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We investigated whether C(-260)-->T polymorphism in the promoter of the CD14 monocyte receptor gene predisposed to coronary atherosclerosis and acute myocardial infarction (AMI) in Japanese men. The frequencies of T allele and T/T homozygotes in patients with AMI were significantly higher than in controls and in patients with angina without prior AMI, suggesting that the CD14 promoter polymorphism is associated with AMI rather than with coronary atherosclerosis, and this polymorphism may be one of the genetic risk factors for AMI in Japanese men. [ABSTRACT FROM AUTHOR]

Background. Epilepsy is prevalent in the elderly, whose brain morphologies and skull electrical characteristics differ from those of younger adults. Here, using a multivariate definition of signal-to-noise ratio (SNR), we explored the detectability of epileptic spikes in scalp EEG measurements in elderly by forward simulations of hypersynchronous spikes generated at 78 cortical regions of interest (ROIs) in the presence of background noise. Methods. Simulated electric potentials were measured at 18, 35, and 70 standard 10-20 electrode positions using three reference methods: infinity reference (INF), common average reference (CAR), and average mastoid reference (M1M2). MRIs of six elderly subjects were used to construct finite element method (FEM) models with age-adjusted skull conductivities. Results. SNRs of epileptic spikes increased with increasing sizes of the brain electrical source areas, although medial and deep brain regions such as the hippocampus showed lower SNRs, consistent with clinical findings. The SNRs were greater in the 70-channel dataset than in the 18-channel and 35-channel datasets, especially for ROIs located closer to the head surface. In addition, the SNRs were lower for the CAR and M1M2 references than for the ideal INF reference. Moreover, we found comparable results in the standard FEM heads with age-adjusted skull conductivities. Conclusions. The results provide insights for evaluating scalp EEG data in elderly patients with suspected epilepsy, and suggest that age-adjusted skull conductivity is an important factor for forward models in elderly adults, and that the standard FEM head with age-adjusted skull conductivity can be used when MRIs are not available., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MEP was, and AS is affiliated with companies that develop and market the software used in this study. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background/objectives: Lactobacillus helveticus GCL1815 is a lactic acid bacterium thought to activate dendritic cells. This randomized, placebo-controlled, double-blind study aimed to evaluate the effects of L. helveticus GCL1815 on human dendritic cells and the onset of the common cold., Methods: Two hundred participants were divided into two groups and took capsules containing either six billion L. helveticus GCL1815 cells or placebo for 8 weeks., Results: In the GCL1815 group, the cumulative incidence days of symptoms such as feverishness, fatigue, tiredness, runny nose, nasal congestion, and phlegm were significantly lower than in the placebo group. Moreover, the change in the expression of HLA-DR on plasmacytoid dendritic cells was significantly higher in the GCL1815 group than in the placebo group at 4 and 8 weeks of intake. The expression of CD86 on plasmacytoid dendritic cells was significantly increased in the GCL1815 group at 4 and 8 weeks compared with before intake. Additionally, the expression of HLA-DR on type 1 conventional dendritic cells was significantly higher in the GCL1815 group than in the placebo group at 8 weeks of intake. The expression of CD86 on type 1 conventional dendritic cells significantly decreased in the placebo group but remained statistically the same in the GCL1815 group after intake compared with before., Conclusions: These results suggest that GCL1815 intake may enhance the response to viruses by activating two types of dendritic cells, thereby preventing the onset of systemic and local common colds in healthy adults.

Macular hole (MH) is a retinal break involving the fovea that causes impaired vision. Although advances in vitreoretinal surgical techniques achieve >90% MH closure rate, refractory cases still exist. For such cases, autologous retinal transplantation is an optional therapy showing good anatomic success, but visual improvement is limited and peripheral visual field defects are inevitable after graft harvesting. Here, using a non-human primate model, we evaluated whether human embryonic stem cell-derived retinal organoid (RO) sheet transplantation can be an effective option for treating MH. After transplantation, MH was successfully closed by continuous filling of the MH space with the RO sheet, resulting in improved visual function, although no host-graft synaptic connections were confirmed. Mild xeno-transplantation rejection was controlled by additional focal steroid injections and rod/cone photoreceptors developed in the graft. Overall, our findings suggest pluripotent stem cell-derived RO sheet transplantation as a practical option for refractory MH treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We previously showed that ARCT-154, a self-amplifying mRNA COVID-19 vaccine, had improved immunogenicity and antibody persistence compared with conventional mRNA or adenovirus vector vaccines. In this study, we compared ARCT-2301, a bivalent self-amplifying mRNA vaccine (Asp614Gly and omicron BA.4/5 variant), with the bivalent Comirnaty omicron BA.4-5 vaccine, to determine whether this improved response persisted in bivalent formulations against different SARS-CoV-2 variants., Methods: This randomised, multicentre, phase 3, observer-masked, active-controlled comparative study was done at nine hospitals in Japan. Eligible participants were healthy Japanese adults, aged at least 18 years, who had previously received a full immunisation series of three to five doses of mRNA COVID-19 vaccines (Comirnaty or Spikevax [Moderna]), with the last dose received at least 3 months before screening for this trial. Participants were randomly assigned (1:1) to either ARCT-2301 or Comirnaty BA.4-5 mRNA vaccine using interactive computer-generated randomisation with a block size of four. Randomisation was stratified by gender (men vs women), age group (<65 years vs ≥65 years), type of vaccine used for last vaccination (bivalent omicron BA.1 vs bivalent omicron BA.4/5), and time since last COVID-19 vaccination (<5 months vs ≥5 months). ARCT-2301 was supplied in vials containing 100 μg lyophilised mRNA, 50 μg mRNA each coding for the full-length spike proteins of the ancestral Asp614Gly SARS-CoV-2 strain and omicron BA.4/5 variant. Immediately before use, each vial was reconstituted with 10 mL saline. The comparator original omicron BA.4/5 mRNA vaccine (Comirnaty BA.4-5) was supplied in ready-to-use vials containing a single dose of 30 μg mRNA in 0·3 mL volume. Both vaccines were administered by intramuscular injection in the deltoid of the non-dominant arm. The primary outcome of the study was to show non-inferiority of immunogenicity of ARCT-2301 versus Comirnaty BA.4-5 at day 29 as neutralising antibody geometric mean titres (GMT) and seroresponse rates against omicron BA.4/5. Primary analyses were done in a per-protocol manner. The trial is registered with the Japan Registry for Clinical Trials, jRCT2031230340., Findings: Between Sept 29 and Nov 18, 2023, we enrolled 930 participants (451 men and 479 women) to receive a booster dose of ARCT-2301 (n=465) or Comirnaty BA.4-5 (n=465). The primary immunogenicity outcome to show that the antibody response at day 29 against omicron BA.4/5 elicited by ARCT-2301 was non-inferior to that elicited with Comirnaty BA.4-5 was achieved, both by GMT ratio (1·49, 95% CI 1·26-1·76) and difference in seroresponse rate (7·2%, 95% CI 0·6-13·7). Furthermore, the differences in antibody response between the groups showed superiority for ARCT-2301 against Wuhan-Hu-1 using both criteria, with a GMT ratio of 1·45 (95% CI 1·28-1·63) and a difference in seroresponse rate of 12·5% (95% CI 5·9-19·0), and omicron XBB.1.5, with a GMT ratio of 1·63 (95% CI 1·36-1·94) and a seroresponse rate difference of 16·7% (95% CI 10·1-23·2). Both vaccines were well-tolerated with mainly mild, transient solicited adverse events and no causally related severe or serious adverse events., Interpretation: Boosting mRNA-immunised adults with ARCT-2301 induced superior immunogenicity compared with Comirnaty BA.4-5 against both Wuhan-Hu-1 and omicron BA.4/5 variant COVID-19, and elicited a higher response against omicron XBB.1.5. Both vaccines had similar tolerability profiles. Self-amplifying mRNA vaccines could provide a substantial contribution to pandemic preparedness and response, inducing robust immune responses with a lower dose of mRNA to allow wider and more equitable distribution., Funding: Japanese Ministry of Health, Labour, and Welfare and Meiji Seika Pharma., Competing Interests: Declaration of interests YO, IO, MO, NI, YI, TM, and YY are full-time employees of and TK is a board member of the study sponsor (Meiji Seika Pharma). YK received fees from Meiji Seika Pharma for medical consultation during this study. IS and YZ are full-time employees of Arcturus Therapeutics, who developed the vaccine. JvB is a full-time employee of CSL Sequiris, which has a marketing agreement for the vaccine. JLW is an independent consultant working for Arcturus Therapeutics., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Factors that affect the change of first-line antimicrobial agents were investigated to further promote their appropriate use., Methods: This descriptive study used an electronic medical records database. Total 16,353 of the 199,896 patients enrolled between 1996 and 2019 met the inclusion criteria and formed the overall pediatric acute otitis media (AOM) cohort. The factors leading to the change in first-line antimicrobial agents within 14 days were analyzed using classification and regression trees (CART) analysis., Results: This antimicrobial treatment cohort, involved 4860 cases of AOM alone and 9567 cases of AOM with other diseases. The size of the medical facility based on number of beds and historical duration of patient registration impacted on antimicrobial changes., Conclusions: The current results show that hospital-wide or nation-wide antimicrobial stewardship promotion could be the most influencing factor for antimicrobial changes. Particularly in cases of AOM where other diseases coexist, a more accurate diagnosis and definition of treatment failure of first-line drug are suggested to be important while establishing future treatment strategies. The current study is important to promote appropriate antimicrobial use for AOM treatment., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: The continuation rates of pharmacotherapy in schizophrenia exhibit variability, a phenomenon influenced by the specific antipsychotic agent prescribed and patient-related factors such as age and duration of illness. In this context, our study aims to elucidate the predictors of medication continuation for asenapine sublingual tablets, characterized by unique formulation properties., Methods: Our investigation leveraged real-world data collected through post-marketing surveillance in Japan, comprising 3236 cases. Utilizing multivariate logistic regression analysis, we identified patient-related factors associated with medication continuation as the primary outcome measure, subsequently employing survival analysis for further evaluation. Additionally, adverse event occurrence was assessed as a secondary outcome measure., Results: Multivariate logistic regression analysis unveiled significant predictors of asenapine continuation, notably including patient-related factors such as a chlorpromazine equivalent dose exceeding 600 mg/day and an illness duration of 25 years or more. While the overall continuation rate stood at 40.6%, patients exhibiting factors such as a chlorpromazine equivalent dose surpassing 600 mg/day or an illness duration exceeding 25 years demonstrated continuation rates of 46.3% and 47.9%, respectively. Remarkably, patients presenting both factors showcased the highest continuation rate at 52.5%., Conclusions: Our findings shed light on distinct patient-related predictors of asenapine continuation, deviating from those observed with other antipsychotic medications. This underscores the necessity of recognizing that predictive factors for antipsychotic medication continuation vary across different agents. Moving forward, elucidating these predictive factors for various antipsychotic medications holds paramount importance in schizophrenia treatment, facilitating the delivery of tailored therapeutic interventions for individual patients., (© 2024. The Author(s).)

Aim: The ingestion of Lactiplantibacillus plantarum OLL2712 (OLL2712) cells has been shown to improve glucose metabolism by suppressing chronic inflammation in murine models and clinical studies. This study aimed to clarify the effect of OLL2712 on glycaemic control in healthy adults with prediabetes., Materials and Methods: The study was a randomized, double-blind, placebo-controlled, parallel-group design. Adult participants with prediabetes [n = 148, glycated haemoglobin (HbA1c) range: 5.6%-6.4%, age range: 20-64 years] were assigned randomly to placebo or OLL2712 groups (n = 74/group) and administered daily for 12 weeks either conventional yogurt or yogurt containing >5 × 10 9 heat-treated OLL2712 cells, respectively. In addition, the participants were followed for 8 weeks after the discontinuation of either yogurt. The primary outcome was the changes in HbA1c levels at weeks 12 and 16 by analysis of covariance., Results: The levels of HbA1c and glycoalbumin decreased significantly in both groups at week 12 in comparison with those at week 0, but only in the OLL2712 group at week 16. HbA1c levels decreased significantly at weeks 12 and 16 in the OLL2712 group in comparison with the placebo group (p = .014 and p = .006, respectively). No significant inter- and intragroup differences in HbA1c levels were observed at week 20., Conclusions: The ingestion of OLL2712 prevents the deterioration of glycaemic control and maintains the HbA1c levels within the normal range in adults with prediabetes; yogurt probably exhibits similar effects, which may contribute to reducing the risk of developing type 2 diabetes., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

A randomized, placebo-controlled, double-blind, parallel-group clinical study was conducted to examine the effects of ingesting a heat-killed lactic acid bacterium, Lactobacillus johnsonii No. 1088 (LJ88) on temporal gastroesophageal reflux-related symptoms in healthy volunteers. A total of 120 healthy Japanese volunteers of both sexes, aged between 21 and 63 years, whose Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) total score was 8 or greater, but who were not diagnosed with functional dyspepsia according to the Rome IV classification, were enrolled. They were randomly assigned to either the LJ88 or placebo group and instructed to ingest the test food (1 billion heat-killed LJ88 or placebo) once a day for six weeks. Gastroesophageal reflux-related symptoms were evaluated using FSSG scores as a primary endpoint. The Gastrointestinal Symptoms Rating Scale (GSRS), stomach state questionnaire, and serum gastrin concentration were used as secondary endpoints. In the FSSG evaluation, the heartburn score was significantly improved at 6 weeks in the LJ88 group compared to the placebo group. No severe adverse events related to the test food were observed. In conclusion, daily ingestion of heat-killed LJ88 improved temporal heartburn symptoms in non-diseased individuals.

Background: Licensed mRNA COVID-19 vaccines require booster doses to sustain SARS-CoV-2-specific responses, creating the need for novel, broadly immunogenic vaccines. We aimed to compare the immunogenicity, safety, and tolerability of ARCT-154-a self-amplifying mRNA vaccine against SARS-CoV-2 D614G variant-with the BNT162b2 (Comirnaty; Pfizer-BioNTech) mRNA vaccine when administered as a fourth-dose booster., Methods: This double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial, conducted at 11 outpatient clinical sites in Japan, enrolled healthy adults aged at least 18 years who had previously been immunised with two doses of an mRNA COVID-19 vaccine (BNT162b2 or mRNA-1273 [Spikevax; Moderna]) followed by a third dose of BNT162b2 at least 3 months before enrolment. Participants were randomly assigned, in a 1:1 ratio using an Interactive Response Technology system with a block size of four, and with stratification by age (18-64 years or ≥65 years) and by interval since last COVID-19 vaccination (<5 months or ≥5 months), to receive either ARCT-154 or BNT162b2 as a fourth-dose booster via deltoid intramuscular injection. Participants and investigators assessing outcomes were masked to group assignment. The primary objective, measured in per-protocol set 1 (consisting of participants with no evidence of previous SARS-CoV-2 infection who received their intended injection according to protocol), was to show that the immune response 28 days after the ARCT-154 vaccine was non-inferior to that of the BNT162b2 vaccine, measured in terms of both pseudovirus neutralising antibody geometric mean titre (GMT) ratios and seroresponse rates against the wild-type Wuhan-Hu-1 strain of SARS-CoV-2. Non-inferiority was declared when the lower limit of the 95% CI of the ARCT-154 to BNT162b2 GMT ratio exceeded 0·67, and when the lower limit for the difference in seroresponse rates exceeded -10%. Key secondary endpoints included the immune response against the omicron BA.4/5 subvariant, which was assessed for non-inferiority and superiority in per-protocol set 1. Safety was assessed in the full analysis set. This study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080, and is ongoing., Findings: Between Dec 13, 2022, and Feb 25, 2023, we enrolled and randomly assigned 828 participants to receive ARCT-154 (n=420) or BNT162b2 (n=408) vaccines as a fourth-dose booster. In per-protocol set 1, the GMTs of surrogate neutralising antibodies induced against the Wuhan-Hu-1 SARS-CoV-2 strain in the ARCT-154 group (5641 [95% CI 4321-7363]) were non-inferior to those in the BNT162b2 group (3934 [2993-5169]) when measured at 28 days after boosting, with a GMT ratio of 1·43 (95% CI 1·26-1·63). Seroresponse rates were 65·2% (95% CI 60·2-69·9) in the ARCT-154 group versus 51·6% (46·4-56·8) in the BNT162b2 group, a difference of 13·6% (95% CI 6·8-20·5). GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687-3859) in the ARCT-154 group and 1958 (1281-2993) in the BNT162b2 group-a GMT ratio of 1·30 (1·07-1·58)-with seroresponse rates of 69·9% (65·0-74·4) and 58·0% (52·8-63·1). Both boosters were equally well tolerated. No treatment-related deaths were reported, nor were there severe or serious adverse events considered to be causally associated related to study vaccination. One serious adverse event, a foot deformity reported in a participant in the BNT162b2 group, was observed but determined not to have a causal relationship to the study vaccination. One severe adverse event, a case of abnormal hepatic function in the ARCT-154 group, was considered to be related to study vaccine. Adverse events of special interest for detection of myocarditis and pericarditis included chest pain (one case in the ARCT-154 group and three cases in the BNT162b2 group) and shortness of breath (two cases in the BNT162b2 group), all of which were considered to have a reasonable possibility of being related to vaccination. Local reactions were reported by 398 (95%) of 420 participants receiving the ARCT-154 vaccine and 395 (97%) of 408 participants receiving the BNT162b2 vaccine, and solicited systemic adverse events by 276 (66%) of those receiving the ARCT-154 vaccine and 255 (63%) of those receiving the BNT162b2 vaccine. Adverse events were mainly mild in severity, occurring and resolving within 3-4 days after vaccination., Interpretation: In adults who had previously received three doses of an mRNA COVID-19 vaccine, immune responses 28 days after an ARCT-154 booster dose were non-inferior to those observed after a BNT162b2 booster dose for the Wuhan-Hu-1 strain of SARS-CoV-2 and superior for the Omicron BA.4/5 variant. Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection. Further studies will assess the immunogenicity induced against more recent SARS-CoV-2 variants., Funding: Japanese Ministry of Health, Labour, and Welfare., Translation: For the Japanese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests YO, MK, YI, IO, TM, and YY are full-time employees of, and TK is a board member of, the study sponsor Meiji Seika Pharma. YK received fees from Meiji Seika Pharma for medical consultation during this study. BG and YZ are full-time employees of Arcturus Therapeutics, which developed the vaccine, and JLW is an independent consultant working for Arcturus Therapeutics., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: TK is a board member and stockholder of Meiji Seika Pharma. YO, MK, YI, IO, TM, and YY are full-time employees of Meiji Seika Pharma. YK received consulting fees from Meiji Seika Pharma. PC and YZ are full-time employees with stock options in Arcturus Therapeutics. JLW received consulting fees from Arcturus Therapeutics.

Aims: A meta-analysis of short-term studies revealed no significant differences between the doses of asenapine, 10 and 20 mg/day, in the acute treatment of schizophrenia. However, it should be noted that many patients from clinical practice were excluded, and the dose-response to asenapine in a real-world setting is still unclear. Additionally, the dose-response in the maintenance phase is not clear. This study aimed to evaluate the differences in the efficacy of different asenapine doses in patients with maintenance phase of schizophrenia in a real-world setting., Methods: This study conducted post-marketing surveillance of asenapine in clinical settings in Japan. It followed patients diagnosed with schizophrenia who received asenapine for the first time for a maximum of 52 weeks. These patients were divided into two categories based on their average daily asenapine dosage: ≤10 mg/day and >10 mg/day. Asenapine efficacy was assessed by adjusting for patient demographics using multivariate logistic regression analysis, employing the Clinical Global Impression-Global Improvement (CGI-I) scale, which has seven categories., Results: A total of 2774 patients were included in the analysis. Of these, 1689 and 1085 patients were treated with asenapine ≤10 mg/day and >10 mg/day, respectively. The CGI-I improvement rate was significantly higher in the asenapine >10 group (p = 0.012) after adjusting for patient background factors., Conclusion: These results suggest that asenapine doses >10 mg/day may be more effective than 10 mg/day in the treatment of schizophrenia; however, further studies are needed to confirm these findings., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Pluripotent stem cell-based therapy for retinal degenerative diseases is a promising approach to restoring visual function. A clinical study using retinal organoid (RO) sheets was recently conducted in patients with retinitis pigmentosa. However, the graft preparation currently requires advanced skills to identify and excise suitable segments from the transplantable area of the limited number of suitable ROs. This remains a challenge for consistent clinical implementations. Herein, we enabled the enrichment of wild-type (non-reporter) retinal progenitor cells (RPCs) from dissociated ROs using a label-free ghost cytometry (LF-GC)-based sorting system, where a machine-based classifier was trained in advance with another RPC reporter line. The sorted cells reproducibly formed retinal spheroids large enough for transplantation and developed mature photoreceptors in the retinal degeneration rats. This method of enriching early RPCs with no specific surface antigens and without any reporters or chemical labeling is promising for robust preparation of graft tissues during cell-based therapy., Competing Interests: Declaration of interests T.M. and M. Matsumura are employees of Vision Care Inc. M.T. is the founder and president of Vision Care Inc. S.O. is a founder and shareholder of ThinkCyte K.K. H.N., Y.K., K.T., and Y.M. are employees of ThinkCyte K.K. and have shares of stock options of ThinkCyte K.K. S.O. and Y.K. have filed patent applications related to this study. All other authors declare they have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study investigated whether Lactobacillus paragasseri SBT2055 (LG2055) activates plasmacytoid dendritic cells (pDCs) and suppresses common cold symptoms in healthy adults. Cell-based experiments showed that a LG2055 treatment upregulated CD86 and HLA-DR expression in pDCs, indicating that LG2055 activates pDCs in vitro. In a subsequent randomized, double-blind, placebo-controlled, parallel-group comparative trial, 200 participants were randomly divided into two groups and consumed three capsules with or without LG2055 once daily for 12 weeks. The primary outcome was the score on a daily physical health questionnaire survey of common cold symptoms. Three participants discontinued the trial and six participants were excluded from the analysis, thus 191 participants (95 in the LG2055 group and 96 in the placebo group) were analyzed. The LG2055 group showed a significantly higher ratio of "without symptoms" responses for runny nose, plugged nose, sneezing, sore throat, hoarseness, and chill than the placebo group. Furthermore, a stratified analysis revealed that LG2055 intake enhanced CD86 and HLA-DR expression in the pDCs of the participants with low secretion rates of salivary secretory immunoglobulin A. These data suggest that LG2055 suppresses the subjective symptoms of the common cold by activating pDCs and improving the host's immune system in healthy adults, especially in immune-weakened individuals (UMIN000049183).

Frailty is a huge concern for the aging population, and dietary nutrition is considered a key factor in the prevention of aging. To solve the problem of frailty in the aging population, we developed a novel dietary intervention program using a novel COMpletely Balanced for Frailty Prevention (COMB-FP) meal, based on the Dietary Reference Intake for Japanese; in addition, we conducted a pilot randomized control trial comparing an exercise program only (control group) with exercise plus the COMB-FP meal program (test group). We included 110 male and female healthy volunteers with pre-frailty or frailty; the trial lasted for 12 weeks. Two daily meals were replaced with the COMB-FP meals during the trial in the test group. Walking speed and cognitive function were significantly improved in the test group compared with the control group. We observed a similar pattern in other frailty-related outcomes, such as occupancy of the microbiome, World Health Organization well-being index (WHO-5), and oxidative stress. Our study might indicate the importance of a well-balanced intake of nutrients for frailty prevention.

Two new monoterpene esters ( 1 and 2 ) and four known compounds ( 3 - 6 ) were isolated from the pericarps of Alpinia zerumbet . Their structures were elucidated by extensive spectroscopic analyses and their anti-inflammatory activity was evaluated by monitoring their inhibitory effects on the interleukin-1 β -induced production of nitric oxide in primary cultured rat hepatocytes. The new compound 1 and cardamonin 3 showed inhibitory activities with IC 50 values of 17.6 ± 1.1 and 10.2  ±  1.3 µM, respectively, which are comparable to that of the positive control N G -methyl-L-arginine acetate salt.

Bifidobacterium animalis subsp. lactis GCL2505 has been shown to have some positive effects on health, including improved defecation frequency and reduced visceral fat. These effects are thought to be due to GCL2505's unique ability to reach the intestine in a viable form and proliferate after a single intake. This leads to an increased number of intestinal bifidobacteria. This randomized, double-blind, placebo-controlled, parallel-group study was conducted to confirm that intake of GCL2505 and inulin (a prebiotic) improve cognitive function ( n = 80). Participants consumed test drinks containing 1 × 10 10 colony-forming units of GCL2505 per 100 g and 2.0 g of inulin per 100 g for 12 weeks. The change in cognitive function assessment scores was set as the primary endpoint. There were significant improvements in scores in the neurocognitive index domain, which is an assessment of overall cognitive function, in addition to overall attention, cognitive flexibility, and executive function domains. The intervention significantly increased the number of fecal bifidobacteria and affected the levels of several inflammatory markers. These results suggest that intake of GCL2505 and inulin improves cognitive function by improving the intestinal environment and alleviating inflammation.

After completion of a 6-week double-blind trial of asenapine sublingual tablets (10 or 20 mg/day) versus placebo in Asian patients with acute exacerbation of schizophrenia, including Japanese patients, this open-label study evaluated the safety and efficacy of a 52-week treatment with asenapine at flexible doses. In 201 subjects, including 44 who had received placebo (P/A group) and 157 who had received asenapine (A/A group) in the feeder trial, adverse events occurred at rates of 90.9% and 85.4% and serious adverse events at rates of 11.4% and 20.4%, respectively. One patient in the P/A group died. No clinically significant abnormal measurements of body weight, body mass index, or glycated hemoglobin, fasting plasma glucose, insulin, and prolactin levels were observed. The sustained efficacy rate, as evaluated by the Positive and Negative Syndrome Scale total score and other measures, remained at approximately 50% between 6 and 12 months of treatment. These results suggest that long-term treatment with asenapine is well tolerated and provides sustained efficacy., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: This study aimed to conduct a preliminary evaluation of the effects of 6-methylsulfinylhexyl isothiocyanate (6-MSITC) contained in wasabi rhizomes on fatigue and sleep and to examine its safety through overdose study., Methods: A total of 20 healthy volunteers who were experiencing daily fatigue were given powder containing 6-MSITC (4.8 mg/day of 6-MSITC) extracted from wasabi for 4 weeks. Then, fatigue, sleep, autonomic nervous functioning, stress, and immunity were evaluated. In addition, an overdose safety study of the extract powder (up to 16 mg/day of 6-MSITC for 4 weeks) was performed with 30 healthy volunteers in a double-blind, placebo-controlled method., Results: The powder containing 6-MSITC did not improve fatigue after a mental task, but fatigue before the mental task, sleep, and mood were improved significantly after 4 weeks intake. No changes were observed in the autonomic nerve function, stress, or immune markers. In the overdose safety study, no changes in the parameters ​​or side effects were observed, and the results showed that high doses of the extract powder containing 6-MSITC is safe., Conclusion: This study confirmed the possibility that this powder extracted from wasabi that contains 6-MSITC might improve fatigue and sleep. However, because the effectiveness evaluation in this study was a single-arm, open-label study and there was no placebo control group, these points must be considered when interpreting the results. Safety was confirmed in an overdose study of more than three times the amount compared to that in the efficacy evaluation study. In the future, further research should be conducted on its effectiveness for treating fatigue and sleep problems., Trial Registration: UMIN clinical trial registration system, UMIN000049913. Registered 27 December 2022 Retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000056818., (© 2023. BioMed Central Ltd., part of Springer Nature.)

IgE plasma cell neoplasm is the rarest subtype of plasma cell neoplasms and is known for its poor prognosis and high incidence of t(11;14). However, t(11;14) has been classified as a standard-risk rather than high-risk cytogenetic abnormality in multiple myeloma. We have been unable to explain the discrepancy that the hallmark of IgE plasma cell neoplasm with a poor prognosis is a standard-risk cytogenetic abnormality. Here, we report a case of IgE primary plasma cell leukemia with extramedullary lesions of the liver, stomach, and lymph nodes. Plasma cell infiltration was pathologically confirmed in each organ. Cytogenetic analysis of plasma cells revealed t(11;14) and amplification of 1q21. Chemotherapy, with immunomodulatory imide drugs, proteasome inhibitors, and CD38 antibodies, was unsuccessful. In IgE plasma cell neoplasm, coexistence of other cytogenetic abnormalities with t(11;14) may be important. Investigating the presence of cytogenetic abnormalities coexisting with t(11;14) is not only useful for evaluating prognosis but also important for understanding the pathogenesis of the disease. Recently, venetoclax, an oral BCL2 inhibitor, has demonstrated promising efficacy in plasma cell neoplasm patients harboring t(11;14). Development of an effective venetoclax-based regimen for treating aggressive IgE plasma cell neoplasm with t(11;14) is expected., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Wataru Nakahara et al.)

Background: Choline, as a neurotransmitter acetylcholine precursor, is reportedly associated with cognitive function. Although there are several cohort and animal studies on choline-containing foods and cognitive function, only a few interventional studies were reported. Egg yolk is a rich source of different choline-containing chemical forms, such as phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and α-glycerophosphocholine (α-GPC). This study aimed to investigate the effect of consuming 300 mg of egg yolk choline per day on cognitive function of Japanese adults., Methods: A 12-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 41 middle-aged and elderly males and females (43.9% female) aged ≥ 60 years and ≤ 80 years without dementia. Participants were randomly assigned to placebo and choline groups. The choline group received a supplement containing egg yolk choline (300 mg/day), and the placebo group received an egg yolk supplement free from choline for 12 weeks. Assessments of Cognitrax, Trail Making Tests (TMT) part A and B, the MOS 36-Item Short-Form Health Survey (SF-36), the Simplified Japanese Version of the WHO-Five Well-Being Index (WHO-5), and plasma choline levels were performed before and 6 and 12 weeks after supplement intake. In the present study, 19 subjects (9 in the placebo group and 10 in the choline group) were excluded due to the violation of the discontinuation criteria or participant compliance, and 41 subjects were analyzed., Results: The change amount of verbal memory scores and verbal memory test-correct hit (delay) was significantly higher in the choline group than in the placebo group at baseline-6 and baseline-12 weeks. The plasma free choline level was significantly higher in the choline group compared with the placebo group at 6 weeks. Conversely, the choline group showed significantly lower Cognitrax processing speed scores, symbol digit coding testing correct responses, and SF-36 physical quality of life summary scores compared to the placebo group at 6 weeks., Conclusions: The results suggested that continued 300 mg/day intake of egg yolk choline improved verbal memory, which is a part of cognitive functions. To confirm the observed effects of egg yolk choline, more well-designed and large-scale studies are warranted., Trial Registration: Study protocols were pre-registered in the Clinical Trials Registration System (UMIN-CTR) (UMIN 000045050)., (© 2023. The Author(s).)

Mixed phenotype acute leukemia (MPAL) is characterized by leukemic blasts that express markers of multiple lineages. Compared with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), MPAL is considered to have a poor treatment outcome. We report a case of MPAL T/myeloid not otherwise specified that was initially presented as multilineage lymphoblastic lymphoma and subsequently developed into leukemic MPAL. An acute lymphoblastic leukemia-based treatment regimen was ineffective, but azacitidine and venetoclax therapy resulted in hematological complete remission. Our case suggests that multilineage lymphoblastic lymphoma should be considered to be the same disease as MPAL, albeit with different clinical presentations. Optimal treatment for MPAL has not been established yet, but azacitidine and venetoclax therapy may be a potential approach., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Mako Ikeda et al.)

This study investigated a new dismantling system for concrete structures using a steam pressure cracking agent. We improved the mechanical systems such that it can drill through reinforcing steel bars. Therefore, the control method of the system and shape of the drill tip were improved. When the drill tip is stuck with chips and stopped, it is automatically pulled out and reinserted to recover the rotation. By changing the tip angle of the drill bit from 75° to 90°, it became possible to cut reinforcing bars, which were difficult to cut previously. In addition, we designed a crawler-type mechanical system and improved it such that it can be moved to the appropriate position and operated at any angle. This study revealed that the energy required for the drilling process accounts for more than 90% of the total dismantling energy. Through experiments using an impact hammer drill and observations of fracture surfaces using a three-dimensional scanner, we analysed the characteristics of reinforced concrete. In addition, the feasibility of the design for dismantling reinforced concrete was confirmed based on the determined energy associated with crack propagation.

Objective: Lactobacillus paragasseri SBT2055 (LG2055) has been reported to show immunostimulating effects. This study aimed to investigate the effects of LG2055 on the subjective symptoms of the physical condition in healthy adults., Materials and Methods: In this randomized, double-blind, placebo-controlled, parallel-group comparative study, Japanese individuals aged 20-64 years were recruited. A total of 200 participants were randomly divided into two groups by an independent controller (LG2055 and placebo groups; 100 participants per group). Drinkable yogurts containing LG2055 or lacking LG2055 (placebo) were used as test samples. The participants ingested one bottle of the test sample once a day for 12 weeks. A daily physical health questionnaire survey (about common cold symptoms) was performed as the primary outcome, and immunological and oxidative stress markers in saliva and serum were evaluated as secondary outcomes., Results: In total, 198 participants completed the scheduled intake of the test samples, and five participants were excluded from the final analysis. Consequently, 193 participants (LG2055 group, n = 97; placebo group, n = 96) in the Per-Protocol Set were included in the efficacy analysis. The cumulative days of each symptom were evaluated, and the LG2055 group showed a significantly higher ratio of "without symptom" in runny nose, plugged nose, sneezing, sore throat, hoarseness, cough, headache, feeling tired, and fever than the placebo group, indicating that the incidence rates of common cold symptoms were lower in the LG2055 group. Additionally, changes in the salivary secretory IgA levels were significantly higher, and the serum derivatives of reactive oxygen metabolites levels were significantly lower in the LG2055 group., Conclusion: Our study revealed that intake of LG2055 decreased common cold symptoms and improved immune parameters in healthy adults. This suggests that LG2055 contributes to the maintenance of physical conditions by improving the host immune system., Clinical Trial Registration: [https://www.umin.ac.jp/ctr/index.htm], identifier [UMIN000045901]., Competing Interests: EK, TA, MK, and TK were employed by MEGMILK SNOW BRAND Co., Ltd. NS was employed by KSO Corporation. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kobatake, Iwama, Arai, Shioya, Kise and Kabuki.)

Discrimination of cues predicting non-nociceptive/nociceptive stimuli is essential for predicting whether a non-painful or painful stimulus will be administered and for eliciting placebo/nocebo (pain reduction/pain enhancement) effects. Dysfunction of the neural system involved in placebo effects has been implicated in the pathology of chronic pain, while female sex is one of the important risk factors for development of chronic pain in young adults. The dorsolateral prefrontal cortex (dl-PFC) is suggested to be involved in placebo effects and is sensitive to sex and age. In this study, to examine the neural mechanisms by which sex and age alter placebo and nocebo effects, we analyzed cerebral hemodynamic activities in the dl-PFC in different sex and age groups during a differential conditioning task. During the training session, two different sounds were followed by low- and high-intensity electrical shocks. In the following recording session, electrical shocks, the intensity of which was mismatched to the sounds, were occasionally administered to elicit placebo and nocebo effects. In young female participants, both placebo effects and hemodynamic responses to the conditioned sounds in the right dl-PFC were significantly lower than those in elderly female participants, while there were no age differences in male participants. The hemodynamic responses to the sound paired with the safe stimulus in the right dl-PFC were significantly correlated with placebo effects, except in the young female group. These results suggest that blunted placebo effects in the young female participants are ascribed to blunted responses to the sound associated with the safe stimulus in the right dl-PFC, and that sex- and age-related factors may alter the responsiveness of the right dl-PFC to associative cues predicting a safe stimulus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Iwama, Takamoto, Hibi, Nishimaru, Matsumoto, Setogawa and Nishijo.)

This study aimed to analyze the time-course of the physical properties of the psoas major muscle (PM) before and after exercise using magnetic resonance elastography (MRE). Muscle stiffness is one of the important properties associated with muscle function. However, there was no research on the stiffness of the PM after exercise. In this study, we investigated time-course changes of the shear modulus of the PM after exercise. Furthermore, T2 values and apparent diffusion coefficient (ADC), as the additional information associated with muscular physical properties, were also measured simultaneously. Healthy young male volunteers were recruited in this study (n = 9) and they were required to perform a hand-to-knee isometric and unilateral exercise (left side). At each time-point before and after exercise, a set of 3 types of MR scans to measure multiple physical properties of the PM [shear modulus (MRE), T2 values, and ADC] were repeatedly taken. On day 1, a single set MR scan was taken before exercise (pre-exercise MR scan), and 6 sets MR scans were taken (5.5 to 38.0 min after exercise). After about 10-min rest (46.0 to 56.0 min after exercise), 4 sets MR scans were taken (57.5 to 77.0 min after exercise). About 10-min rest was taken again (85.0-95.0 min after exercise), 4 sets MR scans were taken (96.5 to 116.0 min after exercise). On days 2 and 7, a single set MR scan (MRE, T2 value, and ADC) was taken on each experimental day. The data were analyzed as relative changes (%) of the given parameters to the pre-exercise values. The results indicated significant decreases in PM shear modulus up to about 30 min after exercise. Then, it gradually increased and showed significant increases at about 100 min after exercise compared to that before exercise. T2 values and ADC showed significant increases up to about 65 min after exercise compared to those before exercise, and then returned to the pre-exercise values. On days 2 and 7, all values showed no significant changes compared to the pre-exercise values. This study is the first to report the time-course of the physical properties of the PM after exercise., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study demonstrates that a single-crystal diamond substrate can be cut along designed lines using the diamond-saw-wire cutting method. We developed an original saw-wire fixed diamond-grain using a bronze solder with a high melting temperature. We created a unique product machine system with a high vacuum furnace and a bronze solder that contains a metallic compound. The diamond cutting mechanism employed in this study is based on the mild wear phenomenon, owing to the friction between the diamond surfaces. A linear relationship between the cutting length and wire feed distance was observed. The relationship can be approximated as y = 0.3622 x , where y (μm) is the cutting depth and x (km) is the wire feed distance. The life of the saw-wire was longer than that of the 6000 km wire feed distance and was tested by reciprocating an 8-m short wire at a speed, tension, and cutting force of 150 m/min, 1 N, and 0.2 N, respectively. A single crystal diamond substrate could be cut along the designed line, which was more than 2 mm long. The cutting speed was maintained constant at 0.36 μm/km.

Purpose: Although pain phenotype affects clinical score in patients with knee osteoarthritis (OA), little information has been available on the relationship between pain phenotype and gait analysis. The purpose was to investigate the relationship between pain phenotype and gait parameters.  METHODS: A total of 34 patients (24 females and 10 males) with end-stage medial compartmental knee OA participated. All the patients were evaluated based on pain detect questionnaire (PD-Q) and pain catastrophizing scale (PCS). They were divided into two categories: Group Low (PD-Q score ≤ 12) and Group High (PD-Q score > 12), PCS + (PCS ≥ 23) and PCS- (PCS < 23). Gait analysis was performed using three-dimensional motion analysis system. Statistical analysis was done to compare gait parameters between groups for each allocation of PD-Q or PCS, separately.  RESULTS: Peak vertical ground reaction forces in Group Low and High were 0.99 ± 0.054 and 0.82 ± 0.17, respectively (P = 0.015). Peak knee adduction moments in Group Low and High were 0.70 ± 0.19 and 0.39 ± 0.14, respectively (P = 0.0022). For PCS allocation, knee extension limitation during mid-stance during gait were significantly larger in PCS- (P = 0.038)., Conclusions: Patients with high PD-Q score had atypical gait pattern with smaller peak vertical ground reaction force and knee adduction moment, compared to patients with low PD-Q score. Moreover, patient with low PCS had different gait pattern in extension limitation, compared to those with high PCS. PD-Q and PCS would affect gait pattern in patients with knee OA., Level of Evidence: III., (© 2022. The Author(s).)

Background: Differences in psychiatric background and dose-response to asenapine in patients with schizophrenia were examined based on efficacy and safety, using data obtained in a double-blind, placebo-controlled trial., Methods: Patients with schizophrenia were classified into three clusters by a cluster analysis based on the Positive and Negative Symptom Scale (PANSS) subscores at baseline, using the data from a 6-week, double-blind, placebo-controlled trial. PANSS Marder factor scores were calculated for each cluster. The efficacy of 10 or 20 mg/day of asenapine on PANSS score was used as the primary endpoint, with the incidence of adverse events evaluated as the secondary endpoint., Results: A total of 529 asenapine-treated patients were classified into 3 clusters: Cluster-P with the higher scores in positive symptoms, disorganized thoughts, and hostility/excitement, Cluster-N with higher scores in negative symptoms, and Cluster-L with overall lower scores. In Cluster-N and Cluster-L, both 10 and 20 mg/day groups showed significant improvement in PANSS scores, while only the 20 mg/day group showed a significant difference in Cluster-P. Cluster-N and Cluster-L had differences in the incidence of adverse events, but this was not seen in Cluster-P., Conclusions: The efficacy and safety of asenapine 10 and 20 mg/day differed between the 3 clusters of patients. This suggests that background information regarding baseline psychiatric symptoms may affect the therapeutic response in patients with schizophrenia.

Purpose: To evaluate the utility of extending the limbus-to-cannula distance to 6.0 mm during pars plana vitrectomy for highly myopic eyes., Methods: Four eyes with axial lengths exceeding 31.0 mm, that underwent 25-gauge pars plana vitrectomy were retrospectively evaluated. Assuming that cannulas were inserted 3.5 mm and 6.0 mm from the corneal limbus, the distance from the cannula to the fovea (CF distance) was preoperatively evaluated using anterior segmental optical coherence tomography. Surgical complications were also investigated., Results: The CF distance was shortened by 1.22 ± 0.05 mm and 1.22 ± 0.09 mm on the temporal and nasal sides, respectively, by inserting the cannula at 3.5 mm to 6.0 mm from the corneal limbus. As per the preoperatively measured CF distance, one of the cannulas was inserted 6.0 mm from the corneal limbus in three eyes. Their cannulas were confirmed to be inserted at the pars plana, and no surgical complications associated with this technique were observed., Conclusion: Extending the limbus-to-cannula distance to 6.0 mm during pars plana vitrectomy could be one of the options to reach the posterior pole in highly myopic eyes. A preoperatively measured CF distance can be a clinical criterion in determining the cannula position.

Background: Enzalutamide is useful for the treatment of castration-resistant prostate cancer (CRPC). Despite its usefulness, adverse events (AEs) sometimes force patients to discontinue treatment. To maximize patient care, we developed an ambulatory care pharmacy practice that allows collaboration between a pharmacist and urologist to manage patients with CRPC receiving enzalutamide. In this study, we investigated the efficacy of this collaborative management. Methods: A retrospective chart review of 103 patients with CRPC receiving enzalutamide in our hospital between May 2014 and December 2020 was performed. Our collaborative management was implemented in October 2016. Before being examined by urologists, patients visited the oncology pharmacy consultation room for a face-to-face consultation, wherein the oncology pharmacists assessed factors such as adherence to enzalutamide, any AEs and their grades, and provided their suggestions to the urologists. The time to enzalutamide discontinuation and prostate-specific antigen progression were compared between patients who started enzalutamide before ( n = 41) and after ( n = 62) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with enzalutamide discontinuation. Results: After implementing collaborative management, the pharmacists had 881 patient consultations. Among the 476 suggestions from pharmacists, 345 were accepted by urologists. The most frequent suggestion was supportive care in enzalutamide treatment (224 suggestions). Multivariate analysis showed that collaborative management [hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.31-0.89, p = 0.017] and higher prostate-specific antigen (PSA; HR 2.41, 95% CI 1.36-4.28, p = 0.003) were significantly associated with enzalutamide discontinuation. The median time to discontinuation (18.9 vs. 7.6 months, p = 0.012), time to discontinuation due to AEs (not reached in both groups, p = 0.001), and time to PSA progression (13.3 vs. 5.8 months, p = 0.002) were all significantly longer in the after group. Conclusions: We implemented a pharmacist-urologist collaborative management program for outpatients with CRPC receiving enzalutamide. The results revealed that collaborative management was useful for prolonging the time to enzalutamide discontinuation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hirabatake, Ikesue, Iwama, Irie, Yoshino, Yamasaki, Hashida, Kawakita and Muroi.)

Background: Clinical outcomes of kinematically aligned total knee arthroplasty (KA-TKA) have been reported as comparable or superior to those of mechanically aligned TKA (MA-TKA). However, cruciate-retaining prostheses have mostly been used for KA-TKA. This study used medial pivot knee prostheses for KA-TKA, and knee kinematics after KA-TKA were assessed and compared with those after MA-TKA., Methods: Thirteen knees in 9 patients undergoing primary TKA (8 KAs, 5 MAs) were subjected to two-dimensional (2D) to three-dimensional (3D) registration analysis at 1 year postoperatively. Each patient performed weight-bearing activities, and movements were recorded as intermittent digital radiographic images. Three-dimensional implant positions during activities were analyzed for anterior-posterior translation in the sagittal plane, condylar liftoff and mediolateral translation in the coronal plane, and femoral rotation in the axial plane., Results: Posterior translation of the lateral femoral condyle from 0° to 100° was larger in KA-TKA than in MA-TKA ( P  = .006). The degrees of condylar liftoff and mediolateral translation were comparable between TKAs. Total external rotation of the femoral component relative to tibial component was significantly greater for KA-TKA (7.7 ± 5.2°) than for MA-TKA (1.3 ± 3.3°; P  = .03). The kinematic path of the femoral component revealed greater medial pivoting motion in KA-TKA than in MA-TKA., Conclusions: KA-TKA using a medial pivot knee prosthesis successfully reproduced the medial pivot pattern and achieved larger femoral external rotation relative to the tibia than MA-TKA. KA-TKA was able to maximize the primary concept of the medial pivot knee prosthesis., (© 2021 Published by Elsevier Inc. on behalf of The American Association of Hip and Knee Surgeons.)

Objectives: We investigated changes in prescriptions for antimicrobial agents to treat children with acute otitis media (AOM)., Methods: A descriptive study using an electronic medical record database. Of 199,896 patients enrolled between 2001 and 2019, a total of 10,797 were aged <16 years and had AOM as their first and primary disease (overall pediatric AOM cohort). In addition, 4786 patients with AOM without other comorbidities (pediatric AOM cohort) were included., Results: In the overall pediatric AOM cohort, the age distribution ranged from 11% to 23% for those younger than 2 years and from 66% to 77% for those younger than 6 years, with no change over time. In the pediatric AOM cohort, the antimicrobial prescription rate was 91% in 2001 but declined to 40% by 2019. Antimicrobial use increased from 0% to 75% for penicillins, whereas use of cephalosporins decreased from 84% to 10%. The prescription rate for acetaminophen alone increased from 33% to 58%. There were no differences in the incidence of adverse reactions among the prescribed antimicrobials., Conclusions: Due to education efforts and promotion of the proper use of antimicrobials through means such as the Clinical practice guidelines for the diagnosis and management of acute otitis media in children (2006) and the Manual of Antimicrobial Stewardship (2016), a change in the use of antimicrobials occurred, leading to a trend to more proper use of these agents., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Although an enormous number of animal studies on blast-induced traumatic brain injury (bTBI) have been conducted, there still remain many uncertain issues in its neuropathology and mechanisms. This is partially due to the complex and hence difficult experimental environment settings, e.g., to minimize the effects of blast winds (tertiary mechanism) and to separate the effects of brain exposure and torso exposure. Since a laser-induced shock wave (LISW) is free from dynamic pressure and its energy is spatially well confined, the effects of pure shock wave exposure (primary mechanism) solely on the brain can be examined by using an LISW. In this study, we applied a set of four LISWs in the impulse range of 15-71 Pa·s to the rat brain through the intact scalp and skull; the interval between each exposure was ~5 s. For the rats, we conducted locomotor activity, elevated plus maze and forced swimming tests. Axonal injury in the brain was also examined by histological analysis using Bodian silver staining. Only the rats with exposure at higher impulses of 54 and 71 Pa·s showed significantly lower spontaneous movements at 1 and 2 days post-exposure by the locomotor activity test, but after 3 days post-exposure, they had recovered. At 7 days post-exposure, however, these rats (54 and 71 Pa·s) showed significantly higher levels of anxiety-related and depression-like behaviors by the elevated plus maze test and forced swimming test, respectively. To the best of the authors' knowledge, there have been few studies in which a rat model showed both anxiety-related and depression-like behaviors caused by blast or shock wave exposure. At that time point (7 days post-exposure), histological analysis showed significant decreases in axonal density in the cingulum bundle and corpus callosum in impulse-dependent manners; axons in the cingulum bundle were found to be more affected by a shock wave. Correlation analysis showed a statistically significant correlation between the depression like-behavior and axonal density reduction in the cingulum bundle. The results demonstrated the dependence of behavior deficits and axonal injury on the shock wave impulse loaded on the brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jitsu, Niwa, Suzuki, Obara, Iwama, Hagisawa, Takahashi, Matsushita, Takeuchi, Nawashiro, Sato and Kawauchi.)

Background and Objectives: Multi-regional clinical trials (MRCTs) are an efficient drug development strategy for eliminating drug lag in East Asian countries. In planning MRCTs according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E17 guideline, it is expected that East Asian populations with relatively similar ethnicity can be pooled as one population. However, evidence supporting this assumption is limited. This study aimed to investigate population/regional differences considering influencing factors among East Asian regions using MRCT data as a research model., Methods: A retrospective analysis was conducted to determine the efficacy of two drugs, asenapine, a schizophrenia drug, and tadalafil, a dysuria drug for benign prostatic hyperplasia, using MRCT data from Japan, Korea, and Taiwan. First, predictive factors and effect modifiers were evaluated. Then, population/regional differences were evaluated using multivariate regression models, with the interaction term Region-by-Treatment group and adjustment for influencing intrinsic/extrinsic factors., Results: Among the 4 outcomes for the two drugs, no significant population/regional differences were detected (P > 0.05) by the adjusted regression models. The effect modifiers, such as pretreatment drug status or concurrent diseases, were common among countries., Conclusions: No significant population/regional efficacy differences were found for the two drugs among the three regions. This finding supported the possible applicability of the region pooling strategy for MRCTs in East Asia, emphasizing the benefits of exploring ethnic difference/influencing factors at an early stage to design further confirmatory studies. However, further evidence for various drugs should be accumulated.

Objectives: This study aims to comprehensively investigate the changes of salivary stress biomarkers, psychological status, and autonomic nervous system (ANS) response due to horticultural activities (HAs)., Design and Methods: A prospective observational study was conducted in twenty Japanese healthy adults (mean age, 58.4 years). Flower appreciation, flower arrangement, and farm work experience were performed as three HAs with different working concepts. Five salivary stress biomarkers (cortisol, α-amylase, S-IgA, chromogranin A, and oxytocin) were measured to quantify the stress levels before and after each HA. The Profile of Mood Status 2nd edition (POMS2) was used as a subjective psychological evaluation. Wearable biosensors were used to visualize the continuous ANS response throughout the process., Results: In the POMS2 investigation, the negative factors, which included Anger-Hostility, Confusion-Bewilderment, Depression-Dejection, Tension-Anxiety, and Total Mood Disturbance, were significantly decreased (p=0.0135, p=0.0004, p=0.0024, p=0.0015, p=0.0063, respectively). In the measurement of salivary stress biomarkers, flower appreciation decreased cortisol (p=0.0134), and farm work experience not only decreased cortisol but also increased oxytocin (p=0.0041, p=0.0128 respectively). In the visualization results of the ANS response, a graph demonstrated that the difference in activity between the sympathetic nerve and the parasympathetic nerve was narrowed by a series of HAs., Conclusions: In healthy adults, HAs had a stress-reducing effect, which was evidenced by neuroendocrinological and psychological evaluations, a study of POMS2, salivary stress biomarkers, and visualization of the ANS response.

Although the external knee adduction moment (KAM) during gait was shown to be a quantitative parameter of medial knee osteoarthritis (OA), it requires expensive equipment and a dedicated large space to measure. Therefore, it becomes a major reason to limit KAM measurement in a clinical environment. The purpose of this study was to estimate KAM using a single inertial measurement unit (IMU) during gait in patients with knee OA. A total of 22 medial knee OA patients (44 knee joints) performed conventional gait analysis using three-dimensional (3D) motion capture system. At the same time, we attached commercial IMUs to six body segments (sternum, pelvis, both thighs, and both shanks), and IMU signals during gait were recorded synchronized with the motion capture system. The peak-to-peak difference of acceleration in the lateral/medial axis immediately after heel contact was defined as the thrust acceleration (TA). We hypothesized that TA would represent the lateral thrust of the knee during the stance phase and correlate with the first peak of KAM. The relationship between the peak KAM and TA of pelvis (R = 0.52, p < 0.001), shanks (R = 0.57, p < 0.001) and thighs (R = 0.49, p = 0.001) showed a significant correlation. The root mean square error (RMSE) of linear regression models of pelvis, shanks, and thighs to estimate KAM were 0.082, 0.079, and 0.084 Nm/(kg·m), respectively. Our newly established parameter TA showed a moderate correlation with conventional KAM. The current study confirmed our hypothesis that a single IMU would predict conventional KAM during gait. Since KAM is known as an indicator for prognosis and severity of knee OA, this new parameter has the potential to become an accessible predictor for medial knee OA instead of KAM.

Background: Knot tying technique is an extremely important basic skill for all surgeons. Clinically, knot slippage or suture breakage will lead to wound complications. Although some previous studies described the knot-tying technique of medical students or trainees, little information had been reported on the knot-tying technique of instructors. The objective of the preset study was to assess surgeons' manual knot tying techniques and to investigate the differences of tensile strength in knot tying technique between surgical instructors and trainees., Methods: A total of 48 orthopaedic surgeons (postgraduate year: PGY 2-18) participated. Surgeons were requested to tie surgical knots manually using same suture material. They were divided into two groups based on each career; instructors and trainees. Although four open conventional knots with four throws were chosen and done with self-selected methods, knot tying practice to have the appropriate square knots was done as education only for trainees before the actual trial. The knots were placed over a 30 cm long custom made smooth polished surface with two cylindrical rods. All knots were tested for tensile strength using a tensiometer. The surgical loops were loaded until the knot slipped or the suture broke. The tensile strength of each individual knot was defined as the force (N) required to result in knot failure. Simultaneously, knot failure was evaluated based on knot slippage or suture rupture. In terms of tensile strength or knot failure, statistical comparison was performed between groups using two-tailed Mann-Whitney U test or Fisher exact probability test, respectively., Results: Twenty-four instructors (PGY6-PGY18) and 24 trainees (PGY2-PGY5) were enrolled. Tensile strength was significantly greater in trainees (83.0 ± 27.7 N) than in instructors (49.9 ± 34.4 N, P = 0.0246). The ratio of slippage was significantly larger in instructors than in trainees (P < 0.001). Knot slippage (31.8 ± 17.7 N) was significantly worse than suture rupture (89.9 ± 22.2 N, P < 0.001) in tensile strength., Conclusions: Mean tensile strength of knots done by trainees after practice was judged to be greater than that done by instructors in the present study. Clinically, knot slippage can lead to wound dehiscence, compared to suture rupture.

The Fist-Edge-Palm (FEP) task, a manual hand task, has been used to detect frontal dysfunctions in clinical situations: its performance failures are observed in various prefrontal cortex (PFC)-related disorders, including schizophrenia. However, previous imaging studies reported that the performance of the FEP task activated motor-related areas, but not the PFC. Here, we aimed to investigate the relationships between the performance of the FEP task and PFC functions. Hemodynamic activity in the PFC, including the dorsolateral PFC (area 46) and frontal pole (area 10), was recorded. Healthy young subjects performed the FEP task as well as a palm tapping (PT) task (control task) three times. The subjects also completed a Wisconsin Card Sorting Test (WCST) and Schizotypal Personality Scale (STA) questionnaire. We found that hemodynamic activity (Oxy-Hb) in the PFC increased in the first trial of the FEP task but decreased considerably in the second and third trials compared to the PT task. The number of performance errors in the FEP task also decreased in the second and third trials. Error reduction (i.e., learning) in the FEP task between the first and second trials was negatively correlated with schizotypal trait and the number of perseveration errors in the WCST. Furthermore, changes in the PFC hemodynamic activity between the first and second trials were positively correlated with error reduction in the FEP task between the first and second trials, and negatively correlated with the number of perseveration errors in the WCST. These results suggest that learning in the FEP task requires PFC activation, which is negatively associated with perseveration errors in the WCST. The results further suggest that the FEP task, in conjunction with near-infrared spectroscopy, may be useful as a diagnostic method for various disorders with PFC dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kobayashi, Iwama, Nishimaru, Matsumoto, Setogawa, Ono and Nishijo.)

The patient was a 79-year-old woman. In January 20XX, upper gastrointestinal endoscopy revealed a duodenal tumor with bleeding and ulceration. This tumor was diagnosed as a duodenal neuroendocrine tumor(NET)based on biopsy findings. In March 20XX, the patient underwent pancreatoduodenectomy with lymph node dissemination. Based on these pathological findings, the tumor was diagnosed as a duodenal NET(G2)with a lymph node metastasis(T2, N1, M0, Stage Ⅲ). Twenty months after the operation, abdominal CT revealed multiple liver metastases(S4, S7, and S8). After this recurrence, she underwent the subcutaneous somatostatin analogue injection therapy every 28 days, and transarterial chemoembolization( TACE)when these recurrent tumors showed remarkable regrowth, once a year, accounting for her age. She has maintained good disease control for 5 years.

Purpose: To describe an optical coherence tomography (OCT) sign preceding macular hole (MH) formation after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD)., Design: Retrospective observational case series., Methods: Patients who underwent PPV for RRD at Osaka Rosai Hospital between January 2014 and December 2017 were examined. First, the medical records of the patients who had secondary MH after RRD repair were examined, and their sequential changes of the OCT images until MH formation were evaluated. Second, the OCT findings and the medical records of all patients who underwent PPV for RRD were evaluated based on the findings of the cases of secondary MH., Results: Ten eyes of 10 patients who had secondary MH after PPV for RRD were enrolled. Before MH formation, all eyes had parafoveal epiretinal membrane (ERM) and a characteristic OCT sign that was termed a foveal crack sign (FCS), a hyperreflective vertical line in the foveola with a deformation of the fovea. FCS was found 255 ± 217 days after PPV for RRD, and MH developed 232 ± 171 days after FCS appearance. Furthermore, among 518 eyes that underwent PPV for RRD, FCS with parafoveal ERM was found in 3 eyes without succeeding MH after RRD repair. FCS of these 3 eyes were found 363 ± 4 days after PPV for RRD., Conclusions: In all cases of secondary MH formation after PPV for RRD, FCS with parafoveal ERM was found before MH formation. This sign may predict secondary MH formation caused by ERM traction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: One aim of an autism spectrum disorder (ASD) diagnosis is to obtain special support for the disorder, though this does not guarantee practical support. We developed a psychoeducational program using cognitive-behavioral therapy (CBT) and Aware and Care for my Autistic Traits (ACAT) for Japanese adolescents with high-functioning ASD and their parents., Methods: This multisite study is a randomized controlled trial. In total, 24 participants will be assigned to the ACAT group and 24 to the treatment-as-usual (TAU) group. The ACAT group will receive a weekly 100-min session for 6 weeks, regular medical care, and one follow-up session. In this ongoing clinical trial, we will compare the scores of the measures recorded in the pre- and post-intervention stages between the ACAT and TAU groups. A total of 41 patients out of a target of 48 have participated in the trial to date. The primary outcome measure is the Autism Knowledge Questionnaire. Secondary outcome measures include Barriers to Access to Care Evaluation 3rd Edition, the Strengths and Difficulties Questionnaire, the Vineland Adaptive Behavior Scales second edition, the Parenting Resilience Elements Questionnaire, the General Health Questionnaire 12, and the Depression Self-Rating Scale for Children assessments, as well as an electroencephalographic recording., Discussion: It is expected that participants in the ACAT group will significantly increase their self-understanding and awareness of ASD symptoms compared to those in the TAU group. Additionally, the ACAT group is expected to exhibit improved social adaptation and mental health if children and parents are able to better understand the ASD characteristics through sessions. This intervention will contribute to the establishment of an effective evidence-based treatment strategy for adolescents with ASD., Trial Registration: UMIN Register 000029851 . Registered on January 06, 2018.

A redox potential controlled intermolecular [2 + 2] cross-cycloaddition has been developed in the presence of a thioxanthylium photoredox catalyst. Electron-rich styrenes such as β-bromostyrene ( E p/2 = +1.61 V vs SCE) were selectively oxidized by a thioxanthylium photoredox catalyst ( E 1/2 (C*/C •- ) = +1.76 V vs SCE) to styryl radical cations and reacted with styrene ( E p/2 = +1.97 V vs SCE) to furnish polysubstituted cyclobutanes in high yields. The present reaction can be successfully applied to intermolecular [2 + 2] cross-cycloaddition of β-halogenostyrenes, which cannot be effectively achieved by the hitherto reported representative organophotoredox catalysts.

Purpose: To evaluate the impact of vitrectomy and air tamponade on aspheric intraocular lens (IOL) tilt and decentration and postoperative internal higher-order aberrations (HOAs) in combined cataract surgery and vitrectomy (phacovitrectomy)., Study Design: Prospective comparative observational study., Methods: Forty-five eyes that underwent phacovitrectomy using aspheric IOLs and 18 eyes that only underwent cataract surgery also using aspheric IOLs were prospectively evaluated. The subjects were divided into three groups: phacovitrectomy without fluid-air exchange (F/Ax) or with F/Ax and cataract surgery alone (Groups A, B, and C, respectively) Surgery-induced changes in lens tilt and decentration and internal HOAs were compared between each pair of groups. Subgroup analysis was conducted for cases with largely tilted (> 7°) or decentered (> 0.40 mm) IOLs 1 month postoperatively., Results: Surgery-induced changes in lens tilt in Group B were significantly more pronounced than those in Group C at 1 week, 1 month, and 3 months postoperatively (P = 0.007, 0.009, and 0.043, respectively), while there was no significant difference in surgery-induced changes in lens decentration among the groups. IOLs in Group B were tilted and decentered toward the inferonasal direction. In contrast, there was no significant difference in internal HOAs among the groups at any postoperative visit. Only Group B included cases with largely decentered IOLs, and the internal total HOAs in these cases were significantly larger than those in the others (P = 0.015)., Conclusion: Although largely decentered IOLs were occasionally found in Group B, aspheric IOLs could be effectively used in phacovitrectomy.