) curve analysis, we estimated the psycho-behavioral characteristics specific to schizophrenia during childhood. Using the obtained logistic regression model, we prototyped a risk-predicting algorithm based on the CBCL scores. Results Among the eight CBCL subscale t-scores, “withdrawn” (p = 0.002), “thought problems” (p = 0.001), and “lack of aggressive behavior” (p = 0.002) were each significantly associated with the later diagnosis of schizophrenia, although none of these mean scores were in the clinical range at the time of childhood. The algorithm of the logistic regression model, based on eight CBCL subscales, had an area under the ROC curve of 82.8% (95% CI: 76–89%), which indicated that this algorithm’s prediction of late development of schizophrenia has moderate accuracy. Conclusions The results suggest that according to guardian reports, participants showed psycho-behavioral characteristics during childhood, different to those of healthy controls, which could be predictive of the later development of schizophrenia. Our newly developed algorithm is available to use in future studies to further test its validity.

Lumbar lateral interbody fusion (LLIF) has been gaining popularity among the spine surgeons dealing with degenerative spinal diseases while LLIF on L5-S1 is still challenging for its technical and anatomical difficulty. OLIF51 procedure achieves effective anterior interbody fusion based on less invasive anterior interbody fusion via bifurcation of great vessels using specially designed retractors. The technique also achieves seamless anterior interbody fusion when combined with OLIF25. A thorough understanding of the procedures and anatomical features is mandatory to avoid perioperative complications.

This paper proposes a sliding-mode set-point position controller for hydraulic excavators. The controller employs a simple switching surface that exponentially drives the actuator position to the desired position with a specified time constant. The discrete-time algorithm of the controller is constructed through a double-implicit implementation scheme, which is for implementing a simple sliding-mode controller to nonsmooth actuators, including hydraulic actuators. We employ a nonsmooth quasistatic model of the hydraulic actuator, which analytically accounts for the pressure saturation caused by the relief valves and check valves and the square-root law of the pressure-flowrate relation. This paper elaborates the analytical form of the model to be combined with the double-implicit implementation. A state predictor based on the actuator model extends the controller to compensate for the deadtime in the hydraulic system. The proposed controller is validated with some simulations and also through experiments employing the swing axis of a 13-ton class excavator.