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Abstract Background Stanford type B-acute aortic dissection (type B-AAD) is often life-threatening without invasive surgery. Multilineage-differentiating stress enduring cell (Muse cells), which comprise several percent of mesenchymal stem cells (MSCs), are endogenous pluripotent-like stem cells that selectively home to damaged tissue and replace damaged/apoptotic cells by in-vivo differentiation. Methods Mortality, aortic diameter expansion, cell localization, cell differentiation, and inflammation of the dissected aorta were evaluated in type B-AAD model mice intravenously injected with human-Muse cells, -elastin-knockdown (KD)-Muse cells, -human leukocyte antigen-G (HLA-G)-KD-Muse cells, or MSCs, all without immunosuppressant. Results Here, we show the Muse (50,000 cells) group has a lower incidence of aortic rupture and mortality of AAD compared with the MSC-50K (50,000 human-MSCs) and vehicle groups. Spectrum computed tomography in-vivo dynamics and 3-dimensional histologic analyses demonstrate that Muse cells more effectively home to the AAD tissue and survive for 8 weeks in the Muse group than in the MSC-750K (750,000 human-MSCs containing 50,000 Muse cells) group. Homing of Muse cells is impeded in the HLA-G-KD-Muse (50,000 cells) group. Differentiation of homed Muse cells into CD31(+) and alpha-smooth muscle actin (+) cells, production and reorganization of elastic fibers in the AAD tissue, and suppression of diameter expansion are greater in the Muse group than in the MSC-750K and elastin-KD-Muse (50,000 cells) groups. Conclusions Intravenously administered Muse cells reconstruct the dissected aorta and improve mortality and diameter enlargement rates. Moreover, small doses of purified Muse cells are more effective than large doses of MSCs. HLA-G is suggested to contribute to the successful survival and homing of Muse cells.

ABSTRACT Aims/Introduction Insulin resistance syndrome and lipoatrophic diabetes are rare conditions characterized by the development of treatment‐refractory diabetes with severe insulin resistance. We recently conducted a 24 week, multicenter, single‐arm trial (EMPIRE‐01) that demonstrated a certain level of effectiveness and safety of empagliflozin for these conditions. To evaluate treatment safety over a longer period, we have now performed an additional 28 week trial (EMPIRE‐02) that followed on from EMPIRE‐01. Materials and Methods The primary and secondary outcomes were safety and efficacy evaluations, respectively. All eight subjects of the EMPIRE‐01 trial participated in EMPIRE‐02. Results Twenty adverse events (AEs) were recorded among five individuals during the combined 52 week treatment period of both trials. Whereas one case of chronic hepatitis B was moderate in severity, all other AEs were mild. There were thus no serious AEs or events necessitating discontinuation or suspension of treatment or a reduction in drug dose. Whereas ketoacidosis or marked increases in serum ketone body levels were not observed, the mean body mass of the subjects was decreased slightly after completion of EMPIRE‐02. The improvement in mean values of glycemic parameters observed in EMPIRE‐01 was not sustained in EMPIRE‐02, mostly because of one individual whose parameters deteriorated markedly, likely as a result of nonadherence to diet therapy. The improvement in glycemic parameters was sustained during EMPIRE‐02 after exclusion of this subject from analysis. Conclusions Empagliflozin demonstrated a certain level of safety and efficacy for the treatment of insulin resistance syndrome and lipoatrophic diabetes over 52 weeks, confirming its potential as a therapeutic option.

BackgroundThe extracellular pH (pHe) is known to be acidic. We investigated the effect of mild (pHe 6.8) and severe (pHe 5.9) acidosis on gene expression in mouse B16-BL6 melanoma cells using cDNA microarray analysis and compared them with the acidic pHe dependence of human tumors.MethodsB16-BL6 cells were treated with pHe 7.4 (control), pHe 6.8, and pHe 5.9. The mRNA expression was analyzed by using the cDNA microarray. Heat map, volcano plot, and gene ontology enrichment analysis were performed. The data were compared with the gene signatures of published data GSE52031 and GSE8401 and compared with the pathological staging by GEPIA2, and the prognostic signature of proteins was searched by the Human Protein Atlas database. If the acidic pHe-induced and -reduced genes were correlated with shortened and prolonged survival times, respectively, and also correlated with pathological staging, we defined it as “hit” and counted the sum of hit points of eight types of tumors such as breast, colorectal, prostate, gastric, liver, prostate, lung, and head and neck and melanoma.ResultsGene expression was differentially and commonly regulated by both pHes. The number of genes upregulated fourfold or more at pHe 6.8 and 5.9 only for 25 and 131 genes, respectively, and 85 genes were common. The number of genes downregulated fourfold or less at pHe 6.8 and 5.9 only for 63 and 82 genes, respectively, and 118 genes were common. Compared with human mRNA expression data (GSE8401), there is no correlation with the overall pattern of the signature. In seven types of cancer (breast, colorectal, gastric, liver, prostate, lung, and head and neck) and melanoma, the relationship between acidic pHe-modulated gene expression and overall survival was evaluated. As a result, acidic pHe dependency contributing to prognosis was higher in colorectal, lung, and head and neck cancers and lower in prostate cancer.ConclusionTumor classification based on response to extracellular acidic pHe will provide new insights into chemotherapy strategy for patients with tumors.

BackgroundFor treating patients with refractory chronic spontaneous urticaria (CSU) resistant to standard doses of 2nd generation H1-antihistamines (H1AH) the International and Japanese guidelines recommend increasing H1AH dose. The latter also recommends switching to a different H1AH. This study explored if the efficacy of the standard dose of bilastine 20 mg is non-inferior to that of double-dose of H1AH in patients with refractory CSU.MethodsThis phase IV, multicenter, open-label, randomized, parallel-group trial evaluated the efficacy and safety of switching treatment to bilastine compared to treatment with a 2-fold dose of H1AH in patients with CSU refractory to standard dose H1AH. The primary endpoint was the mean total symptom score (TSS) at Day 5-7 after the start of administration.ResultsTreatment efficacy and safety were evaluated in 128 patients (bilastine, n=64; 2-fold dose of H1AH, n=64). The mean TSS at Day 5-7 after the start of administration was smaller than the non-inferiority margin of 0.8, demonstrating non-inferiority of the bilastine switching group to the double-dose H1AH group (0.17 (95% CI -0.32, 0.67)). No difference in Japanese version of Epworth Sleepiness Scale (JESS), DLQI, and urticaria activity score over 7 consecutive days (UAS7) was observed between the two groups. There were no serious adverse events in either group. H1AH-related adverse events occurred in 5 subjects (8 cases) and 2 subjects (3 cases) in the double-dose H1AH and bilastine groups, respectively.ConclusionsSwitching treatment to bilastine demonstrated non-inferiority to a double-dose of H1AH in terms of efficacy in patients with CSU refractory to standard dose H1AH with a favorable safety profile.Clinical trial registrationhttps://jrct.niph.go.jp/latest-detail/jRCTs051180105, identifier jRCTs051180105.

Abstract Objective Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early‐onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. Methods Our research commenced with an in‐depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early‐onset ALS (onset age of

Abstract The electromagnetic interaction between Europa and the plasma sheet in the Jovian magnetosphere generates Alfvén waves, ultimately generating auroral footprints in Jupiter's atmosphere. The position of Europa's auroral footprint is a proxy for travel time of the Alfvén waves. We measured Europa's footprint position using the far‐ultraviolet images of Jupiter obtained by the Hubble Space Telescope in two observing campaigns in 2014 and 2022. The measured footprint position indicates a longer Alfvén travel time in the 2022 campaign. We retrieved the plasma sheet parameters at Europa's orbit from the footprint position by tracing the Alfvén waves launched at Europa and found an increase of both mass density and temperature in the plasma sheet in 2022. The Poynting flux generated at Europa is calculated with the retrieved plasma sheet parameters, which suggests the total energy transfer from Europa to its auroral footprint is similar to the case of Io.

Aim: This study aimed to evaluate the efficacy of a non-pharmaceutical multimodal intervention program consisting of physical exercise, cognitive stimulation, and health education in a group setting to slow the progression of mild cognitive impairment (MCI). Methods: A single-arm interventional study was conducted on 27 patients with MCI. To evaluate the efficacy of the intervention program, a pre-post analysis was performed using EuroQol-5 Dimension (EQ-5D), Mini-Mental State Examination (MMSE), Cognitive Function Instrument (CFI), 5 Cog test, depression, and physical performance before and after the 8-month intervention. Additionally, propensity score and the semi-Bayes analyses were performed to compare the intervention program with standard medical care, using the external control patients’ data for MMSE scores. Results: Twenty-four patients completed the intervention program. During the study period, although EQ-5D and MMSE scores remained unchanged (mean change 0.02 [95 % confidence interval (CI): −0.004, 0.04], 0.5 [-0.2, 1.3]), CFI and the subcategories of 5Cog (attention and reasoning) improved (mean change −1.23 [-2.24, −0.21], 4.3 [0.9, 7.7], 3.0 [0.4, 5.6]). In the additional analysis comparing changes in MMSE scores, patients who underwent the intervention program had less decline than the external control patients (mean change −1.7 [-2.1, −1.3]) with an observed mean difference of 2.25 [1.46, 3.03], and propensity score-adjusted difference of 2.26 [1.46, 3.05]. The semi-Bayesian approach also suggested that the intervention slowed the progression of MCI. Conclusion: A non-pharmaceutical multimodal intervention program could contribute to slowing cognitive decline in patients with MCI.

ABSTRACT Whether empirical therapy with carbapenems positively affects the outcomes of critically ill patients with bacterial infections remains unclear. This study aimed to investigate whether the use of carbapenems as the initial antimicrobial administration reduces mortality and whether the duration of carbapenem use affects the detection of multidrug-resistant (MDR) pathogens. This was a post hoc analysis of data acquired from Japanese participating sites from a multicenter, prospective observational study [Determinants of Antimicrobial Use and De-escalation in Critical Care (DIANA study)]. A total of 268 adult patients with clinically suspected or confirmed bacterial infections from 31 Japanese intensive care units (ICUs) were analyzed. The patients were divided into two groups: patients who were administered carbapenems as initial antimicrobials (initial carbapenem group, n = 99) and those who were not administered carbapenems (initial non-carbapenem group, n = 169). The primary outcomes were mortality at day 28 and detection of MDR pathogens. Multivariate logistic regression analysis revealed that mortality at day 28 did not differ between the two groups [18 (18%) vs 27 (16%), respectively; odds ratio: 1.25 (95% confidence interval (CI): 0.59–2.65), P = 0.564]. The subdistribution hazard ratio for detecting MDR pathogens on day 28 per additional day of carbapenem use is 1.08 (95% CI: 1.05–1.13, P < 0.001 using the Fine-Gray model with death regarded as a competing event). In conclusion, in-hospital mortality was similar between the groups, and a longer duration of carbapenem use as the initial antimicrobial therapy resulted in a higher risk of detection of new MDR pathogens.IMPORTANCEWe found no statistical difference in mortality with the empirical use of carbapenems as initial antimicrobial therapy among critically ill patients with bacterial infections. Our study revealed a lower proportion of inappropriate initial antimicrobial administrations than those reported in previous studies. This result suggests the importance of appropriate risk assessment for the involvement of multidrug-resistant (MDR) pathogens and the selection of suitable antibiotics based on risk. To the best of our knowledge, this study is the first to demonstrate that a longer duration of carbapenem use as initial therapy is associated with a higher risk of subsequent detection of MDR pathogens. This finding underscores the importance of efforts to minimize the duration of carbapenem use as initial antimicrobial therapy when it is necessary.

Abstract In the dense and cold atmosphere of Titan, the presence of C2H4 haze has been confirmed by the observations of spacecraft. In the present study, original cryogenic experimental equipment was developed to simulate the low-temperature solid formation of C2H4 in combination with in-situ infrared spectroscopic measurements. As a result, out-of-plane bending vibration ν7 of solid-phase C2H4 located at ~ 10.5 μm was successfully detected with high sensitivity, and two-dimensional spectrographs of C2H4 at low temperatures were obtained. The obtained spectra of C2H4 can be fitted to the double Lorentzian function with various heights, central wavelengths, and full widths at half the maximum (FWHM) of the two-component Lorentzian functions. They were classified into three types using the fitting parameters. However, their spectral shapes are different from the amorphous, metastable, and crystalline forms obtained by the previous laboratory experiment in terms of the distance of two peak wavelengths and FWHM. The results may link to understanding the spectral band properties of C2H4 condensation in the haze component of Titan. Graphical Abstract

Abstract Objective This study was designed to evaluate the postoperative efficacy and safety of using an ibuprofen gargle as a pain management strategy for patients who have undergone mandibular third molar extraction. We also ensured that the quality of treatment was not compromised throughout the study. Material and Methods Patients were randomized in a 1:1 ratio into two groups: the ibuprofen–placebo (IP) group and the placebo–ibuprofen (PI) group. On postoperative Day (POD) 1, the IP group initiated ibuprofen administration, while the PI group started taking placebo. On POD 2, the IP group switched to using placebo, whereas the PI group switched to ibuprofen. From PODs 3–5, both groups were prescribed ibuprofen gargle. The primary endpoint was within‐subject visual analog scale (VAS) score before and 5 min after the first use of the ibuprofen or placebo gargle on PODs 1 and 2 (ΔVAS5_ibuprofen − ΔVAS5_placebo). The incidence and severity of adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0 and a subjective rating scale. Results This study enrolled 40 patients. The within‐subject VAS5 of the IP and PI groups were 1.25 ± 12.0 and −5.26 ± 8.93 mm, respectively. The treatment effect of ibuprofen gargle was −2.01 ± 10.62 mm (p = .246). None of the patients in each group presented with serious adverse events or clinically significant complications (including dry sockets) after extraction. Transient adverse events, such as throat tingling and oral discomfort (grade 1), were observed in each group. Conclusion Ibuprofen gargle was safe but did not provide significant pain relief when used after mandibular third molar extraction.

Abstract Previous studies have shown that auroral kilometric radiation (AKR) can play an important role in the magnetosphere‐atmosphere coupling and has the right‐handed extraordinary (R‐X), left‐handed ordinary (L‐O) and left‐handed extraordinary (L‐X) modes. However, the L‐X mode has not been directly observed in the lower latitude magnetosphere yet, probably because of its very limited frequency range. Here, using observations of the Arase satellite on 6 September 2018, we present an AKR event with two distinct bands (8–20 and 300–1000 kHz) around the location: L = 8 and latitude = −37°. The low (high) band is identified as the L‐X (R‐X) mode based on the polarization and frequency ranges. Simulations of 3‐D ray tracing show that most of ray paths with 14 (11 and 18) kHz pass (miss) the location of Arase, basically consistent with observations. Our study provides direct evidence that the L‐X mode can propagate from high latitudes downward to lower latitudes.

Abstract Background Sepsis occurs as a result of dysregulated host response to infection. However, cytokine adsorption therapy may restore the balance of proinflammatory and anti-inflammatory mediator responses in patients with sepsis. This study aimed to determine the cytokine adsorption ability of two different types of continuous renal replacement therapy (CRRT) hemofilters for polyethyleneimine-coated polyacrylonitrile (AN69ST) (surface-treated) and polymethylmethacrylate (PMMA) CRRT. Methods We performed a randomized controlled trial among sepsis patients undergoing CRRT, who were randomly assigned (1:1) to receive either AN69ST or PMMA-CRRT. The primary outcome was cytokine clearance of hemofilter adsorption (CHA). The secondary endpoints were the intensive care unit (ICU) and 28-day mortalities. Results We randomly selected 52 patients. Primary outcome data were available for 26 patients each in the AN69ST-CRRT and PMMA-CRRT arms. The CHA of high-mobility group box 1, tumor necrosis factor, interleukin (IL)-8, monokine induced by interferon-γ, and macrophage inflammatory protein were significantly higher in the AN69ST-CRRT group than in the PMMA-CRRT group (P

Abstract Plasmaspheric hiss waves are important to shape the Earth’s electron radiation belt. These waves are commonly envisioned to have a long lifetime which allows them to permeate the global plasmasphere from a spatially restricted source. However, this hypothesis has not been experimentally confirmed yet, because of the challenging observational requirements in terms of location and timing. With wave and particle measurements from five magnetospheric satellites and detailed modeling, we present the first report of long lifetime (∼42 s) hiss rays in the substorm‐disturbed plasmasphere. The low‐frequency hiss waves are found to originate from the middle piece of the plasmaspheric plume, bounce between two hemispheres, and eventually drift into the plasmaspheric core. These hiss rays can travel through ∼3 hr magnetic local time and ∼4 magnetic shell. Such a long‐time and large‐scale permeation of hiss rays could benefit from the ducting process by plasmaspheric field‐aligned density irregularities.

Glass is a representative of fragile material. But it can be used as a good protective cover when strengthened. As a method of such strengthening, so-called “physical tempering” is widely used for large glass plates. In this method, heated glass is rapidly quenched so that the outside part of the glass is frozen while the inside cools slowly. Such difference in frozen temperatures causes the excessive shrinkage of the inside than the outside, which generates surface compressive stress. Thus, for better strengthening, higher thermal expansion can be expected. In this research, we investigate glass which has similar expansion coefficient while it is in glassy state but is much larger when they are in the supercooled liquid state. We successfully found that the borosilicate glass system possesses systematically controllable thermal expansion at high temperatures while keeping that at a temperature below glass transition to be similar. It was available due to the systematic but drastic change in configurational entropy related to the alkali-assisted-Si-O-B bonding in the series of borosilicate glasses. Two types of tempering demonstrations show that the developed glass can be strengthened more than twice as large as that of the window glass when applied to a similar strengthening condition.

Abstract Introduction Evidence on treatment effectiveness in patients with psoriasis having anxiety or depressive symptoms helps shared decision-making. This single-arm, open-label, prospective study—ProLOGUE—was conducted to assess the effectiveness of brodalumab on self-assessed anxiety and depressive symptoms in Japanese patients with psoriasis. Methods Patients aged ≥ 18 years with plaque psoriasis without peripheral arthritis symptoms who had responded inadequately to current therapies were enrolled at 15 Japanese facilities and received brodalumab 210 mg subcutaneously. Results A total of 73 patients were enrolled (male, 82%; median age, 54 years). The proportion of patients without anxiety symptoms changed significantly from baseline (72.6%) to weeks 12 (88.9%, p = 0.008) and 48 (87.7%, p = 0.02); the proportion of patients without depressive symptoms did not change significantly. The Generalized Anxiety Disorder-7 score (median [quartile(Q)1–Q3], 1.0 [0.0–5.0] at baseline; 0.0 [0.0–2.0] at week 12, p = 0.008; and 0.0 [0.0–1.0] at week 48, p = 0.007) and Patient Health Questionnaire-8 score (median [Q1–Q3], 2.0 [0.0–4.0] at baseline; 1.0 [0.0–4.0] at week 12, p = 0.03; and 0.0 [0.0–2.0] at week 48, p = 0.004) significantly decreased after treatment. The median Psoriasis Area and Severity Index scores after treatment were

BackgroundHead and neck cancers that cause severe aesthetic and functional disorders normally metastasize to the cervical lymph nodes. Patients with cervical lymph node metastasis are undergoing neck dissection. Shoulder complaints are common after neck dissection, with patients reporting symptoms such as pain, weakness, shoulder droop, and disability. However, no safe and effective treatment is available for this condition at present. We will conduct a double-blinded, randomized controlled trial to evaluate the efficacy of carbon dioxide (CO2) paste in relieving pain in patients after neck dissection. ObjectiveThis will be the first clinical study to compare the efficacy of CO2 paste with placebo in relieving postoperative pain in patients who underwent neck dissection. MethodsWe will perform this trial at the Kobe University Hospital in Japan. Patients will be randomized 1:1 into the CO2 paste and control groups. Patients in the CO2 paste group will have the CO2 paste applied to the cervical surface skin for 10 minutes once per day for 14 consecutive days. The primary end point of the study is a change in the visual analog scale (VAS) scores of neck pain from baseline on day 1 (preapplication) to the end of drug application (day 15). Secondary end points include changes in the following parameters from baseline on day 1 to the end of drug application (day 15) or the study (day 29): neck pain VAS score (days 1-29), grip strength (days 1-15 and 1-29), VAS scores for subjective symptoms (the feeling of strangulation, numbness, swelling, and warmth in the neck and shoulder region) for days 1-15 and 1-29, whether the VAS score improved more than 30% (days 1-15), the arm abduction test (days 1-15 and 1-29), shoulder range of motion (abduction and flexion) for days 1-15 and 1-29, occurrence of skin disorders, and occurrence of serious side effects. Periodic monitoring will be conducted for participants during the trial. This study was approved by the certified review board of Kobe University. ResultsThe intervention commenced in May 2021 and will continue until March 2024. The collected data will provide information on the efficacy of the CO2 paste treatment. The primary end point will be compared using the Wilcoxon test, with the 1-sided significance level set at 5%. Each evaluation item will be summarized. Secondary efficacy end points will be analyzed to provide additional insights into the primary analysis. Findings based on the treatment effects are expected to be submitted for publication in 2025. ConclusionsThis trial will provide exploratory evidence of the efficacy and safety of CO2 paste in relieving pain in patients after neck dissection. Trial RegistrationJapan Registry of Clinical Trials (jRCT) identifier: jRCTs051210028; https://jrct.niph.go.jp/en-latest-detail/jRCTs051210028 International Registered Report Identifier (IRRID)DERR1-10.2196/50500

Abstract Background Congenital cytomegalovirus (CMV) infection (cCMV) can cause sensorineural hearing loss and neurodevelopmental disabilities in children. Oral valganciclovir (VGCV) therapy has been reported to improve long-term audiological and neurodevelopmental outcomes in patients with cCMV. The levels of CMV DNA in whole blood have been monitored in previous studies. However, quantitative methods using whole blood have not been standardized. Recently, the plasma viral load has been standardized and widely used in CMV-associated diseases. Methods CMV viral loads in whole blood and plasma were serially measured in 24 patients with a confirmatory diagnosis of cCMV during oral VGCV therapy using an in-house real-time PCR assay. Plasma samples were assayed using the Cobas 6800 system (Roche Diagnostics) in addition to an in-house assay. Results Plasma CMV viral loads were remarkably decreased at the end of therapy compared to before therapy. A significant correlation of CMV levels between whole blood and plasma was observed (Spearman’s ρ = 0.566). The levels of CMV DNA before therapy were significantly correlated with the period of decreasing the viral loads to below the detection limit, not only in whole blood (Spearman’s ρ = 0.901) but also in plasma (Spearman, ρ = 0.804). Finally, CMV viral loads between the in-house assay and commercially available standardized assay in 75 plasma samples with positive PCR results for CMV were compared; a significant correlation was observed between the results of both assays. Conclusions There was a significant correlation between the two assays (Spearman, ρ = 0.882), suggesting that CMV plasma viral loads measured by the standardized assay are widely used to monitor the levels of CMV DNA in patients with cCMV during oral VGCV therapy.

Abstract Background This study investigated how cognitive function-related simple questions can be used to identify older individuals who are at risk of needing long-term care. Methods This cohort study was conducted in Kobe city, Japan. In 2015, the municipal office distributed the Kihon Checklist by post, a 25-item questionnaire including three cognitive function-related questions (questions 18, 19, 20) to citizens aged ≥ 70 years. Need certification is routinely done by Kobe city as part of the national Long-Term Care Insurance Act. The answers to the 2015 questionnaire were merged with need certification data between the questionnaire delivery and the end of December 2019. Results Of the 77,877 citizens (age: 72.9 ± 2.7 years) who received the questionnaire, 50,154 responded (response rate: 64.4%). During the study period, the cumulative incidence of the need for long-term care was higher in those who did not respond than in those who did (12.5% vs 8.4%; P

Background: Patients with psoriasis report impaired health-related quality of life (HRQoL; Dermatology Life Quality Index score ≥ 2) even after achieving clear or almost-clear skin with biologic treatment. Objective: To assess the effectiveness of brodalumab in HRQoL improvement and the factors associated with incomplete HRQoL improvement in Japanese patients with psoriasis. Methods: As a part of the single-arm, open-label, multicenter, prospective ProLOGUE study (Japan Registry of Clinical Trials identifier: jRCTs031180037), patients were treated with 210 mg of subcutaneous brodalumab in daily clinical practice until week 48. The absolute Psoriasis Area and Severity Index scores and patient-reported outcomes were assessed at baseline and weeks 12 and 48. Results: Seventy-three patients (male, 82.2%; median age, 54.0 years) were enrolled. The Dermatology Life Quality Index and European Quality of Life 5-Dimension 5-Level Utility Index scores significantly improved from baseline to weeks 12 and 48. At week 48, all 13 patients with a Dermatology Life Quality Index score of ≥2 and an absolute Psoriasis Area and Severity Index score of 0 to ≤2 reported itching. Limitations: Unclear generalizability of the results to other biologics. Conclusion: Treatment with brodalumab improved HRQoL in patients with psoriasis. Itching may contribute to incomplete HRQoL improvement in patients who have achieved clear or almost-clear skin.

Abstract Background Large multicenter studies reporting on the association between the duration of broad-spectrum antimicrobial administration and the detection of multidrug-resistant (MDR) bacteria in the intensive care unit (ICU) are scarce. We evaluated the impact of broad-spectrum antimicrobial therapy for more than 72 h on the detection of MDR bacteria using the data from Japanese patients enrolled in the DIANA study. Methods We analyzed the data of ICU patients in the DIANA study (a multicenter international observational cohort study from Japan). Patients who received empirical antimicrobials were divided into a broad-spectrum antimicrobial group and a narrow-spectrum antimicrobial group, based on whether they received broad-spectrum antimicrobials for more or less than 72 h, respectively. Differences in patient characteristics, background of infectious diseases and empirical antimicrobial administration, and outcomes between the two groups were compared using the chi-square tests (Monte Carlo method) for categorical variables and the Mann–Whitney U-test for continuous variables. We also conducted a logistic regression analysis to investigate the factors associated with the detection of new MDR bacteria. Results A total of 254 patients from 31 Japanese ICUs were included in the analysis, of whom 159 (62.6%) were included in the broad-spectrum antimicrobial group and 95 (37.4%) were included in the narrow-spectrum antimicrobial group. The detection of new MDR bacteria was significantly higher in the broad-spectrum antimicrobial group (11.9% vs. 4.2%, p = 0.042). Logistic regression showed that broad-spectrum antimicrobial continuation for more than 72 h (OR [odds ratio] 3.09, p = 0.047) and cerebrovascular comorbidity on ICU admission (OR 2.91, p = 0.041) were associated with the detection of new MDR bacteria. Conclusions Among Japanese ICU patients treated with empirical antimicrobials, broad-spectrum antimicrobial usage for more than 72 h was associated with the increased detection of new MDR bacteria. Antimicrobial stewardship programs in ICUs should discourage the prolonged use of empirical broad-spectrum antimicrobial therapy. Trial registration ClinicalTrials.gov, NCT02920463, Registered 30 September 2016, https://clinicaltrials.gov/ct2/show/NCT02920463

Abstract Background Pulmonary actinomycosis is a chronic disease characterized by abscess formation, draining sinuses, fistulae, and tissue fibrosis. It can mimic other conditions, particularly malignant and granulomatous diseases, and is perhaps extremely challenging to diagnose. Case presentation A 64-year-old Japanese man presented with 6-week history of a painful solid lump in the chest wall. Chest computed tomography scan revealed a mass-like consolidation in the left upper lobe, with rib erosion and direct extension into the anterior chest wall. 18F-fluorodeoxyglucose positron emission tomography scan showed increased metabolic activity in the mass, which is indicative of primary lung cancer. The bronchoscopy and computed tomography scan-guided transthoracic biopsy results were considered nondiagnostic. Finally, the patient was diagnosed with pulmonary actinomycosis via surgical resection. He completed an 8-week course of antibiotic therapy and experienced no recurrence. Conclusions There is no difference in positron emission tomography/computed tomography scan findings between actinomycosis and malignancy. Therefore, pulmonary actinomycosis should be considered in the differential diagnosis of cases involving intensive activity on 18F-fluorodeoxyglucose positron emission tomography scan.

Introduction This is a multicentre, open-label, single-arm clinical trial to evaluate the efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer.Methods and analysis The trial will be performed at 4 university hospitals and 14 city hospitals in Japan. The target number of patients will be 110. The patients will be orally administered 240 mg apalutamide once daily during the treatment period. The primary outcome is the prostate-specific antigen (PSA) response rate. PSA response is defined as ≥50% decline from baseline at 12 weeks. Secondary outcomes are time to PSA progression, progression-free survival, overall survival, progression-free survival during second therapy, ≥50% decline in PSA from baseline at 24 and 48 weeks, ≥90% decline in PSA from baseline or lower PSA detection sensitivity after the initial dose at 12, 24 and 48 weeks, PSA maximal changes, accumulated PSA response from screening to 24 and 48 weeks, and grade 3 or 4 adverse events according to the Common Terminology Criteria for Adverse Events version 4.0.Ethics and dissemination This study has been approved by the Certified Research Review Board of Kobe University (No. CRB5180009). All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The datasets generated during the study will be available from the corresponding author on reasonable request.Trial registration number jRCTs051220077.

Introduction Xeroderma pigmentosum (XP) is a rare intractable disease without a fundamental treatment, presenting with severe photosensitivity, freckle-like pigmented and depigmented maculae and numerous skin cancers before the age of 10 years without strict sun protection. About 70% of the patients exhibit extremely severe sunburn reactions and most of them develop neurological symptoms, including sensorineural hearing impairment and progressive peripheral and central nervous disorders beginning from childhood ages. In the preclinical study, we found that N-acetyl-5-methoxytryptamine was effective in suppressing skin tumour development in addition to improvement of auditory brainstem response in chronically ultraviolet-irradiated XP-A model mice.Methods and analysis On the bases of the preclinical study, we conduct a clinical trial on the efficacy of NPC-15 for patients with XP with exaggerated sunburn reaction type by a multicentre, double-blinded placebo-controlled, two-group crossover study followed by a 52 weeks open study.Ethics and dissemination Ethics approval is overseen by the Kobe University Institutional Review Board and Osaka Medical and Pharmaceutical University Institutional Review Board, and the study is conducted in accordance with the approved protocol. All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The data sets generated during the study will be available from the corresponding author on reasonable request.Trial registration number jRCTs051210181.

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Cancer-associated fibroblasts (CAFs) are the main stromal cells in the tumor microenvironment (TME). As CAFs promote tumor progression and hypoxia in the TME, regulating the conversion of normal fibroblasts (NFs) into CAFs is essential for improving the prognosis of patients with OSCC. We have previously reported the antitumor effects of transcutaneous carbon dioxide (CO2) application in OSCC. However, the effects of reducing hypoxia in the TME remain unclear. In this study, we investigated whether CO2 administration improves the TME by evaluating CAFs marker expression. Human OSCC cells (HSC-3) and normal human dermal fibroblasts (NHDF) were coinjected subcutaneously into the dorsal region of mice. CO2 gas was applied twice a week for 3 weeks. The tumors were harvested six times after transcutaneous CO2 application. The expression of CAFs markers (α-SMA, FAP, PDPN, and TGF-β) were evaluated by using real-time polymerase chain reaction and immunohistochemical staining. The expression of α-SMA, FAP, PDPN, and TGF-β was significantly increased over time after co-injection. In the CO2-treated group, tumor growth was significantly suppressed after treatment initiation. In addition, the mRNA expression of these markers was significantly inhibited. Furthermore, immunohistochemical staining revealed a significant decrease in the protein expression of all CAFs markers in the CO2-treated group. We confirmed that transcutaneous CO2 application suppressed CAFs marker expression and tumor growth in OSCC xenograft mouse model.

Summary: Somatic stem cells are advantageous research targets for understanding the properties required to maintain stemness. Human bone marrow-mesenchymal stromal cells (BM-MSCs) were separated into pluripotent-like SSEA-3(+) Muse cells (Muse-MSCs) and multipotent SSEA-3(−) MSCs (MSCs) and were subjected to single-cell RNA sequencing analysis. Compared with MSCs, Muse-MSCs exhibited higher expression levels of the p53 repressor MDM2; signal acceptance-related genes EGF, VEGF, PDGF, WNT, TGFB, INHB, and CSF; ribosomal protein; and glycolysis and oxidative phosphorylation. Conversely, MSCs had higher expression levels of FGF and ANGPT; Rho family and caveola-related genes; amino acid and cofactor metabolism; MHC class I/II, and lysosomal enzyme genes than Muse-MSCs. Unsupervised clustering further divided Muse-MSCs into two clusters stratified by the expression of cell cycle-related genes, and MSCs into three clusters stratified by the expression of cell cycle-, cytoskeleton-, and extracellular matrix-related genes. This study evaluating the differentiation ability of BM-MSC subpopulations provides intriguing insights for understanding stemness.

Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2 months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells via intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.

Abstract A study using Arase data gives the first observational evidence that the frequency drift of electromagnetic ion cyclotron (EMIC) waves is caused by cyclotron trapping. EMIC emissions play an important role in planetary magnetospheres, causing scattering loss of radiation belt relativistic electrons and energetic protons. EMIC waves frequently show nonlinear signatures that include frequency drift and amplitude enhancements. While nonlinear growth theory has suggested that the frequency change is caused by nonlinear resonant currents owing to cyclotron trapping of the particles, observational evidence for this has been elusive. We survey the wave data observed by Arase from March, 2017 to September 2019, and find the best falling tone emission event, one detected on 11th November, 2017, for the wave particle interaction analysis. Here, we show for the first time direct evidence of the formation of a proton hill in phase space indicating cyclotron trapping. The associated resonance currents and the wave growth of a falling tone EMIC wave are observed coincident with the hill, as theoretically predicted.

Abstract Background This prospective study investigated the change of swallowing ability using the Swallowing Ability Scale System (SASS) and swallowing-related quality of life (QOL) by Performance Status Scale for Head and Neck Cancer patients (PSS-H&N). This study also investigated the risk factors for postoperative dysphagia in patients who received reconstructive surgery for oral cancer. Subjects and Methods This study included 64 patients (33 men and 31 women) who underwent radical surgery with neck dissection and reconstructive surgery for oral cancers between July 2014 and February 2018. We evaluated risk factors for poor swallowing ability after treatment, including demographic factors, preoperative factors and perioperative factors, with univariate and multivariate analyses. The change of swallowing ability by the SASS and swallowing-related QOL by PSS-H&N were evaluated prospectively prior to the initiation of surgery within 1 week and at 1 and 3 months after treatment. Results Advanced T stage (T3, 4) (odds ratio (OR) = 79.71), bilateral neck dissection (OR = 20.66) and the resection of unilateral or bilateral suprahyoid muscles (OR = 17.00) were associated with poor swallowing ability after treatment. The scores for time for food intake and Eating in Public were associated with decrease of QOL in the poor group. Conclusions We propose that clinicians consider the risk factors identified in this study and pay close attention to the management of oral cancer patients with reconstructive surgery. Graphical abstract

Abstract Bright, discrete, thin auroral arcs are a typical form of auroras in nightside polar regions. Their light is produced by magnetospheric electrons, accelerated downward to obtain energies of several kilo electron volts by a quasi-static electric field. These electrons collide with and excite thermosphere atoms to higher energy states at altitude of ~ 100 km; relaxation from these states produces the auroral light. The electric potential accelerating the aurora-producing electrons has been reported to lie immediately above the ionosphere, at a few altitudes of thousand kilometres1. However, the highest altitude at which the precipitating electron is accelerated by the parallel potential drop is still unclear. Here, we show that active auroral arcs are powered by electrons accelerated at altitudes reaching greater than 30,000 km. We employ high-angular resolution electron observations achieved by the Arase satellite in the magnetosphere and optical observations of the aurora from a ground-based all-sky imager. Our observations of electron properties and dynamics resemble those of electron potential acceleration reported from low-altitude satellites except that the acceleration region is much higher than previously assumed. This shows that the dominant auroral acceleration region can extend far above a few thousand kilometres, well within the magnetospheric plasma proper, suggesting formation of the acceleration region by some unknown magnetospheric mechanisms.

Left ventricular hypertrophy commonly occurs in dialysis patients and is associated with a risk of developing cardiovascular disease events and all-cause mortality. Although hypertension treatment reduces left ventricular mass index (LVMI) in hemodialysis patients, the relationships of prescription pattern, dose, and changes in the dose of antihypertensive drugs with LVMI have not been completely elucidated. Here, we hypothesized that volume reduction would lead to a decrease in the antihypertensive drug dose and subsequently to a reduction in LVMI; conversely, fluid retention would lead to an increase in the antihypertensive drug use and, subsequently, to LVMI progression. To assess this hypothesis, we investigated the relationship between changes in the dose of antihypertensive drugs and subsequent changes in LVMI in 240 patients who had just started hemodialysis using a retrospective hemodialysis cohort in Japan. Using multiple linear regression analysis, we assessed the association between changes in the antihypertensive drug dose over 1 year after hemodialysis initiation and changes in LVMI during this period. A decrease and an increase in the antihypertensive drug dose were significantly associated with a reduction in LVMI (vs. no change; β = – 17.386, p < .001) and LVMI progression (vs. no change; β = 16.192, p < .001), respectively. In conclusion, our findings suggested that volume reduction, leading to a decrease in the use of antihypertensive drugs, is a therapeutic strategy in patients undergoing hemodialysis to prevent LVMI progression.

BackgroundExtraction of mandibular third molars is one of the most commonly performed oral surgical procedures, and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management. Oral NSAIDs are associated with adverse events such as gastrointestinal disorders, renal and hepatic dysfunction, and platelet dysfunction. Topical analgesics have been proposed as alternatives to oral and injectable medications to safely improve postoperative pain relief. We will conduct a single-center, placebo-controlled, double-blind, randomized crossover trial to assess the pain-relieving effect of an ibuprofen-containing gargle in patients undergoing extraction of mandibular third molars when compared with a placebo gargle. ObjectiveThis will be the first clinical study to compare the efficacy of an ibuprofen gargle with that of a placebo for relieving postoperative pain in addition to loxoprofen after mandibular third molar extraction. MethodsThis study will be performed at Kobe University Hospital. Participants (N=40) will be randomized equally to 1 of 2 groups. The ibuprofen-placebo group will receive an ibuprofen gargle on postoperative day (POD) 1 and a placebo gargle on POD 2. The placebo-ibuprofen group will receive a placebo gargle on POD 1 and an ibuprofen gargle on POD 2. Both groups will receive ibuprofen gargles on PODs 3-5 at least once daily. The primary objective is to estimate the within-subject difference on a visual analog scale (VAS) before and 5 minutes after using the ibuprofen or placebo gargle on PODs 1 and 2. The secondary objectives are to estimate the within-subject differences in ΔVAS before and 15 minutes after using the ibuprofen or placebo gargle on PODs 1 and 2, ΔVAS before and 5 or 15 minutes after using the ibuprofen gargle on PODs 3-5, overall efficacy (self-completion, 5 scales) on PODs 1-5, daily frequency of use (ibuprofen or placebo gargle and analgesics) on PODs 1-7, and the occurrence of adverse events. ResultsThe Certified Review Board of Kobe University approved the study. The intervention was implemented in May 2021. For the primary analysis, we will calculate the mean and SD of ΔVAS5 on PODs 1 and 2 and the within-study difference in ΔVAS5. The treatment effect will be estimated by dividing the mean ΔVAS5 in the within-subject difference by 2 and calculating the P value using an unpaired t test. For the secondary analysis, we will calculate the mean and SD of ΔVAS15 on PODs 1 and 2 and the within-study difference in ΔVAS15. The treatment effect will be estimated as in the primary analysis. ConclusionsThis trial will provide exploratory evidence of the efficacy and safety of an ibuprofen gargle for pain reduction after mandibular third molar extraction. Trial RegistrationJapan Registry of Clinical Trials jRCTs051210022; https://tinyurl.com/39ej23zu International Registered Report Identifier (IRRID)DERR1-10.2196/35533

Abstract Background Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor–sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor–dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy. Case presentation We report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective. Conclusions Despite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor–mutant tumor.

Abstract Background Prognostic biomarkers provide essential information about a patient’s overall outcome. However, existing biomarkers are limited in terms of either sample collection, such as requiring tissue specimens, or the process, such as prolonged time for analysis. In view of the need for convenient and non-invasive prognostic biomarkers for oral cancer, we aimed to investigate the prognostic values of neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio in patient survival. We also aimed to explore the associations of these ratios with the clinicopathologic characteristics of Japanese oral squamous cell carcinoma patients. Methods This study was a non-randomized retrospective cohort study in a tertiary referral center. We included 433 patients (246 men, 187 women) who underwent radical surgery for oral cancers between January 2001 and December 2013. We evaluated various risk factors for poor prognosis including neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio with univariate and multivariate analyses. The disease-specific survival and overall survival rates of patients were compared among the factors and biomarkers. Results In multivariable Cox proportional hazards analysis, high neutrophil-to-lymphocyte ratio (hazard ratio 2.87, 95% confidence interval 1.59–5.19, P

Abstract Aims/Introduction We compared the results of testing for glutamic acid decarboxylase antibodies (GADAb) using a radioimmunoassay (RIA) and an enzyme‐linked immunosorbent assay (ELISA) in individuals with childhood‐onset type 1 diabetes mellitus. Materials and Methods Serum specimens were collected from 1,024 Japanese children (426 boys and 598 girls) in 2013. The median age at diagnosis was 7 years (0–18 years). The blood specimens were obtained at a median age of 13 years (2–22 years). Results Among the 628 children whose serum specimens were collected within 5 years after diagnosis, the rate of GADAb positivity was 47.9% using RIA and 69.4% using ELISA. The participants were divided into four groups according to their RIA and ELISA results for GADAb as follows: group I (RIA+/ELISA+), group II (RIA+/ELISA−), group III (RIA−/ELISA+) and group IV (RIA−/ELISA−). The clinical and genetic characteristics of group I and group III were quite similar in terms of age at diagnosis, male/female ratio, relatively high positive rates for both autoantibody to protein tyrosine phosphatase IA‐2 and autoantibody to the cation efflux transporter zinc transporter 8, and human leukocyte antigen genotype. Group II contained just five patients, and was characterized by a younger age at diagnosis, low positive rates for both autoantibody to protein tyrosine phosphatase IA‐2 and autoantibody to the cation efflux transporter zinc transporter 8, and a unique human leukocyte antigen genotype. If the positive rates of either autoantibody to protein tyrosine phosphatase IA‐2 or autoantibody to the cation efflux transporter zinc transporter 8 or both were added to the GADAb results using RIA, the percentage of autoimmune type 1 diabetes increased from 47.9% to 78.5%. Conclusions The diagnosis of autoimmune childhood‐onset Japanese type 1 diabetes increased when GADAb results were obtained using a new ELISA method, compared with a previously utilized RIA method.

Abstract We evaluated a method for retrieving vertical temperature and Doppler wind velocity profiles of the Venusian nightside mesosphere from the CO2 absorption line resolved by mid-infrared heterodyne spectroscopy. The achievable sensitive altitude and retrieval accuracy were derived with multiple model spectra generated from various temperature and wind velocity profiles with several noise levels. The temperature profiles were retrieved at altitudes of 70–100 km with a vertical resolution of 5 km and a retrieval accuracy of ± 15 K. The wind velocity was also retrieved at an altitude of approximately 85 km with a vertical resolution of 10 km and a retrieval accuracy of ± 25–50 m/s. In addition, we studied an event and applied our method to spectra obtained by the HIPWAC instrument attached to the NASA/IRTF 3-m telescope on May 19–22, 2012. Retrieved wind velocities in a latitude of 33° S at 3:00 LT were interpreted as subsolar-to-antisolar (SS-AS) flows at altitudes of 84 ± 6 km and 94 ± 7 km, and they were stronger than expected. This result suggested that the transition between the retrograde superrotational zonal (RSZ) wind and SS-AS flow may occur at altitudes below 90 km which previously was predicted to be the transition region. This work provides a basis for our analysis of further observations obtained by a mid-infrared heterodyne spectrometer MILAHI attached to the Tohoku University 60-cm telescope at Haleakalā, Hawaii.

Abstract Background Chronic spontaneous urticaria (CSU) is characterized by the spontaneous appearance of wheals, angioedema, or both for > 6 weeks. Continuous treatment with H1-antihistamines is used as a first-line treatment for CSU. However, H1-antihistamine treatment leads to absence of symptoms in less than 50% of patients with CSU. Although Japanese guidelines for the diagnosis and treatment of urticaria recommend an increase in the H1-antihistamine dose or a switch to other H1-antihistamines, there is no evidence supporting a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. Methods We will conduct a multicenter, open-label, non-inferiority, randomized, parallel, comparison study to determine if the efficacy of bilastine 20 mg is not inferior to that of a twofold H1-antihistamine dose increase in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. This study will be performed at 15 academic hospitals in Japan, and the administration period (increasing the H1-antihistamine dose twofold vs. switching to bilastine 20 mg) will be 7 days. Participants (n = 150) will be randomized to either an increased H1-antihistamine dose or a switch to bilastine 20 mg at a 1:1 ratio. The primary endpoint, mean of the total symptom score of 5–7 days after the intervention, will be evaluated. The secondary objective is to determine if the safety of bilastine 20 mg regarding somnolence is superior to that of a twofold dose increase of H1-antihistamines. This will be measured by a change in the Japanese version of the Epworth Sleepiness Scale from baseline to 7 days after starting the intervention. Discussion This multicenter, open-label, non-inferiority, randomized, parallel, comparison study will be, to our knowledge, the first well-designed clinical study to evaluate the efficacy of a switch to other H1-antihistamines in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed doses. This trial will provide evidence of the efficacy and safety of bilastine when treatment is switched in patients with refractory CSU who are unresponsive to H1-antihistamines at the licensed dose. Trial registration Japan Registry of Clinical Trials (jRCT), jRCTs051180105. Registered on 8 March 2019.

Objective: This study aimed to clarify whether the glial fibrillary acidic protein (GFAP) and soluble protein-100β (S100β) can predict severe traumatic brain injury (TBI) in patients with severe multiple trauma. Methods: This is a single-center retrospective observational study of 179 patients with severe multiple trauma. The GFAP and S100β were measured upon patient arrival at the hospital. We divided the patients into the severe TBI group (with a Traumatic Coma Data Bank classification of ≥III), the non-severe TBI group (non-TBI group [absence of abnormality on the computed tomography scan and extracranial injury], and the mild to moderate TBI group [TCDB classification I and II]). We compared biomarker levels between the two groups and then evaluated the accuracy of predicting severe TBI using a receiver operating characteristic curve. Results: A total of 41 patients had severe TBI, and 138 had non-severe TBI. Mean GFAP levels were significantly higher in the severe TBI group (median, 6000 pg/mL; interquartile range [IQR], 651–15,548 pg/mL) than in the non-severe TBI group (median, 149 pg/mL; IQR, 0–695 pg/mL) (p

Oral lichen planus (OLP) is a type of chronic and refractory stomatitis characterized by abnormal keratinization, which is often painful. There is no consensus regarding treatment options for OLP, particularly in the presence of pain. The current study protocol focuses on the short-term efficacy and long-term safety of an ibuprofen gargle for pain management in patients with OLP. Patients (n = 24) with painful OLP will be enrolled. During a crossover study period, patients in the ibuprofen–placebo (IP) group will receive an ibuprofen gargle (0.6%) on day 1, a placebo gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. Patients in the placebo–ibuprofen (PI) group will receive a placebo gargle on day 1, an ibuprofen gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. The primary endpoint of the crossover study period is the change in pain level as measured by a visual analogue scale score from before gargle administration to 5 min after gargle administration on days 1 and 2. The primary endpoint of the long-term extension study is assessment of long-term safety. The results of this study may support existing evidence regarding the effectiveness of ibuprofen rinses in treating OLP.

Summary: Background: There are an estimated 1·3–4·0 million cases of cholera and 20 000–140 000 cholera-related deaths worldwide each year. The rice-based cholera toxin B subunit (CTB) vaccine, MucoRice-CTB, is an oral candidate vaccine that does not require a cold chain, has shown efficacy in animal models, and could be of benefit in places where there is a paucity of medical infrastructure. We aim to assess the safety, tolerability, and immunogenicity of MucoRice-CTB in humans. Methods: We did a double-blind, randomised, placebo-controlled, dose-escalation, phase 1 study at one centre in Tokyo, Japan. Eligible participants were healthy adult men with measurable serum and faecal antibodies against CTB at screening. Participants were excluded if they had allergy to rice; history of cholera or travellers' diarrhoea; poorly controlled constipation; abnormal results on hepatic, renal, or haematological screening tests; use of any over-the-counter drugs within 7 days before first administration; inability to use a medically acceptable means of contraception; or other reasons by medical judgment of the investigator. Three dose cohorts of participants were randomly assigned by block to receive oral MucoRice-CTB (1 g, 3 g, or 6 g) or placebo (1 g, 3 g, or 6 g), once every 2 weeks for 8 weeks (for a total of 4 doses). The dose groups were performed sequentially, and each dose cohort was completed before the higher dose cohort began. All medical staff, participants, and most trial staff were masked to treatment allocation. The primary outcomes were safety and tolerability, measured by 12-lead electrocardiogram; vital signs; haematology, biochemistry, and urinalysis; rice protein-specific serum IgE antibody concentration; and monitoring of adverse events. Participants were assessed at baseline and at 1, 2, 4, 6, 8, and 16 weeks after the first administration of vaccine or placebo. The safety analysis set included all participants enrolled in the trial who received at least one dose of the study drug or placebo and were compliant with good clinical practice. The full analysis population included all participants enrolled in the trial who received at least one dose of the study drug and for whom any data were obtained after the start of study drug administration. Meta-genomic analysis of study participants was performed using bacterial DNA from faecal samples before vaccination. This trial is registered with UMIN.ac.jp, UMIN000018001. Findings: Between June 23, 2015, and May 31, 2016, 226 participants were recruited and assessed for eligibility. 166 participants were excluded based on health condition or schedule. We then randomly selected 60 male volunteers aged 20–40 years who were enrolled and assigned to MucoRice-CTB (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g), or placebo (10 participants assigned to 1 g, 10 participants assigned to 3 g, and 10 participants assigned to 6 g). All participants received at least one dose of study drug or placebo and were included in the safety analyses. Two participants given MucoRice-CTB 3 g and one participant given MucoRice-CTB 6 g were lost to follow-up and excluded from the efficacy analysis. Serum CTB-specific IgG and IgA antibody concentrations in participants who received 6 g MucoRice-CTB increased significantly in both a time-dependent and dose-dependent manner compared with those in the placebo groups (p for interaction=0·002 for IgG, p=0·004 for IgA). Genome analysis of subjects' faeces before vaccination revealed that compared to non-responders, responders had a gut microbiota of higher diversity with the presence of Escherichia coli and Shigella spp. 28 (93%) of 30 participants who received MucoRice-CTB at any dose had at least one adverse event during the study period, compared with 30 (100%) of 30 participants given placebo. Grade 3 or higher adverse events were reported in four participants in the MucoRice-CTB group (5 events) and four participants in the placebo group (10 events). The most common serious adverse event was haemoglobin decreased (2 events in 2 participants in the pooled MucoRice-CTB group, 2 events in 2 participants in the placebo group; all grade 3). Interpretation: Participants given MucoRice-CTB showed increased CTB-specific serum IgG and IgA antibody concentrations without inducing serious adverse events, indicating that MucoRice-CTB could be a safe and potent vaccine to prevent diarrhoeal disease. MucoRice-CTB induced neutralising antibodies against diarrhoeal toxins in a gut microbiota-dependent manner. A similar phase 1 trial will be done with participants of other ethnicities to substantiate our findings. Funding: Translational Research Acceleration Network Program of Japan Agency for Medical Research and Development; Ministry of Education, Culture, Sports, Science and Technology, Japan; Science and Technology Research Partnership for Sustainable Development; Grant-in-Aid for Scientific Research (S) (18H05280) (to H K) from the Japan Society for the Promotion of Science (JSPS); Grant-in-Aid for Young Scientists (B) (16K16144) (to Y K) from JSPS; Grant-in-Aid for Young Scientists (18K18148) (to Y K) from JSPS; Grant from International Joint Usage/Research Center (K3002), the Institute of Medical Science, University of Tokyo

Introduction This research project addresses the lack of screening tools for the early detection of high-risk individuals for long-term care, through four individual studies.Study 1 investigates the predictive ability of the ‘Kihon Check List’, study 2 the ‘Cognitive Function instrument’ and EuroQol-5 Dimension (EQ-5D) and study 3 the ‘Cognitive Function instrument’ and EQ-5D as well as the ‘Frail Kenshin’ health check-up, for incident long-term care certification over a follow-up period of up to 4 years. This is the first large prospective study to evaluate the predictive ability of these tools for the outcome measure long-term care certification. The last subsection of this project study four aims to explore a mixed methods intervention for delaying the need for long-term care. This section is purely exploratory, looking for clues for further studies.Methods and analysis Baseline data have been collected through local government programs, as well as through postal self-reported questionnaires. The primary outcome variable for all studies is long-term care certification data. Statistical analysis will be carried out using Kaplan-Meier, Multiple Cox regression as well as logistic regression.Conclusion This project hopes to identify tools effective in predicting long-term care need. This will enable identification of citizens that are of higher risk for long-term care in the near future. This subset of high-risk individuals can in the future be addressed for extra support/intervention.Ethics and dissemination All studies have been approved by respective institutional ethical committees and the WHO ethical committee ERC.0002899. In addition, all studies conform to the provisions of the Declaration of Helsinki and are conducted in accordance with Japan’s ‘Ethical Guidelines for Medical and Health Research Involving Human Subjects’. All findings will be disseminated at conferences and published in peer-reviewed journals.Trial registration number UMIN000023283.