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To identify liquid biomarkers that predict clinical outcomes of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), we enrolled patients with EGFR gene mutation-positive non-small-cell lung cancer who were intended to receive gefitinib treatment. Using plasma samples obtained prior to gefitinib treatment from 12 enrolled patients, we performed comprehensive proteomic analysis of plasma exosomes to explore proteins correlating with tumor reduction rate (TRR), progression-free survival (PFS), or overall survival (OS). Of the detected 1769 proteins, 119, 130, or 119 proteins demonstrated a strong correlation (|r| 0.5) with TRR, PFS, or OS, respectively. Interestingly, 34 (29%), 41 (32%), or 27 (23%) of them, respectively, were functionally involved in the regulation of the immune response. CD8α chain was consistently listed as a molecule positively correlated with PFS and OS, suggesting that the long-lasting effects of gefitinib may be due to the antitumor effects of CD8

Background Anti-aminoacyl-tRNA synthetase (ARS) antibody-positive patients present with a variety of symptoms, including interstitial lung disease (ILD), which is termed anti-synthetase syndrome (ASS). But it is rare that ASS-ILD is considered an immune-related adverse event after the use of immune checkpoint inhibitors (ICIs). Case presentation A 47-year-old male with advanced lung adenocarcinoma was treated with platinum and ICI combination immunotherapy and was followed up as an outpatient. Nine months after the start of treatment, he developed a fever and cough, and imaging findings showed lung consolidations in the bilateral lower lung fields. The patient was positive for anti- ARS antibodies and was considered to have developed ASS-ILD due to ICIs remitted with steroid therapy. The patient was found to be positive for anti-ARS antibodies before ICI administration, and the antibody titer was elevated compared to that before ICI administration. Conclusions The examination of anti-ARS antibodies pior to the administration of ICIs may be useful in predicting the development of ASS-ILD.

This work investigated the oxidation suppression effect of a reduced graphene oxide (rGO) film applied to a Cu substrate, which may have application in electrical connectors. To ensure prolonged low electrical contact resistance, a thin GO film was formed using an electrophoretic deposition method and subsequently heated to generate rGO. The surface morphology and thickness of the rGO film were assessed using atomic force microscopy and transmission electron microscopy. The thickness of the rGO film was estimated to be 5–7 nm, and the electrical contact resistance for the Cu substrate with and without an rGO film was 20 and 8 mΩ, respectively, at a contact load of 2 N. After accelerating the oxidation of the substrate by heating for 30 min at 180 °C under a dry air atmosphere, the formation of a Cu2O layer on the Cu substrate was confirmed by Raman spectroscopy and electron energy loss spectroscopy. The thickness of this oxide layer with and without an rGO film was 1.5 and 6 nm, respectively. In addition, the electrical contact resistance for the Cu substrate with and without the rGO film was 40 and 200 mΩ, respectively, at a contact load of 2 N. These results suggest that the thin rGO coating suppressed oxidation of the metal substrate while also suppressing the increase in contact resistance.

Nafamostat mesylate (NM) is used clinically in combination with antiviral drugs to treat coronavirus disease (COVID-19). One of the adverse events of NM is hyperkalaemia due to inhibition of the amiloride-sensitive sodium channels (ENaC). The incidence and risk factors for hyperkalaemia due to NM have been studied in patients with pancreatitis but not in COVID-19. COVID-19 can be associated with hypokalaemia or hyperkalaemia, and SARS-CoV-2 is thought to inhibit ENaC. Therefore, frequency and risk factors for hyperkalaemia due to NM may differ between COVID-19 and pancreatitis. Hyperkalaemia may worsen the respiratory condition of patients. The objective of this study was to determine the incidence and risk factors for hyperkalaemia in COVID-19 patients treated with favipiravir, dexamethasone and NM.This retrospective study reviewed the records of hospitalized COVID-19 patients treated with favipiravir and dexamethasone, with or without NM, between March 2020 and January 2021. Multivariable logistic regression analysis was performed to identify the risk factors for hyperkalaemia.Of 45 patients who received favipiravir and dexamethasone with NM for the treatment of COVID-19, 21 (47%) experienced hyperkalaemia. The duration of NM administration was a significant predictor of hyperkalaemia (odds ratio: 1.55, 95% confidence interval: 1.04-2.31, p = 0.031). The receiver-operating characteristic curve analysis determined that the cut-off value for predicting the number of days until the onset of hyperkalaemia was 6 days and the area under the curve was 0.707.This study revealed that the incidence of hyperkalaemia is high in patients treated for COVID-19 with NM, and that the duration of NM administration is a key risk factor. When NM is administered for the treatment of COVID-19, it should be discontinued within 6 days to minimize the risk of hyperkalaemia.

We have presented the study on magneto-transport properties and hole self-doping due to excess oxygen addition in polycrystalline LaMnO3 (LMO). The polycrystalline LMO samples were prepared by use of a solid-state reaction method. Powder mixtures with a molar ratio of 1:1 between La2O3 and Mn2O3 were pre-annealed at 1100oC for 18 hours in the atmospheres of O2, He and vacuum. By this pre-annealing, non-crystalline LMO samples were produced. After that, the non-crystalline LMO samples were grinded and were pressed into pellets at the pressure of 3t/cm3. The pellets were annealed at 1100oC and 1300oC for 18 hours in the same atmospheres as the pre-annealing. Through these processes, crystalline LMO samples were produced. To investigate the crystallographic structure of the LMO samples, X-ray diffraction (XRD) measurements have been performed by use of Cu-K radiation. From the results of XRD measurements, we have found that all LMO samples have perovskite structure and are polycrystalline. In addition, to investigate the surface structure of the LMO samples, scanning electron microscope (SEM) measurements have been carried out. Electrical resistivities (ERs) for the LMO samples have been measured as a function of temperature (4K-300K). The ERs of the LMO samples produced in O2 atmosphere show lower values as compared with other LMO ones produced in He and vacuum atmospheres. Especially, the temperature dependence of the ER for a LMO sample produced at the annealing temperature of 1100oC in O2 atmosphere shows metallic conduction. Thus, we have considered that this LMO sample has the largest hole self-doping concentration in all LMO ones. In addition, the magnetic field dependences of the magneto-resistance (MR) ratios for the LMO samples have been measured at several temperatures. The ferromagnetic behaviors on the MR ratios have been observed for LMO samples produced in O2 and He atmospheres.

Background: Tocilizumab is considered a critical treatment for severe COVID-19. Thus far, there are no established means of predicting outcomes of administering tocilizumab. Our goal was to determine the factors that predict the prognosis of patients with COVID-19 receiving tocilizumab. Methods: All patients admitted to our hospital from March 2020 to July 2021 who had received tocilizumab for COVID-19 were retrospectively identified from hospital charts. We identified 92 patients who were eligible for this observational cohort study. We assessed age, dyspnoea, number of comorbidities, history of cancer, neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio, lactate dehydrogenase, and total bilirubin. We also analysed the relationship between mortality and oxygen saturation/fraction of inspired oxygen (SpO2/FIO2) and ratio of oxygen concentration to respiratory rate (ROX index). We assessed these data using the Cox proportional hazard and ROC curve models. Results: Survivors (n = 56; mean age 65 years) were younger than those who died (n = 36; mean age 78 years). According to multivariable analysis, multiple comorbidities, history of cancer, CURB-65 score, neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio, and lactate dehydrogenase were all greater in those who died than in those who survived. There were no significant differences in dyspnoea and total bilirubin. The SpO2/FIO2 ratio 3 days after treatment with tocilizumab was strongly associated with subsequent mortality. According to multivariate analysis, of the variables analysed, only the SpO2/FIO2 ratio 3 days after treatment with tocilizumab was significantly associated with mortality rate (p = 0.029; hazard ratio = 0.987, 95% confidence interval 0.977–0.997). Conclusions: The SpO2/FIO2 ratio 3 days after treatment with tocilizumab is a useful prognostic indicator in patients with COVID-19. Our findings indicate that aggressive respiratory therapy and/or additional treatment should be instigated when the SpO2/FIO2 ratio has not improved 3 days after treatment with tocilizumab.

In tourism accommodation statistics, accuracy (variance and bias) is fundamental. However, minimizing both the variance and bias of the estimate is a challenge due to the trade-off between the two....

Purpose: There is a global movement to develop and implement community-based integrated mental health systems. The present study aimed to clarify needs and perceptions of early intervention in those systems among individuals with mental illness and healthy people in Japan. Methods: A new questionnaire was developed for this internet survey. Data from 500 outpatients with depression and 500 healthy subjects were sampled according to the demographics of the Japanese population and were analyzed descriptively. Results: Over 90% of healthy subjects and over 70% of patients were unaware of the common age of onset or lifetime prevalence of mental illness. Over 90% of the healthy subjects and about 70% of the patients could not describe any services where they would feel comfortable discussing mental health problems. In both groups, “adolescents and young adults” were ranked first as a target population for mental health and illness policies. The top requirements for the integrated care systems were mainly related to early intervention, such as promotion and awareness of correct knowledge of mental illness, preventive support for mental health problems before the onset of mental illness, and support for people in the early years after illness onset. Conclusion: The dissemination of correct knowledge and awareness-raising actions for society and the implementation of specific services targeting the early stage of mental illness are societal requirements. These services need to be considered as components in the integrated mental health care systems that are currently being established in Japan.

This study aims to investigate the contribution of visitors’ expenditure to Tokyo Metropolitan’s economy including its decomposition, the interregional repercussion effect between Tokyo and the rest of Japan, and the intersectoral propagation activities between tourism and the other sector in Tokyo based on two-region interregional input–output model and Miyazawa’s partitioned matrix multipliers. Measurement in tworegion model yielded to a higher value compared to single-region model, where domestic visitors lead the major contribution in overall, prominently on services sectors. The indirect and feedback effects to industries in Tokyo were strongly linked to tertiary sector, while spillover effect to the rest of Japan was more widely distributed. The economic activities in Tokyo were highly dependent on the industries in the rest of Japan, in similar manner as tourism on the other sectors within Tokyo. Tourism industries have strong inducible effects on the other sector. Considering these interregional and intersectoral interdependencies, improving the tourism sector in Tokyo may imply a promising effect to benefit the economy of Tokyo and subsequently other Japanese regions.

Family-owned tourism businesses have unique resources to empower women in remote island destinations. There is limited literature that postulates the resource acquisition to mobilize women entrepreneurs within the family business study. Hence, this paper provided empirical knowledge on family tourism businesses methods to mobilize women entrepreneurs in rural Tioman Island in Malaysia. This study employed a qualitative case study approach by applying in-depth interviews for data collection. A successful case study was carried out in Tioman Island with 11 women entrepreneurs who have been actively involved in family tourism business operations since the 1980s. The resulting opportunities from the family organization setting, familiness nature and tourism industry as a setting modifier have greatly mobilized women into family tourism entrepreneurship. Thus, this case study provided comprehensive information on family tourism businesses’ implications on women entrepreneurs’ competitiveness in Tioman Island.

The control of crystal polymorphism and exploration of metastable, two-dimensional, 1T'-phase, transition-metal dichalcogenides (TMDs) have received considerable research attention. 1T'-phase TMDs are expected to offer various opportunities for the study of basic condensed matter physics and for its use in important applications, such as devices with topological states for quantum computing, low-resistance contact for semiconducting TMDs, energy storage devices, and as hydrogen evolution catalysts. However, due to the high energy difference and phase change barrier between 1T' and the more stable 2H-phase, there are few methods that can be used to obtain monolayer 1T'-phase TMDs. Here, we report on the chemical vapor deposition (CVD) growth of 1T'-phase WS

Combined small-cell lung cancer (cSCLC) is a rare type of small-cell lung cancer (SCLC) that includes both SCLC and non-small-cell lung cancer (NSCLC). The molecular biological mechanisms underlying the heterogeneity of histological types in combined or metachronously transformed SCLC (mtSCLC) remain unclear. This study aimed to investigate the relationship between genetic alterations and each histological component heterogeneously detected in cSCLC and mtSCLC.This study included four cSCLC cases and one mtSCLC case. Formalin-fixed and paraffin-embedded sections of each histological component of these tumors were subjected to next-generation sequencing (NGS) and quantitative reverse transcription-polymerase chain reaction to investigate the genetic mutations and expression levels of neuroendocrine cell-specific transcription factors (achaete-scute homolog-1 [ASCL1], brain-2 [BRN2] also known as POU domain class 3 transcription factor 2, nuclear factor 1 B [NF1B], insulinoma-associated protein 1 [INSM1], and thyroid transcription factor-1 [TTF-1]).NGS analysis revealed that SCLC and NSCLC components share the same somatic mutations detected most frequently in TP53, and also in RB1 and EGFR. Gene expression analysis showed ASCL1 expression was significantly lower in the NSCLC component than in the SCLC component.We conclude that the morphological evolution of heterogeneous histological components in cSCLC may be associated with differences in ASCL1 expression levels, but not in acquired somatic gene mutations.

This study aims to explore accessibility indicators influencing the interactions between users, transport service providers (TSPs), and a platform operator, generating a conceptual framework for modeling these interactions under Mobility as a Service context. A systematic literature review was conducted to identify all studies focusing on indicators and modeling the interactions. There are limitations in integrating psychological indicators and dynamic pricing into the existing models. Moreover, there are gaps in considering monthly service packages, the efficiency of transport systems, and the perspectives of the TSPs for modeling the demand–supply interactions. The study ends with conclusions, discussions, and directions for further studies.

Lung cancer (LC) is the most fatal complication of idiopathic pulmonary fibrosis (IPF). However, the molecular pathogenesis of the development of LC from IPF is still unclear. Here, we report a case of IPF‐associated LC for which we investigated the genetic alterations between IPF and LC. We extracted formalin‐fixed paraffin‐embedded DNA from each part of the surgical lung tissue using a laser‐assisted microdissection technique. The mutations in each part were detected by next‐generation sequencing (NGS) using 72 lung cancer‐related mutation panels. Five mutations were found in IPF and four in LC. Almost all somatic mutations did not overlap between the IPF and LC regions. These findings suggest that IPF‐associated LC may not be a result of the accumulation of somatic mutations in the regenerated epithelium of the honeycomb lung in the IPF region., Here, we report for the first time somatic mutations between the epithelium of IPF and LC sites detected by NGS using a laser‐assisted microdissection technique. Almost all somatic mutations did not overlap between the IPF and LC regions.

Background Behçet’s disease (BD) is a systemic inflammatory vasculitis with both autoimmune and autoinflammatory properties. Renal involvement in BD and its spontaneous remission have been rare. We herein describe a case of parallel disease activity of BD with entero and renal involvements, followed by a spontaneous remission without corticosteroid treatment. Case presentation A 54-year-old woman who had a 4-year history of BD, maintained with colchicine treatment, suffered abdominal pain, hemorrhagic stool and diarrhea. Physical examination revealed strong tenderness in the entire abdomen. Laboratory test results showed increased levels of inflammation, and a computed tomography scan revealed edematous intestinal wall thickening with ascites. Blood and stool cultures showed no specific findings. Since she was suspected to have developed panperitonitis with acute enterocolitis, she started treatment with an antibacterial agent under bowel rest. Her abdominal symptoms gradually improved, while diarrhea and high levels of inflammatory reaction persisted. Colonoscopy revealed discontinuous abnormal mucosal vascular patterns and ulcerations in the whole colon except for the rectum, and histological analyses of the intestine demonstrated transmural mucosal infiltration of inflammatory cells without epithelioid granuloma or amyloid deposition. Based on these findings, she was diagnosed with entero BD. Meanwhile, pedal edema appeared during her hospitalization. Urinalysis results were consistent with nephrotic syndrome, thus a renal biopsy was performed. Light microscopy showed no obvious glomerular and interstitial abnormalities, whereas electron microscopy revealed foot process effacement without immune complex deposition or fibrillary structure, compatible with minimal change disease (MCD). Only with conservative therapy, her proteinuria decreased, followed by a complete remission in 3 weeks from the onset of edema. The coincident episode of MCD was finally diagnosed as renal BD that paralleled disease activity to entero BD. She started adalimumab administration, resulting in the further improvement of diarrhea and inflammatory levels. Conclusions This is the first report to demonstrate MCD as renal involvement of BD along with the disease activity of entero BD.

Purpose Multiple sleep latency test (MSLT) is performed as objective assessment of sleepiness, on the following day after polysomnography (PSG). In most clinics, patients are required to stay for 2 days. However, if patients have chronic sleep debt before the examination, even if they get adequate nocturnal sleep during the initial PSG, their sleep debt would not be fully resolved, affecting MSLT results. This may lead to improper administration of psycho‐stimulant medication. To clarify the sleep debt for the patients who showed short sleep latencies, we compared the mean sleep latencies of MSLTs. Methods Twelve hypersomnolent males, who underwent MSLTs (1st MSLT with 1 night and 2nd MSLT with more than 3 nights), were enrolled. We selected these cases based on the longer total sleep time on PSG night compared to the mean total sleep time on pre‐examination sleep logs and shortened sleep latencies on PSG. To evaluate the effect of the sleep debt for the patients who showed short sleep latencies, we extended their hospitalization or re‐hospitalized them. Results The mean sleep latency of 1st MSLT was 5.8 minutes and that of 2nd was 13.9 minutes (P, (a) Mean sleep latency following the nights in the hospital: the plots show mean sleep latencies of multiple sleep latency test (MSLT) in each patient following nights in the hospital. The number of patients was 12, and MSLT was conducted twice per patient. (b) Comparison of mean sleep latency obtained from MSLT between 1st MSLTs and 2nd MSLTs: The longer the hospitalized period, the patients showed longer mean sleep latencies.

We have presented the evidence of hole self-doping due to excess oxygen addition in polycrystal LaMnO3(LMO). The polycrystal LMO samples were prepared by use of a solid-state reaction method. Powder mixtures with a molar ratio of 1:1 between La2O3and Mn2O3were pre-annealed at 1100oC for 18 hours in the atmospheres of oxygen gas, helium gas and vacuum. By this heat treatment, non-crystalline LMO samples were produced. After that, the non-crystalline LMO samples were grinded and were pressed into pellets at the pressure of 3t/cm3. The pellets were annealed at 1100oC and 1300oC for 18 hours in the same atmospheres as the pre-annealing. Through these processes, polycrystal LMO samples were finally produced. To investigate crystallographic structure of the LMO samples, X-ray diffraction (XRD) measurements were performed by use of Cu-K radiation. From the experimental results of XRD measurements, we have found that all LMO samples have perovskite structure and are polycrystals. In addition, to investigate surface structure of the LMO samples, scanning electron microscope (SEM) measurements were carried out. Electrical resistivities (ERs) of the polycrystal LMO samples were measured as a function of temperature (4K-300K). The ERs of polycrystal LMO samples produced in an oxygen gas atmosphere show lower values as compared with other LMO ones in He gas and vacuum atmospheres. Especially, the temperature dependence of the ER for a polycrystal LMO sample produced at the annealing temperature of 1100oC in an oxygen atmosphere shows a metallic behavior. Thus, we have considered that this LMO sample has the largest hole self-doping concentration in all LMO ones.

The expression of programmed cell death-ligand 1 (PD-L1) is a biomarker for administering immune check point inhibitors in patients with advanced stage non-small cell lung cancer. Although the consolidation therapy of durvalumab after definitive chemoradiotherapy has become the new standard of care for patients with unresectable stage III non-small cell lung cancer, the prevalence and prognostic role of PD-L1 expression in this population remain unclear. We retrospectively reviewed data from patients with unresectable stage III non-small cell lung cancer who received definitive chemoradiotherapy at our institution between 2012 and 2017. Levels of PD-L1 were assessed using 22C3 antibody, and associations of progression-free and overall survival rates with PD-L1 statuses at a tumor proportion score cutoff of 1% were analyzed. Among the 104 patients enrolled, PD-L1 statuses were as follows: tumor proportion score

In this paper, we report the direct electron transfer (DET) reaction between debundled single-walled carbon nanotubes (SWCNTs) and the enzyme flavin adenine dinucleotide (FAD)-dependent fructose dehydrogenase (FDH). An anionic surfactant, sodium cholate (SC), was used to debundle the SWCNTs and disperse them in an aqueous solution, and the experimental conditions were optimized. The DET electrode, FDH/SWCNT-SC, was fabricated by the layer-by-layer drop-casting technique. Cyclic voltammetry experiments were conducted, and the experimental results revealed the presence of a high level of fructose concentration-dependent current (FDC). In the control experiment, FDC was not observed with either multi-walled carbon nanotubes (MWCNTs) or graphene flakes. The reported dimension of the FDH molecule is ∼7 nm, which is larger than the diameter of an individual SWCNT (1 nm) but smaller than the diameter of an individual MWCNT (10 nm) and the dimensions of a graphene flake (∼100 nm square). Only individual SWCNTs can reside in close proximity (within the distance for DET) of the cofactors FAD and heme c, both of which remain deeply embedded within the protein shell. The FDH/SWCNT-SC electrode had a sensitivity of 27 μA mM-1 cm-2, a linear dynamic range of 1.4–18.5 mM, and a detection limit of 2.1 μM. The electrode, combined with the enzyme invertase (IVT), can detect the total concentration of fructose and sucrose in samples (using the IVT/FDH/SWCNT-SC electrode). Therefore, fructose and sucrose can be separately quantified when both FDH/SWCNT-SC and IVT/FDH/SWCNT-SC electrodes are used. The amounts of fructose and sucrose in real food samples (100% fruit juice in the present case) determined using these electrodes agreed well with the amounts obtained from high-performance liquid chromatography (HPLC) experiments.

Cataplexy is a sudden drop of antigravity-muscle tone triggered most often by positive emotional factors, which is one of the major symptoms of narcolepsy. Cataplexy has been treated pharmacologically, most often with tricyclic antidepressants. Even though tricyclic antidepressants are effective in reducing sleep paralysis and hypnagogic hallucinations, they even enhance daytime sleepiness, dizziness, and orthostatic hypotension. We assessed the anticataplectic effect of milnacipran, an SNRI, on human and canine narcolepsy. We also assessed the effect of milnacipran on REM sleep suppression in nocturnal sleep. Ten human patients with narcolepsy–cataplexy who changed medication from clomipramine to milnacipran due to side effects were enrolled. The change in the frequency of cataplexy and side effects before and after drug replacement was investigated. To assess milnacipran’s depressant effect on REM sleep, we performed nocturnal polysomnography examinations twice on each eight healthy adult subjects who were administered with milnacipran or placebo. In the study on canine narcolepsy, four genetically narcoleptic Doberman pinschers were enrolled. The food-elicited cataplexy test was used to assess the anticataplectic effect of milnacipran. Milnacipran significantly reduced cataplexy from 9.3 to 5.5 episodes per month in human patients without much side effects. The percentage of REM sleep significantly decreased (p = 0.042) in the subjects with milnacipran (17.5 ± 1.7%) compared to subjects with placebo (21.5 ± 2.3%). Milnacipran also significantly reduced cataplexy dose-dependently in the study on canine narcolepsy. Milnacipran reduced cataplexy in human patients and REM sleep in healthy human subjects. Our study contributes further to previously reported role of adrenergic uptake inhibition in cataplexy. This compound had less side effect than those of tricyclic antidepressant, clomipramine.

Squeezing bubbles and impurities out of interlayer spaces by applying force through a few-layer graphene capping layer leads to van der Waals heterostructures with the ultraflat structure free from random electrostatic potential arising from charged impurities. Without the graphene capping layer, a squeezing process with an AFM tip induces applied-force-dependent charges of Δn ∼ 2 × 1012 cm-2 μN-1, resulting in the significant intensity of trions in photoluminescence spectra of MoSe2 at low temperature. We found that a hBN/MoSe2/hBN prepared with the "graphene-capping-assisted AFM nano-squeezing method" shows a strong excitonic emission with negligible trion peak, and the residual line width of the exciton peak is only 2.2 meV, which is comparable to the homogeneous limit. Furthermore, in this high-quality sample, we found that the formation of biexciton occurs even at extremely low excitation power (Φph ∼ 2.3 × 1019 cm-2 s-1) due to the enhanced collisions between excitons.

Pioneering the construction and application of social accounting matrix (SAM) framework in West Papua Province, Indonesia in 2018, this research aims to examine tourism-induced distribution effects on various socioeconomic groups by estimating SAM multiplier and its decomposition as well elaborating tourism influences through structural path analysis. Tourism brought significant impact on the economy with utmost overall contribution on capital factor and within decomposed cross multiplier effect. Nevertheless, impact on households decreases following a decrease in the level of household income. Accommodation and food services contributed on agricultural workers' income and employment. The latter has exceptional influence on the lowest-income rural household segment transmitted through fisheries, agricultural worker, and capital factor, that is strategic to improve livelihood and reducing regional poverty.

We have studied the magneto-transport properties in LMO thin films on a-SiO2 substrates produced by the metal organic decomposition (MOD) method. LMO thin films have been prepared by the MOD method in the 100 % O2 gas atmosphere on different heat treatment conditions. Although LMO single crystal is an antiferromagnetic insulator, LMO thin films we have produced in the 100 % O2 gas atmosphere by use of the MOD method shows the ferromagnetic metal properties for suitable heat treatment conditions. We consider that the excess of O2- ions in LMO thin films produced in the 100 % O2 gas atmosphere induces the strong hole self-doping into those and changes to ferromagnetic metal. The quantity of excess O2- ions in LMO is sensitive to the heat treatment conditions of the LMO production, especially the temperature, time and atmosphere gas. We have obtained the coercive forces from the magnetic field dependence of magnetoresistance. Based on the temperature dependence of the coercive forces, we have estimated the Curie temperature of LMO thin films.

Recently, highly anisotropic conductors, such as multilayer graphene, have been attracting much attention. The local resistivity can be determined by measuring the contact resistance; however, the theoretical expressions of contact resistance have been developed for isotropic slabs but have not been well developed for highly anisotropic film conductors. We obtain theoretical expressions of the spreading resistance below the circular contact for a highly anisotropic film on a bulk slab. The film spreading resistance of isotropic conductors deviates from the bulk spreading resistance when the film thickness is smaller than the contact radius. Nevertheless, the spreading resistance of anisotropic conducting films can be approximated by that of the bulk slabs even when the film thickness is smaller than the contact radius if the in-plane electrical conductivity is larger than the out-of-plane electrical conductivity. Owing to the high in-plane conductivity, the spreading resistance of anisotropic bulk conductors can be lowered from that predicted by the Holm’s equation obtained using the out-of-plane conductivity and the contact radius. We show that these characteristics are beneficial to use the highly anisotropic film as a cover layer when the in-plane conductivity of the film is high and the conductivity of the base slab is low.

This study attempts to investigate the dynamic impact of a natural disaster on tourism destination image. The data analysis through a case study of Japan confirmed three hypotheses. Firstly, the re...

We herein report a case of refractory exogenous lipoid pneumonia that was successfully attributed to vegetable oil through a lipidomic analysis of bronchoalveolar lavage fluid (BALF). As a 25-year-old woman diagnosed with lipoid pneumonia experienced repeated exacerbations and improvement, we performed a BALF lipidomic analysis. The major lipid components were oleic acid, linoleic acid, and α-linolenic acid, which are constituents of vegetable oil. She stopped consuming any vegetable oil and has since experienced no instances of lipoid pneumonia relapse. A lipidomic analysis appears to be useful for identifying causative lipids, since patients with lipoid pneumonia are sometimes unaware of aspiration episodes.

This study deals with the contribution of visitor expenditure on West Papua’s regional economy. It accomplishes three objectives: (1) to estimate the economic contribution of domestic and inbound visitor expenditure; (2) to measure the economic contribution of tourist spending at various accommodation classes; and (3) to describe the use of local commodities and labor in the regional accommodation industry. To accomplish the first and second objectives, an input-output multiplier analysis was employed. As for the third objective, interviews were conducted with 35 representatives from regional accommodation establishments. Tourism is found to contribute greatly to the regional economy, as shown from the higher overall output multiplier for tourist expenditure as compared to the regional output multiplier. The output multiplier for inbound tourist expenditure is higher than the domestic tourist. Three-star accommodations are found to be the biggest contributor with outstanding inter-sectoral impact on fisheries; food, beverage, and tobacco manufacture; and agriculture. The qualitative analysis suggests the existence of a large leakage (±90%), mainly in produce and chemicals used in daily operations. Fisheries and wood furniture are the exception. Overall, the accommodation sector absorbs a considerable extent of local labor (73%), 23% of which are Indigenous Papuans.

miRNA are a class of evolutionarily conserved non-coding 19- to 22-nt regulatory RNA. They affect various cellular functions through modulating the transcriptional and post-transcriptional levels of their target mRNA by changing the stability of protein-coding transcripts or attenuating protein translation. miRNA were discovered in the early 1990s, and they have been the focus of new research in both basic and clinical medical sciences. Today, it has become clear that specific miRNA are linked to the pathogenesis of respiratory diseases, as well as cancer and cardiovascular disease. In addition, EV, including exosomes, which are small membrane-bound vesicles secreted by cells, were found to contain various functional miRNA that can be used for diagnostic and therapeutic purposes. As body fluids, such as blood and respiratory secretions, are major miRNA sources in the body, EV carrying extracellular miRNA are considered potentially useful for the diagnosis and assessment of pathological conditions, as well as the treatment of respiratory or other diseases. Although research in the field of lung cancer is actively progressing, studies in other respiratory fields have emerged recently as well. In this review, we provide an update in the topics of miRNA and EV focused on airway inflammatory diseases, such as asthma and COPD, and explore their potential for clinical applications on respiratory diseases.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection., 「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.

Chemical vapor deposition using a rapid thermal annealing (RTA) system at atmospheric pressure with diluted methane gas (0.48 vol%)/Ar enabled the growth of high-quality multi-layered graphene on a Cu substrate at 1000 °C within a short time span. The minimum temperature rise time (including the reduction time) and growth time were 300 and 90 s, respectively. These conditions gave graphene films exhibiting 98.6% substrate coverage. The lateral sizes of the resulting graphene domains ranged from 0.2 to 1.2 μm with an average size of 0.46 μm while the film thicknesses were estimated to range from two to several layers based on the Raman 2D/G peak ratios. The Raman D peak indicative of defects was not detected on the graphene films. Precise control of the growth temperature within the range of 900 °C–1000 °C promoted reduction reactions and improved the quality of the graphene.

Objective Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been approved as first-line treatment for patients with untreated extensive disease-small cell lung cancer (ED-SCLC). However, there are few reports about the long-term outcomes in patients with ED-SCLC treated without ICIs. Thus, we analyzed the long-term outcomes in patients with ED-SCLC. Methods We retrospectively examined the medical records of patients with SCLC who were treated at our hospital between September 2002 and September 2019. The main inclusion criteria were as follows: (i) histological or cytological confirmation of SCLC, (ii) diagnosed with ED-SCLC and (iii) received chemotherapy, not including ICIs, as the first-line treatment. To assess the trends of treatment outcomes, we compared the survival outcomes between 2002–2010 (early) and 2011–2019 (late) groups. Results A total of 314 patients were included in this study. Patient characteristics at the time of first-line treatment were as follows: median age was 69 years; 82% of the patients were male and 70% had a performance status of 0 or 1. The median follow-up time of overall survival (OS) was 7.4 years, and 89% of the patients died. The median progression-free survival and survival time were 4.9 and 12.1 months, respectively. Five-year survival rate was 2%. There was no significant difference in survival between the early and late groups. Conclusions We found that the long-term outcomes in ED-SCLC patients treated without ICIs were poor. Prior to the approval of ICI treatment for ED-SCLC, there was no improvement in the OS for ~20 years.

There are limited data on the clinical efficiency of afatinib in non‐small cell lung cancer (NSCLC) patients with uncommon epidermal growth factor receptor (EGFR) mutations. Moreover, the efficacy and safety of afatinib in elderly patients with these mutations has not been established. Here, we describe a case of successful treatment of a patient aged >80 years with lung adenocarcinoma positive for the uncommon EGFR L861Q mutation with low‐dose afatinib. An 83‐year‐old woman presented with cough and dyspnea. A chest computed tomography (CT) scan revealed tumors in the left upper lobe, left pleural effusion, and multiple lung metastases in both lungs. The patient was diagnosed with lung adenocarcinoma with an EGFR L861Q mutation based on cytological findings. The patient received 30 mg/day of afatinib and experienced no severe adverse events. Two weeks later, partial response was observed based on a CT scan. The results of the present case support the effectiveness and safety of low‐dose afatinib in elderly patients with EGFR L861Q mutation‐positive NSCLC.

Now health tourism based on yoga, Ayurveda and meditation is growing sector in Nepalese Tourism. Health tourism as one of the most important forms of tourism is not an exception and preparing strategies for its development will not be possible without considering its specific and extraordinary environment. The objective of preparing and is writing this research paper is to formulate suitable strategies for health tourism development in Nepal. This study uses a qualitative approach. We conduct 38 semi structured interviews with related stakeholder’s of health tourism in Nepal, including health service providers, tourism service providers (as enterprise), and government officials. It was carried out in 2017 in Kathmandu, Bhaktapur, Lalitpur, and Pokhara. For strategy formulation, we employ the Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis method to examine the internal and external factors comprehensively, in terms of health tourism development in Nepal. The strategy to the health tourism development will be considered in terms of four relations: strengths-opportunities (S-O), weaknesses-opportunities (W-O), strengths-threats (S-T), weakness-threats (W-T). The results of this study show that the strategy in health tourism development in Nepal, it is necessary to work on policy and regulation, promotion and branding, introducing the quality standards for health products and service as well as to establish the institutional support in order to successful implementation for the strategy of the health tourism development in Nepal.

We have studied the strong hole self-doping into LaMnO3(LMO) thin films produced by metal organic decomposition (MOD) method. With different heat treatment conditions, LMO thin films have been prepared by the MOD method in the 100 % O2gas atmosphere. We consider that the excess of O2-ions in LMO thin films induces the strong hole self-doping into LMO ones. The quantity of excess O2-ions in LMO is sensitive to the heat treatment conditions of the LMO production, especially the temperature, time and atmosphere gas. Although LMO single crystal is an antiferromagnetic insulator, LMO thin films we have produced in the 100 % O2gas atmosphere by use of the MOD method shows the properties of ferromagnetic metal.

Objective The standard therapies for previously treated advanced non-small cell lung cancer (NSCLC) include docetaxel (DOC). Bevacizumab (BV), an antivascular endothelial growth factor (VEGF) antibody, increases the antitumor effect of cytotoxic anticancer agents. A BV-containing combination regimen is recommended as the primary therapy for advanced non-squamous NSCLC. However, the efficacy of DOC + BV is unknown in patients with previously treated advanced NSCLC. We conducted a phase II clinical study of DOC + BV for patients with previously treated advanced non-squamous NSCLC. Methods Twenty-three patients were enrolled in this study from June 2011 through May 2014. Chemotherapy was repeated every 21 days unless there was evidence of disease progression or intolerance to the study treatment. We assessed efficacy and toxicity. Results The median progression-free survival was 30.7 weeks. The response rate was 47.8%. The most common grade ≥3 adverse events were neutropenia (20 patients, 87.0%) and febrile neutropenia (7 patients, 30.4%). Conclusions The combination of DOC and BV often resulted in serious neutropenia, suggesting that this regimen is difficult to tolerate.

Background Acute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS. Methods Here, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model. Results Transfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1β) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1β expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs. Conclusions These findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.

Objective The objective of this study was to investigate the relationship between the serum concentration of clozapine (C-CLZ), Ndesmethylclozapine (N-CLZ) and the daily dose of CLZ (D-CLZ), and the relationships among CLZ and electroencephalogram (EEG) abnormalities. Methods Twenty-eight patients were recruited to this study, but 8 patients were excluded because clozapine was discontinued before the post-treatment measurement of EEG or C-CLZ. Ultimately, 20 patients (6 men, 14 women) with an average age of 36 years were enrolled. The subjects were divided into EEG normal and abnormal groups. C-CLZ and N-CLZ were measured at 4, 12, 26, and 52 weeks after initiating CLZ administration. Results All patients had normal baseline EEG signals, and 8 patients showed EEG abnormalities later. There were significant correlations between C-CLZ and D-CLZ, and between N-CLZ and D-CLZ. The C-CLZ/D-CLZ, N-CLZ/D-CLZ, and C-CLZ/N-CLZ ratio were not significantly different between the EEG normal and EEG abnormal groups. The EEG abnormal group had significant higher proportion of patients with high intra-individual variability in their C-CLZ/D-CLZ ratio. Conclusion There is no relationship between C-CLZ and EEG abnormalities. However, patients with high intra-individual variability in their C-CLZ/D-CLZ ratio had greater possibility of exhibiting EEG abnormalities.

Purpose The core features of dementia with Lewy bodies (DLB) are cognitive fluctuations, visual hallucinations, and parkinsonian symptoms. Although there have been several reports on the efficacy of treatments for psychotic symptoms in patients with DLB, little is known regarding the treatment effects of aripiprazole. The aim of this study was to evaluate the efficacy and safety of aripiprazole for the treatment of psychotic symptoms in patients with DLB. Patients and methods We employed a 10-week, open-label study design with 11 patients who met the criteria for DLB. The patients had previously experienced persistent or intermittent delusions, hallucinations, or both for at least 1 month. Aripiprazole was initiated at a low dose (3 or 6 mg/day) and titrated to higher doses at 2-week intervals or more rapidly, as needed. The Neuropsychiatric Inventory (NPI), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression-Severity (CGI-S) were administered at baseline and 1, 2, 4, 8, and 10 weeks later. The Simpson-Angus Scale (SAS), Clinical Dementia Rating (CDR), and Mini-Mental State Examination (MMSE) Scale were evaluated at baseline and at week 10. The NPI, CGI-S, and BPRS scores were compared between the baseline and each assessment point and between each assessment point and the one before assessment point. The SAS, CDR, and MMSE scores were compared between the baseline and the end point. Results The mean NPI and BPRS scores improved until the fourth week; they significantly decreased at each assessment point compared to the previous one. Afterward, improvements slowed and continued without significant decrease. The median SAS scores significantly decreased at the end point compared to the baseline (P

To curb the spread of the COVID-19 pandemic, countries around the world have imposed restrictions on their population. This study quantitatively assessed the impact of non-compulsory measures on human mobility in Japan during the COVID-19 pandemic, through the analysis of large-scale anonymized mobile-phone data. The non-negative matrix factorization (NMF) method was used to analyze mobile statistics data from the Tokyo area. The results confirmed the suitability of the NMF method for extracting behavior patterns from aggregated mobile statistics data. Data analysis results indicated that although non-pharmaceutical interventions (NPIs) measures adopted by the Japanese government are non-compulsory and rely largely on requests for voluntary self-restriction, they are effective in reducing population mobility and motivating people to practice social distancing. In addition, the current study compared the mobility change in three cities (i.e., Tokyo, Osaka, and Hiroshima), and discussed their similarity and difference in behavior pattern changes during the pandemic. It is expected that the analytical tool proposed in this study can be used to monitor mobility changes in real-time during the pandemic, as well as the long-term evolution of population mobility patterns in the post-pandemic phase.

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been approved as first-line treatment for patients with untreated extensive disease-small cell lung cancer (ED-SCLC). However, there are few reports about the long-term survival in patients with ED-SCLC treated without ICIs. Thus, we analyzed the long-term survival in patients with ED-SCLC.Methods: We retrospectively examined the medical records of patients with SCLC who were treated at our hospital between September 2002 and September 2019. The main inclusion criteria were as follows: (1) histological or cytological confirmation of SCLC, (2) diagnosed with ED-SCLC, and (3) received chemotherapy, not including ICIs, as the first-line treatment. To assess the trends of treatment outcomes, we compared the survival outcomes between 2002–2010 (early) and 2011–2019 (late) groups.Results: A total of 314 patients were included in this study. Patient characteristics at the time of first-line treatment were as follows: median age was 69 years; 82% of the patients were male; and 70% had a performance status of 0 or 1. The median follow-up time of overall survival (OS) was 7.4 years, and 89% of the patients died. The median progression-free survival and survival time were 4.9 months and 12.1 months, respectively. Five-year survival rate was 2%. There was no significant difference in survival between the early and late groups.Conclusion: We found that the long-term survival in ED-SCLC patients treated without ICIs was poor. Prior to the approval of ICI treatment for ED-SCLC, there was no improvement in the OS for approximately 20 years.