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Under current bioequivalence guidelines in Japan, it is mandatory to establish bioequivalence using a single pivotal study. Clinical trials with limited resources usually have a pre-defined maximum permissible number of participants. In this manuscript, we considered a trial design that would allow for bioequivalence evaluation at an interim analysis in which the total number of participants takes into account the resource constraints. Then, available options at the interim analysis are group sequential designs and adaptive designs, A comparison of the performance of the two methods under same maximum participant number has not been conducted thus far. So we examined which method should be used by conducting a simulation study. Since bioequivalence is expected to be achieved at the interim analysis, a study design using a Pocock-type alpha spending function is preferrable. Simulation results using a Pocock-type alpha spending function showed similar performance between group sequential and adaptive designs. Consequently, due to statistical and operational complexity, it is preferable to choose group sequential designs for bioequivalence study in Japan., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Background: To evaluate the seasonal variability of urinary albumin to creatinine ratio (UACR) and eGFR and these effects on three-year eGFR slope in persons with type 2 diabetes (T2D)., Methods: A total of 1135 persons with T2D were analyzed in this single-center, retrospective cohort study in Japan. The standard deviation (SD) of UACR (SD [UACR]) and SD of eGFR (SD [eGFR]) were calculated for each person's 10-point data during the three years, and a multiple linear regression analysis was performed to evaluate associations with eGFR slope. A sensitivity analysis was performed in a group with no medication changes (n = 801)., Results: UACR exhibited seasonal variability, being higher in winter and lower in spring, early summer, and autumn especially in the UACR ≥ 30 mg/g subgroup, while eGFR showed no seasonal variability. The eGFR slope was significantly associated with SD (eGFR) (regression coefficient -0.170 [95% CI -0.189--0.151]) and SD (UACR) (0.000 [-0.001-0.000]). SGLT-2 inhibitors, baseline eGFR, and baseline systolic blood pressure (SBP) were also significantly associated. These associated factors, except baseline SBP, were still significant in the sensitivity analysis., Conclusions: The UACR showed clear seasonal variability. Moreover, SD (UACR) and SD (eGFR) were independently associated with a three-year eGFR slope in persons with T2D., Trial Registration: This study was not registered for clinical trial registration because it was a retrospective observational study., (© 2024. The Author(s).)

Due to the insufficiency of safety assessments of clinical trials for drugs, further assessments are required for post-marketed drugs. In addition to adverse drug reactions (ADRs) induced by one drug, drug-drug interaction (DDI)-induced ADR should also be investigated. The spontaneous reporting system (SRS) is a powerful tool for evaluating the safety of drugs continually. In this study, we propose a novel Bayesian method for detecting potential DDIs in a database collected by the SRS. By applying a power prior, the proposed method can borrow information from similar drugs for a drug assessed DDI to increase sensitivity of detection. The proposed method can also adjust the amount of the information borrowed by tuning the parameters in power prior. In the simulation study, we demonstrate the aforementioned increase in sensitivity. Depending on the scenarios, approximately 20 points of sensitivity of the proposed method increase from an existing method to a maximum. We also indicate the possibility of early detection of potential DDIs by the proposed method through analysis of the database shared by the Food and Drug Administration. In conclusion, the proposed method has a higher sensitivity and a novel criterion to detect potential DDIs early, provided similar drugs have similar observed-expected ratios to the drug under assessment., (© 2024 John Wiley & Sons Ltd.)

Objectives: Poor cardiorespiratory fitness (CRF) and high body mass index (BMI) increased the risk of developing metabolic Syndrome (MetS) mostly in Caucasians. However, the sex-specific combined association of CRF and BMI on MetS considering health-related behaviors has yet to be thoroughly examined in Japanese. This study aims to investigate the sex-specific independent and combined associations of CRF and BMI with MetS in middle-aged Japanese adults., Methods: 421 participants were included in this cross-sectional study. CRF was estimated using a submaximal cycle ergometer. CRF and BMI were respectively divided into three categories according to tertile distribution. MetS was diagnosed based on five risk factors: waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure, and fasting glucose. Multivariable logistic regression models were used to estimate independent and combined association of CRF and BMI with MetS., Results: Results showed that 154 (57.5%) and 70 (45.8%) of men and women had MetS, respectively. Compared to men with lower CRF or higher BMI, men with middle and higher CRF or middle and lower BMI were less likely to have MetS. Compared with 'unfit and higher BMI' group, 'unfit and lower BMI', 'fit and higher BMI', and 'fit and lower BMI' groups in men showed statistically significant decreased prevalences of MetS. However, no significant associations were found in women., Conclusions: This study found significant independent and combined associations of CRF and BMI with MetS only in men, but not in women. However, prospective studies are warranted to confirm sex-specific associations of CRF and BMI with MetS., (© 2024. The Author(s).)

[Objective] The aim of this study was to compare the efficacy of particle beam therapy (PT) with photon radiotherapy (RT) for treatment of skull base chordoma. [Methods] A systematic review was conducted for skull base chordoma treated with PT or photon RT reported from 1990 to 2022. Data were extracted for overall survival (OS) and progression-free survival (PFS), late adverse events, age, gender, gross total resection (GTR) rates, tumor volume, total irradiation dose, and treatment modality. Random-effects meta-regression analysis with the treatment modality as an explanatory variable was performed for each outcome to compare the modalities. [Results] A meta-analysis of 30 selected articles found 3- and 5-year OS rates for PT vs. photon RT or combined photon RT/proton beam therapy (PBT) of 90.8% (95% CI: 87.4-93.3%) vs. 89.5% (95% CI: 83.0-93.6%), p = 0.6543; 80.0% (95% CI: 75.7-83.6%) vs. 89.5% (95% CI: 83.0-93.6%), p = 0.6787. The 5-year PFS rates for PT vs. photon RT or photon RT/PBT were 67.8% (95% CI: 56.5-76.7%) vs. 40.2% (95% CI: 31.6-48.7%), p = 0.0004. A random-effects model revealed that the treatment modality (PT vs. photon RT or photon RT/PBT) was not a significant factor for 3-year OS ( p = 0.42) and 5-year OS ( p = 0.11), but was a significant factor for 5-year PFS ( p < 0.0001). The rates of brain necrosis were 8-50% after PT and 0-4% after photon RT or photon RT/PBT. [Conclusion] This study shows that PT results in higher PFS compared to photon RT for skull base chordoma, but that there is a tendency for a higher incidence of brain necrosis with PT. Publication and analysis of further studies is needed to validate these findings.

Background: Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study., Methods: Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used., Results: The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA., Conclusions: Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japan Esophageal Society.)

Purpose: The lung is a unique organ with a ventilation-perfusion mismatch, which can cause inhomogeneous incidence rates of lung cancer depending on the location in the lung. We aimed to evaluate the incidence of lung adenocarcinoma in each lobe by analyzing the incidence per unit volume, to evaluate the incidence without being affected by differences in the size of each lobe or in the size of the lungs between individuals., Methods: The number of adenocarcinomas in each lobe was counted. Lung volumes were measured using a three-dimensional computer workstation. The tumor incidence per unit volume was analyzed based on the number of tumors in each lobe., Results: The number of tumors per unit volume was 0.467 in the right upper lobe (RUL), 0.182 in the right middle lobe, 0.209 in the right lower lobe, 0.306 in the left upper segment (LUS), 0.083 in the left lingular segment, and 0.169 in the left lower lobe. The tumor incidence rate of RUL + LUS was 2.269 times that of the other lobes, a value that was significantly higher when using the bootstrap method (p < 0.001)., Conclusions: The incidence of adenocarcinoma per unit volume in both upper lobes was higher than that in other lobes., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

With the emergence of molecular targeted agents and immunotherapies in anti-cancer treatment, a concept of optimal biological dose (OBD), accounting for efficacy and toxicity in the framework of dose-finding, has been widely introduced into phase I oncology clinical trials. Various model-assisted designs with dose-escalation rules based jointly on toxicity and efficacy are now available to establish the OBD, where the OBD is generally selected at the end of the trial using all toxicity and efficacy data obtained from the entire cohort. Several measures to select the OBD and multiple methods to estimate the efficacy probability have been developed for the OBD selection, leading to many options in practice; however, their comparative performance is still uncertain, and practitioners need to take special care of which approaches would be the best for their applications. Therefore, we conducted a comprehensive simulation study to demonstrate the operating characteristics of the OBD selection approaches. The simulation study revealed key features of utility functions measuring the toxicity-efficacy trade-off and suggested that the measure used to select the OBD could vary depending on the choice of the dose-escalation procedure. Modelling the efficacy probability might lead to limited gains in OBD selection.

Smartphone applications aimed at enhancing physical, cognitive, and social activities through mobile health (mHealth) technology are of increasing interest. Their feasibility and acceptability, alongside impacts on frailty phenotype scores and step counts among older adults with frailty, remain to be fully validated. This study presents a 13-week preliminary intervention trial assessing an mHealth app's feasibility in a cohort of 34 eligible older adults, including 5 frail and 29 pre-frail participants. The intervention entailed a 6-week course on app usage, followed by 7 weeks of observation, with four participants withdrawing early. Feasibility was determined by login and active use rates, with a target login rate of 60% or higher. Post-intervention, 100% session attendance and a median login rate of 88.4% were observed. Acceptability was high, with 73% affirming the app's health benefits. Notably, frailty scores and step counts improved post-intervention, underscoring the app's potential for supporting older adults with frailty.

Retardation of growth and development is a well-known late effect after radiotherapy for pediatric patients. The goal of the study was to examine the effect of proton beam therapy (PBT) on the growth of muscles included in the irradiated area. The subjects were 17 pediatric patients (age ≤ 5 years) who received PBT with a treatment field including a muscle on only one side out of a pair of symmetrical bilateral muscles and had imaging evaluations for at least 1 year after PBT. The thicknesses of the irradiated and non-irradiated (contralateral) muscles were measured retrospectively on CT or MRI axial images collected before and after PBT. The change of thickness divided by the period (years) for each muscle was compared between the irradiated and contralateral sides. Correlations of muscle growth with irradiation dose and age at the start of treatment were also evaluated. The median observation period was 39.2 months. The measurement sites included the erector spinae (n = 9), gluteus maximus (n = 5) and rhomboids + trapezius (n = 3) muscles. The average changes in muscle thickness were 0.24 mm/year on the irradiated side and 1.19 mm/year on the contralateral side, showing significantly reduced growth on the irradiated side (P = 0.001). Younger patients had greater muscle growth. Irradiation dose was not significant, but muscle growth tended to decrease as the dose increased, and muscles irradiated at >50 Gy (RBE) showed little growth. These results show that muscle growth is affected by PBT and that long-term follow-up is needed to evaluate muscle growth retardation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The ABC classification, which categorizes gastric cancer risk based on serum Helicobacter pylori (H pylori) antibody and pepsinogen levels, has a limitation of potentially misclassifying high-risk individuals as low risk. To overcome the problem, we previously developed a 4-parameter predictive formula (age, serum H pylori antibody, PGI, and PGII) using logistic regression analysis to accurately identify low-risk truly H pylori-uninfected status. Our predictive formula demonstrated superior sensitivity and specificity in distinguishing between low-risk truly uninfected individuals and high-risk currently/spontaneously eradicated status individuals, compared to the modified ABC classification based on latex immunoassay kits (traditional 3-parameter model). This study aimed to revalidate the diagnostic accuracy of the predictive formula in a new and different study population. We applied the predictive formula to the target population and compared the sensitivity and specificity with those of the traditional 3-parameter model. A total of 788 enrollees were analyzed: 703 were classified as truly uninfected, 45 as currently infected, and 40 as spontaneously eradicated according to the results of stool antigen testing and endoscopic findings. The sensitivities and specificities of the predictive formula and the traditional 3-parameter model were 89.5% and 87.1% versus 89.8% and 80.0%, respectively. The specificity of the predictive formula was superior in the 70 to 89 age range and H pylori antibody < 3 U/mL groups. The predictive formula had higher specificity than the traditional 3-parameter model. The results should contribute to efficient gastric cancer screening by predicting H pylori infection status., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: A prospective multicenter registry study was started May 2016 in Japan to evaluate the efficacy and safety of proton beam therapy (PBT) for hepatocellular carcinoma (HCC)., Methods and Materials: Patients who received PBT for HCC from May 2016 to June 2018 were registered in the database of the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology. Overall survival (OS), progression-free survival (PFS), and local recurrence were evaluated., Results: Of the 755 registered patients, 576 with initial PBT and no duplicate cancer were evaluated. At final follow-up, 322 patients were alive and 254 had died. The median follow-up period for survivors was 39 months (0-58 months). The median OS time of the 576 patients was 48.8 months (95% CI, 42.0-55.6 months) and the 1-, 2-, 3-, and 4-year OS rates were 83.8% (95% CI, 80.5%-86.6%), 68.5% (64.5%-72.2%), 58.2% (53.9%-62.2%), and 50.1% (44.9%-55.0%), respectively. Recurrence was observed in 332 patients, including local recurrence in 45 patients. The median PFS time was 14.7 months (95% CI, 12.4-17.0 months) and the 1-, 2-, 3-, and 4-year PFS rates were 55.2% (95% CI, 51.0%-59.2%), 37.5% (33.5%-41.5%), 30.2% (26.3%-34.2%), and 22.8% (18.5%-27.4%), respectively. The 1-, 2-, 3-, and 4-year OS rates were significantly higher for tumor size <5 versus 5 to 10 cm (P < .001) and <5 versus ≥10 cm (P < .001); Child-Pugh score A/B versus C (P < .001); and distance of the tumor from the gastrointestinal tract <1 versus 1 to 2 cm (P < .008) and <1 versus >2 cm (P < .001). At final follow-up, 27 patients (4.7%) had late adverse events of grade 3 or higher, with liver failure (n = 7), and dermatitis (n = 7) being most common., Conclusions: This multicenter prospective data registry indicated that PBT for HCC gives good therapeutic effects (3-year local control rate of 90%) with a low risk of severe late adverse events., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Radio-Taiso could be a sustainable public health strategy for maintaining quality of life (QoL) in older adults with frailty. This study aimed to investigate whether Radio-Taiso provided greater benefits for health-related quality of life (HR-QoL) and to identify the mechanisms underlying the effectiveness in this population., Methods: A 12-week randomized controlled trial enrolled 226 older Japanese adults with pre-frailty or frailty, assessed using the modified frailty phenotype. Participants were randomly allocated to the intervention (Radio-Taiso + nutrition program) or control (nutrition program) groups. The Radio-Taiso program comprised five 60-min group sessions and daily practice at the participants' homes. The primary outcome was the change in the mental domain of HR-QoL, assessed using the SF-36 ® . The secondary outcomes included six physical fitness items and exercise self-efficacy., Results: Overall, 104 and 105 participants in the intervention and control groups, respectively, were analyzed based on the intention-to-treat principle. The median (interquartile range) daily practice rate of Radio-Taiso was 94.1% (73.2-98.8%). Although general linear models adjusted for baseline values and allocation stratification factors showed that the intervention group obtained greater benefits (adjusted mean differences [95% confidence intervals]) in the up-and-go (0.3 [0.1, 0.6] s), 2-min step-in-place (-3.2 [-6.2, -0.2] steps) tests, and exercise self-efficacy scale (-1.4 [-2.6, -0.1] points) than the control group, there were no group differences in changes in the mental domain score of HR-QoL., Conclusions: Radio-Taiso provided greater benefits for agility/dynamic balance, aerobic endurance, and exercise self-efficacy in older adults with frailty; however, these changes do not improve HR-QoL.

Introduction: For assessing drug safety using spontaneous reporting system databases, quantitative measurements, such as proportional reporting rate (PRR) and reporting odds ratio (ROR), are widely employed to assess the relationship between a drug and a suspected adverse drug reaction (ADR). The databases contain numerous ADRs, and the quantitative measurements need to be calculated by performing the analysis multiple times for each ADR. We proposed a novel, simple, and easy-to-implement method to estimate the PRR and ROR of multiple ADRs in a single analysis using a generalized mixed-effects model for signal detection. Methods: The proposed method simultaneously analyzed the association between any drug and numerous ADRs, as well as estimated the PRR and ROR for a specific combination of drugs and suspected ADRs. Furthermore, the proposed method was applied to detect drug-drug interactions associated with the concurrent use of two or more drugs. Results and discussion: In our simulation studies, the false-positive rate and sensitivity of the proposed method were similar to those of the traditional PRR and ROR. The proposed method detected known ADRs when applied to the Food and Drug Administration Adverse Event Reporting System database. As an important advantage, the proposed method allowed the simultaneous evaluation of several ADRs using multiple drugs., 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 © 2024 Gosho, Ishii, Ohigashi and Maruo.)

Background: Follow-up after treatment for hepatocellular carcinoma (HCC) can be mostly performed using dynamic CT or MRI, but there is no common evaluation method after radiation therapy. The purpose of this study is to examine factors involved in tumor reduction and local recurrence in patients with HCC treated with proton beam therapy (PBT) and to evaluate HCC shrinkage after PBT., Methods: Cases with only one irradiated lesion or those with two lesions irradiated simultaneously were included in this study. Pre- and post-treatment lesions were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by measuring the largest diameter., Results: The 6-, 12-, and 24-month CR + PR rates after PBT were 33.1%, 57.5%, and 76.9%, respectively, and the reduction rates were 25.1% in the first 6 months, 23.3% at 6-12 months, and 14.5% at 13-24 months. Cases that reached CR/PR at 6 and 12 months had improved OS compared to non-CR/non-PR cases., Conclusions: It is possible that a lesion that reached SD may subsequently transition to PR; it is reasonable to monitor progress with periodic imaging evaluations even after 1 year of treatment.

[Proposal] Here, we retrospectively evaluate risk factors for radiation necrosis and local recurrence after PBT for skull base chordoma or chondrosarcoma. [Patients and Methods] We analyzed 101 patients who received PBT for skull base chordomas and chondrosarcomas from January 1989 to February 2021. Multivariable logistic regression models were applied for local recurrence, temporal lobe radiation necrosis rates, and temporal lobe radiation necrosis. [Results] In multivariate analysis, chordoma and large tumor size were independent significant factors for local recurrence. The 1-, 2-, 3-, 4- and 5-year local recurrence rates were 3.9%, 16.9%, 20.3%, 28.5% and 44.0% for chordoma and 0%, 0%, 0%, 0% and 7.1% for chondrosarcoma, respectively. The local recurrence rates of small tumors (<30 mm) were 4.3%, 14.7%, 17.7%, 17.7% and 25.9%, and those for large tumors were 3.6%, 15.1%, 19.2%, 32.7% and 59.6%, respectively. In multivariate analysis, BED Gy 10 and total dose were risk factors for radiation necrosis. [Conclusions] For skull base chordoma and chondrosarcoma, the risk factors of local recurrence were chordoma and large tumor size, and those of radiation necrosis were BED Gy 10 and total dose, respectively. DVH analysis is needed to investigate the risk factors for brain necrosis in more detail.

Background: In patients with atrial fibrillation (AF) and severe blood stasis in the left atrial appendage (LAA), dense spontaneous echo contrast (SEC) disturbs the distinct visualization of the LAA interior, thus making thrombus diagnosis inconclusive. We aimed to prospectively assess the efficacy and safety of a protocol for a low-dose isoproterenol (ISP) infusion to reduce SEC to exclude an LAA thrombus., Methods and results: We enrolled 17 patients with AF and dense SEC (Grade 4 or sludge). ISP was infused with gradually increasing doses of 0.01, 0.02, and 0.03 μg/kg/min at 3-min intervals. After increasing the dose to 0.03 μg/kg/min for 3 min, or when the LAA interior was visible, the infusion was terminated. We reassessed the SEC grade, presence of an LAA thrombus, LAA function, and left ventricular ejection fraction (LVEF) within 1 min of ISP termination. Compared with baseline, ISP significantly increased LAA flow velocity, the LAA emptying fraction, LAA wall velocities, and LVEF (all P<0.01). ISP administration significantly reduced the SEC grade (median) from 4 to 1 (P<0.001). The SEC grade decreased to ≤2 in 15 (88%) patients, and the LAA thrombus was excluded. There were no adverse events., Conclusions: Low-dose ISP infusion may be effective and safe to reduce SEC and exclude an LAA thrombus by improving LAA function and LVEF.

Purpose: To evaluate the safety and pathologic complete response (pCR) rate of radiation therapy with atezolizumab as bladder-preserving therapy for invasive bladder cancer., Methods and Materials: A multicenter, phase 2 study was conducted with patients with clinically T2-3 or very-high-risk T1 bladder cancer who were poor candidates for or refused radical cystectomy. The interim analysis of pCR is reported as a key secondary endpoint ahead of the progression-free survival rate primary endpoint. Radiation therapy (41.4 Gy to the small pelvic field and 16.2 Gy to the whole bladder) was given in addition to 1200 mg intravenous atezolizumab every 3 weeks. After 24 treatment weeks, response was assessed after transurethral resection, and tumor programmed cell death ligand-1 (PD-L1) expression was assessed using tumor-infiltrating immune cell scores., Results: Forty-five patients enrolled from January 2019 to May 2021 were analyzed. The most common clinical T stage was T2 (73.3%), followed by T1 (15.6%) and T3 (11.1%). Most tumors were solitary (77.8%), small (<3 cm) (57.8%), and without concurrent carcinoma in situ (88.9%). Thirty-eight patients (84.4%) achieved pCR. High pCR rates were achieved in older patients (90.9%) and in patients with high PD-L1-expressing tumors (95.8% vs 71.4%). Adverse events (AEs) occurred in 93.3% of patients, with diarrhea being the most common (55.6%), followed by frequent urination (42.2%) and dysuria (20.0%). The frequency of grade 3 AEs was 13.3%, whereas no grade 4 AEs were observed., Conclusions: Combination therapy with radiation therapy and atezolizumab provided high pCR rates and acceptable toxicity, indicating it could be a promising option for bladder preservation therapy., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives　Japan has a high prevalence of low back pain among older adults requiring long-term care, which results in increasing expenses; therefore, prevention measures are necessary. This study aimed to examine the relationship between low back pain and physical activity and sitting time according to sex and age (65-74 years [young-old adults]; ≥75 years [old-old adults]) who had not received long-term care certification.Methods　A self-administered survey was mailed to 7,080 adults >65 years of age residing in Tsuru City (Yamanashi Prefecture, Japan) from January to February 2018, and had not received long-term care certification. Demographic information, health status (body mass index and medical history), lifestyle (dietary habits, alcohol consumption, and smoking), presence of low back pain, physical activity, sitting time, and social participation were measured. Low back pain was evaluated by asking, "Did you experience pain in parts of the body other than the knees for the past month?" Those who answered, "experienced low back pain" were categorized as "with low back pain". The short form of the International Physical Activity Questionnaire was used to assess physical activity, which was categorized into three groups: <150, 150-299, and ≥300 min/week. Sitting time was divided into two groups: <480 and ≥480 min/day. Multiple logistic regression analysis was used to determine the association between low back pain and physical activity and sitting time, according to sex and age.Results　Of the 7,080 individuals surveyed, 4,877 responded (2,217 male, 2,660 female), corresponding to a response rate of 68.9%. The number of older adults with low back pain was 1,542 (31.6%) including 673 (30.4%) males and 869 (32.7%) females. The rate of low back pain in young-old adults was 29.8% and 33.6% in old-old adults. There was no significant relationship between lower back pain and physical activity among the young-old adults. In the old-old adults, there was a significant relationship in the male ≥300 min group (odds ratio [OR] 0.66 [95%CI 0.48-0.89]), and in both female 150-299 (OR 0.69 [95%CI 0.48-0.99]) and ≥300 (OR 0.59 [95%CI 0.44-0.80]) min/week groups.Conclusion　The complaint rate for low back pain was approximately 30%, regardless of sex or age. These results suggest that interventions to prevent low back pain are necessary. Moreover, physical activity, but not sitting time, was associated with low back pain in both males and females among the old-old adults.

Introduction: It has been suggested that the positive symptoms of schizophrenic patients (hallucinations, delusions, and passivity experience) are caused by dysfunction of their internal and external sensory prediction errors. This is often discussed as related to dysfunction of the forward model that executes self-monitoring. Several reports have suggested that dysfunction of the forward model in schizophrenia causes misattributions of self-generated thoughts and actions to external sources. There is some evidence that the forward model can be measured using the electroencephalography (EEG) and magnetoencephalography (MEG) components such as N1 (m) and mismatch negativity (MMN) (m). The objective in this MEG study is to investigate differences in the N1m and MMNm-like activity generated in motor-auditory cross-modal tasks in normal control (NC) subjects and schizophrenic (SC) patients, and compared that activity with N1m and MMNm in the auditory unimodal task., Methods: The N1m and MMNm/MMNm-like activity were recorded in 15 SC patients and 12 matched NC subjects. The N1m-attenuation effects and peak amplitude of MMNm/MMNm-like activity of the NC and SC groups were compared. Additionally, correlations between MEG measures (N1m suppression rate, MMNm, and MMNm-like activity) and clinical variables (Positive and Negative Syndrome Scale (PANSS) scores and antipsychotic drug (APD) dosages) in SC patients were investigated., Results: It was found that (i) there was no significant difference in N1m-attenuation for the NC and SC groups, and that (ii) MMNm in the unimodal task in the SC group was significantly smaller than that in the NC group. Further, the MMNm-like activity in the cross-modal task was smaller than that of the MMNm in the unimodal task in the NC group, but there was no significant difference in the SC group. The PANSS positive symptoms and general psychopathology score were moderately negatively correlated with the amplitudes of the MMNm-like activity, and the APD dosage was moderately negatively correlated with the N1m suppression rate. However, none of these correlations reached statistical significance., Discussion: The findings suggest that schizophrenic patients perform altered predictive processes differently from healthy subjects in latencies reflecting MMNm, depending on whether they are under forward model generation or not. This may support the hypothesis that schizophrenic patients tend to misattribute their inner experience to external agents, thus leading to the characteristic schizophrenia symptoms., 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. The handling editor TS declared a past co-authorship with the author KM., (Copyright © 2023 Okazaki, Yumoto, Kaneko and Maruo.)

Graft failure and delayed hematopoietic recovery are the major limitations of cord-blood transplantation (CBT). Romiplostim, a thrombopoietin-receptor agonist, promotes megakaryopoiesis and multilineage hematopoiesis in aplastic anemia. The decreased number of hematopoietic stem cells in the early phase after CBT and aplastic anemia share certain characteristics. Therefore, we hypothesized that romiplostim administration immediately after CBT may promote multilineage hematopoietic recovery. We investigated the safety and preliminary efficacy of administering romiplostim a day after CBT. This phase 1 dose-escalation study included six adults with hematologic malignancies in remission. Romiplostim was administered subcutaneously within 7 days after single-unit CBT, initially at doses of 5 µg/kg or 10 µg/kg in three patients, then once a week for 14 weeks or until platelet recovery. The maximum dose was 20 µg/kg. The median number of romiplostim administrations was 6 (range, 3-15). Romiplostim-related adverse events included bone pain (3/6) and injection site reaction (1/6). Non-hematological grade ≥ 3 toxicities were observed in four patients; febrile neutropenia was the most common (4/6). All patients achieved neutrophil engraftment and the median time was 14 days (range, 12-32). Platelet counts ≥ 50 × 10 9 /L were recorded in all patients except for one who died on day 48; the median time was 34 days (range, 29-98). No relapse, thrombosis, or bone marrow fibrosis was observed during a median follow-up of 34 months. Romiplostim may be safely administered in the early phase of CBT. Further phase 2 trial is warranted for its efficacy evaluation. Trial registration number: UMIN000033799, August 18, 2018., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are recommended based on certain risk factors. The volume of an institution's treatment experience may be associated with good clinical outcomes. There is a dilemma between the treatment strategy based on risk factors and the experience volume. Therefore, we investigated the clinical outcomes of CAS performed at institutions that selected the treatment strategy based on risk factors and those that performed CAS at the first-line treatment., Materials and Methods: Patients who underwent CAS at 5 institutions were included in this retrospective case-control study. We defined CEA/CAS institutions as those that selected the treatment option based on risk factors, and CAS-first institutions as those that performed CAS as the first-line treatment. We investigated cases of ischemic stroke, hemorrhagic stroke, myocardial infarction, and deaths within 30 days of the intervention between the CEA/CAS- and CAS-first institution groups. One-to-one propensity score matching was performed to compare rates of ischemic and hemorrhagic strokes within 30 days of the intervention., Results: A total of 239 and 302 patients underwent CAS at the CEA/CAS institutions and CAS-first institutions, respectively; ischemic stroke occurred in 12 (5.0%) and 7 patients (2.3%), respectively (p=0.09). No differences in major ischemic strokes (0.8% vs 1.3%; p=0.59), hemorrhagic strokes (0.4% vs 0.3%; p=0.87), or deaths (0.0% vs 0.7%; p=0.21) were observed. Myocardial infarction did not occur in either group. Propensity score analysis showed that ischemic stroke (odds ratio: 1.845, 95% confidence interval: 0.601-5.668, p=0.28) and hemorrhagic stroke (odds ratio: 1.000, 95% confidence interval: 0.0061-16.418, p=1.00) were not significantly associated with either institution group., Conclusions: The CAS-specific treatment strategies for CAS can achieve the same level of outcomes as the treatment strategy based on risk factors. The CAS performed based on risk factors in CEA/CAS institutions and the treatment of more than 30 patients/year/institution in CAS-first institutions were associated with good clinical outcomes.

Background Abnormal sensations were frequently experienced by patients who received irradiation of the brain or head and neck region. We have previously suggested correlations with irradiation of the nasal cavity and retina. Purpose We performed a retrospective dose-volume histogram analysis focused on the brain and head and neck tumor to examine the relationship between these abnormal sensations and the details of irradiation. Methods Multivariate logistic regression models were applied for the presence or absence of light flash and odor. Gender, age, radiotherapy method (proton beam therapy vs. photon radiotherapy), dose of retina, optic nerve, chiasmatic gland, pituitary, nasal cavity, oral cavity, frontal lobe, parietal lobe, occipital lobe, temporal lobe, amygdala, and hippocampus were set as candidates of explanatory variables. Results Light flash and odor during radiotherapy have been suggested to be associated with younger age and retina and nasal cavity irradiation. Multivariate analyses including dose-volume histograms indicated that light flash was related to age, chiasmatic gland irradiation, and pituitary dose, and odor was related to age and nasal cavity irradiation. Conclusion Our results indicate that light flash during radiotherapy is caused by irradiation of the visual pathway and that odor is caused by irradiation of the nasal cavity or olfactory bulb., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Oshiro et al.)

Objective: Relapses and rehospitalization prevent the recovery of individuals with schizophrenia or related psychoses. We aimed to build a model to predict the risk of rehospitalization among people with schizophrenia or related psychoses, including those with multiple episodes., Methods: This retrospective cohort study included individuals aged 18 years or older, with schizophrenia or related psychoses, and discharged between January 2014 and December 2018 from one of three Japanese psychiatric hospital acute inpatient care ward. We collected nine predictors at the time of recruitment, followed up with the participants for 12 months, and observed whether psychotic relapse had occurred. Next, we applied the Cox regression model and used an elastic net to avoid overfitting. Then, we examined discrimination using bootstrapping, Steyerberg's method, and "leave-one-hospital-out" cross-validation. We also constructed a bias-corrected calibration plot., Results: Data from a total of 805 individuals were analyzed. The significant predictors were the number of previous hospitalizations (HR 1.42, 95% CI 1.22-1.64) and the current length of stay in days (HR 1.31, 95% CI 1.04-1.64). In model development for relapse, Harrell's c-index was 0.59 (95% CI 0.55-0.63). The internal and internal-external validation for rehospitalization showed Harrell's c-index to be 0.64 (95% CI 0.59-0.69) and 0.66 (95% CI 0.57-0.74), respectively. The calibration plot was found to be adequate., Conclusion: The model showed moderate discrimination of readmission after discharge. Carefully defining a research question by seeking needs among the population with chronic schizophrenia with multiple episodes may be key to building a useful model., Competing Interests: TAF reports personal fees from Boehringer-Ingelheim, DT Axis, Kyoto University Original, Shionogi and SONY, and a grant from Shionogi, outside the submitted work; In addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. The remaining 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 © 2023 Sato, Moriyama, Watanabe, Maruo and Furukawa.)

Background: It has not been determined whether mentally active sedentary behavior (MASB) and passive sedentary behavior (PSB) differentially affect cognitive function and whether these associations differ according to physical activity (PA) level. We examined the comparative impacts of MASB and PSB on dementia onset and aimed to understand whether the associations differed by PA level., Methods: We conducted a 5-year longitudinal study involving all community-dwelling older adults in a rural area in Japan (n = 5,323). Dementia onset was examined using long-term care insurance data. PA was evaluated using the International Physical Activity Questionnaire and categorized as low (<2.5 metabolic equivalent of task [MET]-h/week), moderate (2.5-16.0 MET-h/week), or high (≥16.0 MET-h/week). We also assessed PSB (TV-watching time; <1 h/day, 1-3 h/day, ≥3 h/day) and MASB (Book-reading time; <10 min/day, 10-30 min/day, ≥30 min/day). To examine the associations of MASB and PSB with dementia onset, we performed the Fine-Gray models accounting for competing risk of death., Results: During the follow-up period, 606 (11.4%) participants developed dementia. MASB was independently associated with a lower risk of dementia; the magnitude of the impact was significant at higher PA levels. There was no association between PSB and developing dementia across all PA levels. Furthermore, dementia risk for individuals with high PA levels and moderate or high MASB levels was approximately 60% lower than those with low PA levels and low MASB., Conclusion: Providing interventions to promote MASB, which reduces dementia risk, and PA, which increases MASB's effect on dementia incidence, can be beneficial in delaying or preventing dementia onset.

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control., Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6-76 Gy (RBE) in 20-22 fr, 13 received 74.0-76.0 Gy (RBE) in 37-38 fr, and 6 received 60-70.2 Gy (RBE) in 20-30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis., Results: The 59 patients (35 men, 24 women; median age: 71 years; range: 41-91 years) had PS of 0 ( n = 47), 1 ( n = 10), and 2 ( n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A ( n = 46), B ( n = 7), and unknown ( n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0-15.2 cm); and the clinical stage was I ( n = 12), II ( n = 19), III ( n = 10), and IV ( n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1-49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8-34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1-11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher., Conclusion: PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Using a generalized estimating equation (GEE) can lead to a bias in regression coefficients for a small sample or sparse data. The bias-corrected GEE (BCGEE) and penalized GEE (PGEE) were proposed to resolve the small-sample bias. Moreover, the standard sandwich covariance estimator leads to a bias of standard error for small samples; several modified covariance estimators have been proposed to address this issue. We review the modified GEEs and modified covariance estimators, and evaluate their performance in sparse binary data from small-sample longitudinal studies. The simulation results showed that GEE and BCGEE often failed to achieve convergence, whereas the convergence proportion for PGEE was quite high. The bias for the regression coefficients was generally in the ascending order of PGEE < $$ < $$ BCGEE < $$ < $$ GEE. However, PGEE and BCGEE did not sufficiently remove the bias involving 20-30 subjects with unequal exposure levels with a 5% response rate. The coverage probability (CP) of the confidence interval for BCGEE was relatively poor compared with GEE and PGEE. The CP with the sandwich covariance estimator deteriorated regardless of the GEE methods under the small sample size and low response rate, whereas the CP with the modified covariance estimators-such as Morel's method-was relatively acceptable. PGEE will be the reasonable way for analyzing sparse binary data in small-sample studies. Instead of using the standard sandwich covariance estimator, one should always apply the modified covariance estimators for analyzing these data., (© 2023 John Wiley & Sons Ltd.)

Introduction: In the Enhanced Recovery After Surgery program, abdominal wall blocks are strongly recommended as postoperative multimodal analgesia for laparoscopic abdominal surgery. The purpose of this study was to compare the efficacy of single-shot rectus sheath block (RSB) with that of thoracic epidural analgesia (TEA) as a method of multimodal analgesia in patients receiving conventional laparoscopic abdominal surgery., Methods: A noninferiority comparison was performed. Patients scheduled for laparoscopic gastric or colorectal surgery were enrolled in this study. Patients were divided randomly into two groups: TEA and RSB. The primary endpoint was the numerical rating scale (NRS) score upon coughing as of 24 hours after surgery., Results: In total, 80 patients were randomly assigned to receive TEA (n = 42) or RSB (n = 38). Three patients were excluded from the TEA group after randomization. The NRS score on coughing as of 24 hours after surgery was significantly lower in the TEA group than in the RSB group (least square mean: 3.59 vs 6.39; 95% confidence interval for the difference: 1.87 to 3.74, P < .001). The NRS scores upon coughing and at rest were significantly lower in the TEA group than in the RSB group as of 4, 24 and 48 hours after surgery. Patient satisfaction with postoperative analgesia was significantly higher in the TEA group. Postoperative adverse events were not significantly different between groups., Conclusion: This is the first report of comparing RSB with TEA in laparoscopic surgery. TEA may be recommended as a multimodal analgesia protocol for laparoscopic gastric and colorectal surgery., (© 2023 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

The number of regulatory T cells (Tregs) and how they behave in the pathogenesis of atopic dermatitis (AD) are still controversial. We identified and quantified Tregs, mite-specific Tregs, and mite-specific effector T cells (Teffs) in patients with AD and healthy controls (HCs). We collected peripheral blood and analyzed the cells using flow cytometry after stimulation with mite antigens. Mite-specific Tregs and mite-specific Teffs were recognized by the expression of CD137 and CD154, respectively. Patients with AD had more Tregs than HCs; however, when focusing on a single antigen, the ratio of mite-specific Tregs/Teffs was lower in patients with AD than in HCs. Furthermore, the mite-specific Teffs in patients with AD were more likely to produce proinflammatory cytokines interleukin (IL)-4 and IL-13. This Teff-dominant imbalance is thought to be the cause of development of atopic status in patients with AD without immune tolerance., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To assess the safety and efficacy of proton beam therapy (PBT) for muscle-invasive bladder cancer (MIBC), we examined the outcomes of 36 patients with MIBC (cT2-4aN0M0) who were enrolled in the Proton-Net prospective registry study and received PBT with concurrent chemotherapy from May 2016 to June 2018. PBT was also compared with X-ray chemoradiotherapy in a systematic review (X-ray (photon) radiotherapy). The radiotherapy consisted of 40-41.4 Gy (relative biological effectiveness (RBE) delivered in 20-23 fractions to the pelvic cavity or the entire bladder using X-rays or proton beams, followed by a boost of 19.8-36.3 Gy (RBE) delivered in 10-14 fractions to all tumor sites in the bladder. Concurrently, radiotherapy was given with intra-arterial or systemic chemotherapy of cisplatin alone or in combination with methotrexate or gemcitabine. Overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 90.8, 71.4 and 84.6%, respectively, after 3 years. Only one case (2.8%) experienced a treatment-related late adverse event of Grade 3 urinary tract obstruction, and no severe gastrointestinal adverse events occurred. According to the findings of the systematic review, the 3-year outcomes of XRT were 57-84.8% in OS, 39-78% in PFS and 51-68% in LC. The weighted mean frequency of adverse events of Grade 3 or higher in the gastrointestinal and genitourinary systems was 6.2 and 2.2%, respectively. More data from long-term follow-up will provide us with the appropriate use of PBT and validate its efficacy for MIBC., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The feasibility and efficacy of particle beam therapy (PBT) using protons or carbon ions were compared with those of photon-based stereotactic body radiotherapy (SBRT) for primary renal cell carcinoma (RCC) via a systematic review and nationwide registry for PBT (Japanese Society for Radiation Oncology [JASTRO] particle therapy committee). Between July 2016 and May 2019, 20 patients with non-metastatic RCC who were treated at six Japanese institutes (using protons at three, using carbon ions at the other three) were registered in the nationwide database and followed up prospectively. The 20 patients comprised 15 men and had a median age of 67 (range: 57-88) years. The total radiation dose was 66-79.6 Gy (relative biological effectiveness [RBE]). Over a median follow up of 31 months, the 3-year rates of overall survival (OS) and local control (LC) were 100% and 94.4%, respectively. No grade ≥ 3 toxicities were observed. Based on a random effects model, a meta-analysis including the present results revealed 3-year OS rates after SBRT and PBT of 75.3% (95% CI: 57.3-86.6) and 94.3% (95% CI: 86.8-97.6), respectively (P = 0.005), but the difference in LC rates between the two methods was not observed (P = 0.63). PBT is expected to have similar if not better treatment results compared with SBRT for primary renal cancer. In particular, PBT was shown to be effective even for large RCC and could provide a therapeutic option when SBRT is not indicated., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Logistic regression models are widely used to evaluate the association between a binary outcome and a set of covariates. However, when there are few study participants at the outcome and covariate levels, the models lead to bias of the odds ratio (OR) estimated using the maximum likelihood (ML) method. This bias is known as sparse data bias, and the estimated OR can yield impossibly large values because of data sparsity. However, this bias has been ignored in most epidemiological studies., Methods: We review several methods for reducing sparse data bias in logistic regression. The primary aim is to evaluate the Bayesian methods in comparison with the classical methods, such as the ML, Firth's, and exact methods using a simulation study. We also apply these methods to a real data set., Results: Our simulation results indicate that the bias of the OR from the ML, Firth's, and exact methods is considerable. Furthermore, the Bayesian methods with hyper-ɡ prior modeling of the prior covariance matrix for regression coefficients reduced the bias under the null hypothesis, whereas the Bayesian methods with log F-type priors reduced the bias under the alternative hypothesis., Conclusion: The Bayesian methods using log F-type priors and hyper-ɡ prior are superior to the ML, Firth's, and exact methods when fitting logistic models to sparse data sets. The choice of a preferable method depends on the null and alternative hypothesis. Sensitivity analysis is important to understand the robustness of the results in sparse data analysis.

To investigate the development of diaphragmatic dysfunction in ventilated extremely preterm infants (EPI) using diaphragm ultrasound (DU). EPI of less than 28 weeks' gestational age who required mechanical ventilation within six hours of birth were included in this prospective, observational study. DU was performed once a day until four days of life. End-inspiratory and end-expiratory thicknesses of the diaphragm were measured, and the diaphragm thickening fraction was calculated. A total of 20 EPI were enrolled. After intubation, there was a progressive reduction in end-inspiratory thickness of the diaphragm from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 0.092), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0). There was also a significant reduction in the diaphragm thickening fraction from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 1.0), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0).    Conclusions: This study provides the first evidence of diaphragmatic dysfunction in ventilated EPI. We demonstrated a rapid progression of ventilator-induced diaphragmatic dysfunction, with a significant reduction in diaphragm thickness and thickening fraction within 24 h of ventilation. What is Known: • Over-assistance of the ventilator suppresses respiratory effort and induces diaphragm unloading, resulting in diaphragm atrophy or dysfunction. • Diaphragmatic dysfunction contributes to prolonged ventilator dependence and poor clinical outcomes. What is New: • Most extremely preterm infants develop diaphragmatic dysfunction after intubation within 24 hours. • Diaphragm thickness and contraction ability measured by ultrasound would be important indicators of worsening breathing or respiratory outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Previous studies have shown that combined use of orthokeratology and 0.01% atropine (AT) eye drops can strongly prevent axial elongation in myopic children. However, the efficacy of combined use with multifocal contact lens (MFCL) and 0.01% AT remains unclear. The aim of this trial is to clarify the efficacy of MFCL+0.01% AT combination therapy for myopia control and safety., Methods: This prospective study is a randomized, double-masked, placebo-controlled trial with four arms. A total of 240 children aged 6 to 12 years with myopia is recruited and randomly assigned to one of the four groups in a ratio of 1:1:1:1 as follows: group 1: MFCL+AT combination therapy, group 2: MFCL monotherapy, group 3: AT monotherapy, and group 4: placebo. The participants will continue the assigned treatment for 1 year. The primary and secondary outcomes are the comparisons of axial elongation and myopia progression in the four groups during the 1-year study period., Discussion: The present trial would determine whether the MFCL+AT combination therapy is more effective in slowing axial elongation and myopia progression in schoolchildren as compared with each monotherapy or placebo, and it also confirm acceptable safety of the combination therapy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Contact Lens Association of Ophthalmologists.)

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose-volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5-20 and lung V5-50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P = 0.042), 26.1% vs 5.6% (P = 0.022) and 39.1% vs 5.6% (P < 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P = 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Atrial fibrillation (AF) is the most common arrhythmia and often recurs despite catheter ablation. The recurrence of AF is often underdiagnosed by standard 24-hour electrocardiogram (ECG) because of its transient and silent nature. A garment-style ECG with a highly conductive textile electrode made of poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate)(PEDOTPSS) and nanofiber (Garment ECG) has been developed that can provide longer-term continuous monitoring. This study investigated whether 2-week Garment ECG can reveal instances of AF recurrence in patients who are diagnosed as remaining in sinus rhythm by 24-hour Holter ECG., Methods: The open-label randomized crossover study enrolled 67 patients (63.1±10.6 years old, 53 men) who had undergone initial AF ablation. Three months after ablation, patients were randomly assigned to group 1 (n = 35), 2-week Garment ECG followed by 24-hour Holter ECG, or group 2 (n = 32), 24-hour Holter ECG followed by 2-week Garment ECG. The detection of AF recurrence was compared between the two devices., Results: The Garment ECG showed AF recurrence in 12 patients (18%) compared to 4 patients for the Holter ECG (6%, p = 0.008). The ECG acquisition rate was higher for Holter ECG than for Garment ECG (100.0% [interquartile range 100.0-100.0%] versus 82.4% [71.1-91.0%], p<0.001), but the Garment ECG provided longer total analysis time (11.0 days [9.0-12.2 days] for Garment; 1.0 day [1.0-1.0 day] for Holter, p<0.001)., Conclusions: Despite the lower ECG acquisition rate, the 2-week Garment ECG revealed instances of AF recurrence after ablation in patients who were underdiagnosed by 24-hour Holter ECG., Trial Registration: Clinical Trial Registration: URL: https://jrct.niph.go.jp/en-latest-detail/jRCTs032180018 Unique Identifier: jRCTs032180018., Competing Interests: Machino T reports research funds from Toray Industries, Inc. for this study (CLE30006). Komatsu Y reports honoraria for lectures and advisory board activities from Johnson & Johnson K.K. Yamasaki H reports consulting fees from Toray Industries, Inc. Igarashi M reports belonging to a department endowed by Boston Scientific Japan, Japan Lifeline Co., Ltd., NIHON KOHDEN CORPORATION, BIOTRONIK Japan, Inc., Toray Industries, Inc., Abbott Medical Japan LLC and ASTEC Co., Ltd. Nogami A reports honoraria for lectures from Abbott Medical Japan LLC and Johnson & Johnson K.K.; and endowments from Medtronic Japan Co., Ltd. and DVx Inc. Ieda M reports scholarship donations from Toray Industries, Inc. The remaining authors have no disclosures to report. This work was supported by Toray Industries, Inc. (CLE30006), which provided the garment-style wearable ECG using hitoe® electrodes. The funding source had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Machino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Allergic diseases are some of the most common diseases worldwide. Genome-wide association studies (GWASs) have been conducted to elucidate the genetic factors of allergic diseases. However, no GWASs for allergen component sensitization have been performed., Objective: We sought to detect genetic variants associated with differences in immune responsiveness against allergen components., Methods: The participants of the present study were recruited from the Tokyo Children's Health, Illness, and Development study, and allergen component-specific IgE level at age 9 years was measured by means of allergen microarray immunoassays. We performed GWASs for allergen component sensitization against each allergen (single allergen component sensitization, number of allergen components analyzed, n = 31), as well as against allergen protein families (allergen protein group sensitization, number of protein groups analyzed, n = 16)., Results: We performed GWAS on 564 participants of the Tokyo Children's Health, Illness, and Development study and found associations between Amb a 1 sensitization and the immunoglobulin heavy-chain variable gene on chromosome 14 and between Phl p 1 sensitization and the HLA class II region on chromosome 6 ( P  < 5.0 × 10 -8 ). A GWAS-significant association was also observed between the HLA class II region and profilin sensitization ( P  < 5.0 × 10 -8 )., Conclusions: Our data provide the first demonstration of genetic risk for allergen component sensitization and show that this genetic risk is related to immune response genes including immunoglobulin heavy-chain variable gene and HLA ., (© 2023 The Authors.)

The purpose of this study was to analyze renal late effects after proton beam therapy (PBT) for pediatric malignant tumors. A retrospective study was performed in 11 patients under 8 years of age who received PBT between 2013 and 2018. The kidney was exposed in irradiation of the primary lesion in all cases. Kidney volume and contour were measured on CT or MRI. Dose volume was calculated with a treatment-planning system. The median follow-up was 24 months (range, 11-57 months). In irradiated kidneys and control contralateral kidneys, the median volume changes were -5.63 (-20.54 to 7.20) and 5.23 (-2.01 to 16.73) mL/year; and the median % volume changes at 1 year were -8.55% (-47.52 to 15.51%) and 9.53% (-2.13 to 38.78%), respectively. The median relative volume change for irradiated kidneys at 1 year was -16.42% (-52.21 to -4.53%) relative to control kidneys. Kidneys irradiated with doses of 10, 20, 30, 40, and 50 GyE had volume reductions of 0.16%, 0.90%, 1.24%, 2.34%, and 8.2% per irradiated volume, respectively. The larger the irradiated volume, the greater the kidney volume was lost. Volume reduction was much greater in patients aged 4-7 years than in those aged 2-3 years. The results suggest that kidneys exposed to PBT in treatment of pediatric malignant tumor show continuous atrophy in follow-up. The degree of atrophy is increased with a higher radiation dose, greater irradiated volume, and older age. However, with growth and maturation, the contralateral kidney becomes progressively larger and is less affected by radiation.

Background: Caregivers for stroke survivors (CSS) suffer from long hours of care, limited support, and financial difficulties, which often affect their mental health., Objectives: This study sought to determine the factors affecting psychological distress and sleep duration among CSS., Methods: We analyzed cross-sectional data from the 2013 Comprehensive Survey of the Living Conditions for Stroke Survivors and CSS. Linked data from 841 pairs of stroke survivors and CSS were extracted. Kessler's Psychological Distress scale (K6) was used to evaluate psychological distress. CSS who slept less than 5 hours per day were classified as having short sleep duration. Factors predictive of psychological distress and short sleep duration were evaluated using multivariable logistic regression analysis with the forward selection method., Results: The mean (SD) age of the CSS was 65.4 (12.5) years. A total of 5.6% of these caregivers presented with serious psychological distress, and 12.0% were sleep deprived. Serious psychological distress was associated with not having someone to consult with, having subjective symptoms within a few days, and having short sleep duration, while having their own houses reduced the risk of serious psychological distress. Furthermore, short sleep duration was associated with stroke survivors in long-term care levels 4 or 5, not having someone to consult with, participation in sponge baths as part of nursing care activities, and having serious psychological distress., Conclusions: This nationwide survey identified several risk factors for psychological stress and sleep deprivation among CSS and suggests the need for multidimensional approaches to reduce their distress., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest related to this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aim: This study examined the relationship between continuity of social participation and progression of frailty among community-dwelling older adults, by baseline frailty level., Methods: This study was part of a 3-year community-based cohort study among adults aged ≥65 years, living independently in a rural municipality in Japan. Mail surveys were carried out in 2016, 2018 and 2019. This study involved 2799 participants who responded to the question about social participation in every survey. Frailty was evaluated by Kihon Checklist total scores. Social participation was categorized into consistent non-participation, interrupted recent non-participation, interrupted recent participation and consistent participation. We assessed the relationship between social participation and change in frailty scores using general linear regression analysis, stratifying the participants into groups by their frailty level at baseline., Results: There was a smaller frailty score increase in the robust (β -0.61, 95% CI -0.99 to -0.22) and prefrail groups (β -0.73, 95% CI -1.18 to -0.27) for consistent participation than consistent non-participation. Interrupted recent participation showed significant suppression in the prefrail group (β -0.96, 95% CI -1.60 to -0.32). Social participation had no clear effect on progression in the frail group., Conclusions: Consistent social participation might reduce the progression of frailty in robust and prefrail people. Inconsistent participation might also help to reduce progression in prefrail older adults. It is important for prefrail older adults to return to their social activities and continue to engage as long as possible, even if their participation was intermittent in the past. Geriatr Gerontol Int 2023; 23: 25-31., (© 2022 Japan Geriatrics Society.)

Aim: Radio-Taiso, a traditional exercise program in Japan, may serve as a coping strategy for older adults with frailty during the COVID-19 pandemic. This phase II trial tested program adherence and safety and explored the potential effectiveness of a home-based Radio-Taiso., Methods: This assessor-blind parallel randomized controlled trial included community-dwelling Jolder Japanese adults with frailty and pre-frailty. Fifty-eight eligible participants were randomly allocated to intervention and control groups. Intervention participants performed 3-5-min sessions of Radio-Taiso one to four times per day for 12 weeks. Feasibility criteria were set at practice and retention rates of ≥75%. Safety was monitored by assessing all adverse events reported by participants during the intervention period, irrespective of causality. Potential effectiveness was exploratorily assessed using items that allow clinical interpretation of changes: mobility and health-related quality of life (HR-QoL), assessed using the modified short physical performance battery (SPPB) and the SF-36, respectively., Results: Both practice (83%) and retention rates (100%) met the predetermined feasibility criteria. Eleven adverse events were reported but were supposedly unrelated to the intervention. In the intention-to-treat analysis, there was no clinically significant difference in the change in SPPB score between groups (-0.4 points, 95% confidence interval [CI], -1.2, 0.3); however, the intervention group scored higher in the mental component of HR-QoL than did the control group (3.4 points, 95% CI: -1.1, 7.8)., Conclusions: The preliminary data indicate that a phase III trial is feasible, focusing on the mental aspect of HR-QoL as the primary outcome. Geriatr Gerontol Int 2023; 23: 32-37., (© 2022 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Objective: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE., Methods: We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug., Results: A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061)., Conclusion: The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT., Trial Registration Number: jRCTs031190160., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Proton beam therapy (PBT) is known to be an effective locoregional treatment for hepatocellular carcinoma (HCC). However, few comparative studies in treatment-naïve cases have been reported. The aim of this study was to compare the survival outcomes of PBT with those of radiofrequency ablation (RFA) in patients with treatment-naïve solitary HCC., Methods: Ninety-five consecutive patients with treatment-naïve HCC, a single nodule measuring ≤5 cm in diameter, and a Child-Pugh score of ≤8 who were treated with PBT at the University of Tsukuba Hospital between 2001 and 2013 were enrolled in the study. In addition, 836 patients with treatment-naïve HCC treated by RFA at the University of Tokyo Hospital during the same period were analyzed as controls. Recurrence-free survival (RFS) and overall survival (OS) were compared in 83 patient pairs after propensity score matching., Results: The 1-year, 3-year, and 5-year RFS rates were 86.6%, 49.5%, and 35.5%, respectively, in the PBT group and 59.5%, 34.0%, and 20.9% in the RFA group ( p = 0.058); the respective OS rates were 97.6%, 77.8%, and 57.1% in the PBT group and 95.1%, 81.7%, and 67.7% in the RFA group ( p = 0.16). Regarding adverse effects, no grade 3 or higher adverse events were noted in the PBT; however, two grade 3 adverse events occurred within 30 days of RFA in the RFA group: one hemoperitoneum and one hemothorax., Discussion: After propensity score matching, PBT showed no significant difference in RFS and OS compared to RFA. PBT can be an alternative for patients with solitary treatment-naïve HCC., Competing Interests: Ryosuke Tateishi has received lecture fees from STARmed Co., Ltd., Medtronic plc, Merk Sharp & Dohme, Chugai Pharmaceutical Co., Ltd., Bristol-Meyers Squibb, Giliad Sciences, AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eisai Co., Ltd., and Bayer Co., Ltd. Hayato Nakagawa has received lecture fees from Bristol-Meyers Squibb, Giliad Sciences, AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., and Sumitomo Dainippon Pharma Co., Ltd. Yoshinari Asaoka has received consultation fees from Eisai Co., Ltd. Shuichiro Shiina has received lecture fees from Starmed Co., Ltd., Medtronic plc, Japan Lifeline Co., Ltd., Canon Medical Co., Ltd., Shionogi Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Giliad Sciences, AbbVie GK, Eisai Co., Ltd., and Bayer Co., Ltd. Kazuhiko Koike has received lecture fees from Eisai, Bayer, MSD, Abbvie, Gilead, and Otsuka Pharmaceutical Co., Ltd., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

COVID-19 has a wide range of clinical presentations, and the susceptibility to SARS-CoV-2 infection and the mortality rate also vary by region and ethnicity. Here, we found that rs12329760 in the TMPRSS2 gene, a missense variant common in East Asian populations, contributes to protection against SARS-CoV-2 infection. TMPRSS2 is a protease responsible for SARS-CoV-2 entry and syncytium formation. rs12329760 (c.478G>A, p. V160M) was associated with a reduced risk of moderate symptoms. The enzymatic activity of Met 160 -TMPRSS2 was lower than that of Val 160 -TMPRSS2, and thus the viral entry and the syncytium formation of SARS-CoV-2 were impaired. Collectively, these results indicate that the genetic variation in TMPRSS2 , which is common in East Asians, is one of the molecular determinants of COVID-19 susceptibility., 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 Sekiya, Ogura, Kai, Kawaguchi, Okawa, Hirohama, Kuroki, Morii, Hara, Hiramatsu, Hitomi, Kawakami, Arakawa, Maruo, Chiba, Suzuki, Kojima, Tachikawa and Yamagata.)

Background: The aim of the trial is to evaluate the effectiveness of interventions provided by online support program apps, adopting health-related quality of life (HR-QOL) scores as indicators., Methods: The design is as an open, randomized, parallel-group trial with longitudinal data collection. The subjects will be female cancer patients receiving treatment in a Japanese National Cancer Hospital. Patients assigned to the experimental group will use three apps: an app for them to monitor their own health (monitoring app), an app to assess their understanding of their diagnosis and treatment and their readiness to receive treatment (confirmation app), and an app to address mental health issues (writing app); patients assigned to the control group will use only the monitoring app. At baseline (before patients undergo cancer treatment) and three other times during the study, evaluation indicators will be obtained from three different standardized HR-QOL scales that are incorporated in the monitoring app. The study hypothesis is that at 6 months after patients' baseline health monitoring, patients in the experimental group will have improved HR-QOL as compared with patients in the control group., Conclusion: This study is based on self-regulation theory, so it is important that the online support program works in an efficient way with respect to patients finding and setting their own health-related goals and adapting their behaviors to achieve those goals. Verifying the effectiveness of the combination of the three apps will show that it is a scientifically valid approach to maintaining or improving the HR-QOL of cancer patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Schizophrenia is a severe mental illness characterized by recurrent psychoses that typically waxes and wanes through its prodromal, acute, and chronic phases. A large amount of research on individual prognostic factors for relapse in people with schizophrenia has been published, and a few logistic models exist to predict psychotic prognosis for people in the prodromal phase or after the first episode of psychosis. However, research on prediction models for people with schizophrenia, including those in the chronic phase and after multiple recurrences, is scarce. We aim to develop and validate a prediction model for this population., Methods: This is a retrospective cohort study to be undertaken in Japan. We will include participants aged 18 years or above, diagnosed with schizophrenia or related disorders, and discharged between January 2014 and December 2018 from one of the acute inpatient care wards of three geographically distinct psychiatric hospitals. We will collect pre-specified nine predictors at the time of recruitment, follow up the participants for 12 months after discharge, and observe whether our primary outcome of a relapse occurs. Relapse will be considered to have occurred in one of the following circumstances: (1) hospitalization; (2) psychiatrist's judgment that the person needs hospitalization; (3) increasing doses of antipsychotics; or (4) suicidal or homicidal ideation or behavior resulting from such ideation. We will develop a Cox regression model and avoid overfitting by penalizing coefficients using the elastic net. The model will be validated both internally and externally by bootstrapping and "leave-one-hospital-out" cross-validation, respectively. We will evaluate the model's performance in terms of discrimination and calibration. Decision curve analysis will be presented to aid decision-making. We will present a web application to visualize the model for ease of use in daily practice., Discussion: This will be the first prediction modeling study of relapse after discharge among people with both first and multiple episodes of schizophrenia using routinely collected data., Trial Registration: This study was registered in the UMIN-CTR (UMIN000043345) on February 20, 2021., (© 2022. The Author(s).)